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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal eyes, and congenital muscular dystrophy with severe mental retardation and cerebellar cysts are nosologically distinct and have been excluded from the known congenital muscular dystrophy loci with structural changes of the central nervous system. Here, we describe a novel congenital muscular dystrophy syndrome which is phenotypically distinct from the recognized forms of congenital muscular dystrophy with brain involvement. Two siblings, a boy and a girl, were born to consanguineous parents from Sicily. Both children were born with adducted thumbs and toe contractures. They were floppy from birth, walked late, showed profound generalized muscle weakness including facial muscles, elevated creatine kinase levels of 200-700U/l, and histological changes compatible with muscular dystrophy. In addition, both showed ptosis, external ophthalmoplegia, mild mental retardation, and mild cerebellar hypoplasia on MRI. Immunocytochemistry showed normal expression of muscle membrane proteins including laminin alpha 2, laminin beta 2, and alpha-dystroglycan. Linkage analysis excluded the candidate loci on chromosomes 6q2, 9q31, and 1q32. The gene locus for congenital muscular dystrophy 1B, MDC 1B, on chromosome 1q42 was also excluded. Adducted thumbs are a distinct clinical sign that has not been reported in congenital muscular dystrophy before and should facilitate recognition of further patients with this disorder.
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PMID:Congenital muscular dystrophy with adducted thumbs, ptosis, external ophthalmoplegia, mental retardation and cerebellar hypoplasia: a novel form of CMD. 1220 29

Complete laminin alpha2 (LAMA2) deficiency causes approximately half of congenital muscular dystrophy (CMD) cases. Many loss-of-function mutations have been reported in these severe, neonatal-onset patients, but only single missense mutations have been found in milder CMD with partial laminin alpha2 deficiency. Here, we studied nine patients diagnosed with CMD who showed abnormal white-matter signal at brain MRI and partial deficiency of laminin alpha2 on immunofluorescence of muscle biopsy. We screened the entire 9.5 kb laminin alpha2 mRNA from patient muscle biopsy by direct capillary automated sequencing, single strand conformational polymorphism (SSCP), or denaturing high performance liquid chromatography (DHPLC) of overlapping RT-PCR products followed by direct sequencing of heteroduplexes. We identified laminin alpha2 sequence changes in six of nine CMD patients. Each of the gene changes identified, except one, was novel, including three missense changes and two splice-site mutations. The finding of partial laminin alpha2 deficiency by immunostaining is not specific for laminin alpha2 gene mutation carriers, with only two patients (22%) showing clear causative mutations, and an additional three patients (33%) showing possible mutations. The clinical presentation and disease progression was homogeneous in the laminin alpha2-mutation positive and negative CMD patients.
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PMID:Clinical and molecular study in congenital muscular dystrophy with partial laminin alpha 2 (LAMA2) deficiency. 1255 56

Glycine is an excitatory amino acid, a neurotransmitter for the brain. A recent experimental study by a 9.3T laboratory spectrometer identified the peak of pure glycine at 3.52 ppm, and in a clinical case this peak was demonstrated at 3.50 ppm by a 1.5 T clinical scanner. This study was undertaken to investigate the brain diseases having the glycine peak. An experiment with a 1.5 T clinical MRI unit was performed. Two grams of pure glycine was dissolved in 200 cc of distilled water and the solution was frozen, and proton MR spectroscopy (TR=1500 ms, TE=20 ms) was obtained. Nine patients with various diseases studied by two-dimensional chemical shift spectroscopy (hybrid CSI) with TR=1500 ms, and TE=40 ms are included in the study. Ten normal cases were available for comparison. In the experiment with the clinical MRI unit, the glycine peak was centered at 3.50 ppm. The disease processes associated with distinct glycine peaks at 3.50 ppm included infarction, high-grade astrocytoma, megalencephalic leukoencephalopathy with cysts, Leigh's disease, adrenoleukodystrophy, congenital muscular dystrophy, Rasmussen's encephalitis, gliosis in neuronal migrational disorder, and hamartoma in tuberous sclerosis. None of the control cases displayed a glycine peak. In conclusion, glycine has a peak centered at 3.50 ppm in in vivo environments. It is distinct from the myoinositol peak. Detection of glycine in a wide variety of brain diseases ranging from infarction, tumor, leukoencephalopathies, infection to gliosis likely reflects presence of excitotoxic brain damage or a disturbance of neurotransmitting mechanisms in these conditions.
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PMID:The glycine peak in brain diseases. 1263 15

