Abstract
Pantothenate kinase-associated neurodegeneration is a rare hereditary neurodegenerative disorder associated with nucleotide variation(s) in mitochondrial human Pantothenate kinase 2 (hPanK2) protein encoding PANK2 gene, and is characterized by symptoms of extra-pyramidal dysfunction and accumulation of non-heme iron predominantly in the basal ganglia of the brain. In this study, we describe a familial case of PKAN from the State of Jammu and Kashmir (J&K), India based on the clinical findings and genetic screening of two affected siblings born to consanguineous normal parents. The patients present with early-onset, progressive extrapyramidal dysfunction, and brain Magnetic Resonance imaging (MRI) suggestive of symmetrical iron deposition in the globus pallidi. Screening the PANK2 gene in the patients as well as their unaffected family members revealed a functional single nucleotide variation, perfectly segregating in the patient’s family in an autosomal recessive mode of inheritance. We also provide the results of in-silico analyses, predicting the functional consequence of the identified PANK2 variant.
Highlights
Pantothenate Kinase-Associated Neurodegeneration (PKAN; OMIM# 234200) is a rare autosomal recessive, progressive neurodegenerative movement disorder characterized by accumulation of non-heme iron in the brain, predominantly in the bilateral globus pallidus region of the basal ganglia[1,2,3]
PKAN is usually classified as an inborn error of mitochondrial CoA biosynthesis from pantothenic acid associated with nucleotide variation(s) in ubiquitously expressed mitochondrial human Pantothenate kinase 2 (hPanK2) protein (EC 2.7.1.33) encoding PANK2 gene (20p13-p12.3; OMIM# 606157) that encodes a 1.85 kb long transcript having 7 exons1, 2, 5, 21, 22. hPanK2 catalyzes the first rate-limiting step, that is, ATP-dependent phosphorylation of pantothenic acid to 4′-phosphopantothenate, of the universal biosynthesis pathway of CoA1
It has been hypothesized that a defective mitochondrial hPanK2 transcribed by PANK2 gene having functional variations can lead to CoA deficiency or defective CoA biosynthesis and subsequently to accumulation of iron and toxic secondary metabolites downstream of the CoA biosynthesis pathway, resulting in the characteristic disease phenotype in PKAN-affected individuals[23]
Summary
Pantothenate Kinase-Associated Neurodegeneration (PKAN; OMIM# 234200) is a rare autosomal recessive, progressive neurodegenerative movement disorder characterized by accumulation of non-heme iron in the brain, predominantly in the bilateral globus pallidus region of the basal ganglia[1,2,3]. The age-of-onset of symptoms is from infancy to late adulthood with variable rate of progression and severity of the motor symptoms, based on which the disorder is clinically classified into two phenotypes –a “classic or typical or early-onset PKAN” with a rapid progression and clinically homogenous phenotype in majority of the cases and “atypical or late-onset PKAN” with a slower progression and variable clinical phenotypes[4, 5] Both familial and sporadic cases of PKAN are known[6, 7]. The molecular pathogenesis of PKAN is not fully understood yet
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