Cases Of Congenital Muscular Dystrophy Research Articles

Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1)

We report clinical and imaging findings in six cases from five families affected by the form of congenital muscular dystrophy with rigid spine linked to the locus rigid spine muscular dystrophy 1 on chromosome 1p35-36. All cases showed rigidity of the spine, predominant neck and trunk weakness and frequent and severe thoracic scoliosis. Respiratory impairment was always observed in the first decade. Muscle imaging showed a marked involvement of adductors, sartorius and biceps femoris while rectus femoris and gracilis were relatively spared. This pattern of selective muscle involvement was consistent in all six cases and could be easily observed on either computerised tomography or magnetic resonance imaging. The results of this study suggest that muscle imaging, in combination with clinical assessment can help to identify the rigid spine muscular dystrophy 1 form of congenital muscular dystrophy and can help to target the appropriate genetic investigations.

An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy.

Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.

Merosin-deficient congenital muscular dystrophy: neuropathology case reports.

The aims of our study were: to present cases of congenital muscular dystrophy (CMD) with deficiency in merosin and the importance of immunohistochemistry in the diagnosis of merosin-deficient CMD. In four years (1997-2000), we found three patients with merosin-deficient CMD, one of them having an unusual clinical and pathological manifestation of the disease. Muscle biopsies of gastrocnemius or quadriceps muscles were investigated. In addition with the conventional HE staining, indirect immunohistochemistry for merosin, dystrophin, utrophin and for the proteins of the dystrophin associated complex (alpha-, beta-, gamma- sarcoglycans; beta-dystroglycan) was performed on cryosections. The findings suggest that there is no correlation between the clinical and histological picture of the disease and the expression of merosin in skeletal muscles. The degree of muscle involvment (assessed by histology) is parallel with the clinical neuromotor deficiency, but not with expression of merosin, which can be absent even in mild cases. The clinical investigations as well as current morphological techniques, only together with immunohistochemistry can differentiate between merosin - deficient CMD and other muscular dystrophy forms.

Laminin alpha2 chain-deficient congenital muscular dystrophy: variable epitope expression in severe and mild cases.

To characterize the expression of distinct fragments of laminin alpha2 chain in patients with partial laminin alpha2 chain deficiency and variable clinical severity. Deficiency of laminin alpha2 chain caused by mutations of the LAMA2 gene on chromosome 6q2 account for approximately 50% of cases of congenital muscular dystrophy (CMD) in white patients. The complete absence of laminin alpha2 is usually associated with a severe phenotype affecting skeletal muscle and the peripheral and central nervous systems. Quantitative assessment of immunofluorescence to study the expression of C- and N-terminal portions of laminin alpha2 chain in five patients with partial laminin alpha2 chain deficiency and variable phenotype. All five patients showed abnormal T2 signal on brain MRI. Immunohistochemistry of muscle specimens showed preserved or minimally reduced expression of the C-terminal region of the laminin alpha2 chain (67 to 74%), but a marked reduction of the N-terminal region in four patients (13 to 19%). One patient with a mild phenotype had a partial reduction (45%) of the C-terminal and the N-terminal (51%) portions of the laminin alpha2 chain. Two patients were unable to walk or sit, although the C-terminal portion of the laminin alpha2 chain was expressed at significant levels (67 to 74%). In contrast, two patients with a similar expression of the C-terminus (67 to 70%) had a milder phenotype and became ambulatory. It was impossible to predict the phenotypes in these four patients with a strong expression of the C-terminus and with low levels of the N-terminus based on the amount of protein expressed. In addition, the laminin beta2 chain was moderately reduced (54 to 75%) in all patients with laminin alpha2 chain deficiency. A strong correlation between the amount of the C-terminus but not for the N-terminus and laminin beta2 reduction could be observed. N-terminal antibodies to the laminin alpha2 chain provide a more precise immunohistochemical detection of partially laminin alpha2 chain-deficient CMD. The secondary reduction of laminin beta2 chain may better define laminin alpha2 chain-deficient CMD. More data are needed to predict which portions of C-terminus and midrod region of the laminin alpha2 chain result in a semifunctional protein and a milder phenotype.

Expression of laminin chains in skin in merosin-deficient congenital muscular dystrophy.

