Mitochondrial Disease in Children

Review Symposium
doi: 10.1111/joim.13054
Mitochondrial disease in children

S. Rahman
From the Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK
Content List – Read more articles from the symposium: “Mitochondria in human disease”
Abstract. Rahman S (Paediatric Metabolic Medicine, neuroimaging and genetic investigations, and
UCL Great Ormond Street Institute of Child Health, emphasizing the problem of phenocopies. The
London, UK). Mitochondrial disease in children impact of next-generation sequencing is discussed,
(Review Symposium). J Intern Med 2020; 287: 609– together with the importance of functional valida-
633. tion of novel genetic variants never previously
linked to mitochondrial disease. The review con-
Mitochondrial disease presenting in childhood is cludes with a brief discussion of currently available
characterized by clinical, biochemical and genetic and emerging therapies. The field of mitochondrial
complexity. Some children are affected by canon- medicine has made enormous strides in the last
ical syndromes, but the majority have nonclassical 30 years, with approaching 400 different genes
multisystemic disease presentations involving vir- across two genomes now linked to primary mito-
tually any organ in the body. Each child has a chondrial disease. However, many important ques-
unique constellation of clinical features and dis- tions remain unanswered, including the reasons
ease trajectory, leading to enormous challenges in for tissue specificity and variability of clinical
diagnosis and management of these heterogeneous presentation of individuals sharing identical gene
disorders. This review discusses the classical defects, and a lack of disease-modifying therapies
mitochondrial syndromes presenting most fre- and biomarkers to monitor disease progression
quently in childhood and then presents an organ- and/or response to treatment.
based perspective including systems less fre-
quently linked to mitochondrial disease, such as Keywords: diagnostic approach, differential diagno-
skin and hair abnormalities and immune dysfunc- sis, mitochondrial genetics, next-generation
tion. An approach to diagnosis is then presented, sequencing, phenomics, phenocopies.
encompassing clinical evaluation and biochemical,
Introduction Architecture of this review

Mitochondrial structure, function and dysfunction In this review, I will discuss the clinical complexity
of mitochondrial disorders presenting in child-
Mitochondria are dynamic subcellular organelles
hood, starting with a description of some of the
with innumerable functions, including energy gen-
classically recognized stereotypic syndromes,
eration via oxidative phosphorylation (OXPHOS),
arranged according to the age at onset of symp-
calcium homeostasis and regulation of apoptotic
toms. I will then take an organ-based approach to
cell death, placing them at the centre of cellular
the clinical features of paediatric mitochondrial
metabolism and signalling. There continues to be
disease. I will also consider the biochemical and
considerable debate about the precise definition of
genetic complexity of these disorders and guide the
primary mitochondrial diseases but we have
reader to a structured approach to diagnosing
recently attempted to define these as genetic dis-
these challenging disorders. Finally, I will discuss
orders leading either to OXPHOS dysfunction or
the problem of phenocopies, and how to distin-
other disturbances of mitochondrial structure and
guish mitochondrial disorders from other complex
function [1]. Primary mitochondrial disorders have
multisystem disorders presenting in childhood,
been estimated to have a minimum birth preva-
including the increasing number of disorders in
lence of 1 in 5000 [2].
ª 2020 The Association for the Publication of the Journal of Internal Medicine 609
Mitochondrial disease in children / S. Rahman
which secondary mitochondrial dysfunction has chain fatty acid oxidation defects, and some
been reported [3]. organic acidurias including biotinidase deficiency,
methylmalonic acidaemia (MMA) and propionic
acidaemia (PA). Metabolic clues to the underlying
Clinical complexity: Canonical syndromic presentations of
diagnosis include a low lactate/pyruvate ratio in
childhood mitochondrial disease
PDH deficiency, hyperammonaemia in PC and
A clinical classification was the first rational clas- carbonic anhydrase VA (CA5A) deficiencies, pro-
sification of mitochondrial disease, since canonical found hypoglycaemia in the gluconeogenesis dis-
syndromes with particular constellations of symp- orders and characteristic organic acid excretion in
toms and signs had been recognized for decades biotinidase deficiency, MMA and PA. Of the mito-
before their genetic basis was understood [4-9]. A chondrial respiratory chain disorders, fatal infan-
selection of these syndromes is described below, tile lactic acidosis (FILA) has most frequently been
according to age at presentation (Fig. 1), and an ‘A reported in children with complex I deficiency [10],
to Z’ of mitochondrial syndromes is provided in but is increasingly recognized as a feature of other
Table 1. However, it is important to remember the mitochondrial disorders. Of note, the lactic acido-
enormous clinical heterogeneity of mitochondrial sis may be transient and resolve within a few days
disease (Fig. 2) and that most children affected by of birth in some primary mitochondrial disorders
mitochondrial disease do not have a classical [11], leading to diagnostic difficulties. Although I
syndromic presentation, particularly at the earliest have started with congenital lactic acidosis as the
stages of their disease when only a single organ earliest onset mitochondrial disease, antenatal
may be involved. mitochondrial disease presentations are increas-
ingly recognized. For example, prenatal presenta-
tion has been reported in some of the early-onset
Congenital lactic acidosis
CoQ10 biosynthesis deficiency syndromes [12,13],
Presentation with lactic acidosis at or shortly after defects of mitochondrial ribosomal proteins [14,15]
birth may reflect an acquired problem such as and even in POLG disease [16].
hypovolaemia, hypoxia or sepsis, but an underly-
ing inborn error of metabolism should be consid-
Infantile-onset mitochondrial DNA depletion syndromes
ered in the differential diagnosis. More common
metabolic causes include deficiencies of pyruvate The mitochondrial DNA (mtDNA) depletion syn-
dehydrogenase (PDH) and pyruvate carboxylase dromes (MDDS) are defined by a quantitative
(PC), as well as mitochondrial respiratory chain reduction of the absolute mtDNA copy number,
disorders, but lactic acidosis may also be a feature which was initially arbitrarily set at < 30% of age-
of disorders of gluconeogenesis (e.g. fructose-1,6- matched controls [17,18]. However, infants with
bisphosphatase deficiency and glycogen storage severe MDDS typically have < 10% residual
disease type 1), tricarboxylic acid cycle and long- mtDNA in the most affected tissues, although
Fig. 1 Paediatric mitochondrial diseases arranged by age of onset. Canonical syndromic presentations of paediatric
mitochondrial disease arranged according to age of onset.
610 ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2020, 287; 609–633
Table 1 An alphabetical classification of mitochondrial syndromes
Disease Clinical features Gene defect(s)a

A ACAD9 deficiency HCM, exercise intolerance, lactic acidosis ACAD9
Alpers syndrome Intractable epilepsy, psychomotor regression, liver disease POLG
B Barth syndrome DCM, myopathy, neutropaenia TAZ
Bjornstad syndrome SNHL, pili torti BCS1L
C Cowchock syndrome Axonal neuropathy, SNHL, cognitive impairment AIFM1
D DARS2 deficiency Leukoencephalopathy with brain stem and spinal cord DARS2
involvement and lactate elevation (LBSL)
E Ethylmalonic Acrocyanosis, petechiae, chronic diarrhoea, developmental delay ETHE1
encephalopathy
F Friedreich ataxia Progressive ataxia, HCM, sensory neuropathy, diabetes mellitus FXN
G GRACILE syndrome Growth retardation, aminoaciduria, cholestasis, iron overload, BCS1L
lactic acidosis, early death
H HUPRA Hyperuricaemia, pulmonary hypertension, renal failure, SARS2
alkalosis
I IOSCA Infantile-onset spinocerebellar ataxia TWNK
J Juvenile-onset POLG Ataxia neuropathy spectrum (ANS) and Myoclonic epilepsy, POLG
syndromes myopathy, sensory ataxia (MEMSA)
K Kearns–Sayre PEO, pigmentary retinopathy, cardiac conduction defects, ataxia, SLSMD
syndrome high CSF protein, (onset < 20 years)
L Leigh syndrome Subacute necrotizing encephalomyelopathy ~100 genes
LHON Leber hereditary optic neuropathy MT-ND1, MT-ND4, MT-
ND6
M MEGDEL 3MGA, deafness, encephalopathy, Leigh-like SERAC1
MELAS Mitochondrial encephalomyopathy, lactic acidosis, stroke-like MT-TL1
episodes
MERRF Myoclonic epilepsy, ragged-red fibres MT-TK
MLASA Myopathy, lactic acidosis, sideroblastic anaemia PUS1, YARS2
MNGIE Mitochondrial neurogastrointestinal encephalopathy TYMP
N NARP Neurogenic muscle weakness, ataxia, retinitis pigmentosa MT-ATP
O OPA1 disease Dominant optic atrophy, variably associated with SNHL and OPA1
multisystemic features
P Pearson syndrome Sideroblastic anaemia, lactic acidosis, pancreatic exocrine SLSMD
insufficiency
PEO Progressive external ophthalmoplegia SLSMD
Perrault syndrome Premature ovarian failure, SNHL, variable neurological CLPP, HARS2, LARS2,
manifestations TWNK, ERAL1
Q QIL1 deficiency Early-onset fatal mitochondrial encephalopathy, liver disease QIL1
R RARS2 deficiency Pontocerebellar hypoplasia type 6 RARS2
S Sengers syndrome Cataracts, HCM, muscle weakness, lactic acidosis AGK
T TMEM70 deficiency 3MGA, HCM, hyperammonaemia, lactic acidosis TMEM70
U Unclassified The majority of children with mitochondrial disease do not have Nearly 400 genes
classical presentations
Table 1 (Continued )
Disease Clinical features Gene defect(s)a

V VARS2 deficiency Severe encephalomyopathy, HCM VARS2
W Wolfram syndrome Diabetes insipidus, diabetes mellitus, optic atrophy, deafness WFS1
(DIDMOAD)
X X-linked deafness– Mohr–Tranebjaerg syndrome (deafness, dystonia, optic TIMM8A
dystonia syndrome neuronopathy)
Y YARS2 deficiency Myopathy, lactic acidosis, sideroblastic anaemia YARS2
3MGA, 3-methylglutaconic aciduria; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; SLSMD, single
large-scale mitochondrial DNA deletion; SNHL, sensorineural hearing loss.
a
The most frequently associated gene defects are listed for each syndrome.
some causes of MDDS are associated with less RRM2B deficiency, which presents shortly after
severe mtDNA depletion, for example 30-40% birth with progressive myopathy variably associ-
residual mtDNA in SUCLA2 deficiency [19]. The ated with sensorineural hearing loss (SNHL),
MDDS may be grouped according to clinical renal tubulopathy and seizures [22]; Alpers–Hut-
presentation (myopathic, encephalomyopathic, tenlocher syndrome (see below) and deficiencies
hepatocerebral or multisystem disorder) or of DGUOK and MPV17, which cause infantile
underlying genetic mechanism (defect of the liver failure with/without encephalopathic fea-
mtDNA replication apparatus, mtDNA repair, tures; and TK2 deficiency, which presents as a
nucleoside metabolism or mitochondrial dynam- severe progressive myopathy with elevated lactate
ics) [20,21]. Infantile-onset MDDS include and creatine kinase [20].
– –
Fig. 2 Clinical complexity of paediatric mitochondrial disease. Mitochondrial disease presenting in childhood may affect
any tissue or organ system in any combination. The right-hand panel highlights the symptoms and signs of mitochondrial
disease associated with each organ system.
‘honeymoon’ period of relatively good health before

