Severe neonatal centronuclear myopathy with autosomal dominant inheritance

We studied a boy with severe infantile centronuclear myopathy (CNM) and his mother with clinical, electrophysiological, and pathological signs of skeletal muscle, peripheral nerve, and brain-stem disorder, and we believe that her condition represents a variation of her son's disease. His brother had similar symptoms and died at 4 days of age. The occurrence of this syndrome in a symptomatic mother and two severely affected sons suggests an autosomal dominant inheritance with variable expressivity. To our knowledge, this inheritance pattern has not been previously reported in severe (fatal) infantile CNM. The different courses in the mother and her offspring may be manifestations of a single or separate abnormal gene causing alteration of muscle and nerve maturation.     

Histochemical and ultrastructural findings in a case of centronuclear myopathy.

A case of centronuclear myopathy is presented. The presence of central nuclei in almost all fibres, the existence of type I fibres only, the histochemical pattern of a negative central zone with a perinuclear halo and a hyperactive rim with oxidative enzymes and the ultrastructural data are discussed in the light of the previous literature. The possible relationships with other myopathies are taken into consideration as well as the fact that central nuclei may be a non-specific change in several conditions. Consequently centronuclear myopathy could turn out to be a syndrome from which different entities can be isolated.     

常染色体显性遗传中央核肌病一家系临床、病理和分子生物学特点

目的分析常染色体显性遗传中央核肌病（centronuclear myopathy，CNM）一家系中患者的临床、病理和基因突变特点。方法对家系中患者及其家属进行详细的神经系统检查，先证者行肌肉活检、组织学和酶组织化学染色，并进行动力蛋白2（dynamin 2，DNM2）基因突变检测。结果2例患者以双下肢无力为首发和主要症状，远端为著，伴有明显的全身肌肉萎缩，渐进性加重；先证者肌酸激酶轻度升高，2例患者肌电图均呈肌源性改变；家系中无其他类似患者。肌肉呈现中央核肌病的典型病理改变，90％的肌纤维中出现中央核，核周肌质带呈放射状排列，Ⅰ型纤维优势和萎缩。DNM2高频突变区域测序证实为外显子81105C→T突变。结论从临床、病理及基因等方面证实本家系为遗传性中央核肌病，致病基因为DNM2。     

Myotonia in centronuclear myopathy

Centronuclear myopathy, which is unusual because of clinical myotonia, is described in two sisters. The diagnosis was established in adult life, but the first symptoms were noticed in infancy. The outstanding points of the clinical picture were mild amyotrophy, paresis, and clinical myotonia.     

Familial centronuclear myopathy

The clinical and histological features of two Negro brothers with a centronuclear myopathy are described. They bring to 19 the number of cases now reported with this constellation of physical signs and pathological changes in the muscles. A review of these patients suggests the existence of several different diseases causing this picture, though presumably the underlying biochemical defects are closely related. It is concluded that these myopathies are degenerative rather than due to arrest of foetal muscle maturation.     

Familial centronuclear myopathy

A girl with typical clinical and histologic features of centronuclear myopathy (CNM) is described. The electromyogram was clearly of myopathic type; the motor conduction velocity was reduced. The analysis of the pedigree, in which three other members were similarly affected, suggests autosomal dominant inheritance with low penetrance.     

3例中央核肌病的临床和病理特点

目的 报道3例中央核肌病的临床和病理特点，讨论其分类和可能的发病机制。方法 3例患儿均在生后发病，表现为运动发育延迟和骨骼畸形，肌无力随年龄的增加而逐渐好转，肌酶正常或轻度升高，肌电图呈肌源性损害。对3例患者进行肌肉活检，肌肉活检标本做组织学和酶组织化学染色。结果 肌肉病理发现在许多肌纤维的中心出现单个的肌核(15％一31％)，主要累及Ⅰ型肌纤维，伴随Ⅰ型纤维呈病理性占优势和Ⅰ型肌纤维发育不良为主的肌型比例失调(Ⅰ型肌纤维直径显著小于Ⅱ型肌纤维)。结论 肌肉活检证实这3例患者为中央核肌病，可能属于预后良好的常染色体隐性遗传型。中央核肌病可以出现腓肠肌肥大、肌型比例失调以及Ⅰ型肌纤维病理性占优势是此病常见的病理改变。     

Phenotype variability and histopathological findings in centronuclear myopathy due to DNM2 mutations

