A Novel PANK2 Mutation in a Patient with Atypical Pantothenate-Kinase-Associated Neurodegeneration Presenting with Adult-Onset Parkinsonism

Background

Pantothenate-kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder that is characterized by progressive extrapyramidal signs, visual loss, and cognitive impairment. PKAN is caused by mutations in the pantothenate kinase gene (PANK2), which is located on chromosome 20p13 and encodes pantothenate kinase, the key regulatory enzyme in coenzyme-A biosynthesis.

Case Report

In this report we describe a case of atypical PKAN with a novel PANK2 mutation, presenting with a 10-year history of postural tremor involving both hands. Upon neurological examination, the patient''s face was masked and he spoke in a monotonous voice. The patient presented with mild bradykinesia and rigidity that involved all of the extremities. Horizontal saccadic eye movements were slow and fragmented. Brain MRI revealed a typical "eye-of-the-tiger" sign. A mutation analysis revealed three PANK2 mutations: two in exon 3 (Asp 378Gly and Leu385CysfsX13) and one in exon 4 (Arg440Pro).

Conclusions

Parkinsonism is not an unusual presenting symptom in patients with atypical PKAN, and so it is important for physicians to consider PKAN in the differential diagnosis of patients presenting with young-onset parkinsonism.     

Novel compound heterozygous mutations in the PANK2 gene in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration.

We investigated the presence of mutations in the pantothenate kinase (PANK2) gene in a 27-year-old male Chinese patient with atypical pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Automated DNA sequence analyses revealed compound heterozygous mutations in the exon 3 and 5. This patient had a 10-year history of PKAN characterized by a slight tremor of the right hand when writing at onset and a slow progressive rigidity of the neck and the right arm and resting tremor in upper extremities. Dysarthria, dysphagia, and dystonic-athetoid movements of the face and right fingers were marked. Magnetic resonance showed the typical "eye-of-the-tiger" sign.     

Pantothenate kinase-associated neurodegeneration in Korea: recurrent R440P mutation in PANK2 and outcome of deep brain stimulation

Background and Purpose: The purpose of this study was to evaluate the mutation status of PANK2 among Korean patients with pantothenate kinase‐associated neurodegeneration (PKAN) and to document the outcome of pallidal deep brain stimulation (DBS). Methods: Direct sequencing and deletion/duplication analysis of PANK2 were conducted in 12 patients (11 unrelated) with PKAN, diagnosed on the basis of extrapyramidal dysfunction and the ‘eye‐of‐the‐tiger sign’ on brain magnetic resonance imaging (MRI). Pallidal DBS was conducted in four patients, and the outcomes were measured using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Results: A PANK2 mutation was identified in both alleles in all patients. The most prevalent mutation was c.1319G>C (p.R440P) in 8/22 mutated alleles (36%). An intragenic deletion ranging from exons 2 to 4 was found in one allele (1/22, 4.5%) using deletion/duplication analysis. The outcome of pallidal DBS was favorable in two patients with atypical PKAN and moderate severity of dystonia. However, two patients with typical PKAN and relatively severe symptoms showed variable responses. Conclusions: The c.1319G>C (p.R440P) mutation appears to be a founder genotype among Korean patients with PKAN. Furthermore, this study provides additional data for the recent international effort to evaluate the efficacy of pallidal DBS in the treatment of patients with PKAN.     

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.     

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.     

Novel compound heterozygous PANK2 gene mutations in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration

Abstract

Aim: Pantothenate-kinase-associated neurodegeneration (PKAN), which is characterised by iron accumulation in the basal ganglia, is a rare autosomal recessive neurodegenerative disorder caused by pantothenate kinase 2 (PANK2) gene mutations. The PANK2 gene is located on chromosome 20p13 and encodes pantothenate kinase. Herein, we identified one patient with PKAN who had mutations in the PANK2 gene.

Materials and methods: We performed clinical and radiographic investigations, and diagnosed this disease at the clinical and genetic levels.