Benign reversible mitochondrial myopathy
the onset of multisystem problems in the Kearns–
Infants with so-called benign reversible mitochon- Sayre syndrome (KSS) spectrum (see below). These
drial myopathy present after a symptom-free inter- multisystem features may include ptosis, progres-
val at about 6 weeks to 3 months’ age with lactic sive external ophthalmoplegia (PEO), renal tubu-
acidosis and a profound myopathy affecting the lopathy, pancreatic exocrine and/or endocrine
limb and respiratory musculature, frequently lead- insufficiency, and gastrointestinal (GI) disturbance
ing to a requirement for gastrostomy feeding and (dysmotility or partial villous atrophy leading to
artificial ventilation. The syndrome has been linked malabsorption).
to two homoplasmic mtDNA variants at the same
nucleotide in the MT-TE gene encoding the mito-
Barth and Sengers syndromes
chondrial tRNA for glutamic acid [23,24]. Not all
individuals with these variants have myopathy, so Two syndromic cardiomyopathies presenting in
it seems that other factors are needed for expres- infancy are Barth syndrome and Sengers syn-
sion of the disease. It has been proposed that the drome. Barth syndrome is an X-linked disorder
phenotype may be induced by a relative cysteine characterized by 3-methylglutaconic aciduria
deficiency in early infancy [25], but possible effi- associated with dilated cardiomyopathy (DCM),
cacy of L-cysteine supplementation in this disorder skeletal myopathy (mainly proximal), impaired
remains to be determined. There is usually a growth and (cyclical) neutropaenia [28]. Other
remarkable recovery with supportive care, which cardiac features include endocardial fibroelastosis,
may include invasive ventilation for up to left ventricular noncompaction and hypertrophic
18 months, with only a mild residual myopathy cardiomyopathy (HCM). TAZ mutations lead to
persisting into adult life. impaired cardiolipin production in the inner mito-
chondrial membrane. Sengers syndrome is a rare
autosomal recessive disorder caused by mutations
Pearson syndrome
in AGK encoding acylglycerol kinase, which is also
Patients with Pearson marrow–pancreas syndrome a component of the mitochondrial import machin-
typically present in early infancy, after a brief ery [29,30]. Affected infants present with congen-
symptom-free interval, with a transfusion-depen- ital cataract and HCM. Other clinical features
dent anaemia and lactic acidosis, variably associ- include skeletal myopathy, exercise intolerance
ated with feeding difficulties and developmental and lactic acidosis. Progressive cardiac failure
delay. Age of onset ranged from birth to 36 months may lead to death in infancy, but long-term
(mean 7 months) and birth to 16 months (mean survival has been reported in some patients [31].
2.5 months) in two large series [26,27]. Ringed
sideroblasts and vacuolated myeloid precursors
Leigh syndrome
are seen in the bone marrow aspirate, and diagno-
sis is made by the identification of a single large- This syndrome, also known as subacute necrotiz-
scale mtDNA deletion (SLSMD) in peripheral blood, ing encephalomyelopathy, was first described as a
bone marrow aspirate, urinary epithelial cells or neuropathological entity by Denis Leigh in 1951
muscle biopsy. Transfusion requirement is usually [5]. Leigh reported the post-mortem brain findings
2-3 weeks initially and gradually becomes less of a 7-month-old baby who had died after a 6-week
frequent over time, with complete resolution of illness involving somnolence and visual and hear-
anaemia typically occurring around 2 years. Other ing impairment. Leigh described bilateral symmet-
bone marrow lineages are frequently affected, rical spongiform lesions, especially in the
leading to neutropaenia, thrombocytopaenia or brainstem, representing vacuolation of the neu-
pancytopaenia. Some patients with Pearson syn- ropil with relative neuronal preservation and asso-
drome are extremely unwell with severe faltering ciated with demyelination, gliosis and capillary
growth, metabolic acidosis and hepatic impair- proliferation. During the last six decades, Leigh
ment; there is an extremely high mortality in this syndrome, as it has come to be known, has been
group. Twelve of 21 cases (57%) died before 4 years recognized as the most frequent presentation of
in one series [26], and mean age at death was mitochondrial disease in childhood. Criteria for
2.5 years in the second series, with only 22% of Leigh syndrome without the need for neuropathol-
cases alive at 18 years [27]. In surviving patients, ogy have been developed, namely a characteristic
resolution of the anaemia is associated with a clinical course (including neurodevelopmental
regression and symptoms and signs related to obscure. Some patients have a prior history of
basal ganglia and/or brainstem dysfunction), ele- Pearson syndrome, but many present with KSS
vated lactate levels in blood or cerebrospinal fluid without a history of documented anaemia [27]. KSS
(CSF) or other evidence of mitochondrial dysfunc- is usually caused by SLSMDs but has also been
tion (e.g. PDH or OXPHOS deficiency) and charac- reported with multiple mtDNA deletions caused by
teristic neuroimaging features of bilateral RRM2B mutations [38].
symmetrical T2 signal hyperintensity variably
involving the basal ganglia, midbrain and brain-
Progressive external ophthalmoplegia
stem structures [32]. Leigh syndrome appears to be
a common end-point of deficient cerebral energy PEO as an isolated finding is a rare presentation of
generation and has been linked to ~ 100 different mitochondrial disease in childhood but does occur,
mitochondrial and nuclear gene defects, frequently usually in association with SLSMDs. More often,
with multisystemic disease involvement (www. paediatric-onset PEO is part of a complex presen-
vmh.life/#leighmap). tation, for example KSS or another multisystem
mitochondrial disorder. There has been a long
debate about distinction between ‘PEO-plus’ and
Alpers–Huttenlocher syndrome
KSS [36], and the current consensus is that there is
Intractable epilepsy and developmental delay asso- a continuous spectrum of clinical phenotype asso-
ciated with characteristic neuropathology were ciated with SLSMDs, ranging from Pearson syn-
first reported by Bernard Alpers in 1931, and the drome at the most severe end through Kearns–
association with hepatic cirrhosis was noted by Sayre syndrome to isolated PEO as the mildest
Peter Huttenlocher in 1976 [4,33]. Onset is typi- manifestation of SLSMDs [27].
cally in infancy or early childhood with initially
focal motor seizures that evolve to bilateral con-
Exercise intolerance
vulsive seizures and often to epilepsia partialis
continua and status epilepticus. The prognosis is Exercise intolerance is a frequent symptom of mito-
extremely poor; most cases have a rapidly progres- chondrial myopathies in childhood, again usually in
sive course leading to death from status epilepticus the context of a multisystem disorder. It may be an
or hepatic failure within a few months of presen- isolated finding in some children with a sporadic
tation [34]. Hepatic involvement is not universal mtDNA mutation, particularly affecting a subunit of
and may be triggered by sodium valproate therapy. complex III or IV [39-42]. Characteristic features
Most cases are caused by biallelic pathogenic include muscle cramps and fatigue on exertion but
variants in POLG encoding the catalytic subunit patients may also present with vomiting after exer-
of DNA polymerase gamma leading to severe cise related to lactic acidosis. Frank rhabdomyolysis
mtDNA depletion, but rarer causes include defects with severe muscle pain and myoglobinuria is a rare
of TWNK (encoding the mitochondrial DNA heli- presentation of mitochondrial myopathies, being
case) or of FARS2, NARS2 and PARS2 (encoding more frequently seen in fatty acid oxidation disor-
three mitochondrial aminoacyl-tRNA synthetases) ders and glycolytic defects, but does occasionally
[35]. occur [40,42]. Mitochondrial rhabdomyolysis was
most recently reported in association with autoso-
mal dominant multiple mtDNA deletions caused by
Kearns–Sayre syndrome
heterozygous variants in DNA2, encoding a mito-
KSS was initially defined clinically as a triad of chondrial helicase/nuclease [43].
PEO, pigmentary retinopathy and heart block
presenting before the age of 20 years, with minor
MELAS
criteria including cerebellar ataxia and elevated
CSF protein levels [36]. In the intervening four The syndrome of mitochondrial encephalomyopa-
decades, the disorder has been recognized to be a thy with lactic acidosis and stroke-like episodes
multisystem condition with heterogeneous clinical (MELAS) was defined clinically in 1984 [9]. Stroke-
manifestations including SNHL, renal tubulopa- like episodes may be heralded by migraine head-
thy, GI dysmotility, endocrine disturbance, car- ache, homonymous hemianopia or quadran-
diomyopathy, basal ganglia calcification and tanopia and seizures, which are often focal but
leukoencephalopathy, often associated with cere- may subsequently generalize as the stroke-like
bral folate deficiency [37] for reasons that remain episode progresses. The first seizure or stroke-like
episode occurred at a mean of 13.7 years in those life, with a median age of onset of ~20 years [55].
with childhood onset in a prospective natural Painless subacute central visual loss typically
history study, with another peak at a mean of affects both eyes sequentially. The disorder is most
35.7 years for adult-onset stroke-like episodes commonly caused by one of three homoplasmic
[44]. Additional symptoms include short stature, mutations (m.3460G>A, m.11778G>A and
cognitive decline, exercise intolerance, SNHL, pto- m.14484T>C) in mtDNA genes encoding complex I
sis, optic atrophy, GI dysmotility and diabetes subunits [55]. There is an increased risk of visual
mellitus [44]. Eighty per cent of cases have the loss in males with these mtDNA variants, which is
same pathogenic mtDNA variant, m.3243A>G in thought to reflect a protective effect of oestrogen in
the MT-TL1 gene [45]. This variant is very common female carriers [56]. Most affected individuals have
in the population, with a point prevalence of 1 in isolated ophthalmological symptoms, but there
400 [46], and is associated with a wide range of may be other clinical features such as dystonia
clinical phenotypes other than MELAS, both in [57] or cardiac conduction problems (Wolff–Parkin-
childhood and in adult life [47]. son–White) [58], and occasionally, LHON may
overlap with Leigh syndrome and/or MELAS [59].
MERRF
Other phenotypes: A systems approach to mitochondrial disease in
Myoclonus epilepsy with ragged-red fibres (MERRF)
childhood
is another canonical mitochondrial syndrome asso-
ciated with a single so-called common mtDNA An alternative approach to clinical classification of
mutation (m.8344A>G in the MT-TK gene) in ~ 80% paediatric mitochondrial disorders is to take an
of cases [48]. MERRF frequently presents in child- organ-based approach, as follows.
hood with an insidious onset that may include
ataxia, SNHL and endocrine disturbance. Onset
Mitochondrial encephalomyopathies
was before 16 years in one-third of a large Italian
cohort [49]. Myoclonus may not be apparent initially The three main, overlapping groups of mitochon-
and may present later, with additional seizure types. drial encephalomyopathy are Leigh syndrome,
Other clinical features of MERRF include cognitive mitochondrial epilepsies and a rapidly growing
impairment, multiple lipomatosis, ptosis/PEO, group of mitochondrial leukoencephalopathies.
myopathy, peripheral neuropathy and cardiomy- Leigh syndrome is the most frequently recognized
opathy [49]. Overlap with MELAS is well recognized, mitochondrial encephalomyopathy, whilst the
including stroke-like episodes [50,51]. most prevalent mitochondrial epilepsy is Alpers–
Huttenlocher syndrome. Epilepsy is also a promi-
nent feature of the canonical syndromes MELAS
Juvenile-onset POLG syndromes
and MERRF and may be seen in many cases of
POLG disease presenting in adolescence may Leigh syndrome and in mitochondrial leukoen-
resemble Alpers–Huttenlocher syndrome, with sev- cephalopathies. Epilepsy is estimated to have a
ere intractable epilepsy and liver disease [52]. prevalence of ~40-60% in paediatric mitochondrial
However, juvenile POLG disease may also mimic disease and has been reported in association with
MERRF, with prominent symptoms of myoclonus defects in >140 mitochondrial disease genes, fre-
and ataxia. Two acronyms have been used to quently as an adverse prognostic factor [60].
describe the main phenotypes of POLG disease Causes of mitochondrial leukoencephalopathy
presenting in adolescence: myoclonic epilepsy, include deficiencies of complex I and II assembly,
myopathy, sensory ataxia (MEMSA) and ataxia defects of iron–sulphur cluster and lipoic acid
neuropathy syndrome (ANS) (reviewed in Ref. biosynthesis and MNGIE.
[21]). Rare presentations of POLG disease in child-
hood/adolescence are with a distal myopathy [53]
Mitochondrial myopathies
or a disorder resembling mitochondrial neurogas-
trointestinal encephalopathy (MNGIE) [54]. Muscle is one of the most affected tissues in
primary mitochondrial disease, reflecting the high
energy demands of muscle contraction [61]. Iso-
Leber hereditary optic neuropathy
lated muscle involvement is a more frequent fea-
Leber hereditary optic neuropathy (LHON) most ture of adult-onset disease but may be observed in
frequently presents in the second or third decade of paediatric mitochondrial disease, as either the
initial or sole manifestation, although more usually finding) and is usually bilateral, symmetrical and
myopathy is part of a complex multisystem disor- progressive. It may be of cochlear origin or be caused
der in childhood. There is a predilection for the by an auditory neuropathy. One study suggested
external eye muscles, and the myopathy is usually that 40% of individuals with mitochondrial disease
proximal rather than distal, but exceptions include have hearing loss [72]. The most frequent genetic
a distal myopathy in some cases of POLG disease variant predisposing to mitochondrial nonsyn-
[53]. The most frequent symptoms of mitochondrial dromic SNHL is m.1555A>G in the MT-RNR gene
muscle disease are fatigability, weakness, exercise encoding a mitochondrial rRNA. This variant is
intolerance and pain. prevalent in ~1 in 500 of the population and confers
exquisite sensitivity to aminoglycoside-induced
SNHL [73]. Without aminoglycoside exposure, indi-
Mitochondrial neuropathies
viduals with this variant may have normal hearing
Mitochondrial neuropathy may be axonal motor, until well into adult life, implying a role for newborn
axonal sensorimotor, sensory ataxia or demyeli- screening for the variant followed by lifelong avoid-
nating [62]. The classical mitochondrial neuropa- ance of aminoglycosides in at-risk individuals [74].
thy syndrome neurogenic muscle weakness, Childhood-onset mitochondrial syndromes in
ataxia, retinitis pigmentosa (NARP) has been linked which hearing loss is a prominent feature include
to pathogenic variants in the MT-ATP6 gene encod- MERRF, MELAS, KSS and deficiencies of SUCLA2,
ing a subunit of complex V [63]. Peripheral neu- BCS1L, RRM2B, SERAC1, RMND1 and TRNT1
ropathy is a frequent feature of multisystem [19,22,27,38,47,49,75-78].
mitochondrial disease in childhood, including defi-
ciencies of SURF1, POLG, PDH and MPV17 [62,64].
Mitochondrial heart disease
Defects of two proteins involved in mitochondrial
dynamics MFN2 and GDAP1 cause Charcot–Marie– The most frequent childhood presentation of mito-
Tooth (CMT) disease types 2A and 4A, respectively chondrial heart disease is with severe HCM in
[65]. In addition, variants in genes previously infancy, although rarely this may be end-stage
recognized to cause mitochondrial encephalomy- DCM at presentation. Pinpointing a mitochondrial
opathies have more recently been reported to cause aetiology to an infantile cardiomyopathy can be
isolated neuropathies resembling CMT, including extremely challenging, since lactic acidosis may be
MT-ATP6, SURF1, SCO2 and C12orf65 [65-69]. secondary to hypoxia or hypovolaemia rather than
an indicator of an underlying primary mitochon-
drial disorder. However, specific echocardiographic
Mitochondrial eye disease
appearances are increasingly recognized, namely
In addition to eye muscle involvement (ptosis/ symmetrical hypertrophy with deep trabeculation
PEO), primary mitochondrial disease can affect any of the myocardium, sometimes fulfilling criteria for
layer of the eye, ranging from corneal opacification noncompaction of the left ventricle. Barth and
(Pearson/KSS) to cataracts (e.g. Sengers syn- Sengers syndromes are described above but other
drome, CLPB deficiency), optic neuropathy (e.g. causes of mitochondrial cardiomyopathy present-
LHON) and pigmentary retinopathy (e.g. NARP). ing in infancy are increasingly recognized, either as
Optic neuropathy is frequently seen in complex I an isolated finding or as part of a complex multi-
deficiencies and may be an isolated finding, as in system disorder. These include disorders of mito-
LHON, or be a feature of an encephalomyopathy chondrial translation and defects of coenzyme Q10
such as the Leigh syndrome spectrum [70]. The biosynthesis [79]. Cardiomyopathy may be seen in
most frequent mitochondrial optic neuropathy is some children and adults with the m.3243A>G
dominant optic atrophy caused by OPA1 mutations mutation and may be a cause of sudden death in
[70]. Recently, variants in SSBP1 encoding the these individuals [47,80]. Cardiomyopathy has
single-stranded binding protein needed for mtDNA been linked to a handful of mutations in the
replication have been shown to cause dominant mitochondrial genome, but in many cases, these
optic neuropathy and retinopathy [71]. mutation reports are unconfirmed (www.mitomap.
org). Nuclear gene defects appear to be a more
frequent cause of mitochondrial cardiomyopathy,
Mitochondrial hearing loss
particularly in infancy, as recently reviewed in Ref.
Mitochondrial hearing loss is sensorineural and [79]. Cardiac conduction defects have been
may be syndromic or nonsyndromic (i.e. an isolated reported frequently in children and adults with
KSS, and complete heart block may be a life- Gitelman syndrome with severe hypomagne-
threatening event in these individuals, indicating a saemia. Tubulopathy is also observed in many
need for regular screening ECGs [81]. Sudden other mitochondrial diseases, including defects of
death is also a feature of PPA2 mutations, and assembly of OXPHOS complexes III and IV (defi-
implantation of a cardiac defibrillator may be life- ciencies of BCS1L, COX10 and SURF1), MDDS
preserving in affected individuals [82]. Wolff– (notably RRM2B deficiency but also seen in some
Parkinson–White has been reported in LHON, cases with DGUOK, MPV17, SUCLA2 and TK2
MELAS and Leigh syndrome caused by the deficiencies) and disorders of mitochondrial trans-
m.13513G>A mutation [44,58,83]. Valvular heart lation (e.g. TFSM) [89]. SRNS is a major feature of
disease is a rare feature of mitochondrial disease several disorders of coenzyme Q10 biosynthesis
but has been documented in individuals with (PDSS2, COQ2, COQ6 and COQ8B deficiencies),
mutations in PDSS1 encoding a coenzyme Q10 variably associated with SNHL, seizures and
biosynthetic enzyme [84]. Recently, we have shown encephalopathy [89,90]. Recognition of this group
that children with Leigh syndrome caused by ADAR and prompt initiation of high-dose coenzyme Q10
mutations are at risk of developing fatal cardiac supplementation may prevent progression of the
valve calcification [85]. renal disease [91]. FSGS is relatively frequently
observed in adults with m.3243A>G disease
but rarely seen in children [92]. Some children
Mitochondrial endocrine disorders
with RMND1 mutations have a pseudohypoaldos-
Any endocrine organ can be involved by primary teronism-like picture with hyperkalaemia, hypona-
mitochondrial disease, as a result of decreased traemia and progressive renal impairment [77].
intracellular production or extracellular secretion
of hormones [86]. Diabetes mellitus is the most
Mitochondrial gastrointestinal disease
frequent endocrine manifestation of adult mito-
chondrial disease in the maternally inherited dia- Nonspecific GI symptoms are a frequent feature of
betes and deafness (MIDD) syndrome [47], but in mitochondrial disease in childhood and may be
childhood is more often seen in Pearson syndrome amongst the first clinical features, presenting in
and KSS, together with growth hormone deficiency, early infancy with vomiting, feeding difficulties and
adrenal insufficiency, hypothyroidism and faltering growth [93,94]. In ethylmalonic
hypoparathyroidism [27]. Premature ovarian failure encephalopathy, caused by hydrogen sulphide
is associated with SNHL in Perrault syndrome, a toxicity resulting from ETHE1 mutations, persis-
genetically heterogeneous disorder linked to defects tent diarrhoea is associated with acrocyanosis,
of several mitochondrial genes including HARS2, petechiae and developmental delay [95]. The
LARS2, TWNK and CLPP, and is also observed in archetypal mitochondrial syndrome with GI dis-
POLG disease and in association with leukoen- turbance is MNGIE, caused by deficiency of
cephalopathy in AARS2 deficiency [86-88]. Mito- thymidine phosphorylase leading to toxic accumu-
chondrial endocrine dysfunction most frequently lation of thymidine and deoxyuridine, which in
occurs in the context of multisystem disease, but turn stalls the mtDNA replication apparatus.
isolated endocrine involvement may be the initial Affected individuals have severe dysmotility and
presentation of a mitochondrial disorder [86]. episodes of pseudo-obstruction associated with
demyelinating peripheral neuropathy and a rela-
tively asymptomatic leukoencephalopathy [96].
Mitochondrial renal disease
Although symptoms frequently start in childhood,
Mitochondrial disease frequently affects the kid- the diagnosis is not usually made until adult life.
neys in children, most commonly in the form of a Dysmotility is also a major feature of mitochondrial
renal tubulopathy or as steroid-resistant nephrotic disease related to the m.3243A>G mutation, and a
syndrome (SRNS) associated with focal segmental MNGIE-like phenotype has been reported in some
glomerulosclerosis (FSGS) on renal histology. Mito- patients with POLG mutations and RRM2B muta-
chondrial renal tubulopathy is most often seen in tions [54,97,98]. Exocrine pancreatic insufficiency
Pearson syndrome/KSS, and replacement of elec- is a major feature of Pearson syndrome but has
trolyte losses can be a severe management problem also been reported in other primary mitochondrial
in affected individuals [27]. The tubulopathy may diseases, including deficiencies of COX4I2, TRNT1
be Fanconi-type or be more reminiscent of and PTRH2 [78,99,100].
sometimes known by the acronym SIFD, for sider-

