Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silver syndrome is a rare autosomal dominant neurodegenerative disorder characterized by marked amyotrophy and weakness of small hand muscles and spasticity in the lower limbs. The locus for Silver syndrome (SPG17) was assigned to a 13 cM region on chromosome 11q12-q14 in a single large pedigree. We recently found heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2, seipin) gene causing SPG17 and distal hereditary motor neuropathy type V (distal HMN V). Here we report the clinical features of two families with heterozygous BSCL2 mutations. Interestingly, both families show a clinical phenotype different from classical Silver syndrome, and in some patients the phenotype is also different from distal HMN V. Patients in the first family had marked spasticity in the lower limbs and very striking distal amyotrophy that always started in the legs. Patients in the second family had distal amyotrophy sometimes starting and predominating in the legs, but no pyramidal tract signs. These observations broaden the clinical phenotype of disorders associated with BSCL2 mutations, having consequences for molecular genetic testing.
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PMID:The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. 1524 82

We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD = 3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype.
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PMID:A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier? 1939 77

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total absence of body fat since birth with predisposition to insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. Three CGL loci, AGPAT2, BSCL2, and CAV1, have been identified previously. Recently, mutations in polymerase I and transcript release factor (PTRF) were reported in five Japanese patients presenting with myopathy and CGL (CGL4). We report novel PTRF mutations and detailed phenotypes of two male and three female patients with CGL4 belonging to two pedigrees of Mexican origin (CGL7100 and CGL178) and one pedigree of Turkish origin (CGL180). All patients had near total loss of body fat and congenital myopathy manifesting as weakness, percussion-induced muscle mounding, and high serum creatine kinase levels. Four of them had hypertriglyceridemia. Three of them had atlantoaxial instability. Two patients belonging to CGL178 pedigree required surgery for pyloric stenosis in the first month of life. None of them had prolonged QT interval on electrocardiography but both siblings belonging to CGL7100 had exercise-induced ventricular arrhythmias. Three of them had mild acanthosis nigricans but had normal glucose tolerance. Two of them had hepatic steatosis. All patients had novel null mutations in PTRF gene. In conclusion, mutations in PTRF result in a novel phenotype that includes generalized lipodystrophy with mild metabolic derangements, myopathy, cardiac arrhythmias, atlantoaxial instability, and pyloric stenosis. It is unclear how mutations in PTRF, which plays an essential role in formation of caveolae, affect a wide variety of tissues resulting in a variable phenotype.
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PMID:Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations. 2068 3

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50-60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts.
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PMID:A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes. 2255 17

Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic.
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PMID:Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. 2255 90

Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), "mutilating sensory neuropathy with spastic paraplegia" owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders.
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PMID:Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. 2389 27

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.
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PMID:Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. 2445 Dec 28

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative diseases characterized by progressive weakness and spasticity of lower limbs. To clarify the genetic spectrum and improve the diagnosis of HSP patients, targeted next-generation sequencing (NGS) was applied to detect the culprit genes in 55 Chinese HSP pedigrees. The classification of novel variants was based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Patients remaining negative following targeted NGS were further screened for gross deletions/duplications by multiplex ligation-dependent probe amplification (MLPA). We made a genetic diagnosis in 61.8% (34/55) of families and identified 33 mutations, including 14 known mutations and 19 novel mutations. Of them, one was de novo mutation (NIPA1: c.316G>A). SPAST mutations (22/39, 56.4%) are the most common in Chinese AD-HSP followed by ATL1 (4/39, 10.3%). Moreover, we identified the third BSCL2 mutation (c.1309G>C) related to HSP by further functional studies and first reported the KIF1A mutation (c.304G>A) in China. Our findings broaden the genetic spectrum of HSP and improve the diagnosis of HSP patients. These results demonstrate the efficiency of targeted NGS to make a more rapid and precise diagnosis in patients with clinically suspected HSP.
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PMID:Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients. 2993 52