Mutation of gene in spinal muscular atrophy respiratory distress type I

Spinal muscular atrophy with respiratory distress type I (SMARD1, MIM #604 320) is an uncommon variant of infantile spinal muscular atrophy type I. Distinguishing features include diaphragmatic palsy, early-onset distal limb wasting, and contracture. This report describes a Chinese male with typical features of spinal muscular atrophy with respiratory distress type I. Direct sequencing of the causative gene, the immunoglobulin mu-binding protein 2 (IGHMBP2) gene, revealed the presence of a novel frameshift mutation caused by deletion of G in exon 13 and a single base pair substitution of G to A in exon 12 resulting in substitution of isoleucine for valine.     

Two Dutch siblings with congenital muscular dystrophy (Fukuyama type)

Two Dutch siblings are described suffering from muscular weakness, hypotonia, severe joint contractures, mental retardation and epileptic fits. E.M.G. showed a characteristic myopathic pattern. Muscle biopsy revealed changes consistent with congenital muscular dystrophy. On CT marked hypodensities of the cerebral white matter were noticed. These findings are consistent with congenital muscular dystrophy of the Fukuyama type, a peculiar form of congenital muscular dystrophy, extremely rare outside Japan.     

Selective type II muscle fiber hypertrophy in severe infantile spinal muscular atrophy

The diagnostic muscle biopsy finding in severe infantile spinal muscular atrophy (Werdnig-Hoffmann disease, SMA type 1) is considered to be large-group atrophy with isolated clusters of hypertrophic type I myofibers. We present a unique case of severe infantile spinal muscular atrophy with selective hypertrophy of type II myofibers. A male infant presented at age 2 months with breathing difficulties and by age 4 months was hypotonic and weak. Electromyography revealed denervation in all extremity muscles, and nerve conduction velocities were normal but with small compound muscle action potentials. Quadriceps muscle biopsy revealed many hypertrophied type II myofibers (myofibers with a mean least diameter of 25.4 microns). In contrast, the largest type I myofibers were 20 microns in least diameter (mean diameter, 14.9 microns), and there was a normal-size population of type II fibers (mean diameter, 15.7 microns). In addition, sheets of atrophic type I and type II fibers averaged 2.0 microns in least diameter. Sural nerve biopsy was normal. Breathing difficulties progressed, with death ensuing at age 5 1/2 months. Autopsy revealed atrophy of ventral spinal roots with normal dorsal roots. There was loss of anterior horn cells, while remnant neurons were reduced in size. No other pathologic changes were identified. This case indicates that in severe infantile spinal muscular atrophy, relative sparing of the motor units with type II myofibers may occur.     

Hypertrophic type of peroneal muscular atrophy and spinal muscular atrophy in siblings

We describe a family with one brother suffering from a hypertrophic type of peroneal muscular atrophy, and a sister suffering from a late infantile from of spinal muscular atrophy. There are no other affected members in the relatives studied. This association has not been previously described, and has appeared as a result of a consanguineous marriage.     

Fukuyama type congenital muscular dystrophy--two Dutch siblings

Two Dutch siblings, diagnosed as suffering from Fukuyama type congenital muscular dystrophy (FCMD) on the basis of clinical, computerized tomography (CT), and muscle and brain biopsy findings, are reported. Hypoplasia of the chorioidea was observed for the first time in FCMD. Autopsy of the first case revealed the major pathological changes of FCMD, i.e. micropolygyria, loss of cytoarchitecture, hypoplasia of the pyramidal tract, leptomeningeal thickening. Heterotopias of nervous tissue in the spinal arachnoidal spaces were found. This is the first case in which brain tissue has been investigated on two separate occasions. In the biopsy specimen--at the age of 14 months--myelination was poor and astrogliosis marked. At autopsy--4 years later--myelination proved to be only slightly less than normal. However, white matter hypodensities on the successive CT's did not change. There is no ready explanation for this discrepancy. Typical FCMD is compared to FCMD-like cases from outside Japan. There are arguments in favor of the concept of a continuum of diseases--with the same (unknown) etiology--representing both typical FCMD and other types of congenital muscular dystrophy with CNS lesions.     

A newborn with spinal muscular atrophy type 0 presenting with a clinicopathological picture suggestive of myotubular myopathy

We report a male term newborn with genetically confirmed spinal muscular atrophy type 0, presenting with arthrogryposis and severe generalized weakness and requiring ventilatory support. Muscle biopsy revealed fibers with central nuclei resembling myotubes and negative myotubularin immunohistochemical staining compared with a control muscle biopsy. The absence of myotubularin associated with survival motor neuron protein deficiency suggests that survival motor neuron protein may have a role in muscle fiber maturation and myotubularin expression. Studying the pathology of this rare and lethal neonatal form of spinal muscular atrophy may further our understanding of spinal muscular atrophy pathogenesis.     

