BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurological degeneration and death in childhood. PLA2G6 mutation is the underlying genetic defect, but rare genetic heterogeneity has been demonstrated. One of the five families we studied did not link to PLA2G6 locus, and in the family one of the two affected siblings additionally had atypical features including facial dysmorphism, pectus carinatum, scoliosis, pes varus, zygodactyly and bilateral cryptorchidism as well as cerebellar atrophy, as previously reported. METHODS: Sural biopsy was investigated by electron microscopy. PLA2G6 was screened for mutations by Sanger sequencing. In the mutation-free family, candidate disease loci were found via linkage analysis using data from single nucleotide polymorphism genome scans. Exome sequencing was applied to find the variants at the loci. RESULTS: PLA2G6 mutations were identified in four families including the one with an unusually severe phenotype that led to death within the first 2 years of life. In the remaining family, seven candidate loci totalling 15.2 Mb were found and a homozygous truncating mutation p.Q642X was identified in NALCN at 13q32.3. The patients are around 20-years-old. CONCLUSIONS: NALCN is the gene responsible for INAD with facial dysmorphism. The patients have lived to adulthood despite severe growth and neuromotor retardation. NALCN forms a voltage-independent ion channel with a role in the regulation of neuronal excitability. Our findings broaden the spectrum of genes associated with neuroaxonal dystrophy. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families.
BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurological degeneration and death in childhood. PLA2G6 mutation is the underlying genetic defect, but rare genetic heterogeneity has been demonstrated. One of the five families we studied did not link to PLA2G6 locus, and in the family one of the two affected siblings additionally had atypical features including facial dysmorphism, pectus carinatum, scoliosis, pes varus, zygodactyly and bilateral cryptorchidism as well as cerebellar atrophy, as previously reported. METHODS: Sural biopsy was investigated by electron microscopy. PLA2G6 was screened for mutations by Sanger sequencing. In the mutation-free family, candidate disease loci were found via linkage analysis using data from single nucleotide polymorphism genome scans. Exome sequencing was applied to find the variants at the loci. RESULTS:PLA2G6 mutations were identified in four families including the one with an unusually severe phenotype that led to death within the first 2 years of life. In the remaining family, seven candidate loci totalling 15.2 Mb were found and a homozygous truncating mutation p.Q642X was identified in NALCN at 13q32.3. The patients are around 20-years-old. CONCLUSIONS:NALCN is the gene responsible for INAD with facial dysmorphism. The patients have lived to adulthood despite severe growth and neuromotor retardation. NALCN forms a voltage-independent ion channel with a role in the regulation of neuronal excitability. Our findings broaden the spectrum of genes associated with neuroaxonal dystrophy. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families.
Authors: Elise Valkanas; Katherine Schaffer; Christopher Dunham; Valerie Maduro; Christèle du Souich; Rosemarie Rupps; David R Adams; Alireza Baradaran-Heravi; Elise Flynn; May C Malicdan; William A Gahl; Camilo Toro; Cornelius F Boerkoel Journal: Am J Med Genet A Date: 2016-08-11 Impact factor: 2.802
Authors: Yingtang Shi; Chikara Abe; Benjamin B Holloway; Shaofang Shu; Natasha N Kumar; Janelle L Weaver; Josh Sen; Edward Perez-Reyes; Ruth L Stornetta; Patrice G Guyenet; Douglas A Bayliss Journal: J Neurosci Date: 2016-08-03 Impact factor: 6.167
Authors: Jessica X Chong; Margaret J McMillin; Kathryn M Shively; Anita E Beck; Colby T Marvin; Jose R Armenteros; Kati J Buckingham; Naomi T Nkinsi; Evan A Boyle; Margaret N Berry; Maureen Bocian; Nicola Foulds; Maria Luisa Giovannucci Uzielli; Chad Haldeman-Englert; Raoul C M Hennekam; Paige Kaplan; Antonie D Kline; Catherine L Mercer; Malgorzata J M Nowaczyk; Jolien S Klein Wassink-Ruiter; Elizabeth W McPherson; Regina A Moreno; Angela E Scheuerle; Vandana Shashi; Cathy A Stevens; John C Carey; Arnaud Monteil; Philippe Lory; Holly K Tabor; Joshua D Smith; Jay Shendure; Deborah A Nickerson; Michael J Bamshad Journal: Am J Hum Genet Date: 2015-02-12 Impact factor: 11.025
Authors: Hanan E Shamseldin; Eissa Faqeih; Ali Alasmari; Maha S Zaki; Joseph G Gleeson; Fowzan S Alkuraya Journal: Am J Hum Genet Date: 2015-12-17 Impact factor: 11.025
Authors: Asbjørg Stray-Pedersen; Jan-Maarten Cobben; Trine E Prescott; Sora Lee; Chunlei Cang; Kimberly Aranda; Sohnee Ahmed; Marielle Alders; Thorsten Gerstner; Kathinka Aslaksen; Martine Tétreault; Wen Qin; Taila Hartley; Shalini N Jhangiani; Donna M Muzny; Maja Tarailo-Graovac; Clara D M van Karnebeek; James R Lupski; Dejian Ren; Grace Yoon Journal: Am J Hum Genet Date: 2015-12-17 Impact factor: 11.025