Autosomal-dominant centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene (DNM2) is a rare congenital myopathy histopathologically characterized by centrally located nuclei and a radial arrangement of sarcoplasmic strands around the central nuclei. A total of 1,582 consecutive muscle biopsies of adult patients (age ≥18 years) were screened for morphologically characteristic signs of CNM. Patients with CNM were screened for mutations in DNM2. Clinical data and complementary neurophysiologic, respiratory, cardiac, and muscle MRI data in these patients were analyzed. Six index patients had histopathological signs of CNM (0.38%). Three had the heterozygous p.R465W and 2 siblings the heterozygous p.E368K DNM2 mutation. In 2 patients mutational screening for DNM2, BIN1, MTM1, and RYR1 was negative. Apart from the siblings, there was no positive history, parental mutation screening in 2 cases was negative. Both the percentage of muscle fibers with centralized nuclei and the ratio of muscle fibers with centralized to internalized nuclei were higher in DNM2-CNM compared to non-DNM2-CNM (50% vs. 18% and 94% vs. 63%). The onset was already neonatal or in infancy in 3/5 patients with DNM2 mutation. Symptoms in DNM2-CNM included bilateral ptosis (n = 3), paresis of the external ocular muscles (n = 2), axonal neuropathy (n = 4), restrictive ventilatory involvement (n = 5), and contractures (n = 5), including muscular torticollis (n = 1) and masticatory muscles (n = 2). DNM2-CNM patients and non-DNM2-CNM patients could not be distinguished by clinical features. DNM2-CNM often shows de novo mutations. In addition to the feature of radial sarcoplasmic strands, the ratio of centrally to internalized nuclei might help to differentiate DNM2-CNM from other forms of CNM. Other genes than currently known seem to cause the clinical and histopathological phenotype of CNM.     

Autosomal dominant centronuclear myopathy]

In a family 6 members in 3 generations were affected by centronuclear myopathy (CNM) of autosomal dominant inheritance. The apparent onset was in the early forties and the disease progressed slowly. Limb weakness was predominant. Strabismus was present in 5 cases and calves hypertrophy in 3. Serum creatinine kinase was always within the normal range. In one case myotonic bursts were found at electromyography. In 2 cases brain stem auditory evoked potential studies demonstrated abnormal prolongation of interpeak latencies I-III and favoured subclinical nervous system involvement. Muscular biopsies showed typical features of centronuclear myopathy with 50 to 80% central nuclei. In two cases immunocytochemical labelling of dystrophin showed staining in the sarcoplasm in favour of an arrest in the morphogenesis of developing myofiber. Others families with autosomal dominant CNM in the literature and also some sporadic adult cases had similar clinical features.     

A case of centronuclear myopathy

Summary The paper presents the clinical features and laboratory data of a 6-year-old boy with centronuclear myopathy. No familial susceptibility was disclosed. The clinical signs are displayed with a congenital foot deformity and with the child's beginning to walk further symptoms and signs appeared. They simulated the picture of the limb-girdle type of muscular dystrophy. EMG findings showed myopathic type of motor unit disintegration at the muscle level. The morphological examination disclosed the characteristic features of the disease: central sarcolemmal nuclear and perinuclear loss of myofibrils. These changes affected both types of muscle fibers.     

Craniopharyngioma in a boy with centronuclear (myotubular) myopathy: clinical and postmortem findings

This report describes a case of centronuclear myopathy which was considered to represent an example of severe x-linked myotubular myopathy [van Wijngaarden et al. 1969]. The neonatal period was dramatic with weak movements and respiratory problems. This was followed by a gradual improvement of muscle strength but he continued to have severe respiratory problems. At the age of four he developed the symptoms of a craniopharyngioma, which was operated upon. He died from respiratory failure two months after the operation.     

Myotonia in DNM2-related centronuclear myopathy

Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon–intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.     

Neuropathy in myotubular or centronuclear myopathy.

A detailed electrophysiological study has been made of the extensor digitorum brevis, thenar, hypothenar and soleus muscles in one patient with myotubular or centronuclear myopathy. The main finding was a noticeable reduction in the population of active motor units in all the investigated muscles. The remainer units showed normal sizes. The experimental observations have been interpreted in terms of a neuropathic process.     

Crural hypertrophy associated with centronuclear myopathy

A case of centronuclear myopathy of adult onset with striking hypertrophy of lower limb muscles in a black South African man is described with details of the light microscopic, histochemical, and ultrastructural features. The association of hypertrophied muscles with centronuclear myopathy has not to our knowledge been reported previously and it is felt that this may be a variant of the condition.     

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene. Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.     

Muscle histochemistry in myotubular (centronuclear) myopathy

We report the clinical and histochemical findings in 7 patients with myotubular (centronuclear) myopathy aged from 2 months to 32 years. The clinical symptoms varied from patient to patient. Three patients developed severe muscle weakness and hypotonia with respiratory distress from infancy, and 4 had muscle weakness from 2-5 years of age with no apparent delay in developmental milestones. In addition to an increased number of fibers with centrally placed nuclei, there were 3 other histochemical characteristics of this disorder, i.e., type 1 fiber predominance, type 1 fiber hypotrophy and type 2B fiber deficiency. Other histological findings included a peripheral halo in the sarcoplasm on NADH-TR staining and an increased number of undifferentiated type 2C fibers, indicating a delay in muscle fiber growth and differentiation due to a probable defective neural supply in the developing muscles.     

Diagnostic challenges in combined multiple sclerosis and centronuclear myopathy

The first case of combined centronuclear myopathy and multiple sclerosis is reported. The difficulties of diagnosing multiple sclerosis in patients with muscular disorders associated with the central nervous system involvement are discussed.