Mitochondrial hepatopathies
oblastic anaemia, immune deficiency, fever and
Hepatic involvement is a frequent feature of early- developmental delay [16]. This condition is char-
onset mitochondrial disease and has been estimated acterized by recurrent debilitating episodes of
to affect ~20% of cases with respiratory chain severe fever. Other features of TRNT1 deficiency
dysfunction [11]. Genetically confirmed mitochon- include cerebellitis, SNHL and pigmentary
drial disease was observed in 17% of a large cohort of retinopathy [78]. TRNT1 is also required to modify
children presenting with acute liver failure before cytosolic tRNAs, and it is not clear whether the B-
the age of 2 years [12]. Presentation may be with cell immune deficiency observed in this disorder is
acute or chronic liver failure and is typically pro- because of mitochondrial dysfunction or whether it
gressive and fatal. However, severe neonatal hepatic is a manifestation of disturbed cytosolic transla-
dysfunction that usually resolves with time has been tion. Abnormal innate immunity occurs in defi-
reported in approaching 50% of children with ciency of the JAK-STAT cytokine STAT2, which is
SERAC1 mutations [76]. Hepatic involvement may part of a phosphorylation signalling cascade. We
be part of a multisystem disorder, but in neonatal or demonstrated abnormal mitochondrial fission in
early infantile mitochondrial liver disease demise muscle and cultured skin fibroblasts of a series of
from liver failure may occur before neurological children with STAT2 deficiency and went on to
symptoms become apparent. Characteristic histo- show that STAT2 is needed for activation of mito-
logical features of mitochondrial liver disease chondrial fission by phosphorylation of a critical
include micro- and macrovesicular steatohepatitis, serine at position 616 of the DRP1 protein [111].
which may progress to micro- or macronodular Immune function has not been well studied in
cirrhosis [13]. The most frequent causes of mito- children with mitochondrial diseases, and it is
chondrial liver disease are the hepatocerebral possible that immune dysfunction may be a feature
MDDS associated with pathogenic variants in of other paediatric mitochondrial diseases.
DGUOK, MPV17, POLG, TWNK or SUCLG1, defects
of complex III and IV assembly and disorders of
Dysmorphology
mitochondrial translation (reviewed in Ref. [14]). Of
these, defects of the mitochondrial translation factor Pattern recognition is an essential tool for the
TRMU have been reported to be potentially rever- diagnostician. Characteristic facial appearances
sible in some cases [15]. have been reported for a few mitochondrial disor-
ders, including deficiencies of RARS2, FBXL4, TAZ
and TMEM70 [28,112-114]. It is possible that other
Haematological involvement in mitochondrial disease
mitochondrial disorders may also be associated
Pearson syndrome is the most common cause of with specific facial appearances, but the ultra-
mitochondrial sideroblastic anaemia (see syndromic rarity of most individual mitochondrial disorders
presentations above). Other marrow lineages are means that no one clinician will see sufficient cases
frequently also involved in Pearson syndrome; in their career to become adept at recognizing
affected children may have neutropaenia and/or mitochondrial disease by facial appearance alone.
thrombocytopaenia in addition to the anaemia [27]. However, it is possible that artificial intelligence
Less frequent causes of mitochondrial sideroblastic tools may enable this sort of facial recognition in
anaemia include TRNT1 deficiency [78,106] and the the future. For example, facial recognition software
syndrome of myopathy, lactic acidosis and siderob- has been used to highlight characteristic facial
lastic anaemia (MLASA), which has been linked to appearances in congenital disorders of glycosyla-
deficiencies of PUS1 and YARS2 [17,108]. Anaemia is tion [115].
a frequent finding in children with mitochondrial
disease and is emerging as an adverse prognostic
Abnormalities of skin and hair
indicator [19]. Interestingly, a laboratory-based
study identified iron as the most important stimula- Hypertrichosis is frequently a striking feature in
tor of mitochondrial biogenesis [110]. children with SURF1 deficiency and was docu-
mented in 41% of cases in a large multicentre
cohort [93]. The mechanism driving the hypertri-
Immune dysfunction and primary mitochondrial disease
chosis remains unknown, but we are increasingly
B-cell immune deficiency appears to be a consis- recognizing this as a feature of other causes of
tent feature of TRNT1 deficiency, which is Leigh syndrome and indeed of other mitochondrial
disorders. Excess hair is typically observed on the

