MITOCHONDRIAL DISEASES

 Mitochondrial diseases are a clinically heterogeneous

group of disorders that arise as a result of dysfunction of the
mitochondrial respiratory chain.
 The mitochondrial respiratory chain is the essential final
common pathway for aerobic metabolism, and tissues and
organs that are highly dependent on aerobic metabolism are
preferentially involved in mitochondrial disorders .
 Mitochondrial respiratory chain is the only metabolic
pathway in the cell that is under the dual control of
the mitochondria DNA (mtDNA) and the nuclear
DNA (nDNA).
 Approximately 80 proteins make up the respiratory
chain, 13 are encoded by mtDNA and all others are
encoded by nDNA.
PREVALENCE:
 It can be said that mitochondrial disorders are the most
common Neurometabolic diseases of childhood.
  One in 5,000 individuals has a genetic mitochondrial disease.
Genetic classification of the mitochondria disease:
  Disorders due to mutations in mtDNA, which are
governed by the rules of mitochondrial inheritance.
 Disorders  due to mutations in nDNA, which are
governed by the rules of mendelian genetics.
MODE OF INHERITANCE

 Mitochondrial inheritance.
 Autosomal recessive inheritance .

 Autosomal dominant inheritance

 X-linked inheritance.
THE MITOCHONDRIAL CHROMOSOME

 The mitochondria, contains a number of copies of a small

circular molecule, the mitochondrial chromosome.
 The mitochondrial DNA molecule is only 16 kb in length
and encodes only 37 genes, 13 protein coding gene, 2
rRNA gene & 22 tRNA genes.
TRANSCRIPTION OF THE MITOCHONDRIAL
GENOME

 The mitochondrial genome has its own transcription and

protein-synthesis system.
 A specialized RNA polymerase, encoded in the nuclear
genome, is used to transcribe the mitochondrial genome,
which contains two related promoter sequences, one for
each strand of the circular genome.
 Each strand is transcribed in its entirety, and the
mitochondrial transcripts are then processed to generate
the various individual mitochondrial mRNAs, tRNAs,
and rRNAs.
 mDNA nDNA
shape circular linear
Size 16,569 base pairs 3.3 billion base pairs
haploid diploid
Genes 37 genes More than 25000 protein
coding genes
Introns absent present
Coding DNA 93% ~ 2%
Copies 100-10000 Single copy in the form
of 46 chromosomes
Histone Absent, DNA is not Present, DNA is packed
packed into chromatin into chromatin
DNA repair No DNA repair or proof Good DNA repair, proof
reading reading
Mutation rate 10 times greater Low mutation rate
 mDNA nDNA
Genetic code Unique genetic code Universal
Mode of inheritance maternal AD, AR & X-linked
DNA replication DNA polymerase DNA polymerase α, δ
Gamma
transcription polycistronic Individual gene
Cell division Fusion, fission Regulated by cell cycle
 Nuclear genes Mutations are being considered the main
reason of pediatric mitochondrial disease.
 Therefore, it can be said that Autosomal recessive
inheritance of nuclear genes disorders is likely the
most common cause of mitochondrial disorders in
children.
Functions controlled by n DNA:
(i) synthesis of assembly proteins.
(ii) intergenomic signaling.
(iii) mitochondrial importation of nDNA-encoded
proteins.
(iv) synthesis of inner mitochondria membrane
phospholipid.
(v) mitochondrial motility and fission.
PRINCIPLE OF MITOCHONDRIAL GENETICS:

 Heteroplasmy : Each cell contains hundreds or

thousands of mtDNA copies, which, at cell division,
distribute randomly among daughter cells.
 In normal tissues, all mtDNA molecules are identical
(homoplasmy).
 Deleterious mutations of mtDNA usually affect some but
not all mtDNAs within a cell, a tissue, or an individual
(heteroplasmy).
 The clinical expression of a pathogenic mtDNA mutation
is largely determined by the relative proportion of
normal and mutant mtDNA genomes in different tissues.
 Threshold effect: the minimum critical
number of mutant mtDNAs is required to
cause mitochondrial dysfunction in a
particular organ or tissue, resulting in
a mitochondrial disease.
 Mitotic segregation: At cell division, the proportion of
mutant mtDNAs in daughter cells may shift and the
phenotype may change accordingly.
 This explains how certain patients with mtDNA-related
disorders may actually manifest different mitochondrial
diseases at different stages of their lives.
  Maternal inheritence: At fertilization, all mtDNA
derives from the oocyte.
 Therefore, A mother carrying a mtDNA point mutation
will pass it on to all her children (males as well as
females), but only her daughters will transmit it to
their offsprings.
 A disease expressed in both sexes but with no evidence
of paternal transmission is strongly suggestive of a
mtDNA point mutation.
Mitochondrial disorders are characterized by:
 Pleiotropy.

