Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations

In recent years, understanding of the syndromes of neurodegeneration with brain iron accumulation (NBIA) has grown considerably. In addition to the core syndromes of pantothenate kinsase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (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 some subforms, bridging the gap to more common neurodegenerative disorders such as Parkinson's disease. NBIA genes map into related pathways, the understanding of which is important as we move toward mechanistic therapies. Our aim in this review is to provide an overview of not only the historical developments, clinical features, investigational findings, and therapeutic results but also the genetic and molecular underpinnings of the NBIA syndromes.     

Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA)

Regulation of iron metabolism is crucial: both iron deficiency and iron overload can cause disease. In recent years, our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. These are characterized by excessive iron deposition in the brain, mainly the basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2) are the core syndromes, but several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). These conditions show a wide clinical and pathological spectrum, with clinical overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies, and neuronal ceroid lipofuscinosis. Lewy body pathology was confirmed in some clinical subtypes (C19orf12-associated neurodegeneration and PLAN). Research aims at disentangling the various NBIA genes and their related pathways to move towards pathogenesis-targeted therapies. Until then treatment remains symptomatic. Here we will introduce the group of NBIA syndromes and review the main clinical features and investigational findings.     

Syndromes of neurodegeneration with brain iron accumulation

In parallel to recent developments of genetic techniques, understanding of the syndromes of neurodegeneration with brain iron accumulation has grown considerably. The acknowledged clinical spectrum continues to broaden, with age-dependent presentations being recognized. Postmortem brain examination of genetically confirmed cases has demonstrated Lewy bodies and/or tangles in some forms, bridging the gap to more common neurodegenerative disorders, including Parkinson disease. In this review, the major forms of neurodegeneration with brain iron accumulation (NBIA) are summarized, concentrating on clinical findings and molecular insights. In addition to pantothenate kinase-associated neurodegeneration (PKAN) and phospholipase A2-associated neurodegeneration (PLAN), fatty acid hydroxylase-associated neurodegeneration (FAHN) NBIA, mitochondrial protein-associated neurodegeneration, Kufor-Rakeb disease, aceruloplasminemia, neuroferritinopathy, and SENDA syndrome (static encephalopathy of childhood with neurodegeneration in adulthood) are discussed.     

Childhood disorders of neurodegeneration with brain iron accumulation (NBIA)

Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, particularly within the basal ganglia. A number of autosomal recessive NBIA syndromes can present in childhood, most commonly pantothenate kinase-associated neurodegeneration (PKAN; due to mutations in the PANK2 gene) and phospholipase A2 group 6-associated neurodegeneration (PLAN; associated with genetic defects in PLA2G6). Mutations in the genes that cause these two neuroaxonal dystrophies are thought to disrupt the normal cellular functions of phospholipid remodelling and fatty acid metabolism. A significant proportion of children with an NBIA phenotype have no genetic diagnosis and there are, no doubt, additional as yet undiscovered genes that account for a number of these cases. NBIA disorders can be diagnostically challenging as there is often phenotypic overlap between the different disease entities. This review aims to define the clinical, radiological, and genetic features of such disorders, providing the clinician with a stepwise approach to appropriate neurological and genetic investigation, as well as a clinical management strategy for these neurodegenerative syndromes.     

Pantothenate kinase‐associated neurodegeneration is not a synucleinopathy

A. Li, R. Paudel, R. Johnson, R. Courtney, A. J. Lees, J. L. Holton, J. Hardy, T. Revesz and H. Houlden (2013) Neuropathology and Applied Neurobiology 39, 121–131 Pantothenate kinase‐associated neurodegeneration is not a synucleinopathy Aims: Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase‐associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases. Methods: All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations. Results: All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α‐synuclein accumulation was detected in any of our PKAN cases. In one case (20‐year‐old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case. Conclusions: These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.     

Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.     

Characterization of sleep in six patients with pantothenate kinase-associated neurodegeneration

