REVIEW
Syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA):
an Update on Clinical Presentations, Histological and Genetic
Underpinnings, and Treatment Considerations
Susanne A. Schneider, PhD,1,2,3* John Hardy, PhD,4 and Kailash P. Bhatia, FRCP2
1
Schilling Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Lübeck, Germany
2
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London, United Kingdom
3
Visting Fellow, Department of Neurology, Imperial College, London, United Kingdom
4
Department of Molecular Neuroscience, Institute of Neurology, UCL, Queen Square, London, United Kingdom
A B S T R A C T : In recent years, understanding of the
syndromes of neurodegeneration with brain iron accumula-
tion (NBIA) has grown considerably. In addition to the core
syndromes of pantothenate kinsase–associated neurode-
generation (PKAN, NBIA1) and PLA2G6-associated neuro-
degeneration (PLAN, NBIA2), several other genetic causes
have been identified. The acknowledged clinical spectrum
has broadened, age-dependent presentations have been
recognized, and we are becoming aware of overlap
between the different NBIA disorders as well as with other
diseases. Autopsy examination of genetically confirmed
cases has demonstrated Lewy bodies and/or tangles in
Recent advances in neurogenetics have demonstrated
that phenotypes of diseases associated with alterations
in a distinct gene are much wider than originally
anticipated. One example is the syndromes of neuro-
degeneration with brain iron accumulation (NBIA).
These present with a progressive extrapyramidal syn-
drome and excessive iron deposition in the brain, par-
ticularly affecting the basal ganglia, mainly the globus
------------------------------------------------------------
*Correspondence to: Priv.-Doz. Dr. med. Susanne A. Schneider,
Schilling Section of Clinical and Molecular Neurogenetics, Department of
Neurology, University Lübeck, Ratzeburger Allee 160, 23538 Lübeck,
Germany; susanne.schneider@neuro.uni-luebeck.de
Funding agencies: We are grateful to the Bachmann Strauss
Foundation, the Medical Research Council, the Michael J. Fox
Foundation, the Wellcome Trust, and the German Research Foundation,
none of whom had any input in the writing of this article.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Received: 28 June 2011; Revised: 9 August 2011; Accepted:
15 2011
Published online 26 October 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23971
42 Movement Disorders, Vol. 27, No. 1, 2012
some subforms, bridging the gap to more common neuro-
degenerative disorders such as Parkinson’s disease. NBIA
genes map into related pathways, the understanding of
which is important as we move toward mechanistic thera-
pies. Our aim in this review is to provide an overview of not
only the historical developments, clinical features, investi-
gational findings, and therapeutic results but also the
genetic and molecular underpinnings of the NBIA syn-
dromes. VC 2011 Movement Disorder Society
Key Words: NBIA; PKAN; PLA2G6; iron
pallidus. The 2 core syndromes are the neuroaxonal
dystrophies pantothenate kinsase-associated neurode-
generation (PKAN, formerly known as Hallervorden–
Spatz disease) and PLA2G6-associated neurodegenera-
tion (PLAN). However, innovative and powerful
approaches such as autozygosity mapping have
recently enabled additional genes to be identified as
causing NBIA (Table 1).
The considerable developments in this field
prompted us to do this review. Our aim in this review
is to provide an overview of not only the historical
developments, clinical features, investigational find-
ings, and therapeutic results, but also the genetic and
molecular underpinnings of the NBIA syndromes. We
particularly want to highlight the broad clinical spec-
trum of these complex disorders. Not only can the
phenotype of 1 distinct disorder range from mild to
severe, but there is often overlap among the different
NBIA disorders as well as with other diseases, making
a diagnosis based purely on clinical grounds challeng-
ing. This may partly reflect the intertwined metabolic
pathways involved.