Results: It is worth mentioning that the patient displayed an eye-of-the-tiger sign. Through scanning the exons and flanking intronic sequences of PANK2 in patient and control subjects, we report a compound heterozygote c. 260A?>?G (NM_001324191) and c.405dupC (NM_153638) for PANK2 mutations in a Chinese patient with clinical manifestation of progressive prosopospasm, dysarthria and gait disturbance. Bioinformatics analysis showed that two variants exhibited highly conserved residues across species.

Conclusion: we reported a patient presenting with atypical PKAN, and identified novel compound heterozygous PANK2 gene mutations..     

Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-the-tiger pattern.

We performed a detailed molecular study in two unrelated families with pantothenate kinase-associated neurodegeneration (PKAN) and the specific magnetic resonance imaging (MRI) eye-of-the-tiger pattern. In the first family with classic PKAN, linkage analysis using polymorphic markers from the PANK2 region ruled out linkage with this locus, and no mutation of the PANK2 gene was found. In the second family with atypical PKAN, we identified a novel homozygous C-to-T transition at nucleotide 1069 of the PANK2 gene, which resulted in an arginine to tryptophane substitution at codon 357. As far as we are aware, this is the first case of classic PKAN with the specific MRI eye-of-the-tiger pattern not carrying a PANK2 mutation. Therefore, the present observation reinforces the notion of the phenotypic and genetic heterogeneity in PKAN.     

Atypical Hallervorden-Spatz disease with preserved cognition and obtrusive obsessions and compulsions.

We describe the case of an adult female with Hallervorden-Spatz disease (HSD), "eye-of-the-tiger" sign on cranial magnetic resonance imaging scan, and two mutations in the pantothenate kinase 2 (PANK2) gene. Symptomatic presentation included stuttering dysarthria, dystonic posturing, increased limb and axial muscle tone, choreoathetosis, stereotyped motor behaviors, and obsessive-compulsive symptomatology since adolescence. Extensive neuropsychological testing at 40 and 44 years of age revealed a relatively normal IQ and stable cognitive pattern overall. This case demonstrates that HSD patients who survive into middle age should not be assumed to have a progressive dementia. In such cases, atypical behavioral problems such as persistent obsessions and compulsions may be present instead.     

Anticholinergic‐responsive gait freezing in a patient with pantothenate kinase‐associated neurodegeneration

A 43‐year‐old male patient suddenly developed freezing of gait (FOG) when making a first step, turning, or passing through a narrow path. Dystonic plantar flexion of his left foot always accompanied with FOG. He could walk without FOG when stepping on visual cues. Brain magnetic resonance imaging study showed typical “eye of the tiger” sign in the globus pallidus. He had heterozygous mutations in the exons 3 and 4 in the PANK2 gene. His FOG dramatically responded to the anticholinergic treatment. We report the first instance of a patient with genetically confirmed pantothenate kinase associated neurodegeneration showing typical FOG that responded to anticholinergic treatment. © 2007 Movement Disorder Society     

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。     

Precision medicine in pantothenate kinase-associated neurodegeneration

Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas,mainly the basal ganglia.The predominant clinical symptoms include spasticity,progressive dystonia,Parkinson's disease-like symptoms,neuropsychiatric alterations,and retinal degeneration.Among the neurodegeneration with brain iron accumulation disorders,the most frequent subtype is pantothenate kinase-associated neurodegeneration(PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2(PANK2)which catalyzed the first reaction of the coenzyme A biosynthesis pathway.Currently there is no effective treatment to prevent the inexorable course of these disorders.The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN.Recently,we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules,mitochondrial dysfunction and a pronounced increase of markers of oxidative stress.In addition,PKAN fibroblasts showed a morphological senescence-like phenotype.Interestingly,pantothenate supplementation,the substrate of the PANK2 enzyme,corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression.However,pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein.The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts.Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations.Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment.The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate.The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available,and monitoring its effect on the pathophysiological changes,can help for a better therapeutic strategy.In addition,these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.     