BackgroundPantothenate kinase-associated neurodegeneration (PKAN) is a rare neurologic disorder included in the group of neurodegeneration with brain iron accumulation diseases (NBIA). Information regarding sleep in patients with PKAN is limited.ObjectivesTo describe the clinical and polysomnographic characteristics of sleep in six patients with genetically confirmed PKAN.MethodsThe evaluation included a clinical interview, sleep questionnaires -Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS)- and a video-polysomnography (VPSG). In addition to standard sleep measures we manually quantified sleep spindle density in stage N2 and rapid eye movements in REM sleep comparing the results with matched controls. Quantification of EMG activity in REM sleep was performed following standard criteria.ResultsAll the patients reported at least one sleep complaint, most commonly sleep fragmentation (4/6) and sleep onset insomnia (3/6). ESS and PSQI were abnormal in 3/6 and 4/6, respectively. VPSG showed in 4/6 decreased ocular movements during REM sleep, an increase in sleep spindles in 3/6 (all of them with deep brain pallidal stimulation), an absence of slow wave sleep in 2 and undifferentiated NREM sleep and delayed sleep phase in one. Three patients had an abnormal sleep apnea/hypopnea index, and 2 periodic limb movements of sleep. REM sleep muscular atonia was preserved in all.ConclusionsSleep disorders are common in patients with PKAN. Although our sample is small and heterogeneous, with different symptomatic treatments possibly influencing the results, it suggests that evaluation of sleep should be considered in their management.     

泛酸激酶相关性神经变性疾病遗传学与临床研究进展

泛酸激酶相关性神经变性疾病是脑组织铁沉积性神经变性(NBIA,曾称为Hallervorden-Spatz综合征)疾病的主要发病类型之一,系由泛酸激酶2(PANK2)基因突变所导致的常染色体隐性遗传性疾病。PANK2基因突变可干扰PANK2蛋白表达水平和催化活性,以及线粒体靶蛋白的成熟与稳定性,引起神经元线粒体脂类代谢异常改变,导致脑组织铁沉积性神经变性疾病。本文对该病分子遗传学机制及其与临床表型和影像学特征相关的研究成果和进展进行概述。     

MRI,MR spectroscopy,and diffusion tensor imaging findings in patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA)

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established disorder that is a subtype of neurodegeneration with brain iron accumulation (NBIA). We presented the first case report of SENDA of a 39-year-old female. She had psychomotor retardation from childhood and remained static for two decades. Then, at the age of 30, she developed severe dystonia and parkinsonism. Brain MRI revealed T2-weighted hypointensity signal in the globus pallidus and substantia nigra, and T1-weighted hyperintensity signal in the substantia nigra with a central hypointensity area. These clinical and imaging findings are characteristic of SENDA. Advanced MRI, including ¹H-MR spectroscopy (MRS) and diffusion tensor imaging (DTI), demonstrated similar findings of pantothenate kinase-associated neurodegeneration (PKAN), which is a major syndrome of SENDA. MRI plays a crucial role in the diagnosis of NBIA, especially SENDA.     

Mitochondrial Membrane Protein–Associated Neurodegeneration Mimicking Juvenile Amyotrophic Lateral Sclerosis

BackgroundMitochondrial membrane protein associated neurodegeneration (MPAN) is the third most common subtype of neurodegeneration with brain iron accumulation (NBIA) and caused by mutations of the orphan gene C19ORF12 encoding a transmembrane mitochondrial protein. Like other NBIA disorders, the hallmark of neuropathology is iron deposition in the basal ganglia, but the clinical presentation is highly variable.MethodsWe present the relevant clinical history, neurological examination, electrophysiological and neuroimaging tests of a currently ten-year-old girl. The genetic analysis was carried out by exome sequencing focused on known NBIA and juvenile amyotrophic lateral sclerosis (ALS) genes.ResultsThe patient presented at four years of age with progressive lower extremity weakness and generalized hypotonia. She was initially diagnosed with juvenile ALS based on clinical signs, negative brain magnetic resonance imaging (MRI) and electromyography findings. As the disease progressed, a repeat brain MRI showed iron deposition in the basal ganglia at nine years of age. Exome sequencing of genes known to be associated with NBIA revealed a compound heterozygous mutation of C19ORF12 gene.ConclusionsA C19orf12 gene mutation should be considered in young children with clinical signs of progressive upper and lower motor neuron disease. Finding iron accumulation in the basal ganglia helps to focus the genetic testing, but it may not be apparent for several years.     

Indian‐subcontinent NBIA: Unusual phenotypes,novel PANK2 mutations,and undetermined genetic forms

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase‐associated neurodegeneration (PKAN)] and 2 (PLA2G6‐associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian‐subcontinent NBIA cases are limited. We report 6 patients from the Indian‐subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA‐associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype–genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent‐onset cases. One of the four had a late‐onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye‐of‐the‐tiger sign only 10 years after onset. Two of the six presented with adult‐onset levodopa (L ‐dopa)‐responsive asymmetric re‐emergent rest tremor, developing L ‐dopa‐induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye‐of‐the‐tiger sign on MRI but were negative for known NBIA‐associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD‐like presentation. © 2010 Movement Disorder Society     

Atypical pantothenate kinase-associated neurodegeneration with PANK2 mutations : clinical description and a review of the literature