TABLE 1. Overview of NBIA conditions and genes (if known)
Condition (acronym)
PKAN
PLAN
Kufor–Rakeb disease
FAHN
Aceruloplasminemia
Neuroferritinopathy
SENDA syndrome
MPAN–NBIA subform identified in a Polish cohorta
Idiopathic late-onset cases
CP, ceruloplasmin; FA2H, fatty acid 2-hydroxylase; FTL, ferritin light chain; MPAN, MIN-associated neurodegeneration; NBIA, neurodegeneration with brain iron
accumulation; PANK2 pantothenate kinase 2; PKAN, pantothenate kinase–associated neurodegeneration; PLA2G6, phospholipase A2; PLAN, PLA2G2-
associated neurodegeneration; SENDA, static encephalopathy of childhood with neurodegeneration in adulthood; SPG, spastic paraplegia; nk, not known.
a
reported by Hartig et al.
Historical Review
Excessive iron is the core feature of NBIA disorders.
Perls’ staining forms blue precipitates with iron,
known as ferric ferrocyanide or Prussian blue.1 Brain
iron research began in the late 19th century with
quantitative analysis of 1 human brain by Zaleski
(1886).2,3 He correlated iron levels with observations
on stained slices and microscopic sections. The first
systematic studies of iron in the human brain were
undertaken in the 1920s by Hugo Spatz (1888–1969),
who classified brain regions into 4 groups according
to staining intensity.4 He observed that the globus pal-
lidus and substantia nigra pars reticulata showed the
most intense staining, thereby drawing attention to the
prominent iron concentrations in the nuclei of the
extrapyramidal motor system.5 Around the same time,
Julius Hallervorden (1882–1965) encountered a pro-
gressive neurological disorder predominated by extrap-
yramidal features. Histology revealed high levels of
brain iron.6 The morphological picture was further
characterized by the presence of ‘‘spheroid bodies,’’
which are usually roundish, homogeneous, or faintly
granular bodies measuring up to 100 lm in diameter.
Occasional spheroids may occur in a variety of condi-
tions, but they predominated in these cases. Interest-
ingly, possible links to Alzheimer’s disease and
Parkinson’s disease were discussed in the 49-page orig-
inal report.6 Within a few years further cases were
reported, and variants were recognized. In 1952, Sei-
telberger described the early-onset form, subsequently
labeled as ‘‘infantile neuroaxonal dystrophy’’ (INAD)
by Cowen and Olmstead,7 who reviewed the literature
and described 2 new cases, distinguishing them from
classical Hallervorden–Spatz disease. For ethical rea-
sons, in view of research during the Nazi regime, the
latter is now referred to as PKAN.8
An important milestone in the further workup of
these diseases was the development of high-field MRI
U P D A T E O N N B I A S Y N D R O M E S
Synonym Gene Chromosomal position
NBIA1 PANK2 20p13
NBIA2, PARK14 PLA2G6 22q12
NBIA3, PARK9 ATP13A2 1p36
SPG35 FA2H 16q23
— CP 3q23
— FTL 19q13
— nk nk
— (Not yet published) (Not yet published)
— Probably heterogeneous Probably heterogeneous
in the 1980s, allowing noninvasive neuroimaging in
vivo with demonstration of decreased T2 relaxation
time caused by iron deposition.5,9 A linear relation
was found between T2 relaxation rate and iron con-
centration in postmortem brains in healthy volunteers,
so that MRI now has become an important diagnostic
tool for the diagnosis of iron disorders including
NBIAs.
NBIA Type 1—PKAN
The core syndrome among the NBIA disorders is
PKAN, a result of mutations in the PANK2 gene on
chromosome 20p, which accounts for approximately
half the cases of NBIA.10 There remains uncertainty
about the diagnosis in cases reported prior to gene
identification, which were based on clinical or patho-
logical findings. Identification of the gene allowed a
broad clinical spectrum to be acknowledged with an
equally broad genetic gamut. In the classic presenta-
tion age at onset is early. Patients with later onset of-
ten show atypical clinical features.
Classic Presentation of PKAN
In the classic variant, onset is around age 3–4 years,
occurring before age 6 in almost 90%.11,12 Gait or
postural difficulty is usually the presenting symptom.12
The phenotype is characterized by pyramidal (spastic-
ity, hyperreflexia, extensor toes) and extrapyramidal
features with prominent dystonia. Prominent oroman-
dibular involvement is a characteristic sign.13 PKAN is
thus one of the main differential diagnoses to consider
in patients with severe tongue protrusion dystonia.13
Other extrapyramidal features like chorea or parkin-
sonism as well as cognitive features including behav-
ioral changes14 and dementia may occur. Oculomotor
abnormalities suggestive of midbrain degeneration are
common.15 They include impaired saccadic pursuits
Movement Disorders, Vol. 27, No. 1, 2012 43
S C H N E I D E R E T A L .

FIG. 1. A: Examples of brain MR imaging in NBIA disorders, showing a case of pantothenate kinase–associated neurodegeneration (PKAN), left,
Kufor Rakeb disease (due to ATP13A2 mutations), center, and neuroferritinopathy (due to FTL mutations), right. In PKAN there is a classic eye-of-
the-tiger sign. Iron accumulation affected the putamen and caudate in our Kufor Rakeb disease patient. In this gene-proven neuroferritinopathy
patient, there was iron deposition in the basal ganglia, with a slight hint of thalamic involvement. B: Brain MRI of a patient with multiple system atro-
phy (MSA), where iron accumulation characteristically affects the posterolateral putamina, rather than the globus pallidus, as seen in the NBIA
disorders.

