RESUMO
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
Classical Menkes disease is an X-linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1-q21. ATP7A encodes a copper-transporting P-type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X-autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three-generation family in which a severe ATP7A mutation, a 5.5-kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long-range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at-risk females in the family for this junction fragment and analyzed their X-inactivation patterns using the human androgen-receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at-risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X-inactivation was observed in all non-carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X-inactivation patterns in female carriers of other X-linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A-related distal motor neuropathy.
Assuntos
Síndrome dos Cabelos Torcidos/genética , Inativação do Cromossomo X/genética , Adenosina Trifosfatases/genética , Adulto , Proteínas de Transporte de Cátions/genética , Cromossomos Humanos X/genética , ATPases Transportadoras de Cobre , Feminino , Deleção de Genes , Testes Genéticos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Adulto JovemRESUMO
Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during i.v. L-DOPA, nitroprusside, or trimethaphan infusion in volunteers; after dopamine infusion in patients with L-aromatic-amino-acid decarboxylase deficiency; in arterial and portal venous plasma of gastrointestinal surgery patients; and in patients with sympathetic neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate only slightly. L-DOPA infusion produced much larger increments in dopamine sulfate than in dopamine; the other drugs were without effect. Patients with L-aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate levels, and patients with sympathetic neurocirculatory failure had normal levels. Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine sulfate/dopamine ratio about 25 times less than that at baseline in volunteers. Surgery patients had large arterial-portal venous increments in plasma concentrations of dopamine sulfate, so that mesenteric dopamine sulfate production accounted for most of urinary dopamine sulfate excretion, a finding consistent with the localization of the dopamine sulfoconjugating enzyme to gastrointestinal tissues. The results indicate that plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous determinants affect plasma dopamine sulfate. The findings suggest an enzymatic gut-blood barrier for detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of endogenous dopamine generated in a "third catecholamine system."
Assuntos
Dopamina/análogos & derivados , Jejum , Alimentos , Adulto , Descarboxilases de Aminoácido-L-Aromático/deficiência , Artérias , Doenças do Sistema Nervoso Autônomo/sangue , Western Blotting , Dopamina/sangue , Dopaminérgicos , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/cirurgia , Humanos , Levodopa/administração & dosagem , Levodopa/sangue , Masculino , Nitroprussiato/administração & dosagem , Veia Porta , Trimetafano/administração & dosagemRESUMO
Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1-12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin-Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cromossomos Humanos Par 16 , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , Humanos , Dados de Sequência Molecular , Proteína 2 Associada à Farmacorresistência Múltipla , FilogeniaRESUMO
A man with onset of obsessive-compulsive disorder (OCD) at age 62 had a large right posterior frontal infarct and occlusion of the ipsilateral internal carotid artery. We review additional cases from the literature with obsessive or compulsive behaviors and structural lesions. OCD may have a structural correlate, and this should be searched for in instances where onset occurs after age 60, is atypical, or is associated with other neurologic signs or symptoms. Rational therapy for OCD will depend on a detailed understanding of the neuronal circuitry and physiologic mechanisms underlying such behaviors, and additional data from thoroughly evaluated patients may be revealing.
Assuntos
Infarto Cerebral/complicações , Lobo Frontal/irrigação sanguínea , Transtorno Obsessivo-Compulsivo/etiologia , Idoso , Infarto Cerebral/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
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
OBJECTIVES: To elucidate the phenotype in aromatic L-amino acid decarboxylase (AADC) deficiency, a rare autosomal recessive disorder of neurotransmitter synthesis, and report preliminary treatment observations with directed therapy of the associated neurotransmitter deficiencies. BACKGROUND: AADC is a required enzyme in dopamine, norepinephrine, epinephrine, and serotonin biosynthesis. Five patients have been previously reported. Responses to treatment interventions in these patients have been mixed. METHODS: Clinical and biochemical evaluation and therapeutic trials were performed in two children over a 26-month period. RESULTS: Characteristic features included axial hypotonia, hypokinesia, and athetosis, with superimposed episodes of ocular convergence spasm, oculogyric crises, dystonia, and limb rigidity. Catecholamine deficiency was manifest by ptosis, nasal congestion, paroxysmal diaphoresis, temperature instability, and blood pressure lability. Abnormal sleep, feeding difficulties, and esophageal reflux were typical. Significant therapeutic benefit was observed in one child with a combination of pergolide, trihexyphenidyl, and tranylcypromine. Preliminary trials using serotonin receptor agonists or reuptake inhibitors resulted in adverse effects. CONCLUSIONS: The movement disorder in AADC deficiency, particularly the characteristic eye movement abnormalities, should facilitate the identification of patients with this rare but possibly underrecognized disorder. Directed therapy of the underlying dopamine and norepinephrine deficiency may be beneficial in some cases.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Descarboxilases de Aminoácido-L-Aromático/deficiência , Catecolaminas/sangue , Erros Inatos do Metabolismo dos Aminoácidos/genética , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , FenótipoRESUMO
OBJECTIVE: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. BACKGROUND: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. METHODS: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. RESULTS: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. CONCLUSIONS: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.