Two siblings with limb-girdle muscular dystrophy type 2E responsive to deflazacort

Two siblings were evaluated for progressive proximal weakness and elevated creatine kinase. Immunohistochemical staining in the brother’s muscle biopsy showed near absence of all four sarcoglycan subunits. Clinical progression prompted a trial of deflazacort in both siblings. At 22 months of drug therapy, both patients have stable or improved strength testing. Further analysis on the muscle biopsy revealed homozygous β-sarcoglycan gene mutation (S114F), consistent with the limb-girdle muscular dystrophy type 2E (LGME 2E). Despite the severe phenotype, deflazacort has a beneficial effect on slowing disease progression in LGME 2E similar to that seen in Duchenne muscular dystrophy.     

X-linked muscular dystrophy

X-linked muscular dystrophy has been separated into two types that are generally considered to be distinct entities. We have investigated three families with X-linked muscular dystrophy who demonstrate remarkable intrafamilial variability. In one family 2 brothers with a benign type had a maternal uncle who was affected with the Duchenne type. In another family, 4 members had the benign type but a fifth was much more severely affected than in the classic Duchenne dystrophy; therefore the presence of an "aggressive form" is proposed. A third family also had both benign and severe types. A search of the literature revealed families in which the severe and benign types coexisted. The genetic determinants of this heterogeneity are not yet known. Clinical similarities between benign and severe types of X-linked muscular dystrophy and the presence of families with both types suggest that the two are intimately related.     

Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease)

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Two of the patients had prolonged evaluations before the diagnosis was made. All patients had Gowers signs and two had pes planus. In patients with proximal muscle weakness the presence of asymmetrical weakness, upper motor neuron signs, or both, may be compatible with spinal muscular atrophy type III. The diagnosis of spinal muscular atrophy should be considered when other possibilities have been excluded.     

Spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin micro-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.     

应用免疫印迹法诊断肢带型肌营养不良2A型

目的 应用免疫印迹法(Western blot)诊断肢带型肌营养不良2A型(LGMD2A)患者并与LGMD2B型相鉴别.方法 收集我院诊治的4例LGMD2型患者的临床、病理及生化检验资料.取肌肉活体组织行组织化学和免疫组织化学染色,用Western blot分析dysferlin蛋白及calpain-3蛋白的表达.结果 LGMD2A与2B型患者的临床症状相似;免疫组织化学染色显示所有患者均出现不同程度的dysferlin缺失.但Western blot揭示:LGMD2A型患者calpain-3蛋白完全缺失,dysferlin蛋白部分缺失;而2B型患者则相反.结论 用Western blot检测calpain-3蛋白可在dysfedin蛋白表达缺失的LGMD患者中鉴别出2A型患者,该方法对临床辅助诊断LGMD2A有很好的价值.     

Dilating cardiomyopathy as the expression of Xp21 Becker type muscular dystrophy.

A 35-year-old man with severe progressive dilating cardiomyopathy and no clinical signs of muscle disease underwent muscular investigations because of markedly increased serum creatine kinase. Muscle biopsy demonstrated Becker type muscular dystrophy with dystrophin of low molecular weight. Genetic analysis showed a deletion spanning from exon 45 to exon 46 in the Xp21 region. Xp21 Becker type muscular dystrophy must be considered in the differential diagnosis of dilating cardiomyopathy.     

Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I

BACKGROUND: Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in alpha-dystroglycan glycosylation. OBJECTIVES: To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations. DESIGN: Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes. RESULTS: Thirteen patients with limb-girdle muscular dystrophy type 2I (6% of all patients tested) were identified by FKRP mutation analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826C>A nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed. CONCLUSIONS: FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involvement. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.     

Charcot-Marie-Tooth neuropathy type 1A combined with Duchenne muscular dystrophy

We report a 24-year-old male with an unusual combination of two inherited neuromuscular disorders – Charcot-Marie-Tooth (CMT) disease type 1A and Duchenne muscular dystrophy (DMD). A phenotypic presentation of this patient included features of both these disorders. Nerve conduction studies revealed demyelinating peripheral neuropathy. Electromyography showed a profound myogenic pattern. The serum creatine kinase level was highly elevated. Muscle biopsy revealed a dystrophic picture with deficient dystrophin immunostaining. CMT1A duplication on chromosome 17p11.2 was found. The frame-shift mutation c.3609–3612delTAAAinsCTT (p.K1204LfsX11) was detected in the dystrophin gene by analysing mRNA isolated from the muscle tissue. The patient inherited both these mutations from his mother. The combination of CMT1A and DMD has not been reported as yet.     

