Genetic Analysis of PLA2G6 in 22 Indian Families with Infantile Neuroaxonal Dystrophy, Atypical Late-Onset Neuroaxonal Dystrophy and Dystonia Parkinsonism Complex.

Saketh Kapoor,Nivedita Singh,Parayil Sankaran Bindu,Gayathri Narayanappa,Arun Kumar,Mohammad Iqbal Rather,Vishwanath Bhat,Mohd Hussain Shah,Sindhura Gopinath,Arun B Taly,Yasha T Chickabasaviah,Madhu Nagappa,Sanjib Sinha,Rose Dawn Bharath,Anita Mahadevan

doi:10.1371/journal.pone.0155605

Abstract

Mutations in PLA2G6 were identified in patients with a spectrum of neurodegenerative conditions, such as infantile neuroaxonal dystrophy (INAD), atypical late-onset neuroaxonal dystrophy (ANAD) and dystonia parkinsonism complex (DPC). However, there is no report on the genetic analysis of families with members affected with INAD, ANAD and DPC from India. Therefore, the main aim of this study was to perform genetic analysis of 22 Indian families with INAD, ANAD and DPC. DNA sequence analysis of the entire coding region of PLA2G6 identified 13 different mutations, including five novel ones (p.Leu224Pro, p.Asp283Asn, p.Arg329Cys, p.Leu491Phe, and p.Arg649His), in 12/22 (54.55%) families with INAD and ANAD. Interestingly, one patient with INAD was homozygous for two different mutations, p.Leu491Phe and p.Ala516Val, and thus harboured four mutant alleles. With these mutations, the total number of mutations in this gene reaches 129. The absence of mutations in 10/22 (45.45%) families suggests that the mutations could be in deep intronic or promoter regions of this gene or these families could have mutations in a yet to be identified gene. The present study increases the mutation landscape of PLA2G6. The present finding will be useful for genetic diagnosis, carrier detection and genetic counselling to families included in this study and other families with similar disease condition.

Highlights

Classic infantile neuroaxonal dystrophy ([INAD], MIM #256600), known as Seitelberger’s disease, is a rare autosomal recessive neurodegenerative disease with a typical age of onset within the first two years of life
It is one of the forms of neurodegeneration with brain iron accumulation (NBIA), which is a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, within the basal ganglia
The axonal swellings that occur in INAD are seen in NBIA and other overlapping diseases such as pantothenate kinase-associated neurodegeneration (PKAN; MIM#610217)

Summary

Introduction

Classic infantile neuroaxonal dystrophy ([INAD], MIM #256600), known as Seitelberger’s disease, is a rare autosomal recessive neurodegenerative disease with a typical age of onset within the first two years of life It is characterized by rapid progression of psychomotor regression and hypotonia evolving into spasticity and visual impairment with nystagmus due to optic atrophy. The pathological hallmarks used in INAD diagnosis are axonal swellings and spheroid bodies in pre-synaptic terminals in both the central and peripheral nervous systems, which can be detected in skin biopsy It is one of the forms of neurodegeneration with brain iron accumulation (NBIA), which is a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, within the basal ganglia. T2-weighted magnetic resonance imaging (MRI) of INAD and ANAD patients typically shows cerebellar atrophy with increased signal in cerebellar cortex and, occasionally, hypointensity in the pallida and substantia nigra [2]

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