Assuntos
Colágeno Tipo VI/deficiência , Distrofias Musculares/complicações , Pneumotórax/etiologia , Esclerose/complicações , Biópsia , Colágeno Tipo VI/genética , Diagnóstico Diferencial , Humanos , Masculino , Músculos/patologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Pneumotórax/genética , Pneumotórax/patologia , Recidiva , Esclerose/genética , Esclerose/patologia , Adulto JovemRESUMO
"Core-rod myopathy" is a rare congenital myopathy characterized by the presence of "cores" and "rods" in distinct locations in the same or different muscle fibres. This association is linked currently to mutations in RYR1, NEB and ACTA1 genes. We report identical twins who presented with polyhydramnios and loss of fetal motility during pregnancy; hypotonia, arthrogryposis and swallowing impairment at birth; need of immediate respiratory support and death at 27 and 50 days of life. Muscle biopsies, performed at 27 days of life in twin 1 and at 49 days in twin 2, showed the presence of separate cores and rods in the muscle fibres, both at light and electron microscopy. The molecular analysis showed a heterozygous de novo mutation (Ile4898Thr) of the RYR1 gene. The molecular study of ACTA1, TMP2 and TMP3 genes did not show abnormalities. This is the first report of a lethal form of congenital "core-rod myopathy". The mutation Ile4898Thr has been previously described in central core disease but not in core-rod myopathy. The report enlarges the phenotypic spectrum of "core-rod myopathy" and highlights the morphological variability associated to special RYR1 mutations.
Assuntos
Mutação , Miopatias da Nemalina/genética , Miopatia da Parte Central/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Gêmeos/genética , Actinas/genética , Análise Mutacional de DNA , Evolução Fatal , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia Eletrônica , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/ultraestruturaRESUMO
Mutations in the gene encoding the phosphoinositide phosphatase myotubularin 1 protein (MTM1) are usually associated with severe neonatal X-linked myotubular myopathy (XLMTM). However, mutations in MTM1 have also been recognized as the underlying cause of "atypical" forms of XLMTM in newborn boys, female infants, female manifesting carriers and adult men. We reviewed systematically the biopsies of a cohort of patients with an unclassified form of centronuclear myopathy (CNM) and identified four patients presenting a peculiar histological alteration in some muscle fibers that resembled a necklace ("necklace fibers"). We analyzed further the clinical and morphological features and performed a screening of the genes involved in CNM. Muscle biopsies in all four patients demonstrated 4-20% of fibers with internalized nuclei aligned in a basophilic ring (necklace) at 3 microm beneath the sarcolemma. Ultrastructurally, such necklaces consisted of myofibrils of smaller diameter, in oblique orientation, surrounded by mitochondria, sarcoplasmic reticulum and glycogen granules. In the four patients (three women and one man), myopathy developed in early childhood but was slowly progressive. All had mutations in the MTM1 gene. Two mutations have previously been reported (p.E404K and p.R241Q), while two are novel; a c.205_206delinsAACT frameshift change in exon 4 and a c.1234A>G mutation in exon 11 leading to an abnormal splicing and the deletion of nine amino acids in the catalytic domain of MTM1. Necklace fibers were seen neither in DNM2- or BIN1-related CNM nor in males with classical XLMTM. The presence of necklace fibers is useful as a marker to direct genetic analysis to MTM1 in CNM.