Approach to diagnosis
forearms, thighs, shins and upper back. The pres-
ence of a low hairline, synophrys and pedal oedema When to suspect mitochondrial disease in childhood?
in children with deficiency of the mitoribosomal
There are probably no absolutely pathognomonic
protein MRPS22 led to the suggestion that this
clinical features of mitochondrial disease in child-
disorder mimics Cornelia de Lange syndrome
hood. Clinical presentations that should arouse
[116]. Hair abnormalities (pili torti) have been
suspicion of an underlying mitochondrial disorder
reported in Bjornstad syndrome, one of the clinical
include stroke-like episodes, acquired ptosis and/
manifestations of deficiency of the complex III
or ophthalmoplegia, sideroblastic anaemia and
assembly factor BCS1L [75]. Interestingly, not all
epilepsia partialis continua. However, it is fre-
patients with BCS1L mutations have pili torti, and
quently the combination of disease pathologies
it is not clear why this phenomenon is present in
affecting multiple seemingly unrelated organs that
some patients but not others. Even more intrigu-
triggers the clinical recognition of a mitochondrial
ingly, alopecia totalis was recently reported in
disorder [122]. In other cases, the initial diagnostic
children with deficiency of the complex III subunit
clue may be a biochemical abnormality such as
UQCRFS1 [117], implying that complex III may be
elevation of blood or CSF lactate, plasma alanine,
critical for hair growth. Cutis laxa syndromes have
urinary 3-methylglutaconic acid or other mitochon-
been associated with pathogenic variants in PYCR1
drial disease biomarkers [123]. Increasingly, a
and ALDH18A1, encoding enzymes involved in de
mitochondrial disorder is not suspected until poten-
novo mitochondrial proline synthesis [118].
tially pathogenic genetic variants are identified in a
known mitochondrial disease gene during next-
Genetic complexity of mitochondrial disease generation sequencing of an exome or genome.
The genetics of mitochondrial disease is complex,
with contributions from two genomes. Mitochondrial Importance of history taking
disease may be inherited by a number of different
With so much focus on the enormous complexity of
genetic mechanisms including maternal (mtDNA
mitochondrial disease and the ‘differentness’ of it,
mutations) and autosomal recessive, autosomal
the similarities to the rest of medicine may easily be
dominant and X-linked for nuclear gene mutations.
overlooked. For example, very often the diagnosis
Sporadic mtDNA mutations have been recognized for
rests in the history; careful attention to detail can
more than three decades, but recently, an increasing
allow the observant physician to win the diagnostic
number of de novo nuclear gene variants have been
lottery. The patient, even a young nonverbal child,
linked to mitochondrial disease, initially for DNM1L
provides many clues about their personal story. The
variants [119]. More recently, de novo variants have
order of events is extremely important. What hap-
been reported in ATAD3A, CTBP1, ISCU, SLC25A4
pened first? Was he or she born with the cataracts or
and SLC25A24 [120]. DiMauro and colleagues were
squint or ptosis or did these features develop later?
the first to classify the nuclear-encoded disorders
How does the mother, especially an experienced
rationally according to the underlying molecular
mother, feel about her child? Are things as
defect [121]. Genetic causes of primary mitochon-
expected? Or subtly different? So much of mito-
drial disease may be subdivided into defects of
chondrial disease starts subtly, insidiously, in the
OXPHOS subunits and complex assembly, disorders
first days and weeks of life. Did the baby not feed
of mitochondrial DNA maintenance, defects of mito-
quite as well as they should, was there more than the
chondrial gene expression, deficiencies of cofactor
usual amount of gastro-oesophageal reflux? Were
biosynthesis and transport, defects of mitochondrial
they thrown off course by the mildest of infections?
solute and protein import, disorders of mitochondrial
How do they compare to peers and siblings at the
lipid membranes and organellar dynamics (fission/
same age? Are developmental milestones being met?
fusion) and disorders of mitochondrial quality con-
Has there been a loss of skills with intercurrent
trol (Table 2), but new disease mechanisms continue
illnesses? Are they slower to recover from intercur-
to be discovered. Since the advent of next-generation
rent illnesses than siblings, peers, other family
sequencing methods, there has been a rapid pace of
members? How many systems are affected? It is
gene discovery for mitochondrial disease and cur-
important to enquire specifically about vision, hear-
rently approaching 400 different gene defects have
ing, language acquisition, cardiorespiratory and
been linked to primary mitochondrial disease
gastrointestinal symptoms, as well as about
(Table 2).
Table 2 Classification of mitochondrial disease genes
Mode of
Disease mechanism Gene defects inheritance
Disorders of Oxidative Phosphorylation (OXPHOS) Complexes and their Assembly
Complex I Subunits and Assembly MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6 mtDNA
Factors NDUFA1 XL
NDUFA2, NDUFA6, NDUFA9, NDUFA10, NDUFA11, NDUFA12, AR
NDUFA13 NDUFB3, NDUFB8, NDUFB9, NDUFB10, NDUFB11,
NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8,
NDUFV1, NDUFV2, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4,
NDUFAF5, NDUFAF6, NDUFAF7, NDUFAF8, ACAD9, ECSIT,
FOXRED1, NUBPL, TIMMDC1, TMEM126B
Complex II Subunits and Assembly SDHA, SDHAF1 AR
Factors SDHB AR/AD
SDHC, SDHD, SDHAF2 AD
Complex III Subunits and MT-CYB mtDNA
Assembly Factors UQCRB, UQCRC2, UQCRFS1, UQCRQ, UQCC2, UQCC3, CYC1, AR
BCS1L, HCCS, TTC19, LYRM7
Complex IV Subunits and MT-CO1, MT-CO2, MT-CO3 mtDNA
Assembly Factors COX7B XL
COX4I1, COX4I2, COX5A, COX6A1, COX6A2, COX6B1, COX8A, AR
NDUFA4, SURF1, SCO1, SCO2, COX10, COX14, COX15, COX20,
COA3, COA5, COA6, COA7, FASTKD2, PET100, PET117, CEP89
Complex V Subunits and Assembly MT-ATP6, MT-ATP8 mtDNA
Factors ATP5F1A, ATP5F1D, ATP5F1E, ATP5MD, ATPAF2, TMEM70 AR
Assembly of Multiple OXPHOS OXA1L AR
Complexes
Disorders of Mitochondrial DNA Maintenance
Nucleotide Pool Maintenance RRM2B AR/AD
DGUOK, TK2, MPV17, TYMP, ABAT, SAMHD1 AR
Replication POLG, POLG2, TWNK, DNA2 AR/AD
SSBP1 AD
MGME1, RNASEH1, TOP3A, FBXL4 AR
Disorders of Mitochondrial Gene Expression
Mitochondrial transfer RNAs MT-TA, MT-TC, MT-TD, MT-TD, MT-TE, MT-TF, MT-TG, MT-TH, MT-TI, mtDNA
MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TP, MT-TQ, MT-TR, MT-
TS, MT-TT, MT-TV, MT-TW, MT-TY, MT-DEL*
Mitochondrial Aminoacyl-tRNA AARS2, CARS2, DARS2, EARS2, FARS2, GARS, HARS2, IARS2, AR
Synthetases KARS, LARS2, MARS2, NARS2, PARS2, RARS2, SARS2, TARS2,
VARS2, WARS2, YARS2, QRSL1, GATB, GATC
HSD17B10 XL
Mitochondrial Transcript TFAM, POLRMT, MTFMT, TRIT1, TRMT5, TRMT10C, TRNT1, PNPT1, AR
Processing and Modification MTO1, TRMU, GTPBP3, PUS1, THG1L, ELAC2, MTPAP, NSUN3,
PDE12
Mode of
Mitoribosome (Ribosomal RNA and MT-RNR1, MT-RNR2 mtDNA
Protein Subunits; Assembly and MRPL3, MRPL12, MRPL44, MRPS2, MRPS7, MRPS14, MRPS16, AR
Recycling Factors; Translation MRPS22, MRPS23, MRPS25, MRPS28, MRPS34, PTCD3 (MRPS39),
Initiation, Elongation and MRM2, ERAL1, RMND1, C12orf65, GFM1, GFM2, GUF1, LRPPRC,
Termination Factors) TACO1, TSFM, TUFM
Disorders of Mitochondrial Membrane Lipids, Import, Dynamics and Quality Control
Mitochondrial Membrane TAZ, TIMM8A XL
Phospholipid Metabolism and AGK, CHKB, DNAJC19, GFER, PAM16, SERAC1, PLA2G6, TIMM22, AR
Protein Import Machinery TIMM50, TIMMDC1
Mitochondrial Solute Carriers SLC25A11, SLC25A24 AD
SLC25A4 AD/AR
SLC25A1, SLC25A3, SLC25A10, SLC25A12, SLC25A13, SLC25A15, AR
SLC25A19, SLC25A20, SLC25A21, SLC25A22, SLC25A26,
SLC25A32, SLC25A38, SLC25A42, SLC25A46, GOT2, MICU1,
MICU2
Mitochondrial Dynamics DNM1L, MFN2, OPA1, GDAP1, MSTO1 AD/AR
MFF, STAT2, TRAK1, MIEF2 AR
Intermembrane Space and MICOS CHCHD10, CHCHD2 AD
Complex QIL1 AR
ER–Mitochondrial Tethering EMC1 AR
Mitochondrial Protein Quality CLPX, HSPE1 AD
Control AFG3L2, ATAD3A, SPG7, HSPA9, HSPD1, HTRA2 AD/AR
PMPCA, PMPCB, MIPEP, XPNPEP3, CLPB, CLPP, LONP1, PITRM1, AR
SACS, TRAP1, PRKN, PINK1, YME1L
Toxicity ETHE1, HIBCH, ECHS1, SQOR AR
Antioxidant Defense TXN2, TXNIP AR
Other Disorders of Energy Metabolism
Tricarboxylic Acid Cycle Enzymes IDH2, DLST AD
FH AD/AR
ACO2, IDH3A, IDH3B, MDH2, OGDH, SUCLA2, SUCLG1 AR
Pyruvate Metabolism PDHA1 XL
DLAT, DLD, MPC1, PC, PDHB, PDHX, PDK3, PDP1, PDPR AR
Fatty Acid Metabolism CRAT, ETFA, ETFB, ETFDH, FA2H, PYCR1 AR
Disorders of Vitamin and Cofactor Metabolism
Coenzyme Q10 Biosynthesis PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, AR
COQ9
Iron–Sulphur Cluster Protein ABCB7 XL
Biosynthesis ISCA1, ISCA2, ISCU, FDXR, FDX2, FXN, LYRM4, NFS1, NFU1 AR
Lipoic Acid Biosynthesis BOLA3, GLRX5, IBA57, LIAS, LIPT1, LIPT2, MECR AR
Cytochrome c Synthesis CYCS AD
Biotin Metabolism BTD, HLCS AR
Mode of
Thiamine Metabolism and TPK1, SLC19A2, SLC19A3 AR
Transport
Riboflavin Metabolism and SLC52A1 AD
Transport FLAD1, SLC52A2, SLC52A3 AR
Nicotinamide Metabolism NMNAT1, NADK2, NAXD, NAXE, NNT AR
Coenzyme A Metabolism COASY, PANK2, PPCS AR
Heavy Metal Metabolism (copper, SLC33A1 AD/AR
manganese) CCS, SLC39A8 AR
Selenocysteine Metabolism SECISBP2, SEPSECS AR
Other Cellular Defects Associated with Mitochondrial Dysfunction
Calcium Homeostasis WFS1 AD/AR
ANO10, C19ORF70, CISD2, CYP24A1 AR
Haem Biosynthesis ALAS2 XL
ABCB6 AD
SFXN4 AR
Apoptosis Defects AIFM1 XL
DIABLO AD
APOPT1, PTRH2 AR
DNA Repair APTX, XRCC4 AR
Miscellaneous or Unknown PNPLA4 XL
Function CTBP1, FGF12, KIF5A, STXBP1 AD
ALDH18A1, C19ORF12, DCC, DIAPH1, OPA3 AD/AR
CA5A, C1QBP, PNPLA8, POP1, PPA2, ROBO3, RTN4IP1, SPART, AR
SPATA5, TANGO2, TMEM65, TMEM126A
AD, autosomal dominant; AR, autosomal recessive; ER, endoplasmic reticulum; mtDNA, mitochondrial DNA; MICOS,
mitochondrial contact site and cristae organizing system; 3MGA, 3-methylglutaconic aciduria; XL, X-linked.
exercise tolerance, fatigue and the presence of on fundoscopy, hypotonia, muscle weakness, dys-
migraines or seizures. Many children with mito- tonia, spasticity, extrapyramidal and cerebellar
chondrial disease do not have symptoms and signs signs, and evidence of peripheral neuropathy. Mus-
that align closely with canonical mitochondrial cle strength may be normal on static testing, and
syndromes (Table 1) but the pattern of organ repeated testing may be needed to elicit the muscle
involvement can be a powerful clue to the underlying fatigability typical of mitochondrial myopathy.
diagnosis (Table 3). The family history may also Tachypnoea may be a clue to lactic acidosis, and
provide useful diagnostic clues, for example if there there may be a hyperdynamic precordium if there is
is consanguinity, previous stillbirths or early neona- significant cardiomyopathy. A search for multisys-
tal deaths, or a strong history of problems running tem features should include assessment by a cardi-
through the maternal lineage. ologist (including ECG and echocardiography),
ophthalmologist and audiological physician.
Physical examination
Diagnostic investigations
A thorough physical examination should be per-
formed, including auxology and full neurological Diagnosis of a mitochondrial disorder requires a
assessment, searching carefully for ptosis, ophthal- multidisciplinary approach, which may include
moplegia, optic atrophy or pigmentary retinopathy metabolic investigations, neuroimaging, muscle
Table 3 Examples of symptom constellations that aid in differential diagnosis of mitochondrial disease
Cardinal clinical
feature Variable additional clinical features Syndrome Gene defect
Epilepsia partialis Movement disorder (choreoathetosis); Alpers POLG
continua hepatic impairment
Stepwise Bilateral symmetrical basal ganglia and/or Leigh ~100 different nuclear
neurodevelopmental brainstem lesions, elevated lactate and mtDNA gene
regression defects
Stroke-like episodes SNHL, lactic acidosis MELAS MT-TL1 (m.3243A>G)
Ptosis/ Ataxia, cardiac conduction defect, Kearns–Sayre SLSMD
ophthalmoplegia pigmentary retinopathy
Progressive myopathy Elevated lactate and CK Myopathic MDDS TK2
Progressive myopathy SNHL, respiratory muscle weakness, renal Encephalomyopathic RRM2B
tubulopathy MDDS
Dilated Neutropaenia (cyclical) and 3MGA Barth TAZ
cardiomyopathy
Hypertrophic Cataracts Sengers AGK
cardiomyopathy
Sideroblastic anaemia Lactic acidosis, pancreatic insufficiency Pearson SLSMD
Sideroblastic anaemia Myopathy, lactic acidosis MLASA PUS1, YARS2
Sideroblastic anaemia B-cell immune deficiency, SNHL, recurrent SIFD TRNT1
fevers, RP
Renal impairment Profound SNHL, myopathy RMND1 deficiency RMND1
Steroid-resistant Seizures, SNHL CoQ10 biosynthesis COQ6, COQ8B, PDSS2,
nephrotic syndrome disorder COQ2,
GI pseudo-obstruction Foot drop (peripheral neuropathy), MNGIE TYMP
leukoencephalopathy
Liver failure Status epilepticus Alpers POLG
Liver failure Peripheral neuropathy Hepatocerebral MPV17
MDDS
Liver failure Recovery TRMU deficiency TRMU
Acrocyanosis Diarrhoea, petechiae, neurodevelopmental Ethylmalonic ETHE1
delay encephalopathy
3MGA, 3-methylglutaconic aciduria; CK, creatine kinase; GI, gastrointestinal; MDDS, mitochondrial DNA depletion
syndrome; MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MLASA, myopathy,
lactic acidosis and sideroblastic anaemia; MNGIE, mitochondrial neurogastrointestinal encephalopathy; RP, retinitis
pigmentosa; SIFD, sideroblastic anaemia, immune deficiency, fever and developmental delay; SLSMD, single large-scale
mitochondrial DNA deletion; SNHL, sensorineural hearing loss.
biopsy and genetic testing. Blood, urine and CSF

