Objective: To study the clinical course, imaging and genetics of a case of late-onset dystonia-parkinsonism suspected to have Neurodegeneration with Brain Iron Accumulation (NBIA).

Background: Pantothenate Kinase-associated Neurodegeneration (PKAN) is a type of NBIA caused by mutations (most common- c.1561G>A) in the Pantothenate Kinase 2 (PANK2) gene.¹ Classic PKAN has an earlier age of onset (1^st or 2^nd decade) and progresses more rapidly than atypical PKAN, which has a later age of onset (2^nd  to 3^rd decade) and  slower progression.^1,2

Method: A 64-year-old lady, a native of Maldives, presented with gradually progressive, abnormal posturing of her feet beginning in her mid-thirties. This was followed by abnormal postures of both hands. She developed symmetric slowing and stiffness of all limbs, multiple falls, abnormal posturing of her neck and involuntary movements of the jaw and tongue. She later developed rest and postural tremors in the limbs. She had no cognitive or psychiatric symptoms.
Higher mental functions were normal. Kayser- Fleischer ring was absent and fundi were normal. Eye movements were full except for restricted upgaze. She had blepharospasm, jaw-closing dystonia, lingual dystonia, right rotacollis, and lateroflexion of the trunk to the left. She had hypomimia, bilateral, symmetric rest tremors, bradykinesia and rigidity.  She was wheelchair bound. Power was normal. There was no spasticity, deep tendon reflexes were brisk and plantar response was flexor bilaterally.  She had no sensory or cerebellar deficits.

Results: Routine biochemical tests and slit lamp examination were normal. Her MRI brain (T2-weighted) showed the ‘eye -of- the- tiger’ sign (figure) and iron accumulation in SWI. Atypical PKAN was suspected because of dystonia-parkinsonism, slow progression and the radiological sign.  Genetic testing for PANK2 mutation was ordered.
Clinical exome sequencing revealed compound heterozygous mutations in exon 1 (c.545_546insA) and exon 5 (c.1432A>G) in the PANK2 gene.  Though two cases, one with each of the two mutations, have been reported, the compound heterozygous mutation is novel in PKAN^3,4.

Conclusion: We report a novel compound heterozygous mutation causing PKAN. It suggests that the mutation may confer some protection from neurodegeneration as evidenced by survival beyond the sixth decade. Further studies are required to understand the functional effects of these mutations.

References: 1. Kurian MA, Hayflick SJ. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol. 2013;110:49-71. doi:10.1016/B978-0-12-410502-7.00003-X
2. Hartig MB, Prokisch H, Meitinger T, Klopstock T. Pantothenate kinase-associated neurodegeneration. Curr Drug Targets. 2012;13(9):1182-1189. doi:10.2174/138945012802002384
3. S M, V L. Neurodegeneration with Brain Iron Accumulation: Two Additional Cases with Dystonic Opisthotonus. Tremor Hyperkinetic Mov N Y N. 2019;9. doi:10.7916/tohm.v0.683
4. Chandrana M V, Kishore A. Unravelling the Genetic Pattern in Patients with Neuronal
Brain Iron Accumulation. Thiruvananthapuram: Sree Chitra Tirunal Institute for
Medical Sciences and Technology; 2020.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-compound-heterozygous-pank2-gene-mutation-in-a-south-asian-sexagenarian-with-atypical-pkan/