Laminin-2 (merosin) is a heterotrimer composed of alpha 2, beta 1 and gamma 1 chains. Approximately half of the cases with the classical form of congenital muscular dystrophy (CMD) have a deficiency of the laminin alpha 2 chain, encoded by the LAMA2 gene on chromosome 6q22. This disorder is often termed merosin-deficient CMD. Skeletal and cardiac muscle, and the peripheral and central nervous systems, all express laminin alpha 2 and can be affected in merosin-deficient CMD. Normal skin also expresses all three chains of laminin-2 at the epidermal/dermal junction, around hair follicles and in the sensory nerves. Skin biopsies can therefore be used to assess merosin status in patients. We show here an absence of laminin alpha 2 in skin from four cases of CMD with a severe phenotype and abnormal magnetic resonance image (MRI) of the brain, in contrast to normal expression in one case of mild CMD with normal MRI, and in five controls. An additional case of CMD had a partial deficiency of laminin alpha 2 in the skin and severe motor disability, but a normal MRI. Sensory nerves in this case showed normal expression of laminin alpha 2, in contrast to its absence in the severe cases. The expression of laminin beta 1 was also reduced in skin from cases of merosin-deficient CMD. In contrast to human fetal muscle, the laminin alpha 2 protein was not detected in fetal skin up to 23 weeks of gestation. The laminin beta 1 and gamma 1 chains, and the mRNA for laminin alpha 2, however, were present. Studies of mRNA of cultured skin cells suggest that fibroblasts are the major source of laminin alpha 2, not keratinocytes. Our data show that skin is useful for the assessment of merosin status in patients with CMD and that skin fibroblasts may be a useful source of tissue-specific RNA. In addition, we show that there is a tissue-specific difference in the developmental expression of the laminin alpha 2 protein.

Variable histomorphology of muscle in congenital muscular dystrophy

Congenital muscular dystrophy (CMD) is a relatively uncommon disease with a controversial nosological status. That collagen synthesis could be the primary abnormality has been suggested earlier ( Fidzianska et al., 1982). Amongst eighteen cases of CMD diagnosed during the past twelve years, muscle biopsy in three cases revealed prominence of myofibre necrosis and phagocytosis, and serum CPK was markedly elevated suggesting a rapidly progressive form. In twelve cases, marked increase in endomysial collagen, pronounced fallout of myofibres and significant fibre diameter variation was seen. This was associated with myonecrosis and regenerative activity of mild degree resembling the classical form of CMD. In the remaining three cases, polyfocal, polyphasic necrosis was noticed. Fibre splitting was more frequently observed, better delineated in the enzyme histochemical preparations, affecting both fibre types, while endomysial fibrofatty tissue was only moderately increased. The histomorphology in the latter group resembled that of limb girdle dystrophy. Ultrastructural findings in all the eighteen cases correlated well with light microscopic observations. Immunohistochemical studies done on three of the eighteen cases showed normal localization of dystrophin protein. Such variable histomorphology, revealing a spectrum of myopathic features, suggests that the primary change in CMD is likely to be in the myofibre rather than in collagen synthesis.

Disruption of muscle basal lamina in congenital muscular dystrophy with merosin deficiency

We studied three new cases of congenital muscular dystrophy (CMD) with homogeneous clinical and laboratory features, represented by congenital muscle hypotonia and weakness, early contractures, elevated serum CK, and dystrophic pattern at muscle biopsy, without clinical impairment of CNS. Merosin, the laminin isoform that contains the alpha 2 heavy chain, was absent in muscle fibers of all the patients by immunohistochemistry and by immunoblot. By electron microscopy, we found a severe disruption of muscle fiber basal lamina, but not of blood vessel basal lamina, which contains the laminin alpha 1 heavy chain isoform. This disruption may play a key role in the degeneration of muscle fibers and in the abnormal proliferation of connective tissue seen in CMD.

