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Muscular Dystrophy Diseases
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
In DM, myotonia in both type I and type II variants differs in the pattern of muscle weakness. In type II, there is early proximal muscle involvement, in contrast to the distal pattern seen in type I. Some literature has differentiated type I from type II variants through histological features. This is inaccurate and has no basis. However, the most predominant feature to say this case is DM is the presence of multiple internal nuclei in every single muscle fiber (Figure 16.5). Otherwise, IHC studies or electron microscopy (EM) would not help in the diagnosis. The muscle pathology in congenital myotonic dystrophy is characteristic as many fibers have large central nuclei with a pale peripheral halo; this resembles centronuclear myopathy. In this case, diagnosis is difficult to establish. Molecular analysis is the best tool to differentiate between these entities.
Diseases of Muscle and the Neuromuscular Junction
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Chris Turner, Anthony Schapira
Centronuclear myopathy may be an X-linked, recessive or dominant disease. Early onset disease is the most common presentation with hypotonia, weakness and respiratory distress at birth. Dysmorphic features, including a thin face and high arched palate, may be present. There is often ptosis and facial asymmetry. Motor milestones are delayed and children are rarely able to run. Muscles are generally thin and there is diffuse weakness with easy fatigability. Muscle weakness usually progresses and most patients are wheelchair-bound by adolescence. Early onset cases tend to be caused by X-linked mutations in the MTM1 gene or recessive mutations in the BIN1.
Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)
Published in Expert Opinion on Investigational Drugs, 2022
Theodora Markati, Gemma Fisher, Sithara Ramdas, Laurent Servais
Finally, key lessons learned from the clinical development of risdiplam could be used in future developments for SMA or for other rare diseases of childhood. For example, the design of a prospective natural history study with inclusion and exclusion criteria which match those of the phase III trial not only allows a rapid and efficient clinical trial inclusion but also enables comparison with the data of the open-label part 1 of the SUNFISH trial [51]. A similar approach has been used recently in centronuclear myopathy and in Duchenne muscular dystrophy [52,53]. Another key challenge relates to the difficulty of conducting a clinical trial in a lethal disease of infants for which there are approved drugs. The FIREFISH trial could only be conducted with the relocation of patients from countries where nusinersen was not available. This constituted a challenge at trial conclusion, when parents had to return to their home country, where standards of care were not the same. Moreover, the SUNFISH trial provided additional evidence of the sensitivity of MFM32 in comparison to HFMSE [54]. It also allowed the first deployment of a new patient-reported outcome measure, the SMA independence scale, which demonstrates good sensitivity to change [55].
Ophthalmological Manifestations of Hereditary Myopathies
Published in Journal of Binocular Vision and Ocular Motility, 2022
Marta Saint-Gerons, Miguel Angel Rubio, Gemma Aznar, Ana Matheu
Centronuclear and myotubular myopathy are characterized by small myofibers with central nuclei and central areas without contractile filaments. The term myotubular myopathy refers only to the X-linked form of the condition (XLMTM), while the term centronuclear myopathy (CNM) is normally used to indicate the autosomal form. Most cases of CNM are inherited in autosomal dominant pattern and less frequently as an autosomal recessive condition.1 CNM is caused by mutations of several genes DNM2 (encodes for dynamin 2), BIN1 (encodes for amphiphysin 2), and RYR1 (encodes for skeletal muscle ryanodine receptor 1).9,10 The most frequent entity in this group is myotubular myopathy linked to the X chromosome, caused by MTM1 mutations in Xq28. It presents with severe hypotonia and weakness at birth or prenatally and can be fatal in childhood. Reduced eye movements and eyelid ptosis are common features.1 Autosomal hereditary centronuclear myopathies are less severe than XLMTM. Ophthalmoparesis with or without ptosis is common in patients with CNM of various genetic backgrounds (DNM2, MTM1, RYR1).1,7,11
Centronuclear myopathy: advances in genetic understanding and potential for future treatments
Published in Expert Opinion on Orphan Drugs, 2018
Centronuclear myopathy (CNM) is a rare disease defined by an increase in centrally placed nuclei on muscle biopsies. It is classified in the congenital myopathy group, a heterogeneous group of hereditary skeletal muscle disorders characterized by an early onset of manifestations, relatively stable or slow progression course, normal or slightly elevated serum creatine kinase (CK) levels and characteristic structural abnormalities in skeletal muscle biopsies [1]. Clinical, genetic, and other histological changes must be taken into consideration to differentiate CNM from other muscle diseases that also present with prominent internalized nuclei. The disease was described by Spiro, Shy and Gonatas [2], and due to the resemblance of the muscle fibers of the patients with those of a fetus in the myotubular stage of myogenesis, the disease was initially called myotubular myopathy. However, this denomination is now restricted to the severe neonatal form, linked to the MTM1 gene whose histological alterations are more akin to fetal myotubes than are the other forms.