We report a two-year-old Caucasian boy who had neonatal seizures and was found to have bilateral occipito-temporal polymicrogyria on neonatal brain MRI. The child had no additional neurological abnormality other than the neonatal seizures, but serum CK was found to be elevated (5 - 7 times normal values) and the muscle biopsy showed evidence of early muscular dystrophy. Detailed protein and genetic studies did not allow the identification of a known form of muscular dystrophy. The boy has been followed regularly and he currently has mild global developmental delay but no clinical signs of muscle involvement. The association of polymicrogyria and muscular dystrophy is known to occur in Fukuyama and Walker Warburg muscular dystrophies, in muscle-eye-brain disease and in some patients with merosin deficient CMD. However the absence of weakness and of eye involvement, the normal expression of merosin and alpha dystroglycan and the pattern of brain involvement make it very unlikely that the child is affected by one of these forms. As the pattern of brain involvement and the muscle pathology is not typical of one of the forms of neuronal migration disorders secondary to a known gene defect, we suspect that the combination of muscle and brain involvement found in this child is not coincidental. Our findings suggest that serum CK should be determined in children with undiagnosed polymicrogyria, even in the absence of weakness. This may lead to an expansion of our understanding of muscle dystrophies and cortical dysplasias.
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PMID:Occipito-temporal polymicrogyria and subclinical muscular dystrophy. 1277 31

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of alpha-dystroglycan. Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, each associated with eye abnormalities and neuronal migration defects, result from mutations in fukutin, POMGnT1 and POMT1, respectively, while mutations in the fukutin-related protein (FKRP) gene cause congenital muscular dystrophy 1C, typically lacking brain involvement. Another putative glycosyltransferase, Large, is mutated in the myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of muscular dystrophy. We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in seven informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1 bp insertion, 1999insT. This 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.
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PMID:Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. 1296 29

It is well known that morphological changes at the cellular level occur in muscle of patients with mitochondrial myopathy (MM), but changes in muscle structure with fat infiltration and gross variation of muscle fiber size with giant fibers, normally encountered in the muscular dystrophies, have typically not been associated with mitochondrial disease. We investigated gross and microscopic muscle morphology in thigh muscles by muscle biopsy and MRI in 16 patients with MM, and compared findings with those obtained in muscular dystrophy patients and healthy subjects. Changes of muscle architecture, similar to those found in the group of muscular dystrophy patients occurred consistently in patients with a high mutation load for single, largescale deletions of mtDNA, but were absent in all patients with the 3243A-->G mtDNA point mutation. Dystrophic changes of muscle architecture were also present in one MM patient with a unique, sporadic mutation in the mtDNA tRNA(Met) gene. These findings provide evidence that morphological changes in muscle of MM patients are common and may resemble those of muscular dystrophies, but that development of dystrophic-like changes in muscle relate to genotype.
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PMID:Muscle structural changes in mitochondrial myopathy relate to genotype. 1464 49

The authors report a girl with autosomal recessive congenital muscular dystrophy linked to chromosome 6 (MDC1A) who carries a homozygous out-of-frame deletion in exon 56 of the LAMA2 gene but has a mild phenotype. She is still ambulant at age 13 years, shows white matter abnormalities on MRI, and traces of laminin alpha2 in her muscle biopsy with one of three antibodies used. This patient suggests that modulating factors can be associated with a less severe clinical phenotype in MDC1A.
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PMID:LAMA2 loss-of-function mutation in a girl with a mild congenital muscular dystrophy. 1545 15

