PANK2 Mutations Research Articles

Global metabolic profiling reveals metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations

Global metabolic profiling reveals metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations

The genetics and neuropathology of Parkinson’s disease

There has been tremendous progress toward understanding the genetic basis of Parkinson's disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA, LRRK2, ATXN2, ATXN3, MAPT, GCH1, DCTN1 and VPS35. We then discuss the identification of mutations in PARK2, PARK7, PINK1, ATP13A2, FBXO7, PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA, in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.

Pantothenate Kinase-Associated Neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological examinations. The discovery of the disease causing mutations in PANK2 has linked the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis. With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of dystonia. Recently, studies in the PANK Drosophila model "fumble" revealed improvement by the compound pantethine which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately powered randomized clinical trial will start in 2012. This review summarizes clinical presentation, neuropathology and pathogenesis of PKAN.

Missense PANK2 mutation without “Eye of the tiger” sign: MR findings in a large group of patients with pantothenate kinase‐associated neurodegeneration (PKAN)

To present some unusual MR findings in a group of patients from the south-west of the Dominican Republic suffering from Pantothenate Kinase Associated Neurodegeneration (PKAN). Twenty patients and one preclinical case homozygous for the PANK2 mutation, 13 heterozygous gene carriers and 14 healthy volunteers were scanned prospectively using a 3 Tesla system. All patients showed the typical signal reduction within the globus pallidus and the substantia nigra. A surprising finding was the absence of the bright spot ("tiger's eye") in the medial part of the pallidum in 6 patients, but not in the preclinical case. Both fractional anisotropy (FA) and mean diffusivity (MD) were increased with high significance in the globus pallidus, whereas a reduction of FA in the anterior parts of the internal capsule was accompanied by an elevation of MD. Our findings support the hypothesis that the absence of the "tiger's eye" in PKAN might be secondary, probably caused by an increased accumulation of iron. This could artificially increase FA and MD values and change fiber tracking results. Except for the fronto-basal tracts, white matter was preserved well. This encouraging finding might support efforts to develop further therapeutic strategies in this devastating dystonia.

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

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). 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). 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. 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.

Transcranial sonography in pantothenate kinase-associated neurodegeneration

After it was reported that increased tissue iron concentrations were associated with increased echogenicity of the substantia nigra (SN) obtained with transcranial sonography (TCS) in animal and postmortem studies, our goal was to use this method in a disorder characterized with iron accumulation in human brain tissue. Therefore, magnetic resonance imaging (MRI) and TCS were conducted in 5 unrelated patients with pantothenate kinase-associated neurodegeneration (PKAN), caused by PANK2 mutations. All patients had an eye of the tiger sign. Hypointense lesions on the T2-weighted MRI images were restricted to the globus pallidus (GP) and SN. TCS also revealed bilateral hyperechogenicity restricted to the LN and SN, with normal DTV values. Both TCS and MRI studies in PKAN patients are in accordance with the pathological findings that accumulation of iron, even in advanced cases, is restricted to the GP and SN, suggesting selective involvement of these structures.

Early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation

Background: Pantothenate kinase-associated neurodegeneration (PKAN) is a neurodegenerative disorder caused by pantothenate kinase (PANK2) gene mutations. Brain magnetic resonance imaging (MRI) typically shows the “eye-of-the-tiger” sign, i.e. bilateral pallidal T2 hypointensity with a small central region of T2-hyperintensity. Aims: To describe clinical and MRI findings of a boy with early-onset neurodegeneration with brain iron accumulation due to PANK2 mutation. Methods: Clinical, neuroradiological and molecular investigations have been performed. Results: At first observation (2years and 10months) the boy presented only with developmental delay and toe-walking and isolated T2 hyperintensity within globi pallidi on brain MRI. One year later, small rounded areas of markedly low signal within the globi pallidi on T2∗- weighted images appeared in association with mild dystonia. PANK2 gene homozygous mutation confirmed the diagnosis of PKAN. Conclusions: In young children, PKAN should be suspected also before clinical and neuroradiological picture is fully indicative, to avoid delayed diagnosis of a genetic disease for which therapeutical options could be potentially useful if administered in paucisymptomatic subjects.