Diagnosis of merosin (laminin-2) deficient congenital muscular dystrophy by skin biopsy

Summary Background The α2 chain of laminin-2 (merosin), encoded by a gene on chromosome 6q22, is deficient in about half the cases of congenital muscular dystrophy. Diagnosis of this condition has relied on immunocytochemical analysis of the α2 chain in muscle biopsy specimens. We have observed that normal skin also expresses laminin α2 in the basement membrane at the junction of the dermis and epidermis. Here we have investigated laminin α2 deficiency in skin biopsy specimens from two patients with congenital muscular dystrophy. Participants Two patients with severe congenital muscular dystrophy gave informed consent to a skin biopsy. The girl was aged 10 and the boy was aged 7. The specimens were labelled with a commercially available mouse monoclonal antibody and a rat monoclonal antibody (4H8-2), which recognise an 80 and a 380 kDa fragment of the α2 chain, respectively. The antibodies were visualised by standard methods. A muscle biopsy specimen was available for each case, and was processed with the skin biopsy samples (from the girl a few months previously, from the boy at age 14 days). Skin biopsies were done on four controls with normal expression of laminin α2 on their skeletal muscle fibres. Findings We did not detect laminin α2 in skin specimens from either case, although the controls were positive. The muscle biopsy specimens from the girl showed a few fibres, with traces of laminin α2; those from the boy showed no laminin α2. Interpretation Skin biopsy specimens will provide a useful alternative to muscle biopsy samples for the assessment of laminin-2 (merosin) status in congenital muscular dystrophy.

Demyelinating Peripheral Neuropathy in Merosin-Deficient Congenital Muscular Dystrophy

It has recently been shown that merosin, a laminin variant, is deficient in a proportion of patients with congenital muscular dystrophy. Merosin is a heterotrimer composed of the alpha 2, beta 1, and gamma 1 subunits, and further studies have shown that it is the alpha 2 subunit that is deficient in these patients. Because the alpha 2 subunit is also expressed in S-merosin, found in Schwann cells, we have investigated whether peripheral nerve function is also affected in these patients. Motor nerve conduction velocities and sensory distal latencies were examined in 25 cases of congenital muscular dystrophy and the results correlated with the merosin expression in their muscle biopsies. All but two of the 10 merosin-deficient cases had reduced motor nerve conduction, whereas all the merosin-positive cases had normal results. Analysis of the biopsies of these two cases showed that they produced merosin in reduced amounts, in contrast to all other merosin-deficient patients that produced no or only traces of merosin. Sensory nerve studies showed no difference between the two groups. These results indicate that a peripheral demyelinating neuropathy is a feature of merosin-deficient congenital muscular dystrophy. The fact that the alpha 2 subunits is also expressed in Schwann cells supports the idea that the alpha 2 gene, located on chromosome 6, is the candidate gene for merosin-deficient congenital muscular dystrophy.

Congenital muscular dystrophy with eye and brain involvement. The Turkish experience in two cases

Eye and brain involvement in congenital muscular dystrophies (CMD) constitite a distinct group with a spectrum of brain malformations. We report two such CMD patients among our series of 58 cases with CMD. Despite known clinical and neuroradiological overlap, we tend to classify them into specific syndromes, though this may not be accurate. Molecular genetic studies hopefull will be the answer. Our cases are the continuum of increasingly reported CMD cases with severe brain manifestations, which come from the area geographically far away from those of original descriptions.

A Case of Congenital Muscular Dystrophy Associated with Hydrocephalus

A Case of Congenital Muscular Dystrophy Associated with Hydrocephalus

Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping.

Congenital muscular dystrophies (CMD) are autosomal recessive, heterogeneous disorders. The commonest forms are the Fukuyama CMD (FCMD), associated with mental retardation and structural brain anomalies, and classical (occidental) CMD, with pure muscle expression. FCMD has been localized to chromosome 9q31-q33. Following the discovery of merosin deficiency in some CMD cases, we have localized, by homozygosity mapping and linkage analysis (Zmax = 5.6; theta = 0.0 for marker AFM127xb2) in four merosin-negative families a CMD gene in a 16 cM region of chromosome 6q2 in the region of the laminin M chain gene. In three consanguineous, merosin-positive, CMD families there was no linkage to either chromosome 6q2 or 9q31-q33.

Dystrophin analysis in the diagnosis of childhood muscular dystrophy: an immunohistochemical study of 75 cases.

