RGD Reference Report - Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. - Rat Genome Database

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Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C.

Authors: Tazir, M  Azzedine, H  Assami, S  Sindou, P  Nouioua, S  Zemmouri, R  Hamadouche, T  Chaouch, M  Feingold, J  Vallat, JM  LeGuern, E  Grid, D 
Citation: Tazir M, etal., Brain 2004 Jan;127(Pt 1):154-63. Epub 2003 Nov 7.
RGD ID: 1358482
Pubmed: PMID:14607793   (View Abstract at PubMed)
DOI: DOI:10.1093/brain/awh021   (Journal Full-text)

Autosomal recessive forms of axonal Charcot-Marie-Tooth (ARCMT2) disease are frequent in some areas, such as North Africa and the Middle East, since consanguineous marriages are still common there. Recently, a unique homozygous mutation in LMNA, which encodes lamin A/C, a component of the nuclear envelope, was identified in members of three Algerian families with ARCMT2 linked to chromosome 1q21.2-q21.3. In the present study we describe a group of 21 ARCMT2 patients from seven unrelated Algerian families with the same R298C mutation in the lamin A/C gene and marked variability of the clinical phenotype. There is a wide range of age of onset, from 6 to 27 years, with a mean of 14.4 +/- 4.6 years. The course of the disease varies considerably from one patient to another. Twelve patients with a disease duration of 10-15 years had a severe CMT phenotype with distal wasting and weakness of all four limbs and areflexia associated with involvement of the proximal lower limb muscles. In contrast, nine patients had the classical CMT phenotype with mild functional disability without proximal lower limb involvement after a disease duration of 5-18 years. Electrophysiological studies showed a median motor nerve conduction velocity (MNCV) in the normal range in almost all the patients. MNCV and compound muscle action potential (CMAP) values were inversely correlated with the disease duration and the MNCV was strictly related to the CMAP, strongly supporting a pure axonal process without a demyelinating component. Six patients had a nerve biopsy, which revealed severe rarefaction of myelinated fibres in all cases and an increased density of unmyelinated fibres in the majority of cases. In conclusion, the ARCMT2 associated with the R298C mutation differs from other types of ARCMT2. The variability among patients in the age of onset and the course of the disease strongly suggests the action of modifying genes, which remain to be identified.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Charcot-Marie-Tooth disease type 2B1  IAGP 1358482DNA:missense mutation:cds:p.R298C (human)RGD 
Charcot-Marie-Tooth disease type 2B1  ISOLMNA (Homo sapiens)1358482; 1358482DNA:missense mutation:cds:p.R298C (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lmna  (lamin A/C)

Genes (Mus musculus)
Lmna  (lamin A)

Genes (Homo sapiens)
LMNA  (lamin A/C)


Additional Information