Neuroimaging phenotypes
metabolites that can help in the delineation of a
specific mitochondrial disorder or in the identifi- Magnetic resonance imaging of the brain can be
cation of a nonmitochondrial multisystem disorder extremely helpful in the diagnosis of mitochondrial
(‘phenocopy’) are detailed in Table 4, together with disease. For example, in MELAS there are typically
a list of histological investigations and enzyme parieto-occipital stroke-like lesions not corre-
assays. sponding to vascular territories, whilst Leigh
syndrome is characterized by bilateral symmetric functional evidence to support pathogenicity of

T2 hyperintense lesions in the basal ganglia, mid- variants of uncertain significance observed on
brain and/or brainstem, with variable lesions next-generation sequencing, or where genetic
elsewhere in the brain and spinal cord. MRS may investigations are ‘negative’ yet clinical suspicion
reveal a lactate peak in many mitochondrial disor- of an underlying mitochondrial disorder remains
ders or a succinate peak in complex II deficiency. A high.
retrospective review of a large French series of
children and adults with biochemical evidence of
Biochemical phenotypes in muscle
mitochondrial dysfunction and a genetic diagnosis
(152 mitochondrial, 37 nonmitochondrial) sug- Until recently, assessment of respiratory chain
gested that the presence of a lactate peak and enzyme activities in biopsies of skeletal muscle
hyperintensity in the basal ganglia/pallidum/ (or another affected tissue such as heart or liver)
brainstem had a high positive predictive value for was considered a first-line investigation of mito-
mitochondrial disease, whereas lesions elsewhere chondrial disease. The ‘diagnostic rate’ of respira-
in the brain were not helpful in either diagnosing or tory chain abnormalities in suspected
excluding a mitochondrial disorder [124]. A normal mitochondrial disease varied widely in historical
MRI brain was found to decrease the likelihood of cohorts, from 28 to 71 % [127,128]. Observed
an underlying mitochondrial disorder but did not abnormalities included isolated deficiencies of sin-
completely exclude it [124]. Cerebral white matter gle respiratory chain enzymes (most frequently
disturbance is increasingly being recognized as a complex I or complex IV) or deficiencies of multiple
manifestation of mitochondrial disease. There are respiratory chain enzymes. Initial dogma was that
frequently cystic changes, and another diagnostic an isolated enzyme deficiency was suggestive of a
clue pointing to an underlying disorder may be the defect in a subunit or assembly factor of that
involvement of grey matter structures (e.g. basal enzyme, whereas multiple respiratory chain
ganglia) as well as white matter lesions. Leukoen- enzyme deficiencies indicated a disorder of mtDNA
cephalopathy was initially reported in deficiencies maintenance or gene expression. However, there
of complexes I, II and IV but is now recognized to be appear to be an increasing number of exceptions to
a feature of many of the mitochondrial translation these rules. For example, we have observed iso-
disorders, particularly the aminoacyl-tRNA syn- lated complex I deficiency with defects of ELAC2
thetase deficiencies [125]. Some mitochondrial and isolated complex IV deficiency associated with
disease genes appear to be associated with very AARS2 mutations. Both genes encode factors
specific neuroimaging appearances (Table 5), required for mitochondrial translation so theoret-
which can be used to direct genetic investigations ically should be associated with multiple respira-
and expedite genetic diagnoses of these cases. tory chain deficiencies. Thus, the dogmatic rules of
However, it could be argued that there may be an thumb are no longer considered so useful. Another
ascertainment bias in identifying patients with issue is the increasing population of patients with
certain gene defects associated with particular genetically confirmed mitochondrial disease who
radiological phenotypes, and it will therefore be have normal respiratory chain enzyme activities in
interesting to see whether the observed correla- muscle biopsies. The explanations may be that the
tions are upheld in multiple large series over time. defects are not expressed in skeletal muscle (the
tissue that is most frequently biopsied in suspected
mitochondrial disease) or possibly that the under-
The role of muscle biopsy in the 21st century
lying molecular defect does not impair the activities
With the increasingly widespread use of next- of the respiratory chain enzymes in the way that
generation sequencing as a first-line diagnostic they are assayed.
test, muscle biopsies are being performed less
frequently in the diagnostic work-up of suspected
Genetic testing
mitochondrial disease in children [126]. In my own
practice, we now tend to reserve first-line muscle Ultimately, identification of pathogenic genetic
biopsies for infants and children presenting criti- variants is required to confirm the diagnosis of a
cally unwell to the intensive care unit, where the primary mitochondrial disorder. Recognition of
risk of demise is great and there is insufficient time particular constellations of clinical features
to wait for a genetic diagnosis. Other reasons to (Table 3) or knowledge of a geographically preva-
perform a muscle biopsy include searching for lent disorder (e.g. LRPPRC mutations causing Leigh
Table 4 Investigation of suspected mitochondrial disease in childhood
Test Tissue Indication

Lactate Blood, CSF Useful if elevateda but may be normal
Lactate/pyruvate ratio Blood, CSF Decreased in PDH deficiency
Blood gas, bicarbonate Blood To determine whether there is acid–base disturbance
Glucose Blood, CSF Hypoglycaemia is a feature of some PMDs, diabetes of others
Amino acids Blood, CSF Alanine, proline and glycine may be increased and arginine and
citrulline decreased in PMD
Acylcarnitines Blood Characteristic elevations of acylcarnitine species in SUCLA2,
SUCLG1, HIBCH and ECHS1 defects; differential diagnosis of
complex multisystem disease; may be secondary carnitine
deficiency in PMD
FGF21, GDF15 Blood Considered biomarkers of PMD, useful if elevated but may be normal
Organic acids Urine Presence of 3MGA and Krebs cycle intermediates may be helpful in
differential diagnosis
Thymidine, deoxyuridine Blood, Urine If clinical suspicion of MNGIE
Thymidine phosphorylase assay Platelets If clinical suspicion of MNGIE
Transferrin electrophoresis Blood Differential diagnosis of complex multisystem disease
Very long-chain fatty acids Blood Differential diagnosis of complex multisystem disease
Creatine and related metabolites Blood, Urine Differential diagnosis of complex multisystem disease; may be
secondary creatine deficiency in PMD
Lysosomal enzymes WBC Differential diagnosis of complex multisystem disease
Neurotransmitters CSF If movement disorder
5-methyltetrahydrofolate CSF May be low, especially in KSS
PDH assay Fibroblasts If clinical suspicion of PDH deficiency
b
Histology Muscle Ragged-red, ragged-blue and COX-negative fibres?
Electron microscopy Muscleb Ultrastructural mitochondrial abnormalities?
Respiratory chain enzyme assays Muscleb To determine which complex(es) is/are deficient
Coenzyme Q10 WBC, Muscle Disorder of coenzyme Q10 biosynthesis?
3MGA, 3-methylglutaconic aciduria; COX, cytochrome c oxidase; FGF21, fibroblast growth factor 21; GDF15, growth/
differentiation factor 15; KSS, Kearns–Sayre syndrome; MNGIE, mitochondrial neurogastrointestinal encephalopathy;
PDH, pyruvate dehydrogenase; PMD, primary mitochondrial disease; WBC, white blood cells.
a
Providing secondary and artefactual causes of hyperlactataemia have been excluded.
b
or other affected tissue.
syndrome in French Canada) may lead to directed PanelApp (https://panelapp.genomicsengland.co.

testing of a specific pathogenic variant. However, uk/). Trio (parent/child) sequencing is invaluable
the rapid rate of gene discovery for mitochondrial in the identification of de novo variants. MtDNA
disease and rarity of some of the newly identified can be sequenced separately or captured within
gene defects makes it difficult to accumulate clin- the exome or genome, and mtDNA can be quanti-
ical experience of these ultra-rare disorders and fied by qPCR or droplet digital PCR of DNA
consider them in the differential diagnosis. There- extracted from an affected tissue. The importance
fore, genome-wide next-generation sequencing is of functional validation of genetic variants identi-
increasingly the genetic testing method of choice. fied by next-generation sequencing methods can-
Often, this is exome or genome sequencing but not be overemphasized. Methods to confirm the
sometimes large gene panels are tested such as the pathogenicity of novel variants include Western
MitoExome [129] or the Genomics England blotting, biochemical assays (e.g. of mitochondrial
Table 5 Examples of mitochondrial gene defects associated with specific neuroimaging phenotypes
Gene defect Neuroimaging features References

AARS2 Leukoencephalopathy with particular involvement of left–right connections, descending [88]
tracts and cerebellar atrophy
DARS2 Leukoencephalopathy with brainstem and spinal cord involvement and lactate [157]
elevation (LBSL)
EARS2 Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) [158]
IBA57 Diffuse cavitating leukoencephalopathy, most prominent posteriorly and in fronto-parietal [159]
regions
ISCA2 Diffusely abnormal white matter signal in cerebrum, cerebellum, brainstem and spinal cord [160]
LYRM7 Multifocal cavitating leukoencephalopathy with multiple small cavitations in [161]
periventricular and deep cerebral white matter
MT-TL1 Parieto-occipital stroke-like lesions, not conforming to vascular territories [9]
m.3243A>G
NDUFV1 Progressive macrocystic leukoencephalopathy (may be confused with vanishing white [162]
matter disease)
NUBPL Predominant signal abnormalities of cerebellar cortex, deep cerebral white matter, basal [163]
ganglia, thalami and corpus callosum
RARS2 Severe progressive pontocerebellar atrophy (rarely pons may be spared) [11]
SDHA SDHAF1 Leukoencephalopathy with signal abnormalities in central corticospinal tracts and spinal [164]
cord, cerebral white matter (sparing of U fibres), corpus callosum, pons, middle cerebellar
peduncles and cerebellar white matter; succinate peak on MRS
SERAC1 Bilateral basal ganglia T2 hyperintensities, initially sparing dorsal putamen [165]
TYMP Asymptomatic leukoencephalopathy (demyelination) [96]
MRS, 1H-magnetic resonance spectroscopy.
translation), mass spectrometric profiling of sequencing methods. We initially used Leigh syn-
OXPHOS complexes, immunocytochemical assays drome as a prototype paediatric mitochondrial
(e.g. in disorders of mitochondrial dynamics) and disorder and showed that use of the ‘Leigh Map’
functional complementation studies (e.g. lentiviral computational resource placed the correct disease
transduction with the wild-type gene of interest to gene amongst the top-ranked genes in 80% of test
rescue the biochemical defect). cases [134].
Harnessing phenomics Differential diagnosis and phenocopies