Seventy-five consecutive pediatric muscular dystrophy (MD) cases were analyzed by dystrophin immunohistochemistry (75/75), Western blot analysis (26/75), DNA analysis (30/75), and immune electron microscopy (8/75). The patients included 64 males and 11 females and the clinical diagnoses were Duchenne MD (DMD) (41), Becker MD (BMD) (8), intermediate/outlier MD (4), female DMD (3), limb girdle or Becker (1), congenital MD (CMD) (10), Fukuyama CMD (1), facioscapulohumeral MD (FSH) (3), limb girdle MD (2), and other uncharacterized dystrophies (2). Dystrophin analysis was performed on all cases using the N- and C-terminal antidystrophin antibodies. Dystrophin analysis helped to exclude an Xp21 dystrophy in four patients. Except for two patients who showed normal staining with the N-terminal and abnormal staining with the C-terminal antibody, all DMD cases showed absent staining except for the immunoreactive revertant fibers, which were generally under 5%. A variety of staining patterns was seen in BMD, ranging from normal to abnormal (variable intensity of staining, partially stained/unstained fibers). Abnormalities were observed with the C-terminal antibody in one case of CMD and Fukuyama CMD, and normal staining was present in the other dystrophies. Immune electron microscopy confirmed absence of staining in DMD and normal membrane staining in other dystrophies. Our study underscores the importance of using antibodies with specificities to different regions of the dystrophin molecule for accurate diagnosis. As abnormal staining may be encountered in non-Xp21 dystrophies such as CMD, dystrophin staining should not be used in isolation to make a diagnosis of a dystrophinopathy.

A large inbred Palestinian family with two forms of muscular dystrophy

This paper reports the results of a clinical, genetic and histopathological study of 19 patients belonging to a large inbred Palestinian family living in Um-El-Fahem, a town located in Israel, which is solely inhabited by Arabs. Their custom of marrying only among relatives has kept the genetic homogeneity of the families intact. There were ten cases of congenital muscular dystrophy (CMD) and nine cases of adult limb-girdle muscular dystrophy (LGMD) belonging to two generations of the same family. Both forms showed autosomal recessive inheritance. The patients with congenital muscular dystrophy had generalized muscular weakness and hypotonia at birth without arthrogryposis or CNS involvement and then had a relatively benign evolution with stabilization of the clinical picture at different ages and variable degree of severity. Muscle biopsy showed a dystrophic pattern. The other nine patients presented with the picture of adult limb-girdle muscular dystrophy but with an unusual tendency to the stabilization of symptoms.

Cortical dysplasia in congenital muscular dystrophy with central nervous system involvement (Fukuyama type).

We report five cases of congenital muscular dystrophy with central nervous system involvement of the Fukuyama type (FCMD) in which cerebral cortical dysplasia was not uniform even in the same brain. We have categorized the dysplasia into three major patterns, each with a predictable topography despite individual variations. Cerebellar micropolygyria was localized to the dorsal halves of each hemisphere. Aberrant fascicles of myelinated nerve fibers, closely associated with micropolygyria, were found in the subarachnoid space of the dorsal cerebellar surface in all but one case. We discuss the characteristics of the cortical dysplasia of FCMD, particularly in relation to that of Walker's lissencephaly, pathogenesis, and the relationship between lesions of the central nervous system and skeletal muscle.

A fluorescent microscopy study of biopsied muscles from infantile neuromuscular disorders.

The Acridine Orange (AO) stain for muscle biopsies is particularly useful to identify regenerating and ongoing hypertrophic muscle fibers under fluorescent microscopy. This method was applied to muscle biopsies from 65 patients who suffered from various childhood neuromuscular disorders. While normal fibers showed dull green cytoplasm with small green-yellow nuclei, striking fluorescent fibers were observed in eight cases of congenital muscular dystrophy (CMD) and 12 cases of Duchenne muscular dystrophy (DMD); these fibers were characterized as follows: (1) small fibers with big oval or spherical nuclei which fluoresced strongly with a bright orange color; (2) fibers of various sizes and different degrees of orange fluorescence; and (3) opaque fibers with bright yellow cytoplasm. The small diameter fibers in Werdnig-Hoffmann (WH) disease, nemaline myopathy, and congenital fiber type disproportion failed to show apparent AO-RNA fluorescence. Although all the atrophic fibers in Kugelberg-Welander (KW) disease showed a vague orange fluorescent color, this was obviously different from that of regenerating fibers seen in CMD and DMD. In addition to these findings, the hypertrophic fibers in a case of unclassified myopathy also showed moderate orange fluorescence around the entire periphery of the cytoplasm.