Distal muscular dystrophy of the Miyoshi type

OBJECTIVE: Miyoshi myopathy is an autosomal recessive muscular dystrophy. It is characterized by distal muscle involvement, especially the gastrocnemius and soleus. The disease starts with weakness and atrophy of the calves. MATERIAL AND METHODS: Here we report on 2 patients, brother and sister, from a Turkish family. Onset of the disease was at the age of 20 and 26 years of age, respectively. In both siblings, there was an early and predominant involvement of the distal muscles of the lower limbs. Creatine kinase activity was elevated 50- to 100-fold above normal values. RESULTS: Electromyography revealed a myopathic pattern. Histology of the biceps muscles indicated some myopathic changes consistent with muscular dystrophy. Occurrence in only these 2 siblings with no other family members was indicative of an autosomal recessive inheritance. CONCLUSIONS: We describe the distinctive clinical features in 2 siblings of a Turkish family with MM as differential diagnosis and histological change.     

Oxidative stress in the brain of Fukuyama type congenital muscular dystrophy: immunohistochemical study on astrocytes

Astrocytes in the cerebrum and medulla oblongata of cases of Fukuyama type congenital muscular dystrophy were examined by immunohistochemistry of oxidative modification products and free-radical scavenging enzymes because abnormal glia limitans formed by astrocytic end feet is considered to be involved in the genesis of brain lesions of Fukuywama type congenital muscular dystrophy. The study was performed on two fetal cases of Fukuyama type congenital muscular dystrophy of 18 and 20 weeks' gestation and seven patients with Fukuyama type congenital muscular dystrophy ranging in age from 2 to 27 years. Eight age-matched control cases were used. Polymerase chain reaction (PCR) was performed to ascertain the gene phenotype of two child cases, in which prenatal gene analysis was not performed. Astrocytes, especially layer I astrocytes, of postnatal cases of Fukuyama type congenital muscular dystrophy were weakly positivefor Nepsilon-(carboxymethyl)lysine and argpyrimidine, suggesting that they were sensitive to oxidative stress, and the accumulation may be related to the abnormal glia limitans. Secondary increase of manganese (Mn) superoxide dismutase against the increase of free radicals was considered in patients with Fukuyama type congenital muscular dystrophy more than 14 years old considered to be homozygous for founder haplotype: homozygosity was suggested by PCR in two cases. In contrast, expression of Mn superoxide dismutase was decreased in 2- and 6-year-old children with Fukuyama type congenital muscular dystrophy that were heterozygous. Moreover, accumulation of argpyrimidine was exclusively found in astrocytes of the 2-year-old child that exhibited severe brain lesions. Function of astrocytes might be impaired or immature in severe or heterozygous cases. These results may confirm that astrocytes play an important role in the etiology of the brain lesion.     

Ocular findings in Fukuyama type congenital muscular dystrophy

In Fukuyama type congenital muscular dystrophy (FCMD), congenital muscular dystrophy and anomalies of the central nervous system are regarded as the major features, but the existence of ocular lesions has hardly been recognized as being important. In the present study, close ophthalmologic examinations were performed on 11 patients with FCMD, and we found myopia, weakness of the orbicularis oculi, congenital nystagmus, cortical blindness, optic atrophy, chorioretinal degeneration, etc. In particular, the chorioretinal degeneration observed in the ocular fundus was considered to be specific to FCMD. It is thought that these ocular lesions or changes are caused by the same mechanism as that involved in the central nervous system anomalies.     

Congenital muscular dystrophy of non-Fukuyama type with characteristic CT images

A 9-year-old Japanese boy with congenital muscular dystrophy (CMD) with normal intelligence was presented. He was extremely floppy and had joint contractures since birth. Motor milestones were delayed and he did not learn to walk alone. Intellectual development was normal and no convulsions were observed. On physical examination at 9 years old, he had diffuse muscle weakness and atrophy and flexion contractures of joints. Creatine kinase was normal and IQ was 95. Biopsied muscle showed myopathic changes consistent with muscular dystrophy. CT scans of the head revealed diffuse low density area in the white matter of the cerebrum. These findings suggest central nervous system involvement in CMD is not confined to Fukuyama-type CMD.     

Vascular alterations in Fukuyama type congenital muscular dystrophy

Blood vessels in muscle biopsy specimens from 6 Fukuyama type congenital muscular dystrophy (FCMD) patients were examined by electron microscopy and compared with ones in non-diagnostic biopsy specimens from age-matched controls and patients with childhood neuromuscular disorders. The most striking feature was the blister-like swelling of vascular endothelial cells in the biopsied muscle specimens from 5 of the 6 patients with FCMD. Morphometric analysis of capillaries in biopsied muscles showed the extremely greater capillary, endothelial and pericyte areas in the FCMD patients than in controls. These phenomena are quite similar to those found in Duchenne muscular dystrophy (DMD) at the preclinical stage and suggest an as yet undetermined process in blood vessels in FCMD as well as DMD. An immunohistochemical study involving dystrophin antibodies showed positive staining in FCMD.