Phenomics is the systematic study of all the Mitochondrial diseases are notorious mimics, long
measurable physical and biochemical attributes recognized to present with any combination of
of an individual [130,131] and is a particularly symptoms affecting one or multiple organs at any
attractive tool for application in the field of inborn age, from intrauterine life to late adulthood (Fig. 2).
errors of metabolism [132]. The development of the This phenotypic heterogeneity, coupled with the
Human Phenotype Ontology has allowed for the biochemical and genetic complexity of mitochon-
quantitation of phenomic traits [133]. We har- dria, leads to enormous diagnostic challenges.
nessed this information to determine whether Next-generation sequencing has introduced unpar-
phenomics could be used to create a computational alleled opportunities for enhanced diagnosis of
diagnostic resource for mitochondrial disease, to mitochondrial disease and led to the discovery of
be used in concert with next-generation new disease genes at an astonishing rate, but has
also revealed that mitochondrial dysfunction may chromosome is indeed the cause of the differing
in many cases be secondary to nonprimary mito- phenotypes in these two siblings. Work on differ-
chondrial genetic defects, leading to even more entiated cells and organoids derived from induced
complexity [3]. Thus, mitochondrial disease could pluripotent stem cells may eventually help to
be thought of as a modern-day syphilis and Sir unravel the complex relationship between genotype
William Osler’s aphorism ‘Know syphilis in all its and phenotype in mitochondrial diseases
manifestations and relations, and all other things [141,142].
clinical will be added unto you’ [135] could be
updated to ‘S/he who knows mitochondrial disease
Monitoring
knows all of medicine’ to reflect the protean man-
ifestations and complexity of mitochondrial dis- Annual investigations should aim to screen for
ease. known treatable complications of mitochondrial
disease. In my clinic, we routinely screen for
anaemia, renal impairment and renal tubulopathy,
Disease mechanisms
hepatic impairment, endocrine dysfunction (dia-
The mechanisms underlying mitochondrial disease betes, hypothyroidism, cortisol insufficiency and
remain incompletely understood. Whilst energy growth hormone deficiency using IGF1 and IGFBP3
insufficiency is widely cited as the cause of mito- as proxy markers) and measure levels of plasma
chondrial disease presentations, it is increasingly amino acids and acylcarnitines. Children are
considered that disturbance of other key mito- reviewed annually or every two years (depending
chondrial functions, including intracellular sig- on the disorder) in a specialist cardiology clinic,
nalling, maintaining redox balance, calcium where echocardiography and ECG are performed.
homeostasis and regulation of apoptosis, is likely More frequent cardiac screening may be indicated
to contribute to disease pathogenesis [1]. In addi- in specific disorders. For example, a systematic
tion, seminal work in cell and animal models of review of electrical heart disease in KSS led to 6
mitochondrial disease has implicated one-carbon monthly ECGs being advocated for this disorder
metabolism and an integrated stress response in [81]. Regular ophthalmological and audiological
the pathogenesis of primary mitochondrial disease review is also recommended. Difficulties with swal-
[136-138], and recent studies have suggested that lowing or episodes of choking should be investi-
oxygen may exert direct neuronal toxicity in Leigh gated by videofluoroscopy with input from a
syndrome [139]. specialist speech and language therapist. In addi-
tion, prominent GI symptoms should prompt
investigation for pancreatic exocrine insufficiency
What influences the phenotype?
(intractable diarrhoea), pancreatitis (severe
Mitochondrial disease is different in every individ- abdominal pain) or GI dysmotility (abdominal pain,
ual that I have encountered in my clinical practice vomiting, constipation, diarrhoea). Because of a
of nearly 30 years. Even siblings sharing the same lack of evidence-based guidelines for mitochondrial
homozygous mutation rarely (I would go so far as to monitoring, a Delphi panel was convened recently
say never) manifest with an identical set of prob- to obtain consensus recommendations [143].
lems and rate of progression. Each has his/her
own unique problems and responses to environ-
Management
mental stressors. Whether these are the result of
their genetic background or environmental factors The multi-layered complexity of mitochondrial dis-
(e.g. timing of exposure to first viral infection [140]) ease, particularly in childhood, has meant that
is unknown in the majority of cases. But some- therapeutic advances have lagged a long way
times we are given small clues. I saw two brothers behind the genetic discoveries. A few gene defects
with the same homozygous mutation in a complex have suggested clear treatment strategies, such as
III assembly gene but one had worse development, coenzyme Q10 supplementation for disorders of
more challenging behaviour, higher blood lactate coenzyme Q10 biosynthesis [90], and riboflavin for
values and a more severe movement disorder. This defects of riboflavin transport and metabolism as
brother’s karyotype was 47XXY, whereas his more well as various flavoprotein disorders, for example
mildly affected brother had the usual male chro- deficiencies of ACAD9, AIFM1 and some complex I
mosomal complement of 46XY. However, it would subunits [144]. However, precision medicine is not
be extremely challenging to prove that the extra X yet available for the vast majority of mitochondrial
disorders presenting in childhood, and for these with intercurrent illnesses? Have they had a pre-
children, supportive measures remain of para- vious episode of respiratory failure necessitating
mount importance. Adjunctive therapies may intensive care admission? Whichever of these is
include hearing aids, cochlear implants, brow true for an individual child, this is the likely
suspension for ptosis, gastrostomy feeds, pancre- trajectory of their disease going forwards. With
atic enzyme supplementation, pacemaker inser- the publication of a number of (largely retrospec-
tion, medical treatment of cardiomyopathy, tive) natural history studies in recent years, we can
electrolyte supplementation to replace renal tubu- finally begin to add some more precise detail to
lar losses, blood transfusion for sideroblastic these general observations, at least for some gene
anaemia, antiepileptic drugs and (in selected situ- defects. It is sobering to note the continuing high
ations, after careful multidisciplinary assessment) mortality of paediatric mitochondrial disease. A
renal, cardiac or hepatic transplantation systematic review of retrospective natural history
[21,145,146]. studies reporting mortality data for 23 mitochon-
drial disorders revealed a mean/median age of
death < 1 year in 13% of disorders, <5 years in
Emerging therapies
57% and < 10 years in 74% of the diseases studied
Many research groups across the globe are explor- [94].
ing novel experimental strategies, which fall
broadly into two categories: pharmacological and
Final thoughts
genetic approaches. These emerging therapies
have been the subject of a number of recent What has been the predominant weather for the
reviews, to which the reader is directed [147-150]. mitochondrial disease field in the last 30 years? I
Disease-agnostic pharmacological approaches can would say mainly overcast with a lot of thunder-
be grouped into antioxidants, interventions aimed showers and occasional bursts of sunshine when
to increase mitochondrial biogenesis, molecules to breakthroughs are made. No rainbows yet, and
stabilize the mitochondrial membrane lipids and certainly no pots of gold at the end of the rainbow.
targeting mitophagy via the mTOR pathway. Some Is the weather finally changing? I think it may be
of these approaches are currently in clinical trial too early to tell for sure. What have been the three
[150,151]. Targeted pharmacological approaches most important landmark moments in this period?
include the use of nucleosides to restore mtDNA The discovery of mtDNA mutations, the demon-
synthesis in myopathic MDDS caused by TK2 stration of the power of next-generation sequencing
deficiency [152]. Genetic therapies targeting the and the possibility of effective therapy for at least
mtDNA include selective elimination of mutant one disorder (COQ2 deficiency) have been the
mtDNA using restriction enzymes delivered as highlights for me. The discovery of the first mtDNA
mitoTALENs [153] or zinc finger nucleases [154], mutations heralded the birth of a new field of
or replacing a mitochondrial protein by expressing medicine, one defined by complexity and uncer-
it from the nucleus, an approach that is currently tainty at every level (clinical, biochemical, genetic,
in clinical trial for LHON [155]. AAV-mediated gene diagnostic, therapeutic). The identification of
therapy directed at nuclear-encoded mitochondrial nuclear gene mutations as a cause of mitochon-
defects has been reported in a number of mouse drial disease was the opening of a window, letting
models [150,156], but has not yet been translated in light and fresh air, whilst the subsequent
to human mitochondrial disease. introduction of next-generation sequencing
brought in unprecedented diagnostic power. Where
previously the journey had been undertaken in the
Prognosis
back of a beaten-up truck with rusty suspension
What about prognosis? Nothing, not the magnitude and inadequate fuel, this was a switching of gears,
of lactate elevation in blood or CSF, the activities of in fact a switching to an entirely different vehicle,
respiratory chain enzymes in biopsied skeletal more like a brand new Ferrari. Are we collectively
muscle, not even the definitive genetic diagnosis, responsible for the lack of progress in finding
can speak to a child’s prognosis as much as his/ effective therapies? Had we been better scientists
her own trajectory to this point in time. Has he or and physicians would we be further forward? Or do
she slowly been making progress? Or progressively the difficulties lie in the complex nature of mito-
deteriorating and acquiring multisystem prob- chondrial diseases? I favour the latter view and
lems? Has there been developmental regression believe that the passion and determination of the
mitochondrial scientific and medical community 13 Smith AC, Ito Y, Ahmed A et al. A family segregating lethal
will find effective therapies for these devastating neonatal coenzyme Q10 deficiency caused by mutations in
COQ9. J Inherit Metab Dis 2018; 41: 719–29.
diseases in the not too distant future.
14 Saada A et al. Antenatal mitochondrial disease caused by
mitochondrial ribosomal protein (MRPS22) mutation. J Med
Acknowledgements Genet 2007; 44: 784–6.
15 Jackson CB et al. A variant in MRPS14 (uS14m) causes
I am greatly indebted to my patients and their perinatal hypertrophic cardiomyopathy with neonatal lactic
families, who have taught me everything I know acidosis, growth retardation, dysmorphic features and neu-
rological involvement. Hum Mol Genet 2019; 28: 639–49.
about mitochondrial disease. My research group
16 Inbar-Feigenberg M, Blaser S, Hawkins C et al. Mitochon-
currently receives grant funding from the National drial POLG related disorder presenting prenatally with fetal
Institute of Health Research Great Ormond Street cerebellar growth arrest. Metab Brain Dis 2018; 33: 1369–
Hospital Biomedical Research Centre, Great 73.
Ormond Street Hospital Children’s Charity, the 17 Vu TH et al. Clinical manifestations of mitochondrial DNA
Lily Foundation and Action Medical Research. depletion. Neurology 1998; 50: 1783–90.
18 Rahman S, Poulton J. Diagnosis of mitochondrial DNA
depletion syndromes. Arch Dis Child 2009; 94: 3–5.
Conflict of interest 19 Elpeleg O et al. Deficiency of the ADP-forming succinyl-CoA
synthase activity is associated with encephalomyopathy and
No conflict of interest was declared. mitochondrial DNA depletion. Am J Hum Genet 2005; 76:
1081–6.
20 Viscomi C, Zeviani M. MtDNA-maintenance defects: syn-
References dromes and genes. J Inherited Meta Dis 2017; 40: 587–99.
1 Rahman J, Rahman S. Mitochondrial medicine in the omics 21 Rahman S, Copeland WC. POLG-related disorders and their
era. Lancet 2018; 391: 2560–74. neurological manifestations. Nat Rev Neurol 2019; 15: 40–
2 Thorburn DR. Mitochondrial disorders: prevalence, myths 52.
and advances. J Inherit Metab Dis 2004; 27: 349–62. 22 Keshavan N, Abdenur J, Anderson G et al. The natural
3 Parikh S, Karaa A, Goldstein A et al. Diagnosis of ’possible’ history of infantile mitochondrial DNA depletion syndrome
mitochondrial disease: an existential crisis. J Med Genet due to RRM2B deficiency. Genet Med 2020; 22: 199–209.
2019; 56: 123–30. 23 Horvath R et al. Molecular basis of infantile reversible
