RESUMO
BACKGROUND: Pathogenic mutations in rapsyn result in endplate acetylcholine receptor (AChR) deficiency and are a common cause of postsynaptic congenital myasthenic syndromes. METHODS: Clinical, electrophysiologic, pathologic, and molecular studies were done in 39 patients. RESULTS: In all but one patient, the disease presented in the first 2 years of life. In 9 patients, the myasthenic symptoms included constant or episodic ophthalmoparesis, and 1 patient had a pure limb-girdle phenotype. More than one-half of the patients experienced intermittent exacerbations. Long-term follow-up was available in 25 patients after start of cholinergic therapy: 21 became stable or were improved and 2 of these became asymptomatic; 3 had a progressive course; and 1 died in infancy. In 7 patients who had endplate studies, the average counts of AChR per endplate and the synaptic response to ACh were less reduced than in patients harboring low AChR expressor mutations. Eight patients were homozygous and 23 heterozygous for the common p.N88K mutation. Six mutations, comprising 3 missense mutations, an in-frame deletion, a splice-site mutation, and a nonsense mutation, are novel. Homozygosity for p.N88K was associated with varying grades of severity. No genotype-phenotype correlations were observed except in 8 Near-Eastern patients homozygous for the promoter mutation (c.-38A>G), who had a mild course. CONCLUSIONS: All but 1 patient presented early in life and most responded to cholinergic agonists. With early diagnosis and therapy, rapsyn deficiency has a benign course in most patients. There was no consistent phenotype-genotype correlation except for an E-box mutation associated with jaw deformities.
Assuntos
Predisposição Genética para Doença/genética , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Síndromes Miastênicas Congênitas/genética , Doenças da Junção Neuromuscular/genética , Receptores Colinérgicos/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Agonistas Colinérgicos/uso terapêutico , Análise Mutacional de DNA , Progressão da Doença , Feminino , Testes Genéticos , Genótipo , Homozigoto , Humanos , Masculino , Mutação/genética , Síndromes Miastênicas Congênitas/metabolismo , Síndromes Miastênicas Congênitas/fisiopatologia , Doenças da Junção Neuromuscular/metabolismo , Doenças da Junção Neuromuscular/fisiopatologia , Fenótipo , Receptores Colinérgicos/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To assess the effect of institution of noninvasive ventilation (NIV) on clinical outcome and quality of life (QOL) in a cohort of children with severe neuromuscular disorders. METHODS: We reviewed records and obtained clinical data from the year prior to commencing NIV and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. RESULTS: Fourteen of 17 (82%) suitable patients were enrolled. Follow-up ranged from 6 to 84 months (median 30). Symptoms of daytime sleepiness (p = 0.003) and headache (p = 0.046) improved after initiation of NIV. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased. QOL remained stable after NIV, despite disease progression. CONCLUSION: Treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life.
Assuntos
Doenças Neuromusculares/terapia , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Respiração Artificial/métodos , Transtornos do Sono-Vigília/prevenção & controle , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Masculino , Doenças Neuromusculares/complicações , Doenças Neuromusculares/diagnóstico , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Dominant mutations in COL6A1, COL6A2, and COL6A3, the three genes encoding collagen type VI, a ubiquitous extracellular matrix protein, are associated with Bethlem myopathy (BM) and Ullrich scleroatonic muscular dystrophy. METHODS: The authors devised a method to screen the entire coding sequence of the three genes by reverse transcriptase-PCR amplification of total RNA from skin fibroblasts and direct sequencing of the resulting 25 overlapping cDNA fragments covering 107 exons. RESULTS: Four splicing and four missense mutations were identified in 16 patients with BM, six of which are novel mutations in COL6A1. Both common and private mutations are localized in the alpha1 (VI) chain between the regions corresponding to the 3' end of the NH2-globular domain and the 5' end of the triple helix, encoded by exons 3 through 14. CONCLUSIONS: The clustering of the mutations in a relatively narrow area of the three collagen type VI chains in patients with Bethlem myopathy (BM) suggests that mutations in different regions could result in different phenotypes or in no phenotype at all. Moreover, the detection of mutations in only 60% of the patients suggests the existence of at least another gene associated with BM. The authors propose the direct sequencing of COL6 cDNAs as the first mutation screening analysis in BM, given the high number of exon-skipping events.