Morphometric quantification of the cervical limb motor cells in various neuromuscular diseases

The number of motor cells was significantly reduced in the C8 segment of the cervical spinal cord in all 12 cases of amyotrophic lateral sclerosis (ALS), in the C6 and/or C8 segments in 1 case of adult onset spinal muscular atrophy, 2 cases of Werdnig-Hoffmann (W-H) disease, 3 of 4 cases of chronic polyneuropathy and in 1 case of poliomyelitis and 1 of ossification of the posterior longitudinal ligament in the cervical spine (OPLL). The numbers of motor cells were normal in the C6 or C8 segment in 6 cases of muscular dystrophy, except in one case of congenital muscular dystrophy, who showed reduced numbers of the motor cells. Examination of the distribution of motor cells per 500 μm thickness in serial sections revealed that reduction in numbers of the motor cells was diffuse and symmetrical in half the cases of ALS and W-H disease and in the cases of chronic polyneuropathy and congenital dystrophy; diffuse but asymmetrical in the other ALS and W-H disease cases and in a case of adult spinal muscular atrophy, and localized and asymmetrical in the cases of poliomyelitis and OPLL. In muscular dystrophy the distribution of motor cells showed segmental variations similar to controls.

Congenital muscular dystrophy: Case reports and reappraisal

We report four cases of congenital muscular dystrophy; all demonstrated hypotonia and multiple contractures at birth. Strength remained stationary or improved, but the tendency for contracture formation persisted. Brief small amplitude polyphasic potentials were recorded on electromyography, and muscle biopsy revealed extensive fat and/or collagen replacement, which was out of proportion to fiber necrosis or patient strength. The consistent clinical and pathologic features of these patients and others described in the literature justify considering this disorder to be a specific nosologic entity.

Congenital muscular dystrophy: benefits of early diagnosis and active rehabilitation

22 cases of congenital muscular dystrophy were reviewed, aged 2 to 13 years. 7 had orthopaedic problems at birth (5 dislocated hips, 1 talipes and 1 arthrogryposis); 2 presented later with scoliosis; 13 had weakness alone. Power improved with age in 12, was static in 8 and worsened in 1. The other case is only 2 months old. 10 children acquired lower limb contractures severe enough to interfere with walking. Only 1 had had regular physiotherapy and late diagnosis was common (mean age 3.3 years). 4 had been immobilized during treatment of congenital dislocated hips. 3 of the 10 have had successful surgical releases; a fourth awaits surgery. Of 6 whose contractures were too severe for surgery, 5 probably would have had sufficient power for ambulation in calipers. 6 children with milder weakness, all walking independently before 2 years, have not had physiotherapy and remain free of contractures. 5 children with severe weakness diagnosed early (mean age 1.2 years) have had regular passive stretching. 1 of these has irreducible dislocated hips but no progression of her contractures; 1 has no contractures and 3 have 5-10° hip flexion. The eldest walked independently at age 6, despite severe weakness at birth. The other 4 are not yet walking (at age 18 months to 3 years 10 months) but 3 are getting stronger. Our findings demonstrate the non-progressive nature of the disease and the value of physiotherapy in preventing contractures, especially if ambulation is delayed by congenital hip dislocation or severe weakness.

Congenital Muscular Dystrophy as a Disease of the Central Nervous System

Profound abnormalities of the brain were noted in a 6-year-old Japanese boy with congenital muscular dystrophy (CMD). Pathological alterations included diffuse cerebral and cerebellar micropolygyria, with bilateral temporal agyria, and abnormal fusion of gray matter in the basal portions of both frontal hemispheres. Microscopically, the architecture of both cerebral and cerebellar cortices was severely distorted, with irregular arrangement of neurons and increased vascularization. Skeletal muscles showed dystrophic changes rather than neurogenic atrophy. Eight autopsy cases of CMD with similar pathologic findings have been reported in Japan, although the lesions in the brain are quantitatively different from case to case. The findings indicate that CMD is a dysplastic disease of the central nervous system, with dystrophic involvement of skeletal muscles.