and hypometric or slowed vertical saccades. Supranu-
clear gaze vertical palsy has also been reported in a
gene-proven case—a sign also associated with Nie-
mann Pick disease and Kufor–Rakeb disease (see
below).16 Square wave jerks and poor convergence
may be present in some. Vertical optokinetic responses
have been found to be abnormal, and there was an
inability to suppress the vestibulo-ocular reflex.15 Fur-
thermore, in a series of 10 patients, 8 had sectoral iris
paralysis and partial loss of the papillary ruff with
similarities to Adie’s pupils in both eyes.15 Similar pu-
pil abnormalities have been observed in other brain
storage diseases.15 Only 4 of 10 had a pigmentary reti-
nopathy, but around 70% of patients had abnormal
electroretinograms, ranging from mild cone abnormal-
ities to severe rod–cone dysfunction.15 None had optic
atrophy (which, however, is common in NBIA type 2;
see below).
The condition has a progressive course, with
affected children becoming wheelchair-bound within a
few years.
Late-Onset (Atypical) PKAN
Gene-proven cases with adult onset (in the 20s and
30s) have been reported.12,17,18 Many such cases are
probably not being recognized, in particular because
the phenotype may be somewhat atypical. For exam-
ple, unilateral dystonic tremor and focal arm dystonia
have been reported as the first sign; in others in whom
extrapyramidal features and retinopathy may be less
severe, cognitive decline and psychiatric features (for
example, palilalia) may be seen first.12,18–20 Overall,
motor involvement tends to be less severe compared
with the classical form.10
Sleep analysis in PKAN has shown altered sleep
architecture with reduction of total sleep time. In con-
trast with other neurodegenerative diseases, no REM
sleep abnormalities, especially REM sleep behavior
disorder, and no significant apnea/hypopnea were
observed. One patient had mild periodic limb move-
ment in sleep.21
In the majority of cases investigations of PKAN
have revealed a characteristic imaging pattern, corre-
sponding to iron accumulation in the globus pallidus,
particularly on T2*-weighted MR images, with the
presence of a central hyperintensity within a surround-
ing area of hypointensity that led to its description as
the eye-of-the-tiger sign (Fig. 1A). Comparing these
hypointense and hyperintense regions with diffusion
tensor MRI (in a cohort of clinically diagnosed cases)
demonstrated increased fractional anisotropy along