4 Alpers B. DIffuse progressive degeneration of the gray matter cytochrome c oxidase deficiency myopathy. Brain 2009;
of the cerebrum. Archiv Neurol Psychiat 1931; 25: 469–505. 132(Pt 11): 3165–74.
5 Leigh D. Subacute necrotizing encephalomyelopathy in an 24 Mimaki M, Hatakeyama H, Komaki H et al. Reversible
infant. J Neurol Neurosurg Psychiat 1951; 14: 216–221. infantile respiratory chain deficiency: a clinical and molec-
6 Kearns TP, Sayre GP. Retinitis pigmentosa, external oph- ular study. Ann. Neurol. 2010; 68: 845–54.
thalmoplegia, and complete heart block: unusual syndrome 25 Boczonadi V et al. Altered 2-thiouridylation impairs mito-
with histologic study in one of two cases. AMA Arch chondrial translation in reversible infantile respiratory chain
Ophthalmol 1958; 60: 280–9. deficiency. Hum Mol Genet 2013; 22: 4602–15.
7 Pearson HA, Lobel JS, Kocoshis SA et al. A new syndrome of 26 Rotig A et al. Spectrum of mitochondrial DNA rearrange-
refractory sideroblastic anemia with vacuolization of marrow ments in the Pearson marrow-pancreas syndrome. Hum Mol
precursors and exocrine pancreatic dysfunction. J Pediatr Genet 1995; 4: 1327–30.
1979; 95: 976–984. 27 Broomfield A, Sweeney MG, Woodward CE et al. Paediatric
8 Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T. Myoclo- single mitochondrial DNA deletion disorders: an overlapping
nus epilepsy associated with ragged-red fibres (mitochon- spectrum of disease. J Inherit Metab Dis 2015; 38: 445–57.
drial abnormalities ): disease entity or a syndrome? Light- 28 Clarke SL, Bowron A, Gonzalez IL et al. Barth syndrome.
and electron-microscopic studies of two cases and review of Orphanet J Rare Dis 2013; 8: 23.
literature. J Neurol Sci 1980; 47: 117–33. 29 Kang Y, Stroud DA, Baker MJ et al. Sengers syndrome-
9 Pavlakis SG, Phillips PC, DiMauro S et al. Mitochondrial associated mitochondrial acylglycerol kinase is a subunit of
myopathy, encephalopathy, lactic acidosis, and strokelike the human TIM22 protein import complex. Mol Cell 2017;
episodes: a distinctive clinical syndrome. Ann Neurol 1984; 67: 457–470.e5.
16: 481–8. 30 Vukotic M, Nolte H, K€ onig T et al. Acylglycerol kinase
10 Fassone E, Rahman S. Complex I deficiency: clinical fea- mutated in sengers syndrome is a subunit of the TIM22
tures, biochemistry and molecular genetics. J Med Genet protein translocase in mitochondria. Mol Cell 2017; 67: 471–
2012; 49: 578–90. 483.e7.
11 Glamuzina E, Brown R, Hogarth K et al. Further delineation 31 Haghighi A et al. Sengers syndrome: six novel AGK muta-
of pontocerebellar hypoplasia type 6 due to mutations in the tions in seven new families and review of the phenotypic and
gene encoding mitochondrial arginyl-tRNA synthetase, mutational spectrum of 29 patients. Orphanet J Rare Dis
RARS2. J Inherit Metab Dis 2012; 35: 459–67. 2014; 9: 119.
12 Brea-Calvo G et al. COQ4 mutations cause a broad spectrum 32 Rahman S, Blok RB, Dahl H-HM et al. Leigh syndrome:
of mitochondrial disorders associated with CoQ10 defi- clinical features and biochemical and DNA abnormalities.
ciency. Am J Hum Genet 2015; 96: 309–17. Ann Neurol 1996; 39: 343–51.
33 Huttenlocher PR, Solitare GB, Adams G. Infantile diffuse 52 Wiltshire E et al. Juvenile Alpers disease. Arch. Neurol. 2008;
cerebral degeneration with hepatic cirrhosis. Arch Neurol 65: 121–4.
1976; 33: 186–92. 53 Pitceathly RD et al. Distal myopathy with cachexia: an
34 Hikmat O, Tzoulis C, Chong WK et al. The clinical spectrum and unrecognised phenotype caused by dominantly-inherited
natural history of early-onset diseases due to DNA polymerase mitochondrial polymerase gamma mutations. J Neurol.
gamma mutations. Genet Med 2017; 19: 1217–25. Neurosurg. Psychiatry 2013; 84: 107–10.
35 Rahman S, Mayr JA. Disorders of oxidative phosphorylation. 54 Van Goethem G et al. Novel POLG mutations in progressive
In: Saudubray J-M, Baumgartner MR, Walter J, eds. Inborn external ophthalmoplegia mimicking mitochondrial neuro-
metabolic diseases diagnosis and treatment. Berlin, Heidel- gastrointestinal encephalomyopathy. Eur J Hum Genet
berg: Springer, 2016; 223-242. 2003; 11: 547–9.
36 Berenberg RA et al. Lumping or splitting? "Ophthalmoplegia- 55 Yu-Wai-Man P, Chinnery PF. Leber hereditary optic neu-
plus" or Kearns-Sayre syndrome? Ann Neurol 1977; 1: 37–54. ropathy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE,
37 Serrano M, Garcıa-Silva MT, Martin-Hernandez E et al. Bean LJH, Stephens K, Amemiya A, eds. GeneReviews
Kearns-Sayre syndrome: cerebral folate deficiency, MRI [Internet. Seattle, WA: University of Washington, Seattle;
findings and new cerebrospinal fluid biochemical features. 1993-2020. http://www.ncbi.nlm.nih.gov/books/NBK1174
Mitochondrion 2010; 10: 429–32. 56 Giordano C et al. Oestrogens ameliorate mitochondrial
38 Pitceathly RD, Fassone E, Taanman J-W et al. Kearns-Sayre dysfunction in Leber’s hereditary optic neuropathy. Brain
syndrome caused by defective R1/p53R2 assembly. J Med 2011; 134(Pt 1): 220–34.
Genet 2011; 48: 610–7. 57 Jun AS, Brown MD, Wallace DC. A mitochondrial DNA
39 Andreu AL et al. Exercise intolerance due to mutations in the mutation at nucleotide pair 14459 of the NADH dehydroge-
cytochrome b gene of mitochondrial DNA. N Engl J Med nase subunit 6 gene associated with maternally inherited
1999; 341: 1037–44. Leber hereditary optic neuropathy and dystonia. Proc Natl
40 Keightley JA, Hoffbuhr KC, Burton MD et al. A microdeletion Acad Sci U S A 1994; 91: 6206–10.
in cytochrome c oxidase (COX) subunit III associated with 58 Dandekar SS, Graham EM, Plant GT. Ladies with Leber’s
COX deficiency and recurrent myoglobinuria. Nat Genet hereditary optic neuropathy: an atypical disease. Eur J
1996; 12: 410–6. Ophthalmol 2002; 12: 537–41.
41 Rahman S et al. A missense mutation of cytochrome oxidase 59 Liolitsa D et al. Is the mitochondrial complex I ND5 gene a
subunit II causes defective assembly and myopathy. Am J hot-spot for MELAS causing mutations? Ann. Neurol. 2003;
Hum Genet 1999; 65: 1030–9. 53: 128–32.
42 Karadimas CL, Greenstein P, Sue CM et al. Recurrent 60 Rahman S. Mitochondrial diseases and status epilepticus.
myoglobinuria due to a nonsense mutation in the COX I Epilepsia 2018; 59(Suppl 2): 70–77.
gene of mitochondrial DNA. Neurology 2000; 55: 644–9. 61 Cohen BH. Mitochondrial and Metabolic Myopathies. Con-
43 Gonzalez-Del Angel A et al. Novel phenotypes and cardiac tinuum (Minneap Minn) 2019; 25: 1732–66.
involvement associated with DNA2 genetic variants. Front 62 Menezes MP, Rahman S, Bhattacharya K et al. Neurophys-
Neurol 2019; 10: 1049. iological profile of peripheral neuropathy associated with
44 Kaufmann P et al. Natural history of MELAS associated with childhood mitochondrial disease. Mitochondrion 2016; 30:
mitochondrial DNA m.3243A>G genotype. Neurology 2011; 162–7.
77: 1965–71. 63 Thorburn DR, Rahman J, Rahman S. Mitochondrial DNA-
45 Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) associated leigh syndrome and NARP. In: Adam MP,
gene associated with the MELAS subgroup of mitochondrial Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens
encephalomyopathies. Nature 1990; 348: 651–3. K, Amemiya A, editors. GeneReviews [Internet]. Seattle,
46 Manwaring N, Jones MM, Wang JJ et al. Population preva- WA: University of Washington, Seattle; 1993-2020. http://
lence of the MELAS A3243G mutation. Mitochondrion 2007; www.ncbi.nlm.nih.gov/books/NBK1173
7: 230–3. 64 Karadimas CL et al. Navajo neurohepatopathy is caused by a
47 Nesbitt V et al. MThe UKMRC Mitochondrial Disease Patient mutation in the MPV17 gene. Am J Hum Genet 2006; 79: 544–
Cohort Study: clinical phenotypes associated with the 8.
m.3243A>G mutation–implications for diagnosis and man- 65 Benarroch L, Bonne G, Rivier F et al. The 2020 version of the
agement. J Neurol Neurosurg Psychiatry 2013; 84: 936–8. gene table of neuromuscular disorders (nuclear genome).
48 Wallace DC, Zheng X, Lott MT et al. Familial mitochondrial Neuromuscul Disord 2019; 29: 980–1018.
encephalomyopathy (MERRF): genetic, pathophysiological, 66 Pitceathly RD, Murphy SM, Cottenie E et al. Genetic
and biochemical characterization of a mitochondrial DNA dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth
disease. Cell 1988; 55: 601–10. disease. Neurology 2012; 79: 1145–54.
49 Mancuso M et al. Phenotypic heterogeneity of the 8344A>G 67 Echaniz-Laguna A, Ghezzi D, Chassagne M et al. SURF1
mtDNA "MERRF" mutation. Neurology 2013; 80: 2049–54. deficiency causes demyelinating Charcot-Marie-Tooth dis-
50 Byrne E, Trounce I, Dennett X et al. Progression from ease. Neurology 2013; 81(17): 1523–30.
MERRF to MELAS phenotype in a patient with combined 68 Rebelo AP, Saade D, Pereira CV et al. SCO2 mutations
respiratory complex I and IV deficiencies. J Neurol Sci 1988; cause early-onset axonal Charcot-Marie-Tooth disease
88: 327–37. associated with cellular copper deficiency. Brain 2018;
51 Miyahara H et al. Autopsied case with MERRF/MELAS 141: 662–72.
overlap syndrome accompanied by stroke-like episodes 69 Tucci A, Liu Y-T, Preza E et al. Novel C12orf65 mutations in
localized to the precentral gyrus. Neuropathology 2019; 39: patients with axonal neuropathy and optic atrophy. J Neurol
212–7. Neurosurg Psychiat 2014; 85: 486–92.
70 Yu-Wai-Man P, Votruba M, Burt e F et al. A neurodegener- 89 Rahman S, Hall AM. Mitochondrial disease–an important
ative perspective on mitochondrial optic neuropathies. Acta cause of end-stage renal failure. Pediatr Nephrol 2013; 28:
Neuropathol 2016; 132: 789–806. 357–61.
71 Jurkute N et al. SSBP1 mutations in dominant optic atrophy 90 Salviati Let al. Primary coenzyme Q10 deficiency. In: Adam
with variable retinal degeneration. Ann Neurol 2019; 86: MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH,
368–83. Stephens K, Amemiya A, editors. GeneReviews [Internet].
72 Scaglia F et al. Molecular bases of hearing loss in multi- Seattle, WA: University of Washington, Seattle; 1993-2020.
systemic mitochondrial cytopathy. Genet Med. 2006; 8: 641– http://www.ncbi.nlm.nih.gov/books/NBK410087/
52. 91 Montini G, Malaventura C, Salviati L. Early coenzyme Q10
73 Bitner-Glindzicz M et al. Prevalence of mitochondrial 1555A– supplementation in primary coenzyme Q10 deficiency. N
>G mutation in European children. N Engl J. Med 1555A; Engl J Med 2008; 358: 2849–50.
360: 640–2. 92 Hall AM, Vilasi A, Garcia-Perez I et al. The urinary proteome
74 Rahman S et al. Hearing in 44–45 year olds with and metabonome differ from normal in adults with mito-
m.1555A>G, a genetic mutation predisposing to aminogly- chondrial disease. Kidney Int 2015; 87: 610–22.
coside-induced deafness: a population based cohort study. 93 Wedatilake Y et al. SURF1 deficiency: a multi-centre natural
BMJ Open 2012; 2: e000411. history study. Orphanet J Rare Dis 2013; 8: 96.
75 Hinson JT et al. Missense mutations in the BCS1L gene as a 94 Keshavan N, Rahman S. Natural history of mitochondrial
cause of the Bjornstad syndrome. N Engl J Med 2007; 356: disorders: a systematic review. Essays Biochem 2018; 62:
809–19. 423–42.
76 Maas RR et al. Progressive deafness-dystonia due to 95 Tiranti V et al. Ethylmalonic encephalopathy is caused by
SERAC1 mutations: a study of 67 cases. Ann Neurol 2017; mutations in ETHE1, a gene encoding a mitochondrial
82: 1004–15. matrix protein. Am J Hum Genet 2004; 74: 239–52.
77 Shayota BJ et al. Characterization of the renal phenotype in 96 Hirano M. Mitochondrial neurogastrointestinal
RMND1-related mitochondrial disease. Mol Genet Genomic encephalopathy disease. In: Adam MP, Ardinger HH, Pagon
Med 2019; 7: e973. RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors.
78 Wedatilake Y, Niazi R, Fassone E et al. TRNT1 deficiency: GeneReviews [Internet]. Seattle, WA: University of Wash-
clinical, biochemical and molecular genetic features. Orpha- ington, Seattle; 1993-2020. http://www.ncbi.nlm.nih.gov/
net J Rare Dis 2016; 11: 90. books/NBK1179/
79 Enns GM. Pediatric mitochondrial diseases and the heart. 97 Chang TM et al. Paralytic ileus in MELAS with phenotypic
Curr Opin Pediatr 2017; 29: 541–51. features of MNGIE. Pediatr Neurol 2004; 31: 374–7.
80 Limongelli G, Tome-Esteban M, Dejthevaporn C et al. Preva- 98 Shaibani A et al. Mitochondrial neurogastrointestinal
lence and natural history of heart disease in adults with encephalopathy due to mutations in RRM2B. Arch Neurol
primary mitochondrial respiratory chain disease. Eur J 2009; 66: 1028–32.
Heart Fail. 2010; 12: 114–21. 99 Shteyer E et al. Exocrine pancreatic insufficiency, dysery-
81 Kabunga P et al. Systematic review of cardiac electrical thropoietic anemia, and calvarial hyperostosis are caused by
disease in Kearns-Sayre syndrome and mitochondrial a mutation in the COX4I2 gene. Am J Hum Genet 2009; 84:
cytopathy. Int J Cardiol 2015; 181: 303–10. 412–7.
82 Kennedy H, Haack TB, Hartill V et al. Sudden cardiac death 100 Hu H et al. Mutations in PTRH2 cause novel infantile-onset
due to deficiency of the mitochondrial inorganic pyrophos- multisystem disease with intellectual disability, micro-
