The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.     

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.     

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。     

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.     

Acanthocytosis, retinitis pigmentosa, pallidal degeneration. Report of two cases without serum lipid abnormalities

We describe two unrelated patients with Hallervorden-Spatz disease characterized by prominent facio-bucco-lingual dyskinesia. Acanthocytosis and retinitis pigmentosa were additional findings. Brain MRI showed the typical ‘tiger's eye’ image of the globus pallidus. This phenotype closely resembled the so-called HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration), but extensive serum lipid study failed to demonstrate any lipoprotein abnormality. Our results raise the question whether HARP syndrome is an autonomous entity or a particular phenotype of Hallervorden-Spatz disease.     

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.     

Cognitive functioning in children with pantothenate-kinase-associated neurodegeneration undergoing deep brain stimulation

Aim To examine the cognitive functioning of young people with pantothenate‐kinase‐associated neurodegeneration (PKAN) after pallidal deep brain stimulation (DBS). PKAN is characterized by progressive generalized dystonia and has historically been associated with cognitive decline. With growing evidence that DBS can improve motor function in adults and children with PKAN, there is now the opportunity to study the cognitive profiles of these patients over time. Method We present a case series of seven children (mean age 11y 7mo, SD 3y 2mo) undergoing bilateral pallidal DBS for the management of severe PKAN‐associated dystonia. We administered standardized measures of intellectual ability and memory where possible, before DBS and 1 to 4 years after DBS. Results No cognitive decline was observed and scores improved in all but one child (whose dystonia could not be adequately controlled owing to multiple medical problems). In line with a stabilization or reduction in their dystonia, all but one child was able to tolerate longer assessment sessions and complete either the same or a greater number of subtests. Interpretation These findings suggest that apparent cognitive impairments may reflect difficulties in accessing cognition owing to severity of dystonia. Intellectual decline previously associated with PKAN may have been overestimated.     

Pallidal stimulation improves pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) causes a progressive generalized dystonia which remains pharmacologically intractable. We performed bilateral internal globus pallidus stimulation in six patients with genetically confirmed PKAN who obtained a major and long-lasting improvement of their painful spasms, dystonia, and functional autonomy. This study shows the benefits of pallidal DBS for the dystonia of PKAN patients.     

A novel PANK2 gene mutation: clinical and molecular characteristics of patients short communication

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive neurodegenerative disorder with autosomal recessive inheritance. The major symptoms of PKAN include the onset before the age of 20 years, progressive pyramidal and extrapyramidal signs, retinitis pigmentosa, optic atrophy, dementia, and iron depositions in the globus pallidus. The authors present 3 patients with proven molecular diagnosis of PKAN, in whom 2 novel mutations of PANK2 gene have been identified.     

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.     

Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with onset in childhood and rapid progression. There is no causative and insufficient symptomatic drug therapy. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been reported to improve motor function. Most case reports, however, are limited to short observational periods. The impact of DBS on the progression and life expectancy in PKAN is unknown. We present a 5-year outcome and video documentation of bilateral GPi-DBS of an adolescent patient suffering from genetically defined PKAN.     

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.     

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.     

A patient with pantothenate kinase-associated neurodegeneration and supranuclear gaze palsy

Pantothenate kinase-associated neurodegeneration (PKAN) is a genetic disease with childhood onset characterized clinically by dystonia, parkinsonism, pyramidal signs, visual failure and mental retardation. Progression is usually relentless culminating in severe disability and death within 15 years of onset. Eye movement abnormalities have been described in patients with PKAN including slowed vertical saccades and saccadic vertical pursuit. We here report a patient with PKAN and supranuclear gaze palsy broadening the phenotypic spectrum of the disease.     

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.     

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.     

Magnetic resonance imaging,susceptibility weighted imaging and quantitative susceptibility mapping findings of pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is extremely rare. In this study, we aimed to evaluate the magnetic resonance imaging (MRI) findings of PKAN patients. Conventional MRI and susceptibility weighted imaging (SWI) sequences and quantitative susceptibility mapping (QSM) maps of six patients from three PKAN families and eight healthy male volunteers were retrospectively analyzed. Iron content was represented by QSM values. The typical eye-of-the-tiger sign (n = 4) and hyperintensity (n = 2) of the bilateral globus pallidus (GP) were observed on T2WI sequences. The SWI signal was low (n = 5), and the QSM values were obviously higher (n = 2), which manifested as a reversed eye-of-the-tiger sign (n = 4) and hyperintensity (n = 2) on the QSM map. The QSM values were higher in the bilateral central GP, bilateral peripheral GP, and bilateral substantia nigra (SN) and lower in the left red nucleus (RN) compared with the healthy controls. No significant differences were observed in the right RN, bilateral thalamus and bilateral occipital regions. Low signals on SWI sequences and high QSM values with a reversed eye-of-the-tiger sign on QSM maps are important for the diagnosis of PKAN, especially in patients who do not show the eye-of-the-tiger sign in early stages. The eye-of-the-tiger sign observed on T2WI is helpful in diagnosing PKAN when the disease has already progressed to an advanced stage.     

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.     

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.