44 Movement Disorders, Vol. 27, No. 1, 2012


with decreased mean diffusivity.22 Importantly, MRI
alterations may precede clinical onset.23 Dopamine
transporter (DaT) SPECT imaging, one measure of
striatal dopamine function, is generally normal in
PKAN patients,24,25 although it was abnormal in 1
gene-proven late-onset case (who had presented with
personality changes, choreoathetosis, and tremor and
who had been treated long term with neuroleptics).17
Postganglionic neuronal dysfunction of the sympa-
thetic nervous system was normal in PKAN as
assessed by cardiac 123I-meta-iodobenzylguanidine
(MIBG), which typically shows decreased uptake in
Parkinson’s disease and other Lewy body disorders.26
Pathology assessment shows brown discoloration
affecting the globus pallidus. A recent pathological
study27 in 6 genetically confirmed cases revealed that
PKAN affects the central nervous system (CNS), and
there is only occasional peripheral manifestation
(including testicular pathology). Microscopic changes
predominantly affect the globus pallidus with variable
involvement of adjacent structures (medial putamen
and internal capsule), whereas the cortex, brain stem,
and remaining deep gray nuclei are remarkably
spared. The optic nerve and cerebellum were not
affected. Occasionally, intact neurons appeared in the
globus pallidus, suggesting accumulation of abnor-
mally ubiquitinated protein may precede other mani-
festations of degeneration and that degenerative
processes may affect the cytoplasm more than do nu-
clear structures or neurons.27 Two types of spheroids
can be distinguished: larger, granular structures reflect-
ing degenerating neurons and smaller, more intensely
eosinophilic spheroidal structures as substrate of dys-
trophic neurons. Iron accumulation was present in the
globus pallidus, in a perivascular distribution, both as
ferric iron (Fe3þ, the paramagnetic form putatively
associated with MRI hypointensity) but to a lesser
degree also ferrous iron. Diffuse iron staining of the
neuropil (‘‘iron dust’’) was also seen. There were also
iron-laden macrophages and iron-loaded astrocytes
that strongly stained for ferritin, but overall there was
little inflammatory response. There was only faint tau
expression. Neurofibrillary tangles and tau-positive
neuritis were absent.27 There was only minimal loss of
neuromelanin of the substantia nigra, red nucleus, and
other brain stem areas (compatible with normal
aging).
Numerous articles have reported Lewy body pathol-
ogy.28–33 However, in the recent series of gene pro-
ven-cases, Lewy bodies were absent (in contrast with
NBIA type 2; see below). This is an important finding,
suggesting to us that some of the historical ‘‘Haller-
vorden–Spatz disease’’ cases with Lewy body pathol-
ogy (published prior to gene identification) may not
actually have had PKAN, but at least a proportion
may have had NBIA type 2. It is clear from the litera-
ture that historical reports lumped together various ge-
U P D A T E O N N B I A S Y N D R O M E S
netically heterogeneous subtypes of iron accumulation
disorders and that, in hindsight, the terms Hallervor-
den–Spatz disease, NBIA, PKAN, and others were
used imprecisely. Interpretation of the older literature
is thus problematic. However, even nowadays, impre-
cision continues, and genetically undetermined forms
may be reported under the heading of PKAN rather
than the wider umbrella term of NBIA. This clouds
the analysis of these disorders, so that precise use of
terminology is essential.
Mutations, mostly missense, have been detected in
all 7 exons of PANK2, but deletions, duplication, and
splice-site mutations as well as exon deletions have
been reported.34 Some mutations may be associated
with milder phenotypes than others.12,18 Two com-
mon mutations (1231G>A and 1253C>T) account
for about one third of all cases; the majority of the re-
mainder carry ‘‘private mutations.’’10
PANK2 is most prominently present in neurons of
the cortex, globus pallidus, nucleus basalis of Mey-
nert, and pontine nuclei. The exact pathophysiology
of PKAN remains unknown. The associated PANK2-
encoded protein governs the first regulatory step of
coenzyme A synthesis by catalyzing the phosphoryla-
tion of pantothenate (vitamin B5) to yield phospho-
pantothenate.35 A role in lipid metabolism has also
been suggested. PANK2 is mainly targeted to mito-
chondria; it may cause metabolic dysfunction.36 It has
been hypothesized that the alteration of ferroportin
expression mediated by PANK2 might be the link to
accumulation of iron in the brain.37
Treatment for NBIA disorders remains symptomatic.
Deep brain stimulation of the globus pallidus may
produce some benefit.38–41 In a recent study, at fol-
low-up 9–15 months postoperatively, dystonia severity
had improved by 20% or more in two thirds of
patients.42 Experimentally, 1-Hz repetitive transcranial
magnetic stimulation of the premotor cortex produced
mild temporary benefit.43 Turning to the underlying
pathophysiology in Drosophila models of PKAN, sup-
plementing pantethine restored CoA levels, resulting in
improved mitochondrial function, enhanced locomotor
abilities, and increased life span.44 PANK2-knockout
mice have so far generally failed as a model for
PKAN.45 Results from human trials assessing a neuro-
protective role of pantothenic acid (vitamin B5) are, to
our knowledge, not yet available. For aspects on che-
lation therapy, see below.
NBIA Type 2—PLA2G6-Associated
Neurodegeneration (PLAN)
The second core NBIA syndrome is a result of
PLA2G6 gene mutations (NBIA type 2). In a manner
similar to PKAN, it seems to have an age-dependent phe-
notype. Early-onset cases have infantile neuroaxonal
Movement Disorders, Vol. 27, No. 1, 2012 45
S C H N E I D E R E T A L .
dystrophy (INAD), characterized by progressive motor
and mental retardation, cerebellar ataxia, marked trun-
cal hypotonia, pyramidal signs, and early visual distur-
bances due to optic atrophy. Fast rhythms on an EEG
are frequently found, and seizures may be present.10,46
When onset of PLA2G6-associated neurodegeneration is
later, the phenotype may be atypical (atypical neuroaxo-
nal dystrophy). We have described a clinical case, and
the overall picture was characterized by subacute onset
of dystonia-parkinsonism combined with pyramidal
signs, eye movement abnormalities, cognitive decline,
and psychiatric features.47 Parkinsonism (the condition
has been assigned the PARK14 locus) was characterized
by the presence of tremor including a pill-rolling rest
component, rigidity, and severe bradykinesia, with a
good response to levodopa in line with the finding of
Lewy body pathology (see below). However, the early
development of dyskinesias is common.47 Cerebellar
signs and sensory abnormalities, which are often promi-
nent in the early childhood variant, were absent.
In line with this, neuroimaging shows cerebellar at-
rophy occurring in the early stages of INAD, but not
with late-onset disease. Soon, INAD patients develop
hypointensity of the globus pallidus, reflecting iron,
noted on T2, T2*, and proton density-weighted
images. Notably, the signal abnormality differs from
the eye-of-the-tiger sign of PKAN in that there is no
central hyperintensity. Iron deposits in the substantia
nigra are present in some atypical cases.48,49 Notably,
iron deposition may also be absent, as demonstrated
in a genetically proven late-onset case, and MRI may
even be completely normal. Others may show some
cortical atrophy or white matter changes. Thus, not
all forms of PLA2G6-related neurodegeneration fall
into the NBIA group, but there is ‘‘neuroradiological
variability.’’47 Thus, PLAN should be considered in
patients with dystonia-parkinsonism even without
increased brain iron on MRI.47
The PLA2G6 gene is on chromosome 22q and con-
tains 17 exons. The encoded protein, iPLA2 beta, is a
group VIA calcium-independent phospholipase A2
that hydrolyzes the sn-2 acyl chain of phospholipids,
thereby generating free fatty acids and lysophospholi-
pids. iPLA2 beta is thought to play a role in remodel-
ing of membrane phospholipids, signal transduction,
cell proliferation, and apoptosis. It has been suggested
that in case of loss of iPLA2 function, lipid composi-
tion of the plasma membrane, vesicles, or endosomes
may be altered. This may then affect proteins and
processes normally involved in regulating the move-
ment of membranes within axons and dendrites, sub-
sequently leading to accumulation of membranes in
distal axons, eventually culminating in progressive
neurological impairment.50–52 Recent functional phe-
notype–genotype studies53 revealed that, compared
with wild-type proteins, mutant proteins associated
with INAD exhibited less than 20% of the specific ac-
46 Movement Disorders, Vol. 27, No. 1, 2012
tivity in both lysophospholipase and phospholipase
assays, which predicted accumulation of PLA2G6
phospholipid substrates. In contrast, mutations associ-
ated with dystonia-parkinsonism did not impair cata-
lytic activity, which may explain the relatively milder
phenotype and absence of iron accumulation in at
least some cases.
Pathologically, in PLA2G6-associated neurodegenera-
tion, changes are more widely distributed throughout
the CNS compared with PKAN.54,55 Early descriptions7
of the pathological pattern noted cerebellar atrophy
and sclerosis, accumulation of lipid and gliosis in the
striatum, and degeneration of the optic pathway and of
some of the long tracts in the brain stem and spinal
cord, that is, the pyramidal, spinocerebellar, spinotha-
lamic, and the gracile and cuneate fasciculi. In recent
studies in both gene-proven mouse models50 and
human brains,49,55 widespread alpha-synuclein-positive
Lewy pathology has been identified, strengthening the
link of PLA2G6 to idiopathic PD. Changes were partic-
ularly severe in the neocortex, corresponding to Braak
stage 6 of the diffuse neocortical type of idiopathic Par-
kinson’s disease (iPD).49 In line with early clinical and
imaging signs of cerebellar involvement, variable deple-
tion of cerebellar cortical neurons (granular cells more
than Purkinje cells) accompanied by marked astrocyto-
sis may be present.49 Accumulation of hyperphosphory-
lated tau in both cellular processes as threads and
neuronal perikarya as pretangles and neurofibrillary
tangles, corresponding to Braak and Braak stage 5, has
also been reported.49 Milder phenotypes in late-onset
disease has tended to show less tau involvement.56,57
Kufor–Rakeb Disease (PARK9)
Kufor–Rakeb disease is a rare autosomal recessive
neurodegenerative disease originally described in a con-
sanguineous Jordanian family58 from the village of
Kufor–Rakeb. The associated gene was later identified
in a large Chilean sibship,59 and since then other cases
have been identified from various countries and carrying
different mutations (Table 2). The clinical phenotype of
Kufor–Rakeb comprises parkinsonism, with pyramidal
tract signs in some. Eye movement abnormalities with
incomplete supranuclear up-gaze palsy can be a clue.
Slowing of vertical and horizontal saccades and saccadic
pursuit have also been described.60 Oculogyric dystonic
spasms, facial-faucial-finger mini-myoclonus and auto-
nomic dysfunction may be present. Cognitive features
include visual hallucinations and dementia. Disease
onset is usually in adolescence.58,59,61–63 A good
response to levodopa has been noted58; however, similar
to other complicated recessive dystonia-parkinsonism
variants, levodopa-induced dyskinesias tend to develop
early.61,62 Brain CT and MRI may show diffuse moder-
ate cerebral and cerebellar atrophy. Iron deposition in

