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|Year : 2017 | Volume
| Issue : 4 | Page : 914-915
Atypical pantothenate kinase-associated neurodegeneration with novel genetic mutation
Anil V Israni1, Anirban Mandal2
1 Department of Pediatrics, Maxcure Suyosha, Woman and Child Hospital, Hyderabad, Telangana, India
2 Department of Pediatrics, Sitaram Bhartia Institute of Science and Research, New Delhi, India
|Date of Web Publication||5-Jul-2017|
Anil V Israni
Department of Pediatrics, Maxcure Suyosha Woman and Child Hospital, Hyderabad - 500 081, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Israni AV, Mandal A. Atypical pantothenate kinase-associated neurodegeneration with novel genetic mutation. Neurol India 2017;65:914-5
A 14-year old boy, the second-born issue of a nonconsanguineous marriage, presented with a history of slurring of speech, difficulty in walking, and intermittent twisting postures for the past 1 year, as well as diminished night vision for the past 8 months. The child was premorbidly normal, studying in the fifth standard, with an average scholastic performance. The symptoms started insidiously and were gradually progressive. For the past 2 months, he had become forgetful and was having difficulty in understanding tasks along with emotional lability in the form of spontaneous crying or laughter. There was no history of seizures, altered sensorium, or sensory disturbances. No past history of jaundice could be elicited. There was no history of similar illness in the family. On examination, there was no pallor or jaundice. The child showed impaired memory (recent and remote), judgement, ability to perform calculations, intelligence, and abstract thinking. There was marked dysarthria and drooling of saliva. Oromandibular and limb dystonia were striking [Figure 1]a. Extrapyramidal gait was observed with an uneven stride length and sudden pauses. Rest of the systemic examination was unremarkable. Fundus examination showed pigmentary changes in the retina and attenuation of vessels consistent with atypical pigmentary retinopathy [Figure 1]b. There was no evidence of acanthocytosis on peripheral smear examination. Magnetic resonance imaging (MRI) of the brain showed hypoattenuation with central hyperintensity in bilateral globus pallidi on T2 and T2 fluid-attenuated inversion recovery images [Figure 1]c. Next Generation Sequencing revealed a novel homozygous missense mutation in exon 3 of the PANK2 gene (chr20:38914S9; A>T) that resulted in amino acid substitution of isoleucine for lysine at codon 406 (p. Iys4O6lle; ENST00000316562). This was confirmed by Sanger sequencing. The c.1217A>T (p. Lys406Ile) homozygous mutation detected in our patient has not been reported in 1000 genomes, exome variant server, and the ExAC databases. The variant is present in the fumble domain of the PANK2 protein. The in-silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv and HumVar) and damaging by LRT, SIFT (sift.jcvi.org), and Mutation Taster 2. The reference codon is conserved across species. Following genetic counselling, the carrier status was confirmed in healthy parents; however, both the siblings were normal.
|Figure 1: (a) The adolescent boy with a bizarre posture of the left upper limb peculiar to dystonia. (b) Fundus photograph showing pigmentary changes (arrow) and attenuation of retinal vessels. (c) T2 MRI image of the brain showing hypointensity with central hyperintensity (arrows) in bilateral globus pallidi giving the characteristic “eye of the tiger” sign|
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Pantothenate kinase-associated neurodegeneration (PKAN; formerly called as Hallervorden Spatz syndrome) or NBIA1 is the most common disorder (35–50%) among the disorders grouped as neurodegeneration with brain iron accumulation (NBIA)., It is also the first described inborn error of coenzyme A metabolism with an estimated prevalence of 1–3 per 1,000,000 population. Clinically, three phenotypes are described. These include classic PKAN: An early-onset ( first decade of life, average age: 3.5 years), rapidly progressive, and clinically homogeneous form seen in a majority of cases; atypical PKAN: A late onset (average age: 13.5 years), slowly progressive form; and, the HARP (hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) syndrome. PKAN is an autosomal recessive disorder caused by mutation of the PANK2 gene on chromosome 20p13. PANK2 gene is expressed in the retina and infant basal ganglia. More than 100 mutations of this gene are reported; however, the genotype-phenotype correlation is not very strong in PKAN. Patients with two null variants consistently have classic PKAN; whereas other combinations of pathogenic variants may present as either classic or atypical phenotypes in no predictable pattern. Interestingly, though the phenotype is fairly consistent in an affected family, greater variance in clinical features is observed in families with an atypical disease.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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