RESUMO
Spinal muscular atrophy (SMA) is an autosomal recessive disorder with progressive muscle atrophy and weakness, caused by biallelic mutations in the survival motor neuron 1 (SNM1) gene. Onasemnogene abeparvovec (OA) is an approved gene replacement therapy for patients with SMA. We report on two patients with SMA type 1, weighing 20 kg, previously treated with Nusinersen, who received OA infusion at 7 years of age. To our knowledge, these two patients are the heaviest treated in the real-world and we describe their different courses after gene therapy, including liver impairment requiring long-term steroid treatment and additional immunosuppression, with only transitory improvement in functional outcomes. Our cases illustrate how careful risk-benefit consideration is required in treating older and heavier SMA patients with OA, especially in view of the multiple treatment choices available for older patients with SMA.
RESUMO
Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.
Assuntos
Distrofia Muscular de Duchenne , Distrofia Muscular de Duchenne/fisiopatologia , Humanos , Criança , Adolescente , Masculino , Pré-Escolar , Teste de Caminhada , Diferença Mínima Clinicamente Importante , Feminino , Caminhada/fisiologia , Atividade Motora/fisiologiaRESUMO
Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024;96:170-174.
Assuntos
Doença de Charcot-Marie-Tooth , Progressão da Doença , Pé , Imageamento por Ressonância Magnética , Músculo Esquelético , Humanos , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Masculino , Feminino , Adolescente , Imageamento por Ressonância Magnética/métodos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Adulto JovemRESUMO
In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.
Assuntos
Doenças Musculares , Peixe-Zebra , Animais , Humanos , Masculino , Conectina/genética , Conectina/metabolismo , Músculo Esquelético , Doenças Musculares/genética , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mutação , Peixe-Zebra/genéticaRESUMO
Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.