Assuntos
Colágeno Tipo VI/genética , Doenças Musculares/genética , Mutação/genética , Adolescente , Adulto , Processamento Alternativo/genética , Substituição de Aminoácidos/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons/genética , Feminino , Testes Genéticos , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Subunidades Proteicas/genética , RNA Mensageiro/análise , RNA Mensageiro/genéticaRESUMO
We report two cases of Duchenne muscular dystrophy that presented with laboratory evidence of acute transient myocardial cell damage. The mechanism for development of cardiomyopathy associated with Duchenne muscular dystrophy is not well understood, and this report raises the possibility that the progressive deterioration of cardiac function is punctuated by acute episodes of cell damage.
Assuntos
Cardiomiopatias/etiologia , Distrofia Muscular de Duchenne/complicações , Cardiomiopatias/fisiopatologia , Dor no Peito/etiologia , Criança , Eletrocardiografia , Humanos , MasculinoRESUMO
OBJECTIVE: To report pathologic findings in 124 Australian and North American cases of primary nemaline myopathy. METHODS: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha-actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW) (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods, fiber-type distribution of rods, and presence or absence of intranuclear rods were documented. RESULTS: Rods were present in all skeletal muscles and diagnosis was possible at all ages. Most biopsies contained nemaline bodies in more than 50% of fibers, although rods were seen only on electron microscopy in 10 patients. Rod numbers and localization correlated poorly with clinical severity. Frequent findings included internal nuclei and increased fiber size variation, type 1 fiber predominance and atrophy, and altered expression of fiber type specific proteins. Marked sarcomeric disruption, increased glycogen deposition, and intranuclear rods were associated with more severe clinical phenotypes. Serial biopsies showed progressive fiber size variation and increasing numbers of rods with time. Pathologic findings varied widely in families with multiple affected members. CONCLUSIONS: Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption were common in nemaline myopathy associated with mutations in skeletal alpha-actin. Nemaline myopathy due to mutations in alpha-tropomyosin(SLOW) was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. Electron microscopy may correlate better with disease severity and genotype.
Assuntos
Músculo Esquelético/patologia , Miopatias da Nemalina/patologia , Actinas/genética , Austrália/epidemiologia , Biópsia , Núcleo Celular/patologia , Progressão da Doença , Glicogênio/metabolismo , Humanos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/ultraestrutura , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Mutação , Miocárdio/patologia , Miopatias da Nemalina/epidemiologia , Miopatias da Nemalina/fisiopatologia , América do Norte/epidemiologia , Tropomiosina/genéticaRESUMO
OBJECTIVE: To review literature pertinent to the epidemiology of epilepsy in developing countries with special reference to Pakistan. METHODS: All the studies published in medical journals related to epilepsy in Pakistan were systematically reviewed. Important findings from various studies are summarized. RESULTS: Overall prevalence of epilepsy in Pakistan is estimated to be 9.99 per 1000 population. Highest prevalence is seen in people younger than 30 years of age. A slight decrease in prevalence is noted between the ages of 40 and 59. Higher prevalence is observed in rural population. Etiology of epilepsy is more commonly identified in pediatric population. Epilepsy was considered idiopathic in 21 to 76% cases. Only 27.5% epileptic persons in urban areas and 1.9% in the rural areas were treated with AEDs. The burden of epilepsy is not fully evaluated and understood. Generalized seizures were the most common seizure type noted. Knowledge about epilepsy and its care is extremely low. CONCLUSION: Epilepsy is a common medical problem in Paksitan, more prevalent is rural population. The majority of people with epilepsy are treated inadequately or inappropriately.