 Reduced penetrance.

 Variable expressivity.
CLINICAL MANIFESTATIONS

 Mitochondrial disorders may present at any age.

 Some mitochondrial disorders affect a single organ (e.g.,
the eye in Leber hereditary optic neuropathy and the ear
in nonsyndromic hearing loss with or without
aminoglycoside sensitivity; but many involve multiple
organ systems and often present with prominent
neurologic and myopathic features.
 Common clinical features of mitochondrial disease
include ptosis, external ophthalmoplegia, proximal
myopathy and exercise intolerance, cardiomyopathy,
sensorineural deafness, optic atrophy, pigmentary
retinopathy, and diabetes mellitus.
 The central nervous system findings are often
fluctuating encephalopathy, seizures, dementia,
migraine, stroke-like episodes, ataxia, and spasticity.
 Chorea and dementia may also be prominent features .
 As a general rule, the involvement of 3 or more organ
symptoms without a unifying diagnosis should raise
suspicion of mitochondrial disease.

 A high incidence of mid- and late pregnancy loss is also

a common feature that often remains unrecognized.
CLASSIFICATION:
 Disorder related to mtDNA defects: this group
can be divided in two main subgroups:
 Disorders that are caused by deletions and
duplications in mitochondrial DNA.
 Disorders that are caused point mutations in
mitochondrial DNA.
 Disorders related to nDNA defects:

 Mutations in genes encoding proteins of the

respiratory chain.
 Defects of intergenomic signaling.
 Mutations of genes indirectly involved in
OXPHOS
 Inheritance pattern of Point mutations are maternal, but
Deletions and duplications in mDNA are commonly
inherited by sporadic pattern.
 mDNA abnormalities cause different disorders based on
clinical view are seen commonly with increasing the age
of the patient.
 mtDNA

Deletion & Point

duplication mutation

Pearson MELAS
MERRF
PEO NARP
KSS LHON
SNHL
Leigh syndrome
MTDNA DELETION & DUPLICATION:
 Progressive external ophthalmoplegia (PEO): Late-
onset bilateral ptosis and ophthalmoplegia, proximal
muscle weakness and wasting, and exercise intolerance
 Kearns Sayer syndrome: Ataxia, neuropathy, PEO< 20
years, pigmentary retinal degeneration, cardiomyopathy,
conduction block, short stature, and high CSF protein .
 Pearson’s syndrome: Frequent death in infancy.
Refractory sideroblastic anaemia with vacuolization of
marrow precursors, exocrine dysfunction of pancrease.
MTDNA POINT MUTATION:
 MELAS: Stroke-like episodes due to focal brain lesions
in the parieto-occipital lobes, lactic acidosis and/or
Ragged-red fibers(RFF)
 MERRF: Myoclonus, epilepsy, muscle weakness and
wasting with RRFs, cerebellar ataxia, deafness and
dementia.
 NARP: Ataxia, pigmentary retinopathy, peripheral
neuropathy and distal neurogenic weakness.
 SNHL: Non-syndromic and aminoglycoside-induced
hearing loss
 Leber Hereditary Optic Neuropathy: Loss of central
vision, large centro-caecal absolute scotoma,
circumpapillary telangiectatic microangiopathy
 nDNA

Mutations in genes Mutations of genes

Defects of intergenomic
encoding proteins of the indirectly involved in
signaling
respiratory chain OXPHOS

Freidreich’s ataxia,
AR-inherited Leigh AD and AR PEO Hereditary spastic
Syndrome MNGIE paraplegia (HSP)
CoQ10 deficiency Alpers X-linked ataxia and
Barth syndrome sideroblastic anemia
MLASA
MUTATIONS IN GENES ENCODING
PROTEINS OF THE RESPIRATORY CHAIN

 Leigh syndrome(AR): Subacute relapsing

encephalopathy, Cerebellar and brain stem signs,
Infantile onset.