ABSTRACT

Panthothenate kinase-associated neurodegeneration (PKAN) is arare neurodegeneration caused by mutations in the pantothenate kinase (PANK2) gene, which is located on chromosome 20p13. These mutations result in iron accumulation in the brain basal ganglia leading to parkinsonism, dysarthria, spasticity, cognitive impairment, and retinopathy. Herein, we report acase of adult-onset PKAN who presented with young-onset action tremor, bradykinesia, dysarthria, and bilateral interossei atrophy. Neuroimaging demonstrated “eye-of-the-tiger signs”. Through analyzing PANK2 gene, PANK2 NM_153638:c.1133A>G (p.Asp378 Gly) and PANK2 NM_153638:c.1502 T > A (p.lle501Asn), were detected. In addition, we reviewed the clinical and genetic features and therapeutic strategies for patients with PKAN.     

Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): Results from a four years follow-up

ObjectiveTo evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA.Methods6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence.ResultsAfter 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP.ConclusionThe data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease.(Clinicaltrials.gov identifier: NTC00907283).     

Update on neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) defines a heterogeneous group of progressive neurodegenerative disorders characterized by excessive iron accumulation in the brain, particularly affecting the basal ganglia. In the recent years considerable development in the field of neurodegenerative disorders has been observed. Novel genetic methods such as autozygosity mapping have recently identified several genetic causes of NBIA. Our knowledge about clinical spectrum has broadened and we are now more aware of an overlap between the different NBIA disorders as well as with other diseases. Neuropathologic point of view has also been changed. It has been postulated that pantothenate kinase-associated neurodegeneration (PKAN) is not synucleinopathy. However, exact pathologic mechanism of NBIA remains unknown. The situation implicates a development of new therapies, which still are symptomatic and often unsatisfactory. In the present review, some of the main clinical presentations, investigational findings and therapeutic results of the different NBIA disorders will be presented.     

Mitochondrial protein associated neurodegeneration – Case report

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders with a progressive extrapyramidal syndrome and excessive iron deposition in the brain, particularly in the globus pallidus and substantia nigra. We present the case of a 31-year-old woman with mitochondrial protein associated neurodegeneration (MPAN). MPAN is a new identified subtype of NBIA, caused by mutations in C19orf12 gene. The typical features are speech and gait disturbances, dystonia, parkinsonism and pyramidal signs. Common are psychiatric symptoms such as impulsive or compulsive behavior, depression and emotional lability. In almost all cases, the optic atrophy has been noted and about 50% of cases have had a motor axonal neuropathy. In the MRI on T2- and T2*-weighted images, there are hypointense lesions in the globus palidus and substantia nigra corresponding to iron accumulation.     

The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN

IntroductionMutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported.MethodsWe sequenced the entire coding region of C19orf12 in 15 Turkish adult probands with idiopathic NBIA. We also performed haplotype analysis in families with a recurrent C19orf12 mutation. Clinical features were collected using a standardized form.ResultsNine of our 15 probands (60%) carried the homozygous c.32C > T mutation in C19orf12 (predicted protein effect: p.Thr11Met). This homozygous mutation co-segregated with the disease in all affected relatives available for testing (16 homozygous subjects).Haplotypes across the C19orf12 locus were identical for a very small region, closest to the mutation, suggesting an old founder, or, two independent founders. The clinical phenotype was characterized by adult onset in most cases (mean 24.5 years, range 10–36), and broad spectrum, including prominent parkinsonism, pyramidal signs, psychiatric disturbances, cognitive decline, and motor axonal neuropathy, in various combinations. On T2- or susceptibility weighted-MRI images, all patients displayed bilateral hypointensities in globus pallidus and substantia nigra, without an eye-of-the-tiger sign; however, hyperintense streaking of the medial medullary lamina between the external and internal parts of globus pallidus was observed frequently.ConclusionThe C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with MPAN. These findings contribute to the characterization of this important NBIA form, and have direct implications for genetic testing of patients of Turkish origin.     

Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration.