TABLE 2. Reported Kufor–Rakeb cases carrying homozygous or compound heterozygous cases to date (adjusted
from Eiberg et al 2011107)
Country of origin Zygosity Nucleotide change
Jordanian Homozygote c.1632_1653dup22
Chilean Compound c.1306þ5G>A, c.3057delC
heterozygote
Brazilian Homozygote c.1510G>C
Japanese Homozygote c.546C>A
Pakistan Homozygote c.1103_1104insGA
Afghan Homozygote c.2742_2743delTT
Italian Homozygote c.2629G>A
Asian Compound c.3176T>G (p.L1059R)
heterozygote and c.3253delC
Inuit Homozygote c.2473C>AA
the basal ganglia affecting the putamen and caudate is
present in some (Fig. 1A), including 1 of our cases and
the Chilean family mentioned above,64,65 although not
all,61,62,66 and classification as NBIA type 3 has been
proposed.64 On transcranial sonography the substantia
nigra was found to be normal,65 in contrast with idio-
pathic PD, where hyperechogenicity can usually be
detected. Dopamine transporter imaging showed
marked bilateral symmetrical reduction of striatal activ-
ity, indicative of diminished presynaptic activity.65 Elec-
trophysiological studies suggested pyramidal tract
damage, in line with clinical findings.67 Motor-evoked
potential latencies were increased in patients. Electro-
physiological abnormalities may also be present in
asymptomatic heterozygous ATP13A2 mutation
carriers.67
Kufor–Rakeb disease is a result of mutations in the
ATP13A259 gene, on chromosome 1p. The 26-kb-
spanning gene contains 29 exons and encodes a lyso-
somal 5 P-type ATPase. Most patients reported to
date have carried homozygous mutations, but com-
pound heterozygous cases have also been identified.
To our knowledge, postmortem studies of human
Kufor–Rakeb disease are so far lacking. Sural nerve bi-
opsy68 has shown acute axonal degeneration, some
regeneration, and a very mild chronic inflammatory
response with endoneurial and epineurial T-cells. In
Schwann cells and perineurial and epineurial cells, but
not in axons, numerous cytoplasmic inclusion bodies
were seen. Electron microscopy revealed the inclusions
to be membrane bound, irregular, and occasionally
folded. Overall, they resembled irregular primary lyso-
somes.68 Recent functional studies have demonstrated
that both truncating and missense ATP13A2 muta-
tions were retained in the endoplasmic reticulum, and
there was premature degradation of mutant ATP13A2
proteins by the proteasomal, but not the lysosomal,
pathways that may contribute to the etiology.69
U P D A T E O N N B I A S Y N D R O M E S
Amino acid change Reference
p.Leu552fs Ramirez et al, Nature. 2006
Ex13skipping/fs Ramirez et al, Nature. 2006;
p.G1019fs Brüggemann et al, Arch Neurol. 2010
p.Gly504Arg Di Fonzo et al., Neurology. 2007;
Chien et al., Mov Disord. 2011
p.Phe182Leu Ning et al, Neurology. 2008
p.Thr367fs Schneider et al., Mov Disord. 2010;
Paisán-Ruiz et al., Mov Disord. 2010
p.Phe851fs Crosiers et al, Parkinsonism
Relat Disord. 2010
p.Gly877Arg Santoro et al, Neurogenetics. 2010
p.L1059R, Park et al, Hum Mutat. 2011
p.L1085WfsX1088
p.Leu825fs Eiberg et al., Clin Genet. 2011
A link to neuronal ceroid-lipofuscinosis (NCL) was
recently established, when mutations in the ATP13A2
gene were identified in animal models of NCL, but
screening humans with the compatible phenotype of
Kuf’s disease did not reveal mutations.70 The finding
of 10-fold increased ATP13A2 expression in the dopa-
minergic substantia nigra neurons of patients with iPD
compared with control samples suggests a possible
role of this gene in the etiology of sporadic, clinically
typical iPD.65
FA2H-Associated
Neurodegeneration (FAHN)/SPG35
FA2H mutations, previously known to cause leuko-
dystrophy71 and a form of hereditary spastic paraple-
gia (HSP),72,73 were recently identified as another
cause of NBIA.56 Like PANK2 and PLA2G6, the met-
abolic pathway of FA2H involves the lipid and cer-
amide metabolism. The FA2H-NBIA index cases were
3 affected brothers from a consanguineous Italian
family and 2 affected brothers from an Albanian kin-
dred. The clinical phenotype was characterized by
childhood-onset gait impairment, spastic quadripare-
sis, severe ataxia, and dystonia. Divergent strabismus
developed. Seizures may be present. Overall, there was
great similarity of the clinical presentation to the
group of neuroaxonal dystrophies. MRI demonstrated
bilateral globus pallidus T2 hypointensity, consistent
with iron deposition, prominent pontocerebellar atro-
phy, mild cortical atrophy, white matter lesions, and
corpus callosum thinning.
FA2H catalyzes hydroxylation at the 2 position of the
N-acyl chain of the ceramide moiety. Glycosphingoli-
pids, which contain a high proportion of 2-hydroxy
fatty acid, are important constituents of myelin
sheaths.72 The involvement in lipid and ceramide
Movement Disorders, Vol. 27, No. 1, 2012 47
S C H N E I D E R E T A L .

