Homozygosity and linkage disequilibrium mapping of autosomal recessive distal myopathy (Nonaka distal myopathy)

Abstract

Autosomal recessive distal myopathy or Nonaka distal myopathy (NM) is characterized by its unique distribution of muscular weakness and wasting. The patients present with spared quadriceps muscles even in a late stage of the disease. The hamstring and tibialis anterior muscles are affected severely in early adulthood. We have localized the NM gene to the region between markers D9S319 and D9S276 on chromosome 9 by linkage analysis. To further refine the localization of the NM gene, we conducted homozygosity and linkage disequilibrium analysis for 14 patients from 11 NM families using 18 polymorphic markers. All of the patients from consanguineous NM families were found to be homozygous for six markers located within the region between markers D9S2178 and D9S1859. We also provided evidence for significant allelic associations between the NM region and five marker loci. Examination of the haplotype analysis identified a predominant ancestral haplotype comprising the associated alleles 199-160-154-109 (marker order: D9S2179-D9S2180-D9S2181-D9S1804), present in 60% of NM chromosomes and in 0% of parent chromosomes. On the basis of the data obtained in this study, the majority of NM chromosomes were derived from a single ancestral founder, and the NM gene is probably located within the 1.5-Mb region between markers D9S2178 and D9S1791.

A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees

“…In this study, we found a novel mutation (V572L) in the GNE gene in homozygous state, which is interestingly shared by all the six Japanese DMRV families. As it has been strongly suggested by previous linkage analyses,16, 19 this study confirmed that DMRV and HIBM are allelic diseases caused by mutations in the GNE gene. The mutation identified in the six Japanese pedigrees is a novel one that has not been described in patients of other ethnic populations.…”

“…After this report, we conducted a linkage analysis of six Japanese DMRV pedigrees and confirmed that DMRV also was linked to 9p1‐q1,1 raising the possibility that HIBM and DMRV are allelic diseases. Asaka and colleagues further conducted a detailed linkage analysis of Japanese DMRV pedigrees and found a strong linkage disequilibrium that allows narrowing of the DMRV critical region 16. Mirabella and colleagues17 also have reported an Italian family with autosomal recessive quadricep‐sparing inclusion body myopathy linked to chromosome 9p1.…”

Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function

“…Over 100 mutations have been reported in GNE, encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase, resulting in an adult-onset progressive myopathy with a characteristic pattern of affected muscles; although the hamstring and tibialis anterior muscles are affected severely by early adulthood, the quadriceps muscles are spared even at a late stage of the disorder (28). Cardiac involvement has been reported in GNE myopathy, although sporadically (29). Reduced protein sialylation has been reported in several studies.…”

Clinical Reasoning: A case of bilateral foot drop in a 74-year-old man

“…5 GNE myopathy typically presents with weakness of ankle dorsiflexion in early to mid-adulthood. 6 Differentiating a distal myopathy and dHMN can be challenging. Frequently, initially affected upper extremity muscles include intrinsic hand muscles in dHMN and forearm/finger flexors in distal myopathies.…”