Double Trouble in Hereditary Neuropathy

Hodapp, Julie A.; Carter, Gregory T.; Lipe, Hillary; Michelson, Sara; Kraft, George H.; Bird, Thomas D.

doi:10.1001/archneur.63.1.112

Cited by 57 publications

(16 citation statements)

References 32 publications

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“…31 Mutations in two or more genes related to Charcot–Marie–Tooth disease have been described as causing a phenotype more severe than that of our proband or other patients affected by the disease. 32–34 Such groups of mutations include a combination of two SNPs at the ACBD1 locus and a copy-number variant affecting PMP22 , as well as the combination of a SNP and a copy-number variant at the same locus. 35,36 There is also a report of mutations in two genes related to Charcot–Marie–Tooth disease segregating in the same family as either a recessive trait or a sporadic trait, the latter of which was attributed to a de novo copy-number variant.…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

Reid²,

et al. 2010

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BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. METHODS We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.

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Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

Reid²,

et al. 2010

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“…For example, severity of disease for CMT can be due to a combination of mutations at more than one CMT locus (Chung et al, 2005; Hodapp et al, 2006; Meggouh et al, 2005) (Figures 4A–4C). …”

Section: Multiple Mutated Genes Underlying Clinical Phenotypesmentioning

confidence: 99%

Clan Genomics and the Complex Architecture of Human Disease

Lupski

Belmont

Boerwinkle

et al. 2011

Cell

343

304

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Human diseases are caused by alleles that encompass the full range of variant types, from single-nucleotide changes to copy-number variants, and these variations span a broad frequency spectrum, from the very rare to the common. The picture emerging from analysis of whole-genome sequences, the 1000 Genomes Project pilot studies, and targeted genomic sequencing derived from very large sample sizes reveals an abundance of rare and private variants. One implication of this realization is that recent mutation may have a greater influence on disease susceptibility or protection than is conferred by variations that arose in distant ancestors.

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“…Currently it is not considered a different entity, but part of the phenotypic spectrum of CMT1, because the underlying genetic defects are known CMT1 genes, like the PMP22 duplication [56,57]. There are case reports on severely affected CMT patients demonstrating the presence of two mutations in two different CMT-related genes (“double trouble”) [58,59]. On the other side of the spectrum, patients can be asymptomatic (1.6% to 17% [26-28]) or only exhibit mild symptoms, like foot deformity, leading to no or only mild problems with walking [26,27].…”

Section: Pmp22 Duplication – Charcot-marie-tooth Disease Type 1a (Cmt1a)mentioning

confidence: 99%

“…We expect that part of the variation of the phenotype is due to genetic factors. Severely affected “double trouble” cases (the presence of two mutations in two different CMT-related genes) are reported [58,59] and show that known CMT genes can act as modifiers. Systematic screening of CMT genes in large cohorts of patients is necessary to identify the more common variants that affect the phenotype.…”

Section: Pmp22 Duplication – Charcot-marie-tooth Disease Type 1a (Cmt1a)mentioning

confidence: 99%

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

Paassen

Kooi

Spaendonck‐Zwarts

et al. 2014

Orphanet J Rare Dis

151

121

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PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal.

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Double Trouble in Hereditary Neuropathy

Cited by 57 publications

References 32 publications

Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

Clan Genomics and the Complex Architecture of Human Disease

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

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