Limb girdle muscular dystrophy 2A is a common variant secondary to mutations in the calpain 3 gene. A proportion of patients has early and severe contractures, which can cause diagnostic difficulties with other conditions. We report clinical and muscle magnetic resonance imaging findings in seven limb girdle muscular dystrophy 2A patients (four sporadic and three familial) who had prominent and early contractures. All patients showed a striking involvement of the posterior thigh muscles. The involvement of the other thigh muscles was variable and was related to clinical severity. Young patients with minimal functional motor impairment showed a predominant involvement of the adductors and semimembranosus muscles while patients with restricted ambulation had a more diffuse involvement of the posterolateral muscles of the thigh and of the vastus intermedius with relative sparing of the vastus lateralis, sartorius and gracilis. At calf level all patients showed involvement of the soleus muscle and of the medial head of the gastrocnemius with relative sparing of the lateral head. MRI findings were correlated to those found in two patients with the phenotype of limb girdle muscular dystrophy 2A without early contractures and the pattern observed was quite similar. However, the pattern observed in limb girdle muscular dystrophy 2A is different from that reported in other muscle diseases such as Emery-Dreifuss muscular dystrophy and Bethlem myopathy which have a significant clinical overlap with limb girdle muscular dystrophy 2A once early contractures are present. Our results suggest that muscle MRI may help in recognising patients with limb girdle muscular dystrophy 2A even when the clinical presentation overlaps with other conditions, and may therefore, be used as an additional investigation to target the appropriate biochemical and genetic tests.
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PMID:Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. 1569 38

Gene and stem cell transfer have shown tremendous potential in rescuing dystrophic muscle in animal models. However, monitoring of gene transfer efficacy in clinical settings currently requires invasive muscle biopsies. We determined whether (1)H-magnetic resonance spectroscopy (MRS) and imaging (MRI) could be used to noninvasively monitor gene correction in dystrophic skeletal muscle. MRI/MRS measurements were performed in murine models of Limb Girdle (gammasg(-/-)) and Duchenne muscular dystrophy (mdx). Viral delivery of gammasg into gammasg(-/-) muscles was achieved using both an adenovirus and an adenoassociated virus. T(2)-weighted MRIs consistently revealed hyperintense regions in muscles of dystrophic mice, which agreed well with histologically determined damaged muscle fibers. (1)H-MRS revealed that the increase in T(2) in dystrophic muscle is not due to fatty tissue infiltration. Reintroduction of the gammasg gene in gammasg(-/-) muscles restored normal muscle histology, membrane stability, and T(2) contrast. Expression of gammasg also significantly decreased the number of pixels with increased T(2) values and MRI contrast agent uptake. Our data demonstrate that therapeutic correction of dystrophic lesions can be noninvasively monitored using endogenous MR contrast. This may be particularly relevant for future interventions in children with muscular dystrophy.
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PMID:Noninvasive monitoring of gene correction in dystrophic muscle. 1626 78

Duchenne muscular dystrophy is a progressive muscle disease characterized by increasing muscle weakness and death by the third decade. mdx mice exhibit the underlying muscle disease but appear physically normal with ordinary lifespans, possibly due to compensatory expression of utrophin. In contrast, double mutant mice (mdx/utrn(-/-)), deficient for both dystrophin and utrophin die by approximately 3 months and suffer from severe muscle weakness, growth retardation, and severe spinal curvature. The capacity of human retinal dystrophin (Dp260) to compensate for the missing 427 kDa muscle dystrophin was tested in mdx/utrn(-/-) mice. Functional outcomes were assessed by histology, EMG, MRI, mobility, weight and longevity. MCK-driven transgenic expression of Dp260 in mdx/utrn(-/-) mice converts their disease course from a severe, lethal muscular dystrophy to a viable, mild myopathic phenotype. This finding is relevant to the design of exon-skipping therapeutic strategies since Dp260 lacks dystrophin exons 1-29.
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PMID:Improvement in survival and muscle function in an mdx/utrn(-/-) double mutant mouse using a human retinal dystrophin transgene. 1648 8


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