Assuntos
Epilepsia/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Criança , Pré-Escolar , Países em Desenvolvimento/estatística & dados numéricos , Epilepsia/etiologia , Humanos , Lactente , Pessoa de Meia-Idade , Paquistão/epidemiologia , Prevalência , População Rural , Distribuição por SexoRESUMO
The alpha-tropomyosin-3 (TPM3) gene was screened in 40 unrelated patients with nemaline myopathy (NM). A single compound heterozygous patient was identified carrying one mutation that converts the stop codon to a serine and a second splicing mutation that is predicted to prevent inclusion of skeletal muscle exon IX. TPM3 mutations are a rare cause of NM, probably accounting for less than 3% of cases. The severity of cases with TPM3 mutations may vary from severe infantile to late childhood onset, slowly progressive forms.
Assuntos
Fibras Musculares de Contração Lenta , Miopatias da Nemalina/genética , Tropomiosina/genética , Substituição de Aminoácidos , Western Blotting , Criança , Pré-Escolar , Códon de Terminação , Análise Mutacional de DNA , Humanos , Masculino , Músculo Esquelético/química , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Mutação de Sentido Incorreto , Miopatias da Nemalina/patologia , Miopatias da Nemalina/fisiopatologia , Mutação Puntual , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , Sarcômeros/patologia , Sarcômeros/ultraestrutura , Tropomiosina/análiseRESUMO
We report 143 Australian and North American cases of primary nemaline myopathy. As classified by the European Neuromuscular Centre guidelines, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset nemaline myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Twenty-two patients had skeletal muscle actin mutations and 4 had mutations in the alpha-tropomyosin(slow) gene. Obstetric complications occurred in 49 cases. Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital nemaline myopathy.
Assuntos
Miopatias da Nemalina/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Adulto , Criança , Humanos , Lactente , Pessoa de Meia-Idade , Mutação/genética , Miopatias da Nemalina/genética , Miopatias da Nemalina/mortalidade , Fenótipo , Prognóstico , Insuficiência Respiratória/genética , Insuficiência Respiratória/mortalidade , Análise de SobrevidaRESUMO
Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.
Assuntos
Arritmias Cardíacas/genética , Cromossomos Humanos Par 17 , Fácies , Paralisias Periódicas Familiares/genética , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Alelos , Sequência de Aminoácidos , Animais , Canais de Cálcio/genética , Primers do DNA , Saúde da Família , Feminino , Expressão Gênica , Ligação Genética , Genótipo , Humanos , Masculino , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.4 , Oócitos/fisiologia , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Canais de Sódio/genética , XenopusRESUMO
Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin-glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to alpha-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD.
Assuntos
Isquemia/enzimologia , Músculo Esquelético/enzimologia , Distrofia Muscular de Duchenne/enzimologia , Óxido Nítrico Sintase/metabolismo , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Músculo Esquelético/irrigação sanguínea , Óxido Nítrico Sintase Tipo IRESUMO
We report the case of a 13-year-old boy with acetylcholinesterase deficiency, a congenital myasthenic syndrome, who developed sleep hypoventilation syndrome during a period of rapid growth. His symptoms were insidious and life-threatening despite changes in strength or lung volume measurements that were not marked. He responded well to noninvasive nocturnal ventilation, with reversal of symptoms and normalization of blood gases. His lung volumes, but not motor function, improved after treatment.
Assuntos
Acetilcolinesterase/deficiência , Hipoventilação/congênito , Hipoventilação/etiologia , Doenças Neuromusculares/congênito , Doenças Neuromusculares/complicações , Humanos , Hipoventilação/terapia , Lactente , Medidas de Volume Pulmonar , Masculino , Doenças Neuromusculares/terapia , Polissonografia , Respiração Artificial , SíndromeRESUMO
Spinal muscular atrophy is a genetic disorder of the motor neurons that causes profound hypotonia, severe weakness, and often fatal restrictive lung disease. Patients with spinal muscular atrophy present a spectrum of disease from the most severe infantile-onset type, called Werdnig-Hoffmann disease (type 1), associated with a mortality rate of up to 90%, to a late-onset mild form (type 3), wherein patients remain independently ambulatory throughout adult life. Although many clinicians agree that patients with spinal muscular atrophy lose motor abilities with age, it is unknown whether progressive weakness occurs in all patients with spinal muscular atrophy. We present here results of the first prospective study of muscle strength in patients with spinal muscular atrophy. There was no loss in muscle strength as determined by a quantitative muscle test during the observation period. However, motor function diminished dramatically in some patients with spinal muscular atrophy. Explanations for this loss of function could not be determined from our data. Decrease in motor function could be caused by factors other than loss of strength. Therefore, it is not clear from our results whether spinal muscular atrophy is a neurodegenerative disease. We conclude that treatment trials in spinal muscular atrophy should be designed with consideration of the natural history of strength and motor function in this disorder.