Hallervorden Spatz syndrome (HSS), also referred to as neurodegeneration with brain iron accumulation (NBIA), is a rare inherited neurodegenerative disorder with childhood, adolescent, or adult onset. Patients with HSS/NBIA have a combination of motor symptoms in the form of dystonia, parkinsonism, choreoathetosis, corticospinal tract involvement, optic atrophy, pigmentary retinopathy, and cognitive impairment. After the recent identification of mutations in the PANK2 gene on chromosome 20p12.3-p13 in some patients with the HSS/NBIA phenotype, the term pantothenate kinase-associated neurodegeneration (PKAN) has been proposed for this group of disorders. To characterize clinically and genetically HSS/NBIA, we reviewed 34 affected individuals from 10 different families, who satisfied the inclusion criteria for NBIA. Relatives of patients who had clinical, magnetic resonance imaging (MRI), or pathological findings of NBIA were included in the study. Four patients were found to have mutations in the pantothenate kinase 2 (PANK2) gene. We compared the clinical features and MRI findings of those with and without PANK2 mutations. The presence of mutation in the PANK2 gene is associated with younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance. Parkinsonism is seen predominantly in adult-onset patients whereas dystonia seems more frequent in the earlier-onset cases. The phenotypic heterogeneity observed in our patients supports the notion of genetic heterogeneity in the HSS/NBIA syndrome.     

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: Novel mutations and neuropsychiatric phenotype in three adult patients

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare neuropsychiatric syndromes characterized by iron accumulation in the basal ganglia. The pantothenate kinase-associated neurodegeneration (PKAN) was the first NBIA form to be genetically identified almost 15 years ago. Nowadays, eight types can be genetically distinguished. More recently, a novel NBIA was delineated and termed Static Encephalopathy of childhood with Neurodegeneration in Adulthood (SENDA), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with an onset in the second to third decade. Very recently, mutations in the WD repeat-containing protein 45 (WDR45) gene located on Xp11.23 were shown to be the causal factor. The protein encoded by WDR45 propels protein interaction important for autophagy. This form was therefore retermed Beta-propeller Protein Associated Neurodegeneration (BPAN). Here, the first three Dutch patients with genetically proven BPAN are comprehensively described with respect to course and neurological as well as neuropsychiatric phenotypes. All three showed a characteristic delayed progression of neurological symptoms with parkinsonism and prominent dystonia. Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease. The specific course and prognosis should implicate restrained psychopharmacological interventions.The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder. However, the identification of a WDR45 mutation is needed for a definite diagnosis of BPAN.     

Neuroaxonal dystrophy in PLA2G6 knockout mice

The PLA2G6 gene encodes group VIA calcium‐independent phospholipase A₂ (iPLA₂β), which belongs to the PLA₂ superfamily that hydrolyses the sn‐2 ester bond in phospholipids. In the nervous system, iPLA₂β is essential for remodeling membrane phospholipids in axons and synapses. Mutated PLA2G6 causes PLA2G6‐associated neurodegeneration (PLAN) including infantile neuroaxonal dystrophy (INAD) and adult‐onset dystonia‐parkinsonism (PARK14), which have unique clinical phenotypes. In the PLA2G6 knockout (KO) mouse, which is an excellent PLAN model, specific membrane degeneration takes place in neurons and their axons, and this is followed by axonal spheroid formation. These pathological findings are similar to those in PLAN. This review details the evidence that membrane degeneration of mitochondria and axon terminals is a precursor to spheroid formation in this disease model. From a young age before the onset, many mitochondria with damaged inner membranes appear in PLA2G6 KO mouse neurons. These injured mitochondria move anterogradely within the axons, increasing in the distal axons. As membrane degeneration progresses, the collapse of the double membrane of mitochondria accompanies axonal injury near impaired mitochondria. At the axon terminals, the membranes of the presynapses expand irregularly from a young age. Over time, the presynaptic membrane ruptures, causing axon terminal degeneration. Although these processes occur in different degenerating membranes, both contain tubulovesicular structures, which are a specific ultrastructural marker of INAD. This indicates that two unique types of membrane degeneration underlie PLAN pathology. We have shown a new pathological mechanism whereby axons degenerate due to defective maintenance and rupture of both the inner mitochondrial and presynaptic membranes. This degeneration mechanism could possibly clarify the pathologies of PLAN, Parkinson disease and neurodegeneration with iron accumulation (NBIA), which are assumed to be due to the primary degeneration of axons.     

ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation

Kufor Rakeb disease (KRD, PARK9) is an autosomal recessive extrapyramidal‐pyramidal syndrome with generalized brain atrophy due to ATP13A2 gene mutations. We report clinical details and investigational results focusing on radiological findings of a genetically‐proven KRD case. Clinically, there was early onset levodopa‐responsive dystonia‐parkinsonism with pyramidal signs and eye movement abnormalities. Brain MRI revealed generalized atrophy and putaminal and caudate iron accumulation bilaterally. Our findings add KRD to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). KRD should be considered in patients with dystonia‐parkinsonism with iron on brain imaging and we suggest classifying as NBIA type 3. © 2010 Movement Disorder Society