Centronuclear myopathy: histopathological aspects in ten patients with chilfhood onset

Abstract

-Centronuclear myopathy is a rare congenital myopathy. According to the period of onset of signs and symptoms and the degree of muscular involvement three clinical forms are distinguished: severe neonatal; childhood onset; and adult onset. We describe herein the muscle biopsy findings of ten patients with the childhood onset form of the disease including three cases with ultrastructural study. The biopsies disclosed increased nuclear centralization that varied from 25 to 90% of the fibers, type 1 predominance, great variability in fiber diameters, involvement in the internal fiber's architecture, and focal areas of myofilament disorganization. The main histopathologic differential diagnoses included type I fiber predominance, congenital fiber type disproportion, and myotonic dystrophy. The histologic abnormalities in centronuclear myopathy may be due to an arrest of maturation on the fetal myotubular stage. The cause of this arrest remains elusive.KEY WORDS: centronuclear myopathy, myotubular myopathy, histochemical, ultrastructure. Miopatia centronuclear: aspectos histopatológicos em dez pacientes com a forma clínica de início na infânciaRESUMO -A miopatia centronuclear (MCN) é uma forma rara de miopatia congênita. De acordo com a época do início dos sinais e sintomas e com o grau de envolvimento muscular são distinguidas três formas clínicas: forma neonatal severa; forma de início na infância; e de início na vida adulta. São apresentados neste estudo os achados histopatológicos de dez pacientes portadores da forma de início na infância da MCN. Os fragmentos musculares foram processados através de colorações de rotina e histoquímica, e em três casos foi realizado estudo ultraestrutural. Dentre os resultados obtidos, destacou-se o aumento da centralização nuclear na fibra muscular, que variou de 25 a 90%. Adicionalmente, foram observadas predominância de fibras do tipo I, variabilidade entre o diâmetro das fibras musculares, alterações da arquitetura interna das fibras musculares e presença de áreas focais de desorganização dos miofilamentos. Devido a estes aspectos, os principais diagnósticos diferenciais considerados foram as miopatias por predominância de fibras e por desproporção de fibras, e a distrofia miotônica. As anormalidades histológicas observadas na MCN podem ser devidas a uma parada no processo maturacional do músculo esquelético na fase miotubular fetal. A causa deste defeito ainda permanece sem explicação completa. PALAVRAS-CHAVE: miopatia centronuclear, miopatia miotubular, histoquímica, ultra-estrutura.Centronuclear myopathy (CNM) is a rare disease, classified in the congenital myopathy group, described in 1966 by Spiro, Shy and Gonatas 31 . It presents with diffuse involvement of skeletal muscles, including those innervated by the cranial nerves, with onset in early childhood and a slowly progressive evolution. The basic histological abnormality is the high percentage of centrally placed nuclei associated, in most cases, with a perinuclear halo without myofibrils and a high oxidative ...

Centronuclear (myotubular) myopathy

“…On muscle biopsy, centronuclear (myotubular) myopathy is characterised by centrally placed nuclei surrounded by a perinuclear halo devoid of myofilaments [ 2 ] and occupied by mitochondrial and glycogen aggregates (Figure 2 ) The characteristic central nuclei are seen in all muscles, including extra-ocular muscles [ 141 ], and may affect up to 90% of fibres [ 52 ]. Some autosomal cases of centronuclear myopathy may also feature a radial arrangement of sarcoplasmic strands on NADH staining [ 50 ]; it currently appears that this is a feature in most cases of centronuclear myopathy caused by mutations in the DNM2 gene [ 76 ]: Whilst radial arrangement of sarcoplasmic strands appears to be common in mild forms of DNM2 -related CNM due to mutations affecting the middle domain [ 77 ], this finding appears not to be as prominent in more severe and early presentations due to mutations affecting the pleckstrin homology (PH) domain, or in other genetically distinct forms of CNM.…”

“…The autosomal-recessive form [ 10 , 41 - 52 ] is characterised by facial weakness including severe involvement of the masticatory muscles [ 53 ], and ocular abnormalities such as ptosis and external ophthalmoplegia. A recent French series distinguishes early and late onset forms with or without ophthalmoplegia; it remains to be seen if those distinctions are reflective of underlying genetic heterogeneity [ 50 ].…”

“…Other skeletal deformities including high arched palate and scoliosis are common [ 55 ]. Respiratory involvement may be severe [ 52 ], and an associated cardiomyopathy has been documented in a few recurrent and sporadic cases [ 44 , 56 , 57 ]. As in carriers of the X-linked form, urinary incontinence may be an associated feature [ 58 ].…”

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

“…Histopathologic features: CNM is characterized by numerous centrally located nuclei in approximately ≥ 25% of muscle fibers [73]. The number of centralized nuclei may increase with age, confounding the minimum number required for diagnosis [74].…”

Abordagem multidisciplinar nas miopatias de núcleos centrais

“…No Brasil, o primeiro caso descrito de MMT foi em 1977 23 , seguido de outros relatos de casos isolados 24,25,26,27 . Acrescenta-se que a única série de casos nacionais foi apresentada por Zanoteli e cols em 1998 28,29 .…”