Novel PANK2 gene mutations in two Chinese siblings with atypical pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive disorder characterized by neurodegeneration and iron accumulation in the brain. Classic and atypical PKAN are distinguished on the basis of age at onset and disease progression. PANK2, localized on chromosome20p13, is confirmed as the responsible gene. We report two Chinese siblings with atypical PKAN, who had a 26- and 24-year disease course, respectively. Brain MRI scans of the two siblings showed the specific “eye of the tiger” sign. Genetic analysis identified novel compound heterozygous mutations (IVS1-2 A>T, c.T1130C) in PANK2 gene, which were confirmed to be deleterious. We verify the clinical heterogeneity even in siblings with identical genotype and expand the gene mutation pool for PKAN.     

The eye-of-the-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome

Pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome, is a rare autosomal recessive disorder characterized by extrapyramidal dysfunction as demonstrated by dystonia, rigidity, and choreoathetosis. Iron deposition in conjunction with destruction of the globus pallidus gives rise to the characteristic eye-of-the-tiger sign in MRI. It has been postulated that pantothenate kinase 2 mutations underlying all cases of classic Hallervorden-Spatz syndrome are always associated with the eye-of-the-tiger sign. Here, we report a patient with classic Hallervorden-Spatz syndrome and a homozygous pantothenate kinase 2 mutation in whom the initially present eye-of-the-tiger sign vanished during the course of the disease. Thus, the alleged one-to-one correlation between the eye-of-the-tiger sign and the presence of pantothenate kinase 2 mutation does not hold true over the course of the disease in PKAN.     

Intellectual and adaptive behaviour functioning in pantothenate kinase-associated neurodegeneration

Background Pantothenate kinase‐associated neurodegeneration (PKAN), an extremely rare autosomal recessive disorder resulting in iron accumulation in the brain, has a diverse phenotypic expression. Based on limited case studies of one or two patients, intellectual impairment is considered part of PKAN. Investigations of cognitive functioning have utilized specific neuropsychological tests, without attention to general intellectual skills or adaptive behaviour. Methods Sixteen individuals with PKAN completed measures of global intellectual functioning, and participants or care providers completed measures of adaptive behaviour skills and day‐to‐day functional limitations. Clinicians provided global ratings of condition severity. Results Testing with standardized measures documented varied phenotypic expression, with general cognitive skills and adaptive behaviour ranging from high average to well below average. Age of disease onset correlated with measures of intellectual functioning, adaptive functioning and disease severity. Conclusions Findings support previously described clinical impressions of varied cognitive impairment and the association between age of onset and impairment. Further, they add important information regarding the natural history of the disease and suggest assessment strategies for use in treatment trials.     

HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration

HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is a rare syndrome with many clinical similarities to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). Despite these common features, lipoprotein abnormalities have not been reported in PKAN. After the recent discovery of the genetic defect in PKAN, we report a homozygous nonsense mutation in exon 5 of the PANK2 gene that creates a stop codon at amino acid 371 (R371X) in the original HARP patient. This finding establishes that HARP is part of the PKAN disease spectrum.     

Infantile neuroaxonal dystrophy and pantothenate-kinase-associated neurodegeneration: locus heterogeneity

Common clinical, radiologic, and pathologic features in infantile neuroaxonal dystrophy (INAD) and pantothenate kinase-associated neurodegeneration (PKAN) have led to the hypothesis of an allelic relationship. With the discovery of the gene defect in PKAN, this can now be tested directly. The authors excluded linkage in one consanguineous INAD family by haplotype analysis. Moreover, sequencing in seven INAD families revealed no mutations in PANK2 or in other genes of CoA biogenesis. Thus, INAD and PKAN are genetically heterogeneous disorders.     

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     

Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration.

We report on a patient with late-onset, pantothenate kinase-associated neurodegeneration (PKAN) who revealed two new heterozygous mutations at gene testing and showed asymmetric moderately reduced striatal dopamine transporter binding with single photon emission computed tomography, possibly due to prolonged neuroleptic treatment. These findings expand the genetic and imaging spectrum of this rare disorder.     

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.