Kept in Mind Infantile Neuroaxonal Dystrophy

Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder usually presenting between the ages of six months and two years, characterized by rapidly regression of cognitive and motor functions, axial hypotonia, gait disturbance, limb spasticity, cerebellar signs, optic atrophy and confirmed by PLA2G6 gene. PLA2G6 is causative of PL^Gd-associated neurodegeneration (PLAN), which is a subgroup of neurodegeneration with brain iron accumulation (NBIA). This group includes: 1) Infantile neuroaxonal dystrophy (INAD); 2) Atypical later-onset NAD; 3) Karak syndrome; 4) early onset dystonia-parkinsonism with cognitive impairment (2,5). INAD patients' progression is rapid and death occurs often at the end of the first decade (3,5).We would like to share a case experience of a 20 month-boy who was admitted to our clinic for difficulty in walking and frequent falls. He started walking and talking at the age of one. He couldn't make two words sentences. He had three siblings of whom one of them had similar findings. His sister' early psychomotor development was normal till 1 year of age. From age one, she stopped making progress and subsequently she developed seizures, mental regression, became bedridden and died. His other sister was at the age of 16 and brother was at the age of 6, their medical histories was unremarkable. The parents have a third-degree consanguinity. Neurological examination of ornease showed hypotonia and had areflexia. His initial MRI revealed insignificant vermin hypoplasia, whereas the following MRI after nine months revealed cerebellar vermian hypoplasia and apparent claval hypertrophy (Fig. 1). Metabolic screening tests were normal (tandem mass spectroscopy, very long chain fatty acid, plasma and urine aminoacids, transferrin isoelectric focusing for CDG). Electromyography (EMG) showed distal axonal type sensory-motor neuropathy. His visual examination was normal at the beginning. But control visual examination showed optic atrophy without strabismus and nystagmus. Delayed visual evoked potentials (VEP) was seen. By these findings, a genetic evaluation was initiated after obtaining appropriate parental consent. To make a precise diagnosis, we then performed targeted Next Generation Sequencing (NGS) of related PLA2G6 gene. PLA2G6 gene sequencing analysis was performed using the MiSeq next generation sequencing (NGS) platform (Illumina, San Diego, CA, USA). Exons 1 to 17 of the PLA2G6 gene and their flanking splice site junctions were amplified using primers and protocols from PRIMER® - Primer Designer v.2.0 (Scientific & Educational Software Program). Obtained sequences were compared with the reference sequences deposited in the public database (NM_003560). Sequencing analysis showed missense mutation in exon 14 of PLA2G6 gene (c,1756G>A, p.G586R). The proband was homozygous whereas both parents were heterozygous mutant allele. Detected mutation occurred at highly conserved sites in the multi-sequence alignment and is predicted by three different in silico analyses: the SIFT (Sorting Intolerant From Tolerant) program (http://sift.jcvi.org/), Mutation Taster program (http://www.mutationtaster.org) and the PolyPhen2 program (http://genetics.bwh. harvard.edu/pph2/) approaches to be non-tolerated changes that affect protein function. Molecular analysis of PLA2G6 (gene sequencing) gene demonstrated a novel homozygous p.G586R (c.1756G>A) mutation. By now he is 38 months and unable to walk, can sit without support only a few minutes. He only says a word and has bulbar dysfunction (drooling).Infantile neuroaxonal dystrophy is RL42G6-associated neurodegeneration (PLAN) which comprises a continuum of four phenotypes with overlapping clinical and radiologic features (2,5). PLA2G6 is located at chromosome 22ql3.1. and encodes IPLA2-VI, calcium independent phospholipase and dysfunction of it causes neurodegeneration and brain-iron dyshomeostasis (7, 8). Pathological features are axonal swelling and storage of spheroids throughout the central nervous system and peripheral tissues. …