Mutations of the LMNA gene can mimic autosomal dominant proximal spinal muscular atrophy.
The molecular basis of autosomal dominant spinal muscular atrophy (AD-SMA) is largely unknown. Because the phenotypic spectrum of diseases caused by LMNA mutations is extremely broad and includes myopathies, neuropathies, and cardiomyopathies designated as class 1 laminopathies, we sequenced the LMNA gene in index patients with the clinical picture of proximal SMA, who had a family history suggestive of autosomal dominant inheritance. Among the 19 families investigated, two showed pathogenic mutations of the LMNA gene, resulting in the diagnosis of a class 1 laminopathy in about 10% of our series. We found one novel truncating mutation (c.1477C > T, Q493X) and one previously described missense mutation (c.1130G > T, R377H) in the LMNA gene of two unrelated patients with adult-onset proximal SMA followed by cardiac involvement 14 and 22 years after the onset of weakness. The pedigrees of both families revealed a high frequency of cardiac abnormalities or sudden deaths. Our findings extend the spectrum of laminopathies and are of relevance for genetic counseling and clinical care of families presenting with adult-onset proximal SMA. Particularly, if neurogenic atrophy is combined with a cardiac disease in a family, this should prompt LMNA mutation analysis.
Rudnik-Schöneborn
Sabine
S
Institute for Human Genetics, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany. srudnik-schoeneborn@ukaachen.de
Botzenhart
Elke
E
Eggermann
Thomas
T
Senderek
Jan
J
Schoser
Benedikt G H
BG
Schröder
Rolf
R
Wehnert
Manfred
M
Wirth
Brunhilde
B
Zerres
Klaus
K
D000328:Adult; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006331:Heart Diseases / Q000150:complications*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics; D055532:SMN Complex Proteins
D017362:Cyclic AMP Response Element-Binding Protein; C494847:LMNA protein, human; D034904:Lamin Type A; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins