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Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that SMA patients exhibit impaired proprioception, and their proprioceptive sensory synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show that loss of excitatory afferent synapses and altered potassium channel expression in SMA motor neurons are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.
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Seminal vesicle cysts are a very rare condition and its often associated with ipsilateral renal agenesis. The diagnosis of seminal vesicle cysts may be delayed or missed because of the non-specific symptoms of this condition. This article reports a triad of right renal agenesis, ipsilateral seminal vesicle cyst, and ejaculatory duct obstruction (Zinner syndrome) in a 56 years old man.
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ß2-agonists reduce airflow limitation by improving airway diameter as a consequence of a direct action on airway smooth muscle. ß;2-agonists can be broadly classified according to their duration of action: short-acting ß2-agonists (SABAs), including albuterol, terbutaline and fenoterol, have pharmacodynamics halflives between 2 and 6 h and long-acting ß2-agonists (LABAs), including salmeterol and formoterol, require twice daily treatment. SABAs are often used as needed for asthma exacerbations and before exercise in the presence of exercise-induced bronchospasm. LABAs provide longer symptom control, which is a particularly useful feature for preventing night-time symptoms. There are two main LABAs, salmeterol and formoterol. This review focused on the recent data published on this topic.
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INTRODUCTION: This study aims to assess the effectiveness of combined procedure of cryoablation and vertebroplasty (CVT) for reduction of pain and improvement of the quality of life in patients with single painful metastatic vertebral fractures. METHODS: We retrospectively analyzed data from 23 patients with single vertebral metastasis treated with combined procedure of CVT, compared with those obtained in 23 patients treated by vertebroplasty. Pain intensity was evaluated by a visual analog scale (VAS) score administered before and 1 day, 1 week, and 1, 3, and 6 months after procedure. Quality of life was evaluated by an Oswestry Disability Index (ODI) score administered before and at 3 and 6 months after procedure. RESULTS: Procedural success was achieved in all patients without any complications. The VAS and ODI scores showed a reduction in both groups during follow-up (VAS score, p < 0.05 and p < 0.001, respectively; ODI score, p < 0.0001). No difference of the VAS and ODI scores were observed before treatment (p = 0.33 and 0.78, respectively). VAS score showed a difference at 1 week and 1, 3, and 6 months after treatment (p < 0.001). ODI score showed a difference at 3 and 6 months after treatment (p < 0.001). CONCLUSION: Our findings suggested that combined procedure of CVT is safe and effective for pain relief in single metastatic vertebral fractures, especially when other standard palliative treatments have failed, and improves disability. Careful needle positioning and accurate fluoroscopic and CT guidance are mandatory for a complication-free treatment.
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Angiografia/métodos , Criocirurgia/métodos , Fraturas da Coluna Vertebral/terapia , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/terapia , Vertebroplastia/métodos , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Rotação , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/etiologia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning. METHODS: We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives). RESULTS: Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives. CONCLUSIONS: Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.
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DNA Mitocondrial/genética , Predisposição Genética para Doença/genética , Síndrome MELAS/genética , Mutação Puntual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: In spinal muscular atrophy (SMA), weakness, decreased endurance, and fatigue limit mobility. Scales have been developed to measure function across the wide spectrum of disease severity. However, these scales typically are observer dependent, and scores are based on sums across Likert-scaled items. The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children. METHODS: To study the performance of the 6MWT in SMA, 18 ambulatory participants were evaluated in a cross-sectional study. Clinical measures were 6MWT, 10-m walk/run, Hammersmith Functional Motor Scale-Expanded (HFMSE), forced vital capacity, and handheld dynamometry. Associations between the 6MWT total distance and other outcomes were analyzed using Spearman correlation coefficients. A paired t test was used to compare the mean distance walked in the first and sixth minutes. RESULTS: The 6MWT was associated with the HFMSE score (r = 0.83, p < 0.0001), 10-m walk/run (r = -0.87, p < 0.0001), and knee flexor strength (r = 0.62, p = 0.01). Gait velocity decreased during successive minutes in nearly all participants. The average first minute distance (57.5 m) was significantly more than the sixth minute distance (48 m) (p = 0.0003). CONCLUSION: The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA.