P18.6 Neurodegeneration with brain iron accumulation due to PANK2 mutation in a young child

P18.6 Neurodegeneration with brain iron accumulation due to PANK2 mutation in a young child

Identification of a second major locus for neurodegeneration with brain iron accumulation

Introduction: Neurodegeneration with brain iron accumulation (NBIA) is a rare disorder defined by iron deposits in basal ganglia. Mutations in PANK2 (mitochondrial pantothenate kinase gene) are a major cause of NBIA in children. But in almost half of the cases the genetic cause is unknown.

“Progressive delayed‐onset postanoxic dystonia” diagnosed with PANK2 mutations 26 years after onset—An update

“Progressive delayed‐onset postanoxic dystonia” diagnosed with PANK2 mutations 26 years after onset—An update

‘Eye-of-the-Tiger’ Sign and Classic Pantothenate Kinase Associated Neurodegeneration

A five-year-old girl presented with one-year history of gradual onset repeated falls while walking, dysarthria, increasing stiffness, toe walking and abnormal posturing of limbs. There was no diurnal variation and symptoms progressively worsened. On examination, she had masklike facies with horizontal smile and generalized dystonia. Ocular examination revealed waxy pallor of the disc, arteriolar attenuation and alteration in retinal pigmentation with normal foveal reflex suggesting retinitis pigmentosasine-pigmento (Fig. 1). Magnetic resonance imaging (MRI) of brain revealed bilateral symmetrical hypointensity in the globus-pallidus with central hyperintensity, giving an ‘eyeof-tiger’ appearance on T2 weighted and FLAIR images (Fig. 2). Retinitis pigmentosa in eyes and characteristic MRI findings gave the diagnosis of Pantothenate kinase associated neurodegeneration (PKAN). PKAN, formerly known as Hallovorden-Spatz syndrome is an autosomal recessive disorder caused by mutation of the pantothenate kinase-2 gene [1]. The MRI finding, ‘eye-of-the-tiger’sign is pathognomonic of classic PKAN [2]. The hypointensity on T2 weighted image is because of iron deposition and the central hyperintensity is due to the glioses and spongioses due to cell death [3]. There is an absolute correlation between the presence of a mutation in PANK2 and the eye-of-the-tiger sign; that is, all patients with the PANK2 mutation have this MR imaging pattern, which also is not seen in any mutation-negative patients [4]. Eye-of-tiger-sign can sometimes be seen in few cases of neuroferritinopathy, but in these cases careful scurtinization will reveal involvement of other basal ganglia nuclei (caudate and putamen), thalamus and cerebral cortex which is not seen in PKAN [1]. Another condition, where the ‘eye of tiger’ like appearance is seen is dihydropteridine reductase deficiency in which there will be associated features like cortical calcifications and cysts. Even the clinical presentation varies with microcephaly, parkinsonism, oculogyric crisis and disturbed psychomotor development [5]. The eye-of-the-tiger sign can also be seen in non-NBIA conditions such as corticobasal ganglia degeneration and progressive supranuclear palsy [1]. However the clinical features like age of onset differentiate these from PKAN. In conclusion, though important neuroimaging finding like ‘eye-of-the-tiger’ sign can be seen in other conditions, the presence of this finding along with other clinical clues Fig. 1 Ophthalmoscopic findings of right fundus: Retinal examination shows waxy pallor of the disc, arteriolar attenuation and alteration in retinal pigmentation. Macula is normal with normal foveal reflex. Features are consistent with retinitis pigmentosa sine pigmento

Nigropallidal iron accumulation in pantothenate kinase-associated neurodegeneration demonstrated by susceptibility-weighted imaging