phatase PPA2. Am J Hum Genet 2016; 99: 674–82. cephaly, progressive ataxia, and muscle weakness. Ann Clin
83 Sudo A, Honzawa S, Nonaka I et al. Leigh syndrome Transl Neurol 2014; 1: 1024–35.
caused by mitochondrial DNA G13513A mutation: fre- 101 Darin N et al. The incidence of mitochondrial encephalomy-
quency and clinical features in Japan. J Hum Genet 2004; opathies in childhood: clinical features and morphological,
49: 92–6. biochemical, and DNA abnormalities. Ann Neurol 2001; 49:
84 Mollet J, Giurgea I, Schlemmer D et al. Prenyldiphosphate 377–83.
synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyl- 102 McKiernan P, Ball S, Santra S et al. Incidence of primary
transferase (COQ2) mutations in ubiquinone deficiency and mitochondrial disease in children younger than 2 years
oxidative phosphorylation disorders. J Clin Invest 2007; presenting with acute liver failure. J Pediatr Gastroenterol
117: 765–72. Nutr 2016; 63: 592–7.
85 Crow Y et al. Cardiac valve involvement in ADAR-related type 103 Cormier-Daire V, Chretien D, Rustin P et al. Neonatal and
I interferonopathy. J Med Genet 2019. https://doi.org/10. delayed-onset liver involvement in disorders of oxidative
1136/jmedgenet-2019-106457 [Epub ahead of print]. phosphorylation. J Pediatr 1997; 130: 817–22.
86 Chow J, Rahman J, Achermann JC et al. Mitochondrial 104 Rahman S. Gastrointestinal and hepatic manifestations of
disease and endocrine dysfunction. Nat Rev Endocrinol mitochondrial disorders. J Inherit Metab Dis 2013; 36: 659–
2017; 13: 92–104. 673.
87 Pagnamenta AT et al. Dominant inheritance of premature 105 Zeharia A et al. Acute infantile liver failure due to mutations
ovarian failure associated with mutant mitochondrial DNA in the TRMU gene. Am J Hum Genet 2009; 85: 401–7.
polymerase gamma. Hum Reprod 2006; 21: 2467–73. 106 Chakraborty PK, Schmitz-Abe K, Kennedy EK et al. Muta-
88 Dallabona C, Diodato D, Kevelam SH et al. Novel (ovario) tions in TRNT1 cause congenital sideroblastic anemia with
leukodystrophy related to AARS2 mutations. Neurology immunodeficiency, fevers, and developmental delay (SIFD).
2014; 82: 2063–71. Blood 2014; 124: 2867–71.
107 Bykhovskaya Y et al. Missense mutation in pseudouridine 126 Witters P, Saada A, Honzik T et al. Revisiting mitochondrial
synthase 1 (PUS1) causes mitochondrial myopathy and diagnostic criteria in the new era of genomics. Genet Med
sideroblastic anemia (MLASA). Am J Hum Genet 2004; 74: 2018; 20(4): 444–51.
1303–8. 127 Uusimaa J, Remes AM, Rantala H et al. Childhood
108 Shahni R et al. A distinct mitochondrial myopathy, lactic encephalopathies and myopathies: a prospective study in a
acidosis and sideroblastic anemia (MLASA) phenotype asso- defined population to assess the frequency of mitochondrial
ciates with YARS2 mutations. Am J Med Genet A 2013; 161: disorders. Pediatrics 2000; 105(Pt 1): 598–603.
2334–8. 128 Scaglia F et al. Clinical spectrum, morbidity, and mortality
109 Hikmat O et al. The presence of anaemia negatively influ- in 113 pediatric patients with mitochondrial disease. Pedi-
ences survival in patients with POLG disease. J Inherit atrics 2004; 114: 925–31.
Metab Dis 2017; 40: 861–6. 129 Calvo SE, Compton AG, Hershman SG et al. Molecular
110 Rensvold JW et al. Complementary RNA and protein profil- diagnosis of infantile mitochondrial disease with targeted
ing identifies iron as a key regulator of mitochondrial next-generation sequencing. Sci. Transl. Med. 2012; 4:
biogenesis. Cell Rep 2013; 3: 237–45. 118ra10.
111 Shahni R, Cale CM, Anderson G et al. Signal transducer and 130 Bilder RM, Sabb FW, Cannon TD et al. Phenomics: the
activator of transcription 2 deficiency is a novel disorder of systematic study of phenotypes on a genome-wide scale.
mitochondrial fission. Brain 2015; 138(Pt 10): 2834–46. Neuroscience 2009; 164: 30–42.
112 Rankin J, Brown R, Dobyns WB et al. Pontocerebellar 131 Houle D, Govindaraju DR, Omholt S. Phenomics: the next
hypoplasia type 6: A British case with PEHO-like features. challenge. Nat Rev Genet 2010; 11: 855–66.
Am J Med Genet A 2010; 152A: 2079–84. 132 Rahman J, Rahman S. The utility of phenomics in diagnosis
113 Gai X et al. Mutations in FBXL4, encoding a mitochondrial of inherited metabolic disorders. Clin Med (Lond) 2019; 19:
protein, cause early-onset mitochondrial encephalomyopa- 30–6.
thy. Am J Hum Genet 2013; 93: 482–95. 133 Robinson PN, K€ ohler S, Bauer S et al. The human phenotype
114 Magner M, Dvorakova V, Tesarova M et al. TMEM70 ontology: a tool for annotating and analyzing human hered-
deficiency: long-term outcome of 48 patients. J Inherit Metab itary disease. Am J Hum Genet 2008; 83: 610–5.
Dis 2015; 38: 417–26. 134 Rahman J, Noronha A, Thiele I et al. Leigh map: a novel
115 Ferreira CR,Altassan R, Marques-Da-Silva D et al. Recog- computational diagnostic resource for mitochondrial dis-
nizable phenotypes in CDG. J Inherit Metab Dis 2018; 41: ease. Ann Neurol 2017; 81: 9–16.
541–53. 135 Osler SW. Know the manifestations of syphilis. In: Silverman
116 Smits P et al. Mutation in mitochondrial ribosomal protein ME, Murray TJ, Bryan CS, eds. The quotable Osler. Amer-
MRPS22 leads to Cornelia de Lange-like phenotype, brain ican College of Physicians, 2008; 151.
abnormalities and hypertrophic cardiomyopathy. Eur J Hum 136 Bao XR, Ong S-E, Goldberger O et al. Mitochondrial
Genet 2011; 19: 394–9. dysfunction remodels one-carbon metabolism in human
117 Gusic M, Schottmann G, Feichtinger RG et al. Bi-allelic cells. eLife 2016; 5. https://doi.org/10.7554/eLife.10575
UQCRFS1 variants are associated with mitochondrial com- 137 Nikkanen J, Forsstr€ om S, Euro L et al. Mitochondrial DNA
plex III deficiency, cardiomyopathy, and alopecia totalis. Am replication defects disturb cellular dNTP pools and remodel
J Hum Genet 2020; 106: 102–111. one-carbon metabolism. Cell Metab 2016; 23: 635–48.
118 Zampatti S, Castori M, Fischer B et al. De Barsy Syndrome: 138 Khan NA, Nikkanen J, Yatsuga S et al. mTORC1 regulates
a genetically heterogeneous autosomal recessive cutis laxa mitochondrial integrated stress response and mitochondrial
syndrome related to P5CS and PYCR1 dysfunction. Am J myopathy progression. Cell Metab 2017; 26: 419–428.e5.
Med Genet A 2012; 158A: 927–31. 139 Jain IH, Zazzeron L, Goldberger O et al. Leigh syndrome
119 Waterham HR, Koster J, vanRoermund CWT et al. A lethal mouse model can be rescued by interventions that normalize
defect of mitochondrial and peroxisomal fission. N Engl J brain hyperoxia, but Not HIF activation. Cell Metab 2019;
Med 2007; 356: 1736–41. 30: 824–832.e3.
120 Thompson K, Collier JJ, Glasgow RIC et al. Recent advances 140 Fassone E et al. Mutations in the mitochondrial complex I
in understanding the molecular genetic basis of mitochon- assembly factor NDUFAF1 cause fatal infantile hypertrophic
drial disease. J Inherit Metab Dis 2019; 43: 36–50. cardiomyopathy. J Med Genet 2011; 48: 691–7.
121 DiMauro S, Moraes CT. Mitochondrial encephalomy- 141 Hamalainen RH et al. Tissue- and cell-type-specific mani-
opathies. Arch Neurol 1993; 50: 1197–208. festations of heteroplasmic mtDNA 3243A>G mutation in
122 Munnich A, R€ otig A, Chretien D et al. Clinical presentation of human induced pluripotent stem cell-derived disease model.
mitochondrial disorders in childhood. J Inherit Metab Dis Proc Natl Acad Sci USA 2013; 110: E3622–30.
1996; 19: 521–7. 142 Fatica EM, DeLeonibus GA, House A et al. Syndrome:
123 Boenzi S, Diodato D. Biomarkers for mitochondrial energy exploring cardiac metabolism with induced pluripotent stem
metabolism diseases. Essays Biochem 2018; 62: 443–54. cell-derived cardiomyocytes. Metabolites 2019; 9: 306.
124 de Beaurepaire I, Gr event D, Rio M et al. High predictive 143 Parikh S et al. Patient care standards for primary mitochon-
value of brain MRI imaging in primary mitochondrial respi- drial disease: a consensus statement from the Mitochondrial
ratory chain deficiency. J Med Genet 2018; 55: 378–83. Medicine Society. Genet Med 2017; 19. https://doi.org/10.
125 Fine AS, Nemeth CL, Kaufman ML et al. Mitochondrial 1038/gim.2017.107 [Epub ahead of print].
aminoacyl-tRNA synthetase disorders: an emerging group of 144 Balasubramaniam S, Christodoulou J, Rahman S. Disor-
developmental disorders of myelination. J Neurodev Disord ders of riboflavin metabolism. J Inherit Metab Dis 2019; 42:
2019; 11: 29. 608–19.
145 Davison JE, Rahman S. Recognition, investigation and 157 Scheper GC et al. Mitochondrial aspartyl-tRNA synthetase
management of mitochondrial disease. Arch Dis Child deficiency causes leukoencephalopathy with brain stem and
2017; 102: 1082–90. spinal cord involvement and lactate elevation. Nat Genet
146 Parikh S, Karaa A, Goldstein A et al. Solid organ transplan- 2007; 39: 534–9.
tation in primary mitochondrial disease: proceed with cau- 158 Steenweg ME, Ghezzi D, Haack T et al. Leukoencephalopa-
tion. Mol Genet Metab 2016; 118: 178–84. thy with thalamus and brainstem involvement and high
147 El-Hattab AW, Zarante AM, Almannai M et al. Therapies for lactate ’LTBL’ caused by EARS2 mutations. Brain 2012; 135
mitochondrial diseases and current clinical trials. Mol Genet (Pt 5): 1387–94.
Metab 2017; 122: 1–9. 159 Torraco A, Ardissone A, Invernizzi F et al. Novel mutations in
148 Hirano M, Emmanuele V, Quinzii CM. Emerging therapies IBA57 are associated with leukodystrophy and variable
for mitochondrial diseases. Essays Biochem 2018; 62: 467– clinical phenotypes. J Neurol 2017; 264: 102–11.
81. 160 Alfadhel M et al. Further delineation of the phenotypic
149 Garone C, Viscomi C. Towards a therapy for mitochondrial spectrum of ISCA2 defect: A report of ten new cases. Eur J
disease: an update. Biochem Soc Trans 2018; 46: 1247–61. Paediatr Neurol 2018; 22: 46–55.
150 Rahman S. Advances in the treatment of mitochondrial 161 Dallabona C et al. LYRM7 mutations cause a multifocal
epilepsies. Epilepsy Behav 2019; 101: 106546. cavitating leukoencephalopathy with distinct MRI appear-
151 Khayat D, Kurtz TL, Stacpoole PW. The changing landscape ance. Brain 2016; 139(Pt 3): 782–94.
of clinical trials for mitochondrial diseases: 2011 to present. 162 Schuelke M et al. Mutant NDUFV1 subunit of mitochondrial
Mitochondrion 2020; 50: 51–7. complex I causes leukodystrophy and myoclonic epilepsy.
152 Dominguez-Gonzalez C, Madruga-Garrido M, Mavillard F Nat Genet 1999; 21: 260–1.
et al. Deoxynucleoside therapy for thymidine kinase 2- 163 Kevelam SH, Rodenburg RJ, Wolf NI et al. NUBPL mutations
deficient myopathy. Ann Neurol 2019; 86: 293–303. in patients with complex I deficiency and a distinct MRI
153 Bacman SR, Kauppila JHK, Pereira CV et al. MitoTALEN pattern. Neurology 2013; 80: 1577–83.
reduces mutant mtDNA load and restores tRNA(Ala) levels in 164 Helman G, Caldovic L, Whitehead MT et al. Magnetic
a mouse model of heteroplasmic mtDNA mutation. Nat Med resonance imaging spectrum of succinate dehydrogenase-
2018; 24: 1696–1700. related infantile leukoencephalopathy. Ann Neurol 2016; 79:
154 Gammage PA, Viscomi C, Simard M-L et al. Genome editing 379–86.
in mitochondria corrects a pathogenic mtDNA mutation 165 Wortmann SB, vanHasselt P, Bari c I et al. Eyes on MEGDEL:
in vivo. Nat Med 2018; 24: 1691–5. distinctive basal ganglia involvement in dystonia deafness
155 Jurkute N, Harvey J, Yu-Wai-Man P. Treatment strategies syndrome. Neuropediatrics 2015; 46: 98–103.
for Leber hereditary optic neuropathy. Curr Opin Neurol
2019; 32: 99–104. Correspondence: Shamima Rahman, Mitochondrial Research
156 Suzuki-Hatano S et al. AAV-mediated TAZ gene replacement Group, Genetics and Genomic Medicine, UCL Great Ormond
restores mitochondrial and cardioskeletal function in barth Street Institute of Child Health, London WC1N 1EH, UK.
syndrome. Hum Gene Ther 2019; 30: 139–54. (fax: +44-2074046191; e-mail: shamima.rahman@ucl.ac.uk).

Mitochondrial Disease in Children

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Mitochondrial Disease in Children

Uploaded by

Copyright:

Available Formats

Review Symposium

Mitochondrial disease in children

Introduction Architecture of this review

Table 1 An alphabetical classification of mitochondrial syndromes

Disease Clinical features Gene defect(s)a

Disease Clinical features Gene defect(s)a

‘honeymoon’ period of relatively good health before

sometimes known by the acronym SIFD, for sider-

disorders. Excess hair is typically observed on the

Table 2 Classification of mitochondrial disease genes

biopsy and genetic testing. Blood, urine and CSF

syndrome is characterized by bilateral symmetric functional evidence to support pathogenicity of

Table 4 Investigation of suspected mitochondrial disease in childhood

Test Tissue Indication

syndrome in French Canada) may lead to directed PanelApp (https://panelapp.genomicsengland.co.

Gene defect Neuroimaging features References

MRS, 1H-magnetic resonance spectroscopy.

Harnessing phenomics Differential diagnosis and phenocopies

You might also like