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Teste de Esforço/métodos , Fadiga/diagnóstico , Fadiga/etiologia , Atrofia Muscular Espinal/complicações , Caminhada/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dinamômetro de Força Muscular , Estudos Retrospectivos , Estatísticas não Paramétricas , Capacidade Vital/fisiologia , Adulto JovemAssuntos
Autoanticorpos/imunologia , Troca Materno-Fetal/imunologia , Miastenia Gravis/diagnóstico , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Adulto , Criança , Pré-Escolar , Criptorquidismo/imunologia , Criptorquidismo/fisiopatologia , Transtornos de Deglutição/imunologia , Transtornos de Deglutição/fisiopatologia , Disartria/imunologia , Disartria/fisiopatologia , Músculos Faciais/inervação , Músculos Faciais/fisiopatologia , Feminino , Perda Auditiva Condutiva/imunologia , Perda Auditiva Condutiva/fisiopatologia , Humanos , Masculino , Palato/inervação , Palato/fisiopatologia , Gravidez , Subunidades Proteicas/imunologia , Receptores Colinérgicos/química , SíndromeRESUMO
Although linked with cardiac dysfunction, the association of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and pulmonary artery hypertension (PAH) has not been previously described. PAH and right ventricular heart failure were identified by echocardiography in a 3-year-old boy with a history of hypotonia, microcephaly and developmental delay. He initially presented with a 10-day history of dyspnoea, dependent oedema and reduced oral intake. Lactic acidosis was noted on serial arterial blood sampling and cerebrospinal fluid. Muscle biopsy demonstrated cytochrome-c oxidase-positive 'ragged-red' fibres consistent with MELAS; subsequent analyses revealed the m.3243A>G point mutation most commonly associated with MELAS. The mutation was heteroplasmic, representing 92% of the total mtDNA from a lung sample. Nitric oxide and epoprostenol were administered without significant clinical or echocardiographic improvement of his PAH. A 'mitochondrial cocktail' including biotin, riboflavin, carnitine and coenzyme Q10 also was provided. Five months after presentation, he developed seizures; MRI imaging of his brain demonstrated multiple focal lesions. His clinical status worsened with increasing cardiopulmonary failure. He died two months later. Although therapy for both MELAS and PAH remains limited, recent investigations suggest a beneficial role for l-arginine in both conditions, implying a possible common pathophysiology. Mitochondrial diseases such as MELAS should be considered in cases of idiopathic PAH, particularly when associated with multisystem involvement including short stature, hearing loss, renal dysfunction, retinopathy, diabetes mellitus, migraines, seizures, ophthalmoplegia, fatigability and weakness.
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BACKGROUND: Noninvasive ventilation has become increasingly available to spinal muscular atrophy (SMA) patients since the early 1990 s. This is expected to have improved survival for SMA type 1 patients. OBJECTIVE: To assess whether there has been a change in survival in patients with SMA type 1 between 1980 and 2006. METHODS: We used deidentified, family-reported data from participants in the International Spinal Muscular Atrophy Patient Registry and obtained additional clinical information through a mail-in questionnaire. One hundred forty-three patients with SMA type 1 were included in the analysis. Survival of patients born in 1995-2006 (n = 78) was compared with that of patients born in 1980-1994 (n = 65), using the Kaplan-Meier method and Cox proportional hazards models with age at death as the outcome. RESULTS: Patients born in 1995 though 2006 had significantly increased survival compared with those born in 1980-1994 (log-rank test, p < 0.001). In a Cox model, patients born in 1995-2006 had a 70% reduction in the risk of death compared with those born in 1980-1994 (hazard ratio [HR] 0.3, 95% CI 0.2-0.5, p < 0.001) over a mean follow-up of 49.9 months (SD 61.1, median 22.0). However, when controlling for demographic and clinical care variables, year of birth was no longer significantly associated with age at death (HR 1.0, 95% CI 0.6-1.8, p = 0.9), whereas ventilation for more than 16 h/d, use of a mechanical insufflation-exsufflation device, and gastrostomy tube feeding showed a significant effect in reducing the risk of death. CONCLUSION: Survival in spinal muscular atrophy type 1 patients has increased in recent years, in relation to the growing trend toward more proactive clinical care.