Assuntos
Coreia/genética , Cromossomos Humanos Par 16 , Ligação Genética/genética , Espasmos Infantis/genética , Adolescente , Adulto , Criança , Pré-Escolar , Coreia/diagnóstico , Mapeamento Cromossômico , Feminino , Triagem de Portadores Genéticos , Marcadores Genéticos/genética , Haplótipos/genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Espasmos Infantis/diagnósticoRESUMO
Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.
Assuntos
Genes Recessivos , Variação Genética , Miopatias da Nemalina/genética , Miopatias da Nemalina/fisiopatologia , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Ligação Genética , Humanos , Lactente , Escore Lod , Proteínas Musculares/genética , LinhagemRESUMO
The motor skills of patients with spinal muscular atrophy, type I (SMA-I) are very limited. It is difficult to quantify the motor abilities of these patients and as a result there is currently no validated measure of motor function that can be utilized as an outcome measure in clinical trials of SMA-I. We have developed the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders ("CHOP INTEND") to evaluate the motor skills of patients with SMA-I. The test was developed following the evaluation of 26 infants with SMA-I mean age 11.5 months (1.4-37.9 months) with the Test of Infant Motor Performance and The Children's Hospital of Philadelphia Test of Strength in SMA, a newly devised motor assessment for SMA. Items for the CHOP INTEND were selected by an expert panel based on item mean and standard deviation, item frequency distribution, and Chronbach's alpha. Intra-rater reliability of the resulting test was established by test-retest of 9 infants with SMA-I over a 2 month period; Intraclass correlation coefficient (ICC) (3,1)=0.96. Interrater reliability was by video analysis of a mixed group of infants with neuromuscular disease by 4 evaluators; ICC (3,4)=0.98 and in a group of 8 typically developing infants by 5 evaluators ICC (3,5)=0.93. The face validity of the CHOP INTEND is supported by the use of an expert panel in item selection; however, further validation is needed. The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy.
Assuntos
Desenvolvimento Infantil/fisiologia , Destreza Motora/fisiologia , Psicometria/métodos , Índice de Gravidade de Doença , Atrofias Musculares Espinais da Infância/diagnóstico , Atrofias Musculares Espinais da Infância/fisiopatologia , Pré-Escolar , Avaliação da Deficiência , Feminino , Humanos , Lactente , Masculino , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosAssuntos
Convulsões/classificação , Convulsões/diagnóstico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticoncepcionais Orais/metabolismo , Diagnóstico Diferencial , Eletroencefalografia , Feminino , Humanos , Gravidez/efeitos dos fármacos , Prognóstico , Convulsões/tratamento farmacológicoRESUMO
OBJECTIVE: To determine whether survival motor neuron (SMN) expression was stable over time. METHODS: We developed a multiplex real-time reverse transcriptase (RT)-PCR assay to quantify SMN transcripts in preclinical blood samples from 42 patients with spinal muscular atrophy (SMA) drawn for three time points per patient; most blood samples were shipped to a centralized laboratory. RESULTS: We obtained a sufficient amount (9.7 +/- 5.6 microg) of good-quality total RNA, and RNAs were stable for up to a 3-year interval. This allowed RNA samples collected during a 9- to 12-month period to be analyzed in a single run, thus minimizing interexperimental variability. SMN expression was stable over time; intersample variability for baseline measures, collected during a 17-month interval, was less than 15% for 38 of 42 SMA patients analyzed. This variability was well below the 1.95-fold increase in full-length SMN (flSMN) transcripts detected in SMA fibroblasts treated with 10 mM valproic acid. CONCLUSION: Real-time quantification of SMN messenger RNA expression may be a biomarker that is amenable to multicenter SMA clinical trials.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/análise , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Proteínas de Ligação a RNA/análise , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Biomarcadores , Estudos de Coortes , Sistemas Computacionais , Predisposição Genética para Doença/genética , Humanos , Projetos Piloto , Reprodutibilidade dos Testes , Proteínas do Complexo SMN , Sensibilidade e EspecificidadeRESUMO
The distal arthrogryposis (DA) syndromes are a distinct group of disorders characterized by contractures of two or more different body areas. More than a decade ago, we revised the classification of DAs and distinguished several new syndromes. This revision has facilitated the identification of five genes (i.e., TNNI2, TNNT3, MYH3, MYH8, and TPM2) that encode components of the contractile apparatus of fast-twitch myofibers and cause DA syndromes. We now report on the phenotypic features of a novel DA disorder characterized primarily by plantar flexion contractures in a large five-generation Utah family. Contractures of hips, elbows, wrists, and fingers were much milder though they varied in severity among affected individuals. All affected individuals had normal neurological examinations; electromyography and creatinine kinase levels were normal on selected individuals. We have tentatively labeled this condition distal arthrogryposis type 10 (DA10).