Assuntos
Atrofia Muscular Espinal/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Estudos Prospectivos , Valores de ReferênciaRESUMO
Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.
Assuntos
Actinas/genética , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Miopatias da Nemalina/genética , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação , Mutação Puntual , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNA , Homologia de Sequência de AminoácidosRESUMO
The purpose of this study was to determine whether spinal muscular atrophy affects masticatory muscle strength and mandibular range of motion. A sample of 15 subjects with spinal muscular atrophy was compared to a sample of age-matched and sex-matched controls. Maximum bite force, masticatory muscle electromyography activity, mandibular ranges of motion and masticatory muscle endurance were evaluated. Results showed that maximum bite forces were one-half as great for the sample with spinal muscular atrophy than for the controls, even though their EMG activity was not significantly different. Slopes of the relationship between electromyography activity and bite force were two to four times steeper for patients with spinal muscular atrophy than controls. Maximum opening and protrusion were reduced to approximately one-half control values. Fatigue times of patients with spinal muscular atrophy were reduced by 30% (17.9 seconds versus 11.1 seconds). We conclude that the masticatory muscles of patients with spinal muscular atrophy are weakened, that their muscles are less efficient, and that they fatigue more quickly than controls. In addition, mandibular movements of these patients take place over a more limited range than unaffected controls.
Assuntos
Músculos da Mastigação/fisiopatologia , Atrofia Muscular Espinal/fisiopatologia , Adolescente , Adulto , Força de Mordida , Estudos de Casos e Controles , Criança , Pré-Escolar , Eletromiografia , Feminino , Humanos , Lactente , Masculino , Fadiga Muscular , Resistência Física , Amplitude de Movimento Articular , Estatísticas não Paramétricas , Articulação Temporomandibular/fisiopatologiaRESUMO
The myogenin gene encodes an evolutionarily conserved basic helix-loop-helix transcription (bHLH) factor that is required for differentiation of skeletal muscle, and its homozygous deletion in mice results in perinatal death from respiratory failure due to the lack of muscle fibers. Since the histology of skeletal muscle in myogenin null mice is reminiscent of that found in severe congenital myopathy patients, many of whom also die of respiratory complications, we sought to test the hypothesis that an aberrant human myogenin (myf4) coding region could be associated with some congenital myopathy conditions. With PCR amplification, we found similarly sized PCR products for the three exons of the myogenin gene in DNA from 37 patient and 40 control individuals. In contrast to previously reported sequencing of human myogenin (myf4), we describe with automated sequencing several base differences in flanking and coding regions plus an additional 659 and 498 bp in the first and second introns, respectively, in all 37 patient and 40 control samples. We also find a variable length (CA)-dinucleotide repeat in the second intron, which may have utility as a marker for future linkage studies. In summary, no causative mutations were detected in the myogenin coding locus of genomic DNA from 37 patients with severe congenital myopathy.
Assuntos
Sequências Hélice-Alça-Hélice , Miogenina/genética , Doenças Neuromusculares/genética , Fatores de Transcrição/genética , Sequência de Bases , DNA Complementar , Humanos , Lactente , Dados de Sequência Molecular , Mutagênese , Doenças Neuromusculares/congênitoRESUMO
Disorders known to be caused by molecular and cytogenetic abnormalities of the proximal short arm of chromosome 17 include Charcot-Marie-Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), Smith-Magenis syndrome (SMS), and mental retardation and congenital anomalies associated with partial duplication of 17p. We identified a patient with multifocal mononeuropathies and mild distal neuropathy, growth hormone deficiency, and mild mental retardation who was found to have a duplication of the SMS region of 17p11.2 and a deletion of the peripheral myelin protein 22 (PMP22) gene within 17p12 on the homologous chromosome. Further molecular analyses reveal that the dup(17)(p11.2p11.2) is a de novo event but that the PMP22 deletion is familial. The family members with deletions of PMP22 have abnormalities indicative of carpal tunnel syndrome, documented by electrophysiological studies prior to molecular analysis. The chromosomal duplication was shown by interphase FISH analysis to be a tandem duplication. These data indicate that familial entrapment neuropathies, such as carpal tunnel syndrome and focal ulnar neuropathy syndrome, can occur because of deletions of the PMP22 gene. The co-occurrence of the 17p11.2 duplication and the PMP22 deletion in this patient likely reflects the relatively high frequency at which these abnormalities arise and the underlying molecular characteristics of the genome in this region.
