Objective: To describe two unrelated individuals with progressive, late-onset Pantothenate kinase-associated neurodegeneration (PKAN) and a common missense variant in the PANK2 gene

Background: Neurodegeneration with Brain-Iron Accumulation (NBIA) is a group of rare neurodegenerative disorders with abnormal brain iron deposition. Biallelic pathogenic variants in the  PANK2 gene result in typical PKAN with onset in the first decade or the rarer syndrome of atypical, late-onset PKAN. Genotype-phenotype correlations are less well described in atypical PKAN.

Method: Case1: A 40-year-old lady presented with unilateral blepharospasm at the age of 37 years followed by rapid progression of symptoms to dysarthria and truncal dystonia. Case 2: A 50-year-old lady presented with retrocollis for 10 years, followed by lower limb and truncal dystonia with prominent dystonic opisthotonus. Cranial MRI in both patients showed T2 hypointensities in bilateral globus pallidus with central hyperintensity. We performed Whole Exome Sequencing on DNA isolated from peripheral blood using Illumina platform with mean of 80-100X coverage. Pathogenic variants were identified by using GATK pipelines. The variant was classified based on the joint guidelines of ACMG (American College of Medical Genetics and Genomics) and AMP (Association of Molecular Pathology).

Results: Whole Exome Sequencing identified compound heterozygous mutations in the PANK2 gene in both cases.  In case 1, WES revealed a pathogenic c.1700T>A (p.Leu567Ter) nonsense variant and a likely pathogenic c.1432A>G (p.Lys478Glu) missense variant. In case 2, we found the pathogenic c.434C>A (p.Ser145Ter) nonsense variant along with the likely pathogenic c.1432A>G (p.Lys478Glu) missense variant. The c.1432A>G (p.Lys478Glu) variant was common to both patients, belonging to unrelated families.

Conclusion: Two Indian patients with atypical PKAN from unrelated kindreds harboured the c.1432A>G (p.Lys478Glu) common missense variant. This variant has been previously reported in another Indian patient with adult onset PKAN [1]. Future studies are required to explore whether these findings may point towards a founder effect for this variant in the Indian population.

References: 1.Mehta S, Lal V. Neurodegeneration with Brain Iron Accumulation: Two Additional Cases with Dystonic Opisthotonus. Tremor Other Hyperkinet Mov (N Y). 2019;9:10.7916/tohm.v0.683. Published 2019 Aug 21. doi:10.7916/tohm.v0.683

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MDS Abstracts - https://www.mdsabstracts.org/abstract/compound-heterozygous-pank2-variants-in-two-unrelated-kindreds-with-atypical-pkan/