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Atrofias Musculares Espinais da Infância/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Atrofia Muscular Espinal , Estudos Prospectivos , Sistema de Registros , Atrofias Musculares Espinais da Infância/mortalidade , Atrofias Musculares Espinais da Infância/fisiopatologia , Taxa de Sobrevida/tendênciasRESUMO
Duchenne muscular dystrophy (DMD) is a progressive pediatric disorder that affects both muscle and brain. Children with DMD have mean IQ scores that are about one standard deviation lower than population means, with lower Verbal IQ than Performance IQ scores. For the present study, verbal skills and verbal memory skills were examined in males with DMD with the Clinical Evaluation of Language Fundamentals, 3rd edition, and the California Verbal Learning Test for Children. Performance of 50 males with DMD (age range 6-14 y, mean 9 y 4 mo [SD 2 y 1 mo]) was compared to normative values. Two subsets of the probands were also compared with two comparison groups: unaffected siblings (n=24; DMD group age range 6-12 y, mean 9 y 1 mo [SD 1 y 8 mo]; sibling age range 6-15 y, mean 9 y 11 mo [SD 2 y 4 mo]) and males with cerebral palsy (CP); (n=23; DMD group age range 6-9 y, mean 7 y 8 mo [SD 1 y 2 mo]; CP age range 6-8 y, mean 6 y 8 mo [SD 0 y 8 mo]). Results demonstrated that although males with DMD performed slightly more poorly than normative values, they performed comparably to the controls on most measures. Consistent deficits were observed only on tests requiring immediate repetition for verbal material (Recalling Sentences, and Concepts and Directions). On other language tasks, including tests of understanding and use of grammar, and understanding of semantic relationships, the males with DMD performed well. Moreover, the males with DMD performed well on multiple indices of verbal recall, and there was no evidence of declarative memory deficits. DMD is a single-gene disorder that is selectively associated with decreased verbal span capacity, but not impaired recall.
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Memória/fisiologia , Distrofia Muscular de Duchenne/fisiopatologia , Comportamento Verbal/fisiologia , Aprendizagem Verbal/fisiologia , Adolescente , Criança , Pessoas com Deficiência , Humanos , Testes de Linguagem , Masculino , Análise Multivariada , Testes Neuropsicológicos , IrmãosRESUMO
Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a matching-to-sample test with four types of visual recognition (Object, Face, Affect, and Situation matching) developed by Lucci and Fein. Within-group analyses on 50 boys with MD found decreased Affect matching relative to the other matching conditions. Between-group comparisons on 20 sibling pairs found the boys with Duchenne performed more poorly only on the Affect-matching condition. Thus, mildly impaired facial affect recognition may be part of the phenotype associated with Duchenne or Becker MD.
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Afeto , Transtornos Globais do Desenvolvimento Infantil/psicologia , Expressão Facial , Distrofia Muscular de Duchenne/psicologia , Reconhecimento Visual de Modelos , Aptidão , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Aprendizagem por Discriminação , Humanos , Masculino , Distrofia Muscular de Duchenne/genética , Testes Neuropsicológicos , Teoria da Construção Pessoal , Fenótipo , IrmãosRESUMO
AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.