TABLE 3. Comparison of aceruloplasminemia and neuroferritinopathy

Aceruloplasminemia Neuroferritinopathy

Genetics Autosomal recessive loss-of-function mutations Autosomal dominant (dominant-negative) mutations

Ceruloplasmin gene Ferritin light-chain gene
Presentation Third decade—diabetes Third through sixth decades
Fifth decade—neurologic
Defect Brain iron recycling Brain iron storage
Pathogenesis Brain iron accumulation Brain iron accumulation
Systemic iron accumulation
Clinical Diabetes, anemia, dementia Dementia, dystonia, dysarthria
Dystonia, dysarthria
Pathology Iron accumulation in astrocytes neuronal loss Iron accumulation in astrocytes neuronal loss

Reproduced from Madsen and Gitlin.105

metabolism is a functional link to NBIA1, NBIA2, and
other neurodegenerative diseases.74 Thus, the clinical
and radiological overlap is not too surprising.
FA2H deficiency results in abnormal myelin, giving
rise to the allelic disorders leukodystrophy and the
HSP subform SPG35, which show radiological over-
lap. White matter changes are present in FAHN and
are also a core element of leukodystrophies. The pres-
ence of a thin corpus callosum seen in FAHN is also a
hallmark feature in some of the HSPs.75 Notably, a
link between HSP and dystonia-parkinsonism was
recently also unraveled for SPG11, SPG15, and geneti-
cally undetermined HSP forms,76–79 and Lewy body
pathology has been present in individual HSPs cases
with parkinsonism, with or without dystonia.79,80
Mouse models of FA2H have recently been devel-
oped.81 In these, significant demyelination and pro-
found axonal loss could be demonstrated in the
CNS.81 Axons were abnormally enlarged, and there
was abnormal cerebellar histology. In contrast, struc-
ture and function of peripheral nerves were largely
unaffected. Pathological studies of human FAHN
brains are still awaited.
Aceruloplasminemia
Aceruloplasminemia results from mutations in the
ceruloplasmin gene, on chromosome 3q. (Tables 1 and
3, Fig. 2). Inheritance is autosomal recessive. The clin-
ical presentation is characterized by adult-onset move-
ment disorders and dementia. A recent literature
review82 revealed an average age at diagnosis of 51,
with a range from 16 to 71 years. For the 28 homozy-
gous cases, the most common presenting feature was
cognitive impairment (42%), accompanied by cranio-
facial dyskinesia (28%), cerebellar ataxia (46%), and
retinal degeneration (75%).82 Diabetes mellitus may
be associated.
The encoded protein plays a crucial role in the mo-
bilization of iron from tissues and carries 95% of
plasma copper. Protein dysfunction results in excessive

