Gene replacement therapy for spinal muscular atrophy: safety and preliminary efficacy in a Brazilian cohort.

Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Onasemnogene abeparvovec is the first gene replacement therapy (GT) approved to treat this condition. An observational retrospective study was conducted to assess adverse events and efficacy of GT in SMA patients. Forty-one patients with SMA (58.5% females and 80.1% SMA type 1) were included. The mean age at GT dosing was 18 (±6.4) months. Thirty-six patients (87.8%) were under previous treatment with nusinersen, and 10 (24.4%) continued nusinersen after GT. Mean CHOP-INTEND increased 13 points after 6 months and this finding did not differ between groups according to nusinersen maintenance after GT (p = 0.949). Among SMA type 1 patients, 14 (46.6%) reached the ability to sit alone. Liver transaminases elevation at least two times higher than the upper limit of normal value occurred in 29 (70.7%) patients. Thrombocytopenia occurred in 13 (31.7%) patients, and one presented thrombotic microangiopathy. Older age (>2 years) was associated with more prolonged use of corticosteroids (p = 0.021). GT is effective in SMA patients, combined nusinersen after GT did not appear to add gain in motor function and older age is associated with prolonged corticosteroid use.

Phenotypic, molecular, and functional characterization of COQ7-related primary CoQ10 deficiency: Hypomorphic variants and two distinct disease entities.

Primary coenzyme Q10 (CoQ10) deficiency is a group of inborn errors of metabolism caused by defects in CoQ10 biosynthesis. Biallelic pathogenic variants in COQ7, encoding mitochondrial 5-demethoxyubiquinone hydroxylase, have been reported in nine patients from seven families. We identified five new patients with COQ7-related primary CoQ10 deficiency, performed clinical assessment of the patients, and studied the functional effects of current and previously reported COQ7 variants and potential treatment options. The main clinical features included a neonatal-onset presentation with severe neuromuscular, cardiorespiratory and renal involvement and a late-onset disease presenting with progressive neuropathy, lower extremity weakness, abnormal gait, and variable developmental delay. Baker's yeast orthologue of COQ7, CAT5, is required for growth on oxidative carbon sources and cat5Δ strain demonstrates oxidative growth defect. Expression of wild-type CAT5 could completely rescue the defect; however, yeast CAT5 harboring equivalent human pathogenic variants could not. Interestingly, cat5Δ yeast harboring p.Arg57Gln (equivalent to human p.Arg54Gln), p.Arg112Trp (equivalent to p.Arg107Trp), p.Ile69Asn (equivalent to p.Ile66Asn) and combination of p.Lys108Met and p.Leu116Pro (equivalent to the complex allele p.[Thr103Met;Leu111Pro]) partially rescued the growth defects, indicating these variants are hypomorphic alleles. Supplementation with 2,4 dihydroxybenzoic acid (2,4-diHB) rescued the growth defect of both the leaky and severe mutants. Overexpression of COQ8 and 2,4-diHB supplementation synergistically restored oxidative growth and respiratory defect. Overall, we define two distinct disease presentations of COQ7-related disorder with emerging genotype-phenotype correlation and validate the use of the yeast model for functional studies of COQ7 variants.

First unprovoked seizure: clinical and electrographic aspects

OBJECTIVE: To evaluate classification, EEG tracings and neuroimage following the first episode of unprovoked epileptic seizure in a pediatric population. METHODS: Patients diagnosed with first episode of unprovoked epileptic seizure from May 2000 to May 2005 were included. All subjects were submitted to EEG and cranial CT in the first 72 hours after the event. Seizures were classified according to the ILAE classification criteria of 1981. RESULTS: 387 patients, 214 (55.3 percent) male, average age 4.2 years. Neuropsicomotor development was normal in 315 (81.4 percent) patients. Seizure classification: 167 (43.15 percent) generalized, tonic-clonic being the most frequent of these (105/62.85 percent), followed by typical absence (22/13.17 percent), clonic (20/11.98 percent), tonic (13/7.78 percent) and atonic (7/4.19 percent). Focal seizures: 220 (56.85 percent), complex partial with secondary generalization as the most common of these (81/36.82 percent). EEG was normal in 208 (53.75 percent) cases. Brain atrophy was the most frequent abnormality on cranial CT. DISCUSSION: The majority of the children had normal neurodevelopment after a first unprovoked epileptic seizure. Partial seizures were more frequent than generalized seizures. Early EEG identifies interictal paroxysms or focal slowing in virtually half the patients.

OBJETIVO: Avaliar a classificação, resultados de EEG e de neuroimagem após a primeira crise epiléptica não-provocada em uma população pediátrica. METODOLOGIA: Pacientes atendidos entre maio de 2000 e maio de 2005 com diagnóstico de primeira crise epiléptica não-provocada. Todos foram submetidos a EEG e tomografia de crânio nas primeiras 72 horas após o evento. As crises foram classificadas segundo a Classificação da ILAE, 1981. RESULTADOS: 387 pacientes, sendo 214 (55.30 por cento) do sexo masculino, com idade média de 4.2 anos. O desenvolvimento neuropsicomotor foi normal em 315 (81.40 por cento) pacientes. Classificação das crises: 167 (43.15 por cento) generalizadas, das quais a mais freqüente foi a crise tônico-clônica (105/62.85 por cento), seguida pelas crises de ausência típica (22/13.17 por cento), clônica (20/11.98 por cento), tônica (13/7.78 por cento) e atônica (7/4.19 por cento). Crises focais: 220 (56.85 por cento), sendo a crise parcial complexa com generalização secundária a mais freqüente (81/36.82 por cento). EEG normal em 208 (53.75 por cento) casos. A anormalidade mais observada na tomografia de crânio foi atrofia cerebral. CONCLUSÕES: A maioria das crianças apresentou desenvolvimento neuro-psicomotor normal após a primeira crise epiléptica não-provocada. Crises parciais foram mais freqüentes que as generalizadas. EEG realizado precocemente identifica paroxismos interictais ou alentecimentos focais em praticamente metade dos pacientes.