Neurodegeneration with brain iron accumulation (NBIA, formerly known as Hallervorden-Spatz syndrome) defines a group of genetic disorders characterized by brain iron deposition. The major form of NBIA is pantothenatekinase associated neurodegeneration, or PKAN, caused by mutations in the PANK2 gene [1, 2]. The other known causes of NBIA include neuroferritinopathy, infantile neuroaxonal dystrophy, and aceruloplasminemia [2, 3]. Because of extensive phenotypic overlap, the clinical diagnosis of different subtypes of NBIA can be challenging, particularly in the early stages [2, 3]. Previous MRI studies with an emphasis on T2-weighted imaging (T2WI) demonstrated a central region of hyperintensity in the globus pallidus with surrounding hypointensity, called an eye-of-the-tiger sign [1, 2]. Newer MR imaging technologies, susceptibility-weighted imaging (SWI), has been shown to be superior in its ability to demonstrate brain iron deposition than other conventional MR imaging [4]. We report herein SWI findings in a patient with PKAN2 gene mutation to characterize the patterns of iron deposition in this disorder. A 17-year-old boy presented with dysarthria and progressive generalized dystonia for 2 years. Initially, he developed twisting postures in his right hand, which progressively worsened and spread to involve the neck, trunk, and his left arm. His birth, perinatal, growth and development histories were unremarkable. There was no family history of neurological disorders. On examination, he showed blepharospasm, retrocollis, and backward tilting of the trunk. He complained of severe pain in his left shoulder which took an intermittent dystonic posture with internal rotation. He also had dystonic posture in both hands and feet. However, he could walk without difficulty. The result of neuropsychological tests showed mild mental retardation. Ophthalmic examination revealed no Kayser-Fleisher rings, optic neuropathy, or pigmentary retinopathy. His motor, sensory, and cerebellar function tests were normal. Deep tendon reflexes were normoactive, and plantar reflexes were flexor bilaterally. Routine laboratory tests were all normal as well as measurements of serum ceruloplasmin, CK, ferritin, and lactate levels. EEG was normal. Brain magnetic resonance imaging showed the eye-of-the-tiger sign on T2-weighted imaging (Fig. 1a). Susceptibility-weighted images dramatically showed the tracts of iron deposition from substantia nigra to globus pallidus (Fig. 1c–f). Genetic testing confirmed compound heterozygous mutations in exon 3 [c. (999A [ G), p. (K335E)] and exon 4 [c. (1270_1272del), p. (L424del)] in the PKAN2 gene. MRI has been particularly useful in distinguishing the forms of NBIA. The eye-of-the-tiger sign (Fig. 1a) is specific for PKAN and showed a high correlation with the presence of a PANK2 mutation [1, 2]. However, the J.-H. Lee (&) D.-S. Kim Department of Neurology, Medical Research Institute, Pusan National University Yangsan Hospital, Beomo-ri, Mulgum-eup, Gyeongnam 626-770, Korea e-mail: drleejae@hanmail.net; jhlee.neuro@pusan.ac.kr

P1.060 Pathological observations in seven cases with neurodegeneration with brain iron accumulation (NBIA) with mutations in PANK2 and PLA2G6

P1.060 Pathological observations in seven cases with neurodegeneration with brain iron accumulation (NBIA) with mutations in PANK2 and PLA2G6

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

BackgroundPantothenate-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 ReportIn 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).ConclusionsParkinsonism 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.

Crystal Structures of Human Pantothenate Kinases: INSIGHTS INTO ALLOSTERIC REGULATION AND MUTATIONS LINKED TO A NEURODEGENERATION DISORDER

Pantothenate kinase (PanK) catalyzes the first step in CoA biosynthesis and there are three human genes that express four isoforms with highly conserved catalytic core domains. Here we report the homodimeric structures of the catalytic cores of PanK1alpha and PanK3 in complex with acetyl-CoA, a feedback inhibitor. Each monomer adopts a fold of the actin kinase superfamily and the inhibitor-bound structures explain the basis for the allosteric regulation by CoA thioesters. These structures also provide an opportunity to investigate the structural effects of the PanK2 mutations that have been implicated in neurodegeneration. Biochemical and thermodynamic analyses of the PanK3 mutant proteins corresponding to PanK2 mutations show that mutant proteins with compromised activities and/or stabilities correlate with a higher incidence of the early onset of disease.