Assuntos
Síndrome do Túnel Carpal/genética , Cromossomos Humanos Par 17 , DNA/análise , Rearranjo Gênico , Genes Dominantes , Adolescente , Feminino , Humanos , Masculino , LinhagemRESUMO
The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number.
Assuntos
Efeito Fundador , Dosagem de Genes , Atrofia Muscular Espinal/genética , Mutação , Proteínas do Tecido Nervoso/genética , Alelos , Centrômero/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Análise Mutacional de DNA , Éxons/genética , Mutação da Fase de Leitura/genética , Proteínas Fúngicas/metabolismo , Análise Heteroduplex , Heterozigoto , Humanos , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Polimorfismo Genético , Proteínas de Ligação a RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas do Complexo SMN , Deleção de Sequência , Telômero/genéticaRESUMO
The history of the spinal muscular atrophies (SMA) began in the 1890s with Guido Werdnig and Johann Hoffmann. Together, their papers present a rather complete picture of the clinical and pathologic aspects of infantile SMA: onset during the first year of life, occurrence in siblings with normal parents, progressive floppiness and weakness, hand tremor, and death from pneumonia in early childhood. Based on the work of an international collaboration, the following is current nomenclature: SMA type 1 (or I) for onset of symptoms before age 6 months, SMA type 2 (II) for onset between 6 and 18 months, and SMA type 3 (III) for onset after age 18 months. Linkage of autosomal recessive SMA to chromosome 5q11.2-13.3 was reported by Gilliam et al in 1990. A novel gene, whose function remains unknown, called the survival motor neuron gene (SMN) at 5q13, contains deletions in more than 98% of SMA patients. Some patients with atypical forms of SMA have been shown to have mutations in SMN. Because there is no effective therapy for SMA, management consists of preventing or treating the complications of severe weakness, such as restrictive lung disease, poor nutrition, orthopedic deformities, immobility, and psychosocial problems.
Assuntos
Atrofias Musculares Espinais da Infância , Criança , Pré-Escolar , Educação Médica Continuada , Humanos , Lactente , Atrofias Musculares Espinais da Infância/classificação , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/terapiaRESUMO
We previously reported that patients with spinal muscular atrophy do not lose muscle strength over time as measured quantitatively. However, we noted that many patients with spinal muscular atrophy suffer from what they call fatigue. We wondered if we could measure fatigue during a single maximal voluntary contraction, whether fatigue might increase with time, independent of muscle strength, and whether increasing fatigue might correlate with loss of function in some patients. We measured fatigue during a single maximal voluntary contraction in a cohort of patients having spinal muscular atrophy using quantitative strength testing. We included only patients with spinal muscular atrophy aged 5 years or older, so they could follow instructions regarding muscle contraction, and who were followed for at least 2 years. Seventy-six children with spinal muscular atrophy and 24 untrained individuals, aged 5 to 57 years (mean, 16.8 years), were studied. There was no discernible abnormal fatigue in patients with spinal muscular atrophy compared to untrained controls using our methodology. Thus, spinal muscular atrophy may not be associated with fatiguability. Moreover, spinal muscular atrophy does not appear to cause progressive muscle fatigue with age or loss of function. It is possible that fatigue was undetectable by our methods. An alternative explanation is that what patients describe as fatigue may be caused by factors outside the neuromuscular system. Such factors may include chronic respiratory insufficiency with hypoventilation and carbon dioxide retention as well as chronic malnutrition and negative nitrogen balance.