Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rigid spine syndrome is a term first proposed by Dubowitz to describe a subset of patients affected by myopathy with early spinal contractures as a prominent feature. While spinal rigidity is a nonspecific feature, found in Emery-Dreifuss muscular dystrophy and in some congenital myopathies, it is also a prominent feature in a group of patients with merosin-positive congenital muscular dystrophy, where it is generally associated with stable or only slowly progressive weakness and early respiratory insufficiency. Recently, the first locus for congenital muscular dystrophy in association with rigid spine syndrome was mapped to chromosome 1p35-p36 in consanguineous Moroccan, Turkish, and Iranian families. We present here a detailed phenotypic description of the familial syndrome linked to this locus, describing 4 siblings (3 boys and 1 girl) of Northern European-American heritage who are the offspring of a nonconsanguineous marriage. All 4 siblings were affected by hypotonia and prominent neck weakness in infancy, early spinal rigidity, and early scoliosis. After initial improvement, muscle strength stabilizes or slowly declines, and skeletal deformities and respiratory insufficiency supervene. Muscle biopsy in an affected child at age 9 months revealed minimal, nonspecific myopathic changes, leading to a diagnosis of "minimal change myopathy." Muscle biopsy in his sibling, at the age of 14 years, revealed chronic and severe myopathic (dystrophic) changes, with normal staining for laminin-2 and for proteins of the dystrophin-glycoprotein complex. A possible explanation for these biopsy findings is that magnetic resonance imaging of the thighs reveals stereotyped selective muscle involvement, with the selectivity more pronounced early in the disease course followed by widespread muscular signal abnormalities in the late stages of the disease. In this family, linkage to the chromosome 1p rigid spine syndrome locus (RSMD1) is supported by maximum LOD scores for several markers of 1.81 at theta = 0, representing the maximum statistical power possible for this family. In combination with the previous report, this syndrome is linked to the RSMD1 locus with a summated maximum LOD score of 6.29, and analysis of recombination events in our family narrows the previously reported RSMD1 locus to 3 centiMorgans.
 ...
PMID:Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. 1066 83

Multi-minicore disease (MmD) is an infrequent congenital myopathy, defined by structural changes in optic and electron microscopy, namely, multiple small areas lacking oxidative enzyme activity and focal disorganization of contractile proteins involving at most a few sarcomeres. The classical form of the disease manifests as more or less severe hypotonia and generalized weakness with predominance in axial and proximal limb muscles. Clinical variants also exist. Usually MmD is inherited as an autosomal recessive trait. Genetic heterogeneity is recognized and up to now mutations in the genes of RYR1 and SEPN1 have been detected. We record three unrelated cases of MmD. Case 1, with the classical benign form, was followed-up for 15 years. Case 2, presenting pharyngolaryngeal involvement and severe delay of head control, improved gradually, until independent gait was acquired at age of six years. A moderate restriction of daily life activities remains. Case 3, of antenatal-onset, was expressed by arthrogryposis of hands, predominance of scapular girdle deficit and a stable course after ten years on physiotherapy. All cases were selected by the characteristic morphological abnormalities in biceps brachii samples, including electron microscopy. Emphasis is given to case 2 due to type 1 fiber uniformity and mild endomysial fibrosis, posing a difficult differential diagnosis with congenital muscular dystrophy were it not for the significant number of multi-minicores.
 ...
PMID:Multi-minicore disease revisited. 1560 48

Mutations in the gene coding for selenoprotein N (SelN), a selenium containing protein of unknown function, cause different forms of congenital muscular dystrophy in humans. These muscular diseases are characterized by early onset of hypotonia which predominantly affect in axial muscles. We used zebrafish as a model system to understand the function of SelN in muscle formation during embryogenesis. Zebrafish SelN is highly homologous to its human counterpart and amino acids corresponding to the mutated positions in human muscle diseases are conserved in the zebrafish protein. The sepn1 gene is highly expressed in the somites and notochord during early development. Inhibition of the sepn1 gene by injection of antisense morpholinos does not alter the fate of the muscular tissue, but causes muscle architecture disorganization and greatly reduced motility. Ultrastructural analysis of the myotomes reveals defects in muscle sarcomeric organization and in myofibers attachment, as well as altered myoseptum integrity. These studies demonstrate the important role of SelN for muscle organization during early development. Moreover, alteration of myofibrils architecture and tendon-like structure in embryo deficient for SelN function provide new insights into the pathological mechanism of SelN-related myopathy.
 ...
PMID:Loss of selenoprotein N function causes disruption of muscle architecture in the zebrafish embryo. 1712 13

We report a sporadic case of congenital muscular dystrophy (CMD) in a 13-year-old girl with early manifestation of muscle weakness and hypotonia, severe contractures, bulbar syndrome, progressive external ophtalmoplegia, and white matter changes on magnetic resonance imaging (MRI) of the brain, but no mental defect. Serum creatine kinase (CK) level was normal. Muscle biopsy revealed a dystrophic picture with a prominent inflammatory infiltrate mimicking inflammatory myopathy-typical histological findings in CMD. Immunostaining showed normal expression of merosin, alpha and beta-dystroglycans. Mutation analyses of calpain3, dysferlin, and SEPN1 genes were negative. An electron microscopy revealed the accumulation of abnormally enlarged mitochondria located under the sarcolemma. Measurement of respiratory chain enzyme activities did not reveal any biochemical defect and mitochondrial genetic studies, including sequencing of the entire mitochondrial genome, were unremarkable. Phenotypic presentation of our patient is very unusual and differs considerably from other CMD variants.
 ...
PMID:An unusual case of congenital muscular dystrophy with normal serum CK level, external ophtalmoplegia, and white matter changes on brain MRI. 1739 6

The selenoprotein N1-related myopathies comprise rigid spine muscular dystrophy, the "classical" form of multiminicore disease, a desmin-related myopathy with Mallory body like inclusions and a form of congenital fiber-type disproportion. To define the phenotype and long-term clinical course in juvenile Selenoprotein N1-related myopathies 11 juvenile patients from eight families with SEPN1 mutations were assessed over a mean period of 7.2 years. Clinical findings, histomorphological studies, respiratory investigations and genetic data were analyzed: age of manifestation varied within the first 2 years of life with muscle hypotonia, lag of head control and delayed motor development. Further gross motor development was normal in 9/11 patients. All patients were ambulant for at least 1000 m at a mean age of 13.7 years. Eight patients exhibited a rigid spine diagnosed at a mean age of 10 years. All patients had respiratory impairment with a vital capacity ranging from 18% to 65%. Four patients were intermittently nocturnally ventilated at a mean age of 11 years. Body mass index was below 20 (kgm(-2)) in all patients. Muscle biopsies of eight individuals revealed multiminicores (n=2), congenital fiber-type disproportion (n=1), myopathic changes with single cores (n=2) and unspecific myopathic features (n=3). Mutations were distributed throughout the entire SEPN1 gene. Although the phenotype of juvenile selenoprotein N1-related myopathies is homogenous regarding the main symptoms we describe a variable degree of clinical severity. Major complications were early respiratory failure, impaired increase in weight and orthopedic problems. There seems to be no correlation between skeletal muscle weakness and respiratory failure.
 ...
PMID:The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy. 1795 Oct 86

Congenital fiber type disproportion (CFTD) is a rare congenital myopathy characterized by hypotonia and generalized muscle weakness. Pathologic diagnosis of CFTD is based on the presence of type 1 fiber hypotrophy of at least 12% in the absence of other notable pathological findings. Mutations of the ACTA1 and SEPN1 genes have been identified in a small percentage of CFTD cases. The muscle tropomyosin 3 gene, TPM3, is mutated in rare cases of nemaline myopathy that typically exhibit type 1 fiber hypotrophy with nemaline rods, and recently mutations in the TPM3 gene were also found to cause CFTD. We screened the TPM3 gene in patients with a clinical diagnosis of CFTD, nemaline myopathy, and with undefined congenital myopathies. Mutations in TPM3 were identified in 6 out of 13 patients with CFTD, as well as in one case of nemaline myopathy. Review of muscle biopsies from patients with diagnoses of CFTD revealed that patients with a TPM3 mutation all displayed marked disproportion of fiber size, without type 1 fiber predominance. Several mutation-negative cases exhibited other abnormalities, such as central nuclei and central cores. These results support the utility of the CFTD diagnosis in directing the course of genetic testing.
 ...
PMID:Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion. 1995 33

Congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of neuromuscular disorders that typically present at birth or in early infancy with hypotonia, weakness, and histologic evidence of a dystrophic myopathy. CMD biochemical types include various abnormalities of alpha-dystroglycan O-mannosyl glycosylation as well as defects in integrin matrix receptors, the extracellular matrix proteins laminin-alpha(2) and collagen VI, nuclear proteins such as lamin A/C, and a protein of the endoplasmic reticulum, selenoprotein N. Current therapies are directed mostly at supportive care; however, recent advances in biotechnology and increased knowledge of the pathophysiology underlying the various CMD types have helped identify potential therapeutic strategies directed at genetic, molecular, and biochemical pathways involved in these disorders. In this article, we review our current understanding of the molecular pathogenesis of several CMD types and how these mechanisms may be therapeutically targeted.
 ...
PMID:Congenital muscular dystrophies: toward molecular therapeutic interventions. 2042 32

Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico-pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis. Case 2 is a 7-year-old boy with hypotonia, feeding difficulties, motor delay and scoliosis, also requiring non-invasive ventilation while ambulant. Muscle biopsies in both cases showed fibre type disproportion. Muscle MRI (Case 1) showed mild uniformly increased interstitial tissue in and around the muscles. Sequencing of TPM3 in case 1 revealed a previously described heterozygous c.503G > A(pArg168His) missense variant in exon 5 and a novel heterozygous missense mutation c.521A > C(pGlu174Ala), also in exon 5, in case 2. A mild abnormality in the single fibre EMG was documented on electrophysiology in both cases. These cases highlight the neuromuscular transmission defect in CFTD secondary to TPM3 mutations.
 ...
PMID:Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia. 2095 Oct 40

Congenital myopathies (CMs) are a heterogeneous group of muscle diseases characterized by hypotonia, delayed motor skills and muscle weakness with onset during the first years of life. The diagnostic workup of CM is highly dependent on the interpretation of the muscle histology, where typical pathognomonic findings are suggestive of a CM but are not necessarily gene specific. Over 20 loci have been linked to these myopathies, including three exceptionally large genes (TTN, NEB and RYR1), which are a challenge for molecular diagnosis. We developed a new approach using massive parallel sequencing (MPS) technology to simultaneously analyze 20 genes linked to CMs. Assay design was based on the Ion AmpliSeq strategy and sequencing runs were performed on an Ion PGM system. A total of 12 patients were analyzed in this study. Among the 2534 variants detected, 14 pathogenic mutations were successfully identified in the DNM2, NEB, RYR1, SEPN1 and TTN genes. Most of these had not been documented and/or fully characterized, hereby contributing to expand the CM mutational spectrum. The utility of this approach was demonstrated by the identification of mutations in 70% of the patients included in this study, which is relevant for CMs especially considering its wide phenotypic and genetic heterogeneity.
...
PMID:New massive parallel sequencing approach improves the genetic characterization of congenital myopathies. 2684 30

Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular junction caused by compromised synaptic transmission. Clinical features include early-onset weakness of limbs and oculobulbar muscles resulting in hypotonia, bulbar paresis, ptosis, and hypoventilation. The first dropped head syndrome in children were detected in 2 patients with LMNA and SEPN1 mutations. We report a 17-month-old boy with dropped head and limb-girdle weakness, who had no ptosis or ophthalmoplegia at presentation. We performed whole exome sequencing, which revealed a homozygous missense variant in the AGRN gene c.5023G>A, p.Gly1675Ser in the LG2 domain, which is predicted to be likely disease causing by in silico tools. Agrin is known to play a critical role in the development and maintenance of the neuromuscular junction. Agrin-related CMS is one of the rarest subtypes. Of note, our patient is the first described patient with agrin-related CMS with dropped head phenotype.
 ...
PMID:A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop. 2822 5


1 2 Next >>