title: Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.
abstract: Nemaline myopathy is among the most common congenital myopathies. We describe for the first time a novel double de novo mutation in two adjacent codons resulting in two amino acid changes E74D and H75Y in the ACTA1 gene. The hypotonic male infant was the first son of healthy unrelated parents with no family history of neuromuscular disorders. Pregnancy was complicated: decreased fetal movements were noted on the 25th week of gestation, premature labour pains were present from the 29th week onwards and because of breech presentation a Caesarian section was carried out in the 39th week. The patient presented with multiple congenital fractures and joint contractures. He was dependent on ventilatory support until his death at 2 months. Muscle biopsy revealed severely atrophic and rounded muscle fibers with considerable variation in diameter and pronounced disorganization of the myofibers. Electron microscopy indicated a distinct disturbance of the myofibrillar architecture and nemaline rods. In view of previously described cases carrying different single missense mutations of the amino acid residues E74 or H75, we suggest that the particular genotype E74D/H75Y is compatible with the severity of the patient's phenotype. The possibility of germ cell mosaicism should be taken into account in genetic counseling.
authors: Friedrich-Baur-Institute and Department of Neurology, Ludwig-Maximilians-University, Marchioninistrasse 17, Munich, Germany.
authors: Natalia
authors: N
authors: Garcia-Angarita
authors: Janbernd
authors: J
authors: Kirschner
authors: Mandy
authors: M
authors: Heiliger
authors: Christian
authors: C
authors: Thirion
authors: Maggie C
authors: MC
authors: Walter
authors: Susanne
authors: S
authors: Schnittfeld-Acarlioglu
authors: Matthias
authors: M
authors: Albrecht
authors: Klaus
authors: K
authors: Müller
authors: Dagmar
authors: D
authors: Wieczorek
authors: Hanns
authors: H
authors: Lochmüller
authors: Sabine
authors: S
authors: Krause
mesh_terms: D000199:Actins / Q000235:genetics*; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007231:Infant, Newborn; D007596:Joints / Q000002:abnormalities; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D017696:Myopathies, Nemaline / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics; D012131:Respiratory Insufficiency / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D000199:Actins; D003062:Codon