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

University of Belgrade, Beograd, Central Serbia, Serbia
Annals of Neurology (Impact Factor: 9.98). 02/2006; 59(2):248-56. DOI: 10.1002/ana.20771
Source: PubMed


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.

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    • "Although not reaching statistical significance, parkinsonism was more likely to happen in patients with atypical PKAN (42% versus 12%). In general, results in previous studies were concordant with ours [3] [7] except the prevalence of tremor. Our study showed tremors were more common in atypical PKAN. "
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    ABSTRACT: Objectives: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. Methods: Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. Results: We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations--lower prevalence of pyramidal signs, mental impairment, and parkinsonism--than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. Conclusions: Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients.
    Full-text · Article · Nov 2013 · The Scientific World Journal
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    • "Numerous mutations in the PANK2 gene have been identified [3]. Homozygous null mutations (resulting in protein truncation) result in classic early onset disease with rapid progression and missense mutations that likely result in partial enzyme function have been associated with atypical late onset disease and slower progression [3, 14]. The mechanism by which PANK2 gene mutations cause abnormal iron accumulation and neurodegeneration is unclear. "
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    ABSTRACT: Introduction. Pantothenate-kinase-associated neurodegeneration (PKAN) is a rare genetic disease and a form of neurodegeneration with brain iron accumulation (NBIA). It most commonly begins in the first two decades of life but should be considered in the differential diagnosis of patients at any age with an atypical progressive extrapyramidal disorder and cognitive impairment. Few late-adult cases have been reported. Case Report. A 50-year-old woman presented with a history of progressive dysarthria and dysphagia secondary to orolingual dystonia. Initial work-up was normal. There was no family history. Her initial symptoms were followed by the onset of blepharospasm, cervical dystonia, Parkinsonism, and cognitive impairment. Follow-up MRI four years after presentation revealed the diagnostic "eye-of-the-tiger" sign. Genetic testing confirmed a homozygous missense mutation consistent with the diagnosis of PKAN. Conclusion. Although PKAN is a rare genetic disorder most commonly seen in childhood, it should be considered in adult patients with a history of progressive focal dystonia or atypical Parkinsonism. As the radiographic findings are quite characteristic, genetic testing should be performed if the MRI shows evidence of iron accumulation. Optimal treatment strategies are not known, and at the current time therapies should be directed at the specific manifestations of the disease.
    Full-text · Article · Mar 2013
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    • "Clinical presentations include dystonia, dysarthria, and dysphasia. Dementia, severe mental retardation and severe movement disability may develop at later stages.8 Rare clinical features include rigidity, parkinsonism, choreoathetosis, seizures, optic atrophy, and pigmentary retinopathy. "
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    ABSTRACT: Pantothenate kinase associated neurodegeneration (PKAN) is the most prevalent type of neurodegeneration with brain iron accumulation (NBIA) disorders characterized by extrapyramidal signs, and 'eye-of-the-tiger' on T2 brain magnetic resonance imaging (MRI) characterized by hypointensity in globus pallidus and a hyperintensity in its core. All PKAN patients have homozygous or compound heterozygous mutation in PANK2 gene. Three sibling patients were diagnosed based on clinical presentations especially extrapyramidal signs and brain MRI. The exons and flanking intronic sequences of PANK2 were sequenced from DNA of leukocytes of the affected individuals. All patients were homozygous for c.C1069T, p.R357W in PANK2 gene. This mutation is well conserved in the homologous protein of distally related spices. In the current study we identified three siblings affected with PKAN, all of them have mutations in PANK2 gene. In MRI of all patients with PANK2 mutation eye-of-the-tiger sign was apparent.
    Full-text · Article · Apr 2012 · Iranian Journal of Neurology
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