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Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Hypotonia: – Prader-Willi syndrome – mat UPD15 disorder with severe hypotonia, gradual development of morbid obesity. Spinal muscular atrophy: SMN1 and SMN2 mutations cause degeneration of anterior horn cells with progressive muscle weakness. Poor weight gain, scoliosis and contractures. Congenital myotonic dystrophy: caused by expansion of a CTG trinucleotide repeat in the non-coding region of DMPK. Cataract; skeletal and smooth muscle involvement; reduced life span. X-linked myotubular myopathy: MTM1 mutation; affected male pregnancies show prenatal polyhydramnios and reduced fetal movement; ventilator dependent.
Gene therapy strategies for X-linked myotubular myopathy
Published in Expert Opinion on Orphan Drugs, 2018
The congenital myopathies are a diverse and heterogenous group of skeletal muscle diseases that – due to the use of next-generation sequencing – are becoming associated with an ever-expanding array of mutations in a number of different genes. The congenital myopathies are classified according to the presence of characteristic histopathological features occurring in a non-dystrophic appearing muscle biopsy, although nowadays it is becoming more common for a genetic diagnosis to also be achieved [1]. Myotubular myopathy, also known as X-linked myotubular myopathy (XLMTM) due to its pattern of inheritance, is one of the centronuclear myopathies (CNMs) and it is considered to be a member of the congenital myopathy family of genetic muscle disorders [1,2].
Addressing high dose AAV toxicity – ‘one and done’ or ‘slower and lower’?
Published in Expert Opinion on Biological Therapy, 2022
Takashi Kei Kishimoto, Richard Jude Samulski
Adverse events related to elevated liver transaminases have now been widely reported in AAV gene therapy clinical trials, with increased prevalence at higher vector doses. AAV gene therapy for neuromuscular diseases has typically required doses of 1–3E14 vg/kg. Onasemnogene abeparvovec, an AAV9 therapy for spinal muscular atrophy (SMA) and the first systemic AAV gene therapy approved by the FDA, has been administered to over 1400 patients. Approximately one-third of the patients receiving a dose of 1.1E14 vg/kg have experienced at least one adverse event of hepatotoxicity [1]. Three patients have been reported to experience severe hepatoxicity 7–8 weeks after treatment. Liver biopsies indicated hepatocyte degeneration and inflammatory infiltrates comprised primarily of CD8 T cells. All three patients recovered after treatment with methylprednisolone. However, tragically, three patients with X-linked myotubular myopathy (XLMTM) died 20–40 weeks after receiving a vector dose of 3.5E14 vg/kg. The patients presented with signs of severe hepatotoxicity, with bilirubin levels 35–60 times the upper limit of normal and delayed elevation in AST and ALT, and evidence of cholestasis, periportal and bile ductal reaction, and secondary fibrosis at autopsy. All three patients showed preexisting evidence of hyperbilirubinemia and intrahepatic cholestasis prior to treatment. Reports indicated a lack of inflammatory cellular infiltrates and ineffective treatment with steroids and immunosuppressants. However, an early innate immune response to the massive AAV dose could have contributed to hepatic stress resulting in exacerbation of the underlying disease [8]. The clinical trial was halted and eventually restarted at a lower dose of 1.3E14 vg/kg. Unfortunately, a fourth patient died after treatment with the lower dose [9].
New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges
Published in Expert Review of Clinical Pharmacology, 2019
Federica Ricci, Martina Vacchetti, Chiara Brusa, Liliana Vercelli, Chiara Davico, Benedetto Vitiello, Tiziana Mongini
X-linked myotubular myopathy (XLMTM, #OMIM 310400) is caused by mutations in myotubularin gene (MTM1). The age of onset varies from birth to young adulthood, and the clinical spectrum ranges from severe forms requiring mobility aids and full time breathing support to moderate weakness with no significant limitations. Symptoms include a peculiar elongated face with facial and eye muscles weakness, hypotonia, and generalized muscle weakness. Muscle biopsy reveals central nucleated fibers, resembling myotubes [34].