MPAN should also be considered in the differential diagnosis of "eye of the tiger" sign. Lack of typical clinical phenotype should not preclude the diagnosis of MPAN., ">
A Novel Mutation in Neurodegeneration with Brain Iron Accumulation - A Case Report
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.271257
Source of Support: None, Conflict of Interest: None
Keywords: Brain iron metabolism, Hallervorden Spatz disease, mitochondrial membrane protein-associated neurodegeneration, neurodegeneration, pantothenate kinase-associated neurodegeneration (PKAN)
Neurodegeneration with brain iron accumulation (NBIA) consists of a group of inherited heterogenous neurodegenerative disorders. Prevalence data is incomplete, but all forms of NBIA are considered to be “ultra-rare” with less than 1/1000000 affected. Advances in sequencing technologies have greatly facilitated rapid gene discovery and have improved our understanding of the disease processes. Ten NBIA genes have been identified to date. Mutations within C19orf12 have recently been identified in patients with NBIA. This gene C19orf12 codes for a mitochondrial membrane protein. The corresponding phenotype was named mitochondrial membrane protein-associated neurodegeneration (MPAN, NBIA 4, MIM# 614298) which has an autosomal recessive inheritance. We present a typical case of MPAN with a novel mutation of C19orf12 gene.
A 12-year-old previously healthy boy, born of consanguineous parentage, was brought with the complaints of difficulty in walking from when he was 10 years of age. There were no adverse antenatal or perinatal events present. He was first noticed to have frequent falls, difficulty walking on uneven surfaces, difficulty in ascending and descending stairs without support. He developed stiffness of both his lower limbs and tended to walk on his toes. There was no history of cognitive decline, personality or behavioral disturbance, visual or hearing disturbance, involuntary movements or seizures. Two second cousins in the family were diagnosed with NBIA.
On examination, the patient had equinus deformity of both feet, spasticity of both lower limbs with exaggerated DTRs, bilateral ankle clonus and spastic gait. An MRI scan of the brain [Figure 1] revealed bilateral symmetrical T2, FLAIR hypointensities in the globus pallidi, and substantia nigra. Signals from the brainstem and cerebellum were normal. Nerve conduction study were normal. Complete blood picture and peripheral smear was normal. Serum copper and ceruloplasmin, 24-hr urinary copper, serum iron, and ferritin were normal. Screening for inborn errors of metabolism including serum lactate and urine for amino acids and organic acids. No abnormality was detected. Ophthalmological assessment was normal.
Multigene panel testing for PANK2 and NBIA associated genes was sought. Exome sequencing analysis revealed a homozygous missense variation in exon 2 of the C19orf12 gene (chr19:30199203; A>C) that results in the amino acid substitution of valine for phenylalanine at codon 51 (p.F51V. This is consistent with the MPAN (mitochondrial membrane protein-associated neurodegeneration) subtype. This is a novel variant but predicted to be pathogenic by mutation prediction.
Symptomatic therapy with Baclofen and physiotherapy was initiated. Genetic counseling of his parents was performed. A confirmation of carrier status in parents was recommended. The autosomal recessive pattern of inheritance, absence of curative therapy, progressive nature of disease and prognosis were explained to the parents.
Our patient with NBIA has a novel gene mutation but with a lack of the characteristic features of MPAN such as cognitive decline, optic atrophy and neuropathy. According to Hardig et al. 2013, 67 MPAN patients have been described in the literature. A compilation of all these cases shows that MPAN leads to a distinctive phenotype with optic atrophy and motor axonal neuropathy (lower motor neuron signs) as the most distinctive features.
Twenty-eight different mutations have been described in C19orf12 in 55 published families (67 cases) including frameshift mutations, missense mutations, nonsense mutations, and splice-site mutations. Gagliardi et al. (2015) further described six novel mutations after the screening of C19orf12 in five unrelated NBIA families.
This case report reveals a novel homozygous missense variation in exon 2 of the C19orf12 gene (chr19:30199203; A>C) that results in the amino acid substitution of valine for phenylalanine at codon 51 (p.F51V; ENST00000392278). This variant is predicted to be possibly damaging by PolyPhen and damaging LRT and Mutation Tester. This mutation has not been previously reported.
Pallidal and nigral iron accumulation is observed on the brain MRI scan on the T2 and GRE sequences, variably accompanied by hyperintense streaking of the globus pallidus in the region of the medial medullary lamina. This may be interpreted as an “eye of the tiger”, leading to an erroneous diagnosis of PKAN. Cortical and cerebellar atrophy may be seen in advanced stages of the disease. The MRI scan of the brain in our patient had shown hyperintense streaking in the region of the medial medullary lamina and surrounding hypointensity suggesting the “eye of tiger sign” mimic. This MRI finding has been described in a series of patients with MPAN. The “eye of tiger sign” seen in PKAN is typically larger, more hyperintense and is not confined to the medial medullary lamina, thus differentiating the PKAN from MPAN. Considering the high proportion and the small size of the gene with only three exons, C19orf12 should always be analyzed in NBIA patients.
Although not pathognomonic for PKAN, the “eye of the tiger sign” is still very distinctive for PKAN, but MPAN should also be considered in the differential diagnosis.
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