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Ataxia/etiologia , Encefalopatias Metabólicas Congênitas/dietoterapia , Encefalopatias Metabólicas Congênitas/etiologia , Deficiências do Desenvolvimento/etiologia , Transportador de Glucose Tipo 1/deficiência , Convulsões/etiologia , 3-O-Metilglucose/farmacocinética , Anticonvulsivantes/uso terapêutico , Encefalopatias Metabólicas Congênitas/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/dietoterapia , Erros Inatos do Metabolismo dos Carboidratos/etiologia , Criança , Dietoterapia , Feminino , Transportador de Glucose Tipo 1/genética , Humanos , Lactente , Vértebras Lombares , Masculino , Convulsões/tratamento farmacológico , Punção Espinal , Síndrome , Resultado do TratamentoRESUMO
Mitochondrial diseases are a heterogeneous group of disorders caused by mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Mitochondrial disease leads to impaired respiratory chain function and reduced ATP production. The aim of this study was to compare disturbances in mitochondrial function by measuring ATP synthesis in fibroblasts derived from patients with nDNA and mtDNA defects. Skin fibroblasts derived from 22 patients with either nDNA-related disorders (n = 8) or mtDNA-related disorders (n = 14) were analysed. ATP synthesis was markedly decreased in fibroblasts derived from patients with nDNA-related disorders but only variably so in patients with mtDNA mutations. In fibroblasts with the MELAS 3243A > G mutation, ATP synthesis correlated with mutant load. We believe that the observed differences in ATP production between cell lines derived from patients with nDNA-related disorders and mtDNA-related disorders may help in the assessment of patients with undiagnosed mitochondrial disease. The clinical comparisons observed in patients with nDNA- and mtDNA-related disorders may be explained by differences in the disturbance of ATP synthesis measured in the two conditions.
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Trifosfato de Adenosina/biossíntese , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Mutação , Trifosfato de Adenosina/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Humanos , Lactente , Síndrome MELAS/genética , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.
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Ácido Dicloroacético/efeitos adversos , Síndrome MELAS/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Adolescente , Adulto , Criança , Estudos Cross-Over , Ácido Dicloroacético/uso terapêutico , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Nervo Fibular/fisiopatologia , Nervo Sural/fisiopatologiaRESUMO
AIM: To define this genetic syndrome. DEVELOPMENT: The constellation of infantile epilepsy, acquired microcephaly and hypoglychorrachia is characteristic of glucose transporter type 1 (Glut1) deficiency syndrome, a prototype neurometabolic disorder caused by inheritable mutations in the gene SLC2A1. All known mutations reduce the function of Glut1 in the blood brain barrier and thus limit brain glucose availability. As the cerebral metabolic rate for glucose increases during infancy, patients become gradually symptomatic, a phenomenon that underscores the importance of early diagnosis via lumbar puncture and treatment, which has meet with some success in ameliorating several --but not all-- features of the disease. CONCLUSION: The increasing number of mild phenotypic variants being described, owing to the improved awareness of the disease, has led to the consideration of Glut1 deficiency in the diagnosis of infantile seizures, mental retardation, familial epilepsy and movement disorders.
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Encefalopatias Metabólicas Congênitas/genética , Proteínas de Transporte de Monossacarídeos/deficiência , Proteínas de Transporte de Monossacarídeos/genética , Animais , Barreira Hematoencefálica/fisiologia , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/fisiopatologia , Diagnóstico Diferencial , Transportador de Glucose Tipo 1 , Humanos , Lactente , Deficiência Intelectual/etiologia , Transtornos dos Movimentos/etiologia , Fenótipo , Espasmos Infantis/etiologia , SíndromeRESUMO
OBJECTIVE: To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). METHODS: The authors studied 91 individuals from 34 families with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects. RESULTS: The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels. CONCLUSIONS: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.
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Acidose Láctica/diagnóstico , Acidose Láctica/metabolismo , Ventrículos Cerebrais/metabolismo , Síndrome MELAS/fisiopatologia , Síndrome MERRF/fisiopatologia , Acidose Láctica/etiologia , Adulto , Glicemia , Doença Crônica , Análise Mutacional de DNA , Heterozigoto , Humanos , Ácido Láctico/sangue , Ácido Láctico/metabolismo , Síndrome MELAS/complicações , Síndrome MELAS/genética , Síndrome MERRF/complicações , Síndrome MERRF/genética , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos , Mutação Puntual , Valor Preditivo dos Testes , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Deficiency of aromatic L-amino acid decarboxylase (AADC) is associated with severe developmental delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. OBJECTIVE: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. RESULTS: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-O-methyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. CONCLUSIONS: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predominant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned.