A rare case of centronuclear myopathy with DNM2 mutation: genotype­phenotype correlation

Centronuclear myopathy (CNM) is a group of rare genetic muscle disorders characterized by muscle fibers with centrally located nuclei. The most common forms of CNM have been attributed to X-linked recessive mutations in the MTM1 gene; autosomal-dominant mutations in the DNM2 gene-encoding dynamin-2, the BIN1 gene; and autosomal-recessive mutations in BIN1, RYR1, and TTN genes. Dominant CNM due to DNM2 mutations usually follows a mild clinical course with the onset in adolescence. Currently, around 35 mutations of the DNM2 gene have been identified in CNM; however, the underlying molecular mechanism of DNM2 mutation in the pathology of CNM remains elusive, and the standard clinical characteristics have not yet been defined. Here, we describe the case of a 17-year-old female who presented with proximal muscle weakness along with congenital anomalous pulmonary venous connection (which has not been described in previous cases of CNM), scoliosis, and lung disease without a significant family history. Her creatine kinase level was normal. Histology, special stains, and electron microscope findings on her skeletal muscle biopsy showed CNM with the characteristic features of a DNM2 mutation, which was later confirmed by next-generation sequencing. This case expands the known clinical and pathological findings of CNM with DNM2 gene mutation.

Mutation studies in x-linked myotubular myopathy in three indian families.

Congenital myopathies are a group of genetic disorders characterized by generalised muscle hypotonia and weakness of varying severity. They are distinct entities and do not include muscular dystrophies, metabolic myopathies and mitochondrial disorders. Myotubular myopathy is a rare sub type within this group of disorders. Clinical differentiation of the various types is difficult and requires muscle biopsy with histopathological and immunohistochemical studies for specific diagnosis. Gene studies are a prerequisite for genetic counseling adn prenatal diagnosis. Here presented three cases of X-linked myotubular myopathy in three Indian families where the diagnosis was established by mutation analysis in the MTM1 gene in all, and supported his histopathology in two. All three families had history of previous male neontal deaths with similar complaints. Molecular analysis revealed hemizygous mutations in the MTM1 gene including c.1261-10A>G in case, 1, c.70C>T (R24X) in case 2, and a previously unreported mutation, c.924_926delCTT(p. F308del), in case 3. Genetic counseling was performed regarding the X-linked inheritance, their 50% risk of recurrence in boys in subsequent pregnancies, and a feasibility of prenatal diagnosis. This is the first report of cases of X-linked Myotubular myopathy from India.

Diagnosis of myopathies using histology, histochemistry, immunohistochemistry and electron microscopy: a single center experience

Skeletal muscle biopsy is important for the diagnosis of motor unit disorders, systemic diseases and metabolic disorders. In some cases, routine histopathologic methods are not conclusive and histochemistry, immunohistochemistry and even an electron microscopic study are required. In this study, we describe our experience in the diagnosis of myopathies, considering all of the above-mentioned methods. During a period of 18 months, 43 specimens of patients with the impression of myopathy were submitted to the Pathology Department and were evaluated with H and E and histochemical stainings [PAS, Oil red O, ATPase, NADH-TR, Gomori Trichrome], immunohistochemistry [IHC] for dystrophin and electron microscopy. Three specimens were excluded from the study because there were only adipose tissues and no adequate muscle was present for evaluation. Twenty three [57.5%] males and 17 [42.5%] females with a mean age of 34 years were evaluated. The results were as follows: Becker's muscular dystrophy [5 cases, 12.5%], Duchenne's muscular dystrophy [3 cases, 7.5%], fascioscapulohumeral dystrophy [3 cases, 7.5%], limb girdle dystrophy [2 cases, 5%], polymyositis [6 cases, 15%], dermatomyositis [2 cases 5%], McArdle's disease [1 case, 2.5%], hypothyroidism myopathy [1 case, 2.5%], type 2 atrophy secondary to drugs and systemic diseases [2 cases 12.5%], congenital myopathy [2 cases 5%], McArdle [1 case 2.5%], unclassified myopathy [2 cases, 5%], and normal muscle biopsy [8 cases, 20%]. Although a genetic study was not available to confirm the diagnosis of cases such as fascioscapulohumeral myopathy, the diagnosis was made after putting all of the findings together including clinical presentation, family history, NCV, EMG, etc. In the cases with no definite diagnosis by the histology, histochemistry and IHC, we should perform an EM study to find out the distinct ultra-structural changes which can be diagnostic for some muscle disorders. EM study in conjunction with light microscopy of muscle biopsy could be very helpful in establishing the diagnosis of some types of myopathies

Floppy infant caused by MTM1 mutation: a first genetically-confirmed X-linked myotubular myopathy patient in Thailand.

Floppy infant syndrome (FIS) refers to a condition wherein an infant manifests generalized hypotonia since birth or in early life. It is heterogeneous and can be caused by various central nervous system disorders, neuromuscular diseases and genetic disorders. X-linked myotubular myopathy (XMTM) is a progressive congenital myopathy morphologically characterized by the presence of centrally placed nuclei in numerous muscle fibers without any other particular pathological abnormalities. Patients are frequently born with floppiness and respiratory distress. The vast majority of patients carry a truncating or missense mutation in MTM1. The authors report here a full term male baby with clinicopathological features of XMTM. The diagnosis is validated by the finding of a c. 141-144delAGAA mutation ofMTM1. To the best of the authors' knowledge, the present case is the first genetically confirmed XMTM in Thailand. A brief review of various neuromuscular disorders causing floppy infant syndrome is also included.

Comparison of Clinical Characteristics Between Congenital Fiber Type Disproportion Myopathy and Congenital Myopathy with Type 1 Fiber Predominance

Congenital myopathies are clinical and genetic heterogeneous disorders characterized by skeletal muscle weakness and specific structural changes in muscle fiber. Congenital myopathy with fiber type disproportion (CFTD) is an established disorder of congenital myopathy. CFTD is characterized by non-progressive childhood neuromuscular disorders with a relatively good prognosis and type 1 fiber predominance and smallness. Congenital myopathy with type 1 fiber predominance (CMT1P) is also a distinct entity of congenital myopathy characterized by non-progressive childhood neuromuscular disorders and type 1 fiber predominance without smallness. Little is known about CMT1P. Clinical characteristics, including dysmorphic features such as hip dislocation, kyphoscoliosis, contracture, and high arch palate, were analyzed along with laboratory and muscle pathologies in six patients with CMT1P and three patients with CFTD. The clinical manifestations of CFTD and CMT1P were similar. However, the frequency of dysmorphic features is less in CMT1P than in CFTD. Long term observational studies of CMT1P are needed to determine if it will change to another form of congenital myopathy or if CMT1P is a distinct clinical entity.

Tubular Aggregate Myopathy: A Case Report

We report a first Korean case of presumably dominantly inherited primary tubular aggregate myopathy in a 19-yr-old man, who presented with slowly progressive proximal muscle stiffness and weakness. In hematoxylin and eosin stain, it showed subsarcolemmal, or central pale basophilic granular vacuoles, which stained red with modified Gomori's trichrome and intensive blue with nicotinamide adenonine dinucleotide-tetrazolium reductase, respectively. Ultrastructurally, aggregates of 60 nm-sized hexagonal tubules were found in both type 1 and type 2 fibers. We briefly review the pathologic findings of the previously reported cases of tubular aggregate myopathy and discuss the possible pathogenesis of this disease. We briefly discuss the possible pathogenesis of sarcoplasmic reticulum and review the ultrastructural characteristics.