PANK2 gene analysis confirms genetic heterogeneity in neurodegeneration with brain iron accumulation (NBIA) but mutations are rare in other types of adult neurodegenerative disease

Mutations in the pantothenate kinase 2 gene ( PANK2) are the cause of pantothenate kinase associated neurodegeneration (PKAN), an autosomal recessive (AR) disorder characterized by motor symptoms as such as dystonia or parkinsonism, mental retardation, retinitis pigmentosa and iron accumulation in the brain. As many neurodegenerative conditions have similar clinical features we screened a number of adult and childhood onset movement disorders for PANK2 mutation. This included cases with neurodegeneration and brain iron accumulation, corticobasal degeneartion, progressive supranuclear palsy (PSP), Parkinson's disease (PD), multiple system atropy, giant axonal neuropathy (GAN), neuroaxonal dystrophy (NAD), Guam dementia and HARP syndrome (pallido-pyramidal syndrome and hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration). From our series of patients one patient with PKAN and a progressive severe dystonic syndrome, cerebellar ataxia, retinitis pigmentosa and eventual anarthria had a novel combination of two compound heterozygote mutations identified in the PANK2 gene, G → A transition at base 1238 (G411R) and a C → A transition at base 1184 (A395E). In the patient with HARP syndrome two compound heterozygote mutations (Met327Thr and IVS5–1 G to T) in the PANK2 gene were found. No other mutations were found in any of the other patient groups, suggesting that PANK2 mutations are not associated with the aetiology of these adult degenerative conditions and confirms the genetic heterogeneity in neurodegeneration with brain iron accumulation.

The “Eye-of-the-Tiger” Sign Is Not Pathognomonic of the PANK2 Mutation

and mental retardation was evaluated for a 3-year history of gait difficulties, cognitive decline, and seizures.HerbrainMRimages(Figure, A-C) showed the classic eye-of-thetigersign,butgenetictestingformutationsinthePANK2genewasnegative. All 7 coding exons of the PANK2 gene were amplified by means of polymerase chain reaction and then cycle sequenced in both forward and reverse directions from genomic DNA. PATIENT 2 A 31-year-old man with a history of lifelongmildlearningdisabilitywas evaluated for a 14-year history of ataxia and a 4-year history of cognitive decline. Brain MR imaging showed the eye-of-the-tiger sign (Figure,D-F).Genetictestingforthe PANK2 mutation and for the mutation in the ferritin light-chain proteinseeninneuroferritinopathywere negative.

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.

Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by magnetic resonance imaging (MRI) changes in basal ganglia. Both missense and nonsense mutations have been found in such patients in a gene encoding the mitochondrial pantothenate kinase (PANK2). We completed a mutation screen in 72 patients with the diagnosis NBIA based on clinical findings and radiological imaging. The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions. We uncovered both mutant alleles in 48 patients. Deletions accounted for 4% of mutated alleles. Patients with two loss-of-function alleles (n = 11) displayed symptoms always at an early stage of life. In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase. Progression of disease measured by loss of ambulation was variable in both groups. We did not observe a strict correlation between the eye-of-the-tiger sign and PANK2 mutations. In 24 patients, no PANK2 mutation was identified. Deletion screening of PANK2 should be part of the diagnostic spectrum. Factors other than enzymatic residual activity are determining the course of disease. There are strong arguments in favor of locus heterogeneity.

Biochemical Properties of Human Pantothenate Kinase 2 Isoforms and Mutations Linked to Pantothenate Kinase-associated Neurodegeneration

The PANK2 gene encodes the human pantothenate kinase 2 protein isoforms, and PANK2 mutations are linked to pantothenate kinase-associated neurodegeneration. Two PanK2 protein forms are proteolytically processed to form a mitochondrially localized, mature PanK2. Another isoform arose from a proposed initiation at a leucine codon and was not processed further. The fifth isoform was postulated to arise from an alternative splicing event and was found to encode an inactive protein. Fourteen mutant PanK2 proteins with single amino acid substitutions, associated with either early or late onset disease, were evaluated for activity. The PanK2(G521R), the most frequent mutation in pantothenate kinase-associated neurodegeneration, was devoid of activity and did not fold properly. However, nine of the mutant proteins associated with disease possessed catalytic activities that were indistinguishable from wild type, including the frequently encountered PanK2(T528M) missense mutation. PanK2 was extremely sensitive to feedback inhibition by CoA thioesters (IC50 values between 250 and 500 nM), and the regulation of the active PanK2 mutants was comparable with that of the wild-type protein. Coexpression of the PanK2(G521R) and wild-type PanK2 did not interfere with wild-type enzyme activity, arguing against a dominant negative effect of the PanK2(G521R) mutation in heterozygous patients. These data described the unique biochemical features of the PanK2 isoforms and suggested that catalytic defects may not be the sole cause for the neurodegenerative phenotype.