FIG. 2. Pathways of cellular iron homeostasis and neurological disorders associated with iron accumulation associated with these, adjusted from
Madsen and Gitlin.105 Iron uptake can occur via the divalent transporter DMT1 (ferrous iron, Fe21, shown in the lower right) or via endocytosis of
the transferrin receptor (ferric iron, Fe31, shown in the upper right). Steap3 is a ferrireductase critical for transferrin-mediated iron release into the
cell. Ferritin is the predominant storage protein consisting of heavy chains and light chains. Mutations in the gene encoding ferritin light chains are
associated with neuroferritinopathy (1). Iron homeostasis is regulated by hepcidin, which binds to ferroportin, the only known cellular iron. Cerulo-
plasmin is a ferroxidase-mediating efficient cellular iron release. Mutations in the gene encoding ceruloplasmin cause aceruloplasminemia (2). Iron
enters mitochondria via mitoferrin, Frataxin is a mitochondrial protein mediating Fe-S cluster formation and heme biosynthesis. Mutations in frataxin
cause Friedreich ataxia (3).

48 Movement Disorders, Vol. 27, No. 1, 2012


iron accumulation, not only in the brain (basal ganglia
nuclei, thalami, dentate nuclei, and cerebral and cere-
bellar cortices), but also in the pancreas and liver.
Diagnostically, in homozygotes, ceruloplasmin is typi-
cally undetectable in the serum, and copper and iron
serum levels are low. On the other hand, ferritin is
elevated 3- to 40-fold.82 Hypometabolism in the basal
ganglia and thalamus has been detected on FDG-PET.
Neuroferritinopathy
Neuroferritinopathy, a result of mutations in the
FTL gene on chromosome 19q (Fig. 1A), differs from
the other disorders discussed in this review, as its in-
heritance is autosomal dominant. Mean-onset age is in
midlife, around age 40, with extrapyramidal features
including chorea and dystonia with phenotypic simi-
larity to Huntington’s disease.83 Pyramidal involve-
ment and ataxia are usually absent.84 Because of a
founder effect, there is clustering in the Cumbrian
region of England, but independent cases have been
reported from various countries including France,
India, and Japan.83,85,86
In contrast to aceruloplasminemia, serum ferritin
concentration may be low. MRI may reveal cystic
changes in the basal ganglia and bilateral pallidal ne-
crosis, in addition to iron accumulation in the cau-
date, globus pallidus, putamen, substantia nigra, and
red nuclei.87 Pathology88 has revealed ferritin-positive
spherical inclusions in iron-rich areas, often colocaliz-
ing with microglia, oligodendrocytes, and neurons.
Neuroaxonal spheroids immunoreactive to ubiquitin
and tau, and neurofilaments have been reported,
bridging the gap to the group of neuroaxonal dystro-
phies discussed above. The main sites of involvement
are the posterior putamen and cerebellum, but extra-
cerebral pathology such as hepatic iron deposits may
be present.89 A recently developed mouse model con-
firmed the buildup of iron in the brain reminiscent of
the human disease, and suggested a key role of
mitochondria.90
SENDA Syndrome, MIN, and Other
Genetically Yet Undetermined NBIA
Forms
A genetically yet undetermined form has recently
been described under the umbrella of static encephal-
opathy of childhood with neurodegeneration in adult-
hood (SENDA syndrome).91 The clinical phenotype
consists of early-onset spastic paraplegia and mental
retardation that remains static until the late 20s to
early 30s but then progresses to parkinsonism and
dystonia. Additional features include eye movement
abnormalities, sleep disorders, frontal release signs,
U P D A T E O N N B I A S Y N D R O M E S
and dysautonomia. Imaging has shown brain iron
accumulation affecting the globus pallidus and hypoin-
tensities in the substantia nigra, as well as white mat-
ter changes. Therapeutically, there was a marked
response to L-dopa in those in whom it was tried. The
underlying (genetic) cause remains unknown.
Hartig et al described a cohort of 54 Polish NBIA
patients including a subgroup with spastic paraparesis,
dystonia, psychiatric symptoms, neuropathy, and optic
atrophy. Genetic workup led to identification of a new
NBIA gene, and 4 different mutations could be identi-
fied in 21 of their patients.92 The acronym MPAN
(MIN-associated neurodegeneration) has been pro-
posed. Precise data await publication.
In addition, there remain single case reports of
patients with NBIA including late-onset cases with a
parkinsonian phenotype resembling Parkinson’s dis-
ease.18,93 Rest tremor was asymmetric with a reemer-
gent component. Levodopa treatment led to the
development of dyskinesias, but deep brain stimula-
tion was of good benefit.
Finally, brain iron accumulation also occurs in other
conditions, such as Friedreich’s ataxia (Fig. 2),
DRPLA, mannosidosis, superficial siderosis, and others
but with different areas of highest iron accumulation
density (personal communication; refs. 94 and 95).
Finally, MRI iron deposition, sometimes resembling
the eye-of-the-tiger sign, has occasionally been
observed in other neurodegenerative diseases including
multiple system atrophy.96–99 However, in the latter,
iron accumulation characteristically affects the pos-
terolateral putamina, rather than the globus pallidus,
as seen in NBIA disorders.100
Conclusions
We have summarized the causes of NBIA including
major forms as well as clinically characterized sub-
groups of as-yet-undetermined genetic etiology. The
NBIA syndromes teach us the lessons of clinical and
genetic heterogeneity. FA2H, for example, demon-
strates how mutations in a single gene can give rise to
numerous different disease manifestations. In time it is
likely that yet wider phenotypes will emerge for the
core syndromes. Furthermore, we expect that new
genes underlying NBIA will be discovered. However,
any search for a genetic cause still relies on meticulous
clinical characterization. We thus encourage our col-
leagues to report their NBIA cases.
Notably, many of the NBIA disorders map into
related metabolic pathways, and gene products of yet
undetermined forms may also lie on related biochemi-
cal routes.74 We may also discover that other genes
involved in as-yet-uncharacterized related pathways
may be associated with similar syndromes.47,101 In
fact, ceramide, a central molecule in sphingolipid
Movement Disorders, Vol. 27, No. 1, 2012 49
S C H N E I D E R E T A L .