Assuntos
Artrogripose/genética , Contratura/genética , Adolescente , Adulto , Idoso , Artrogripose/patologia , Pré-Escolar , Contratura/patologia , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , SíndromeRESUMO
We report a 2-year-old boy with phosphofructokinase deficiency presenting in the newborn period with congenital arthrogryposis and severe myopathy, who has had significant improvement on a ketogenic diet since its institution at 4 months of age. We provide a rationale for use of this treatment and hypothesize it may be beneficial in other patients with phosphofructokinase deficiency and progressive muscular involvement. Confirmation awaits further clinical trials in carefully selected patients.
Assuntos
Artrogripose/dietoterapia , Fosfofrutoquinase-1/deficiência , Artrogripose/urina , Biópsia , Gorduras na Dieta/administração & dosagem , Eletromiografia , Humanos , Recém-Nascido , Masculino , Músculo Esquelético/química , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Fosfofrutoquinase-1/análise , Resultado do TratamentoRESUMO
A 7-month-old infant, son of consanguinous Indian parents, presented with recurrent chewing of his digits in a median nerve distribution as the primary manifestation of carpal tunnel syndrome, in conjunction with features consistent with congenital insensitivity to pain. Electromyography (EMG) demonstrated severe median nerve entrapment at the wrist bilaterally, but other nerves were normal. In spite of clinical evidence of diffuse pain insensitivity, sural nerve and skin biopsies were normal, and he had no evidence of autonomic dysfunction. Hand findings evolved with scarring and infection of median innervated digits and loss of fine motor skills. Carpal tunnel release resulted in complete clinical resolution and significant EMG improvement. Milder symptoms and EMG evidence of median nerve entrapment were demonstrated in both parents, paternal grandparents, and several of his father's siblings. We hypothesize this child may be homozygous for a mutant allele that in its heterozygous state predisposes to familial autosomal dominant carpal tunnel syndrome. Homozygosity for this or another mutant allele may be responsible for his congenital insensitivity to pain.
Assuntos
Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/psicologia , Nervo Mediano/fisiopatologia , Automutilação/fisiopatologia , Potenciais de Ação , Adulto , Idoso , Idoso de 80 Anos ou mais , Boston , Síndrome do Túnel Carpal/fisiopatologia , Síndrome do Túnel Carpal/cirurgia , Consanguinidade , Eletromiografia , Dedos , Humanos , Índia/etnologia , Lactente , Masculino , Mastigação , Nervo Mediano/anormalidades , Nervo Mediano/anatomia & histologia , Neurônios Motores/fisiologia , Neurônios Aferentes/fisiologia , Linhagem , Automutilação/etiologia , Comportamento Autodestrutivo , SíndromeRESUMO
BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by short episodes of involuntary movement attacks triggered by sudden voluntary movements. Although a genetic basis is suspected in idiopathic cases, the gene has not been discovered. Establishing strict diagnostic criteria will help genetic studies. METHODS: The authors reviewed the clinical features of 121 affected individuals, who were referred for genetic study with a presumptive diagnosis of idiopathic PKD. RESULTS: The majority (79%) of affected subjects had a distinctive homogeneous phenotype. The authors propose the following diagnostic criteria for idiopathic PKD based on this phenotype: identified trigger for the attacks (sudden movements), short duration of attacks (<1 minute), lack of loss of consciousness or pain during attacks, antiepileptic drug responsiveness, exclusion of other organic diseases, and age at onset between 1 and 20 years if there is no family history (age at onset may be applied less stringently in those with family history). In comparing familial and sporadic cases, sporadic cases were more frequently male, and infantile convulsions were more common in the familial kindreds. Females had a higher remission rate than males. An infantile-onset group with a different set of characteristics was identified. A clear kinesigenic trigger was not elicited in all cases, antiepileptic response was not universal, and some infants had attacks while asleep. CONCLUSIONS: The diagnosis of idiopathic paroxysmal kinesigenic dyskinesia (PKD) can be made based on historical features. The correct diagnosis has implications for treatment and prognosis, and the diagnostic scheme may allow better focus in the search for the PKD gene(s).