 CoQ10 deficiency(AR): low coenzyme Q in muscle,

unexplained cerebellar ataxia, pyramidal signs, and
seizures, unspecific myopathic change.
DEFECTS OF INTERGENOMIC
SIGNALING:
 Alpers syndrome(AR): Hypotonia,dementia, Seizures,
Liver failure & renal tubulopathy.

 Barth’s syndrome (XR): An abnormality of cardiolipin

metabolism, myopathy, cardiopathy, neutropenia, short
stature and 3-methyl glutaconic aciduria.
 MLASA(AR):  myopathy, lactic acidosis,
and sideroblastic anemia. 
 Mitochondrial neurogastrointestinal encephalopathy
(MNGIE) disease(AR): progressive gastrointestinal
dysmotility, ptosis/ophthalmoplegia or
ophthalmoparesis; leukoencephalopathy; and
demyelinating peripheral neuropathy (paresthesias) and
symmetric and distal weakness more prominently
affecting the lower extremities
Mutations of genes indirectly involved in OXPHOS

Secondary mitochondrial dysfunction is also seen in a

number of different genetic disorders, including:
 Freidreich’s ataxia(AR): Ataxia, loss of DTR, sensory
neuropathy, Babinski sign, cardiomyopathy, diabetes.

 X-linked ataxia and sideroblastic anaemia: Ataxia,

sideroblastic anaemia

 Hereditary spastic paraplegia(AR)

  The term mitochondrial disorder usually refers to
primary disorders of mitochondrial metabolism affecting
oxidative phosphorylation.
DIAGNOSIS:
 Mitochondrial dysfunction should be considered in the
differential diagnosis of any progressive multisystem
disorder.
 A full evaluation for a mitochondrial disorder is often
warranted in children with a complex neurologic picture
or a single neurologic symptom and other system
involvement.
INVESTIGATIONS:

Plasma/CSF Lactate/pyruvate
 Measurement of plasma or CSF lactate concentration is
indicated in individuals with features of a myopathy or CNS
disease.
 Fasting blood lactate concentrations above 3 mm/L support a
diagnosis of mitochondrial disease.
 Fasting CSF lactate concentrations above 1.5 mm/L support a
diagnosis of mitochondrial disease.

 Normal plasma or CSF lactic acid concentration does not

exclude the presence of a mitochondrial disorder.
Magnetic resonance spectroscopy and
exercise testing: may also be of use to
detect an elevated lactate level in brain or
muscle at rest, or a delay in the recovery
of the ATP peak in muscle after exercise.
Neuroimaging is indicated in individuals with suspected
CNS disease.
 CT may show basal ganglia calcification and/or diffuse
atrophy.
 MRI may show focal atrophy of the cortex or
cerebellum, or high signal change on T2-weighted
images, particularly in the occipital cortex.
 There may also be evidence of a generalized
leukoencephalopathy .
 Cerebellar atrophy is a prominent feature in children .
Neurophysiologic studies
 Electroencephalography (EEG) is indicated in
individuals with suspected encephalopathy or seizures.
 Encephalopathy may be associated with generalized
slow wave activity on the EEG. Generalized or focal
spike and wave discharges may be seen in individuals
with seizures.
 Peripheral neurophysiologic studies are indicated in
individuals with limb weakness, sensory symptoms, or
areflexia.
 Electromyography (EMG) is often normal but may
show myopathic features.
 Nerve conduction velocity (NCV) may be normal or may
show a predominantly axonal sensory motor
polyneuropathy.
Glucose. An elevated concentration of fasting blood
glucose may indicate diabetes mellitus.
 Cardiac: Both electrocardiography and
echocardiography may indicate cardiac involvement
(cardiomyopathy or atrioventricular conduction defects)
TREATMENT
 No effective therapy is available for mitochondrial
disorders.
 Antioxidants, vitamins, and auxiliary factors as the
mainstay treatments of patients with mitochondrial
diseases, among which arginine, CoQ10, L-carnitine and
creatine are the most commonly prescribed drugs.
 Most doctors use a combination of three to six drugs, the
so-called “cocktail therapy”. It is not efficient, but can
partly improve symptoms.
  several supportive measures, such as improvement of
nutrition, surgical correction of ptosis, treatment of
seizures and other complications, correction of lactic
acidosis, can ameliorate specific problems and improve
the quality of life in several cases.