FIG. 3. Simplified metabolic pathways of ceramide, which is derived from 2 main sources operating in different cellular compartments: hydrolysis of
membrane-derived sphingomylin and de novo synthesis from palmitoyl CoA and serine. Neurological diseases along the pathways are demonstrated
(incomplete list); see King (2008)106 and http://www.sphingomap.org/ (1, pantothenate kinase–associated neurodegeneration [PKAN]; 2, Farber dis-
ease [ceraminidase deficiency]; 3, Krabbe disease [beta galactosidase deficiency]; 4, Fabry disease [alpha galactosidase A deficiency]; 5, metachro-
matic leukodystrophy [cerebroside sulfatase deficiency]; 6, Gaucher disease [glucocerebroisidase deficiency]; 7, Tay Sachs disease [hexosaminidase
A deficiency]; 8, GM2 gangliosidosis [beta-galactosidase deficiency]; 9, Sandhoff disease (hexosaminidase A 1 B deficiency]; 10, PLA2G6-associ-
ated neurodegeneration; 11, Nieman Pick disease [sphingomyelinase deficiency]).

metabolism composed of an N-acylated (14–26 car-
bons) sphingosine (18 carbons), may play a central
role in these pathways (Fig. 3), in line with the inter-
twined role of ceramide and mitochondria in apopto-
sis. Ceramide is involved in many cell processes (for
reviews, see references 102 and 103) including Lewy
body pathophysiology and tauopathies bridging the
gap to the more common idiopathic diseases including
PD and possibly Alzheimer’s disease.9,56,74 The role of
iron in their neurodegenerative processes is strength-
ened by the finding of iron in idiopathic PD cases in
the substantia nigra and within structures affected by
beta-amyloid plaques deposition, and iron may play a
crucial role in their pathogenesis and the understand-
ing of the role of iron will have implications for neu-
rodegenerative processes per se.
To date, the therapeutic options for NBIA disorders
remain symptomatic and often unsatisfactory. Thus
understanding the pathophysiology, clinical course,
diagnostic criteria, and prognosis of the distinct NBIA
syndromes is crucial in searching for mechanistic
therapies. With the assumption that iron plays a caus-
ative role, chelators that reduce the amount of free
iron are being explored. Promising animal models ini-
tiated trials in humans, and single cases with beneficial
effects have been reported. Most recently, the results
of the first phase II pilot open trial in PKAN have
been published, assessing the clinical and radiological
effects of the oral iron-chelator deferiprone at a dose
of 25 mg/kg/day over a 6-month period.104 Of 9
patients who completed the study, 6 had classic dis-
ease and 3 had atypical disease. Median disease dura-
tion was 11 years. Deferiprone was well tolerated
overall. Side effects included nausea and gastralgia
(44%), but no serious adverse event occurred. The
authors observed a significant (median, 30%) reduc-
tion in globus pallidus iron content, ranging from
15% to 61%. However, there was no clinical benefit,
as rated on the BFMDRS and SF-36 scale, which may
have been a result of the relatively short treatment du-
ration or already long disease duration or neuronal
damage too advanced to allow for a rescue of func-
tion. Further studies are awaited.
Acknowledgments: We thank W. Christie and R. Gorenflos for
useful discussion, T. Wolf for technical support, and N. Quinn for criti-
cal review of the manuscript.
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