Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports

Hassan Dastsooz,Majid Fardaei,Mohammad Ali Farazi Fard,Hamid Nemati,Mohammad Ali Faghihi

doi:10.1186/s12881-017-0439-y

Hassan Dastsooz, Majid Fardaei + Show 3 more

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https://doi.org/10.1186/s12881-017-0439-y

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Abstract

BackgroundNeurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The disease is initially diagnosed on the basis of changes in brain magnetic resonance imaging which indicate an abnormal brain iron accumulation in the basal ganglia. However, the diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17. The purpose of this study was to investigate disease-causing mutations in two patients with distinct NBIA disorders.Case presentationWhole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in these two affected patients. A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476 fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea. In addition, our study revealed a novel missense mutation in PLA2G6 gene (c.3G > T:p.M1I) in one and half-year-old boy with muscle weakness and neurodevelopmental regression (speech, motor and cognition). The novel mutations were also confirmed by Sanger sequencing in the proband and their parents.ConclusionsCurrent study uncovered two rare novel mutations in PANK2 and PLA2G6 genes in patients with NBIA disorder and such studies may help to conduct genetic counseling and prenatal diagnosis more accurately for individuals at the high risk of these types of disorders.

Highlights

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition
Neurodegeneration with brain iron accumulation (NBIA) is etiologically and clinically a heterogeneous group of inherited neurological disorders characterized by basal ganglia iron deposition, mainly in the globus pallidus and/or substantia nigra
It has been reported that the major percentage of NBIA is attributed to autosomal recessive mutations in Pantothenate Kinase 2 (PANK2) gene [18], which is resulted in Pantothenate kinase-associated neurodegeneration (PKAN) [16], and Phospholipase A2 Group VI (PLA2G6) gene, leading to PLA2G6-associated neurodegeneration (PLAN) [19]

Summary

Introduction

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17. Neurodegeneration with brain iron accumulation (NBIA) is etiologically and clinically a heterogeneous group of inherited neurological disorders characterized by basal ganglia iron deposition, mainly in the globus pallidus and/or substantia nigra. The hallmark of NBIA include dystonia, dysarthria, spasticity, and Parkinsonism [1,2,3,4] Apart from these neurological manifestations and neuropathological findings, other abnormalities like retinal degeneration and optic atrophy are common in patients with NBIA [3, 4]. It has been reported that the major percentage of NBIA is attributed to autosomal recessive mutations in Pantothenate Kinase 2 (PANK2) gene [18], which is resulted in PKAN [16], and Phospholipase A2 Group VI (PLA2G6) gene, leading to PLAN [19].

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