Merosin-negative Congenital Muscular Dystrophy Research Articles

Magnetic resonance imaging and spectroscopy in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by congenital muscular dystrophy and associated with neuropathological anomalies such as polymicrogyria and pachygria. Cerebral abnormalities in FCMD have been well documented by neuropathological examinations and cranial imaging studies. However, the pathologic mechanism of white matter lesions remains controversial. In the present study, magnetic resonance imaging (MRI) of a 7-month-old boy with FCMD showed the previously reviewed characteristic morphological features such as thick cortices with shallow sulci corresponding to polymicrogyria involving the frontal lobe. MRI also showed markedly prolonged T1 and T2 signals in the white matter, while diffusion-weighted images showed no abnormalities. The results of magnetic resonance spectroscopy showed an increase in choline and N-acetylaspartate resonances but normal myo -inositol resonance. The simulation of these findings with those of merosin-negative congenital muscular dystrophy should suggest a further study with larger population using a combination of different imaging techniques.

Peripheral neuropathy in merosin-negative congenital muscular dystrophy

Peripheral neuropathy in patients with merosin-negative congenital muscular dystrophy (MN-CMD) has been sporadically investigated and has been considered to be motor and demyelinating in nature on the basis of nerve conduction studies. We performed neurophysiologic studies in 12 children with MN-CMD to establish the spectrum and evolution of peripheral nervous system involvement. In our patients, nerve conduction studies for both motor and sensory nerves were near normal in the children younger than six months and abnormal in the older children. The older children had the relatively slowest nerve conduction velocities suggesting a progressive, age-related dysmyelinating neuropathy. We hypothesize that the findings are due to a myelination arrest as a result of insufficient synthesis and maintenance of the peripheral myelin sheath. (J Pediatr Neurol 2004; 2(4): 213–218).

Merosin deficient congenital muscular dystrophy: Clinical, neuroimaging and immunohistochemical study of 8 Egyptian pediatric patients

Congenital muscular dystrophies (CMD) are a group of heterogeneous inherited autosomal recessive disorders characterized by muscular weakness, hypotonia and contractures. The Merosin Negative CMD (MNCMD) is considered to be the most severe form and is usually associated with white matter abnormalities as seen with brain imaging. Merosin is also expressed in the nervous system and its deficiency could affect its development. This article describes the clinical picture, muscle biopsy findings and neuroimaging abnormalities of eight Egyptian Pediatric patients with the clinical presentation of merosin negative congenital muscular dystrophy. The leading clinical presentation in almost all patients was severe hypotonia, muscular weakness and failure to achieve motor developmental milestones, only Case 2 walked at 2 years of age. Mentality was normal in most patients with exception of Case 2 in whom scholastic achievement was poor and was associated with behavior abnormality. Serum Creatine kinase ranged from moderate to severe elevation, 536–3563 U/L, Electromyography demonstrated a myopathic pattern in all patients. Brain MRI showed extensive demyelination of the cerebral white matter in 6/8 patients with extension to cerebellar demyelination in Case 5. 5/8 patients underwent muscle biopsy for which immunofluorescence staining for merosin demonstrated complete deficiency of laminin α2 in Case 5 & partial deficiency of laminin α2 in Case 2. This report demonstrates the utility of Immunofluorescence staining as a guide to confirm the diagnosis of MDCMD especially when molecular diagnosis is not available.

Evaluation of one hundred pediatric muscle biopsies during a 2-year period in mofid children and toos hospitals.

Muscle biopsy is a very important diagnostic test in the investigation of a child with suspected neuromuscular disorder. The goal of this study was to review and evaluate pediatric muscle biopsies during a 2-year period with focus on histopathology diagnosis and correlations with other paraclinic studies. We investigated 100 muscle biopsies belonging to patients with clinical impression of neuromuscular disorder. These patients have been visited consecutively by pediatric neurologists during 2010 to 2012. Samples were investigated by standard enzyme histochemical and immunohistochemical techniques. Sixty-nine (69%) males and 39 (39%) females with a mean age of 5.7 years were evaluated. Major pathologic diagnoses were Muscular dystrophy (48 cases), Neurogenic atrophy (18 cases), nonspecific myopathic atrophy (12cases), congenital myopathy (6 cases), storage myopathies (4 cases) and in 6 cases there was no specific histochemical pathologic finding. EMG was abnormal in 79 cases. Degree of correlation between EMG and biopsy result was significant in children ≥ 2 years of age. This study confirms the high diagnostic yields of muscle biopsy especially only if standard and new techniques such as enzyme study and immunohistochemistry are implemented. Also, we report 11 cases of Merosin negative congenital muscular dystrophy. This is the largest documented case series of Merosin deficient congenital muscular dystrophy reported from Iran.

Brain MRI features of merosin‐negative congenital muscular dystrophy

The purpose of this article is to report brain MRI findings of merosin-negative congenital muscular dystrophy (CMD) in two cases and to discuss its differentiation from other CMD subtypes. The cases were investigated by 1.5 Tesla MRI equipment using T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR), 3D fast spoiled gradient recalled (SPGR) and post-contrast gadolinium enhanced sequences and the diagnosis was confirmed by muscle biopsy with immunohistochemical staining for merosin. Magnetic resonance imaging showed bilateral subcortical U-fibre white matter changes with periventricular sparing in the first case. Though this imaging finding is non-specific and could be seen in other white matter diseases like Canavan disease, the absence of other distinguishing MRI and clinical features of those conditions allowed a proper diagnosis. The second case showed diffuse subcortical and deep white matter involvement and cerebellar cysts. There was no brainstem involvement, polymicrogyria or cobblestone lissencephaly in both of our cases which allowed differentiation of merosin-negative CMD from other CMDs. Muscle biopsy in both these patients showed dystrophic changes with absent staining for merosin confirming the diagnosis. Merosin-negative CMD should be considered in the imaging differential diagnosis of white matter diseases. In a patient presenting with features of CMD, MRI can be of help in further differentiation of the various CMD subtypes.

Merosin-Negative Congenital Muscular Dystrophy: Diffusion-Weighted Imaging Findings of Brain

Merosin-negative congenital muscular dystrophy is a rare genetic disease of childhood involving the central and peripheral nervous system. There were high signal intensities throughout the centrum semiovale, periventricular, and sub-cortical white matters on T2-weighted images in a 4-year-old girl with merosin-negative congenital muscular dystrophy. An apparent diffusion coefficient map revealed increased signal intensity and apparent diffusion coefficient values in the periventricular and deep white matters. It may be attributable to increased water content in the white matter because of an abnormal blood-brain barrier rather than to decreased or abnormal myelination.

Human melanoma/NG2 chondroitin sulfate proteoglycan is expressed in the sarcolemma of postnatal human skeletal myofibers: Abnormal expression in merosin-negative and Duchenne muscular dystrophies

NG2 is the rat homologue of the human melanoma chondroitin sulfate proteoglycan (MCSP) preferentially expressed in dividing progenitor cells of the glial and mesenchymal lineage but downregulated after differentiation. It has recently been demonstrated that MCSP/NG2 expression is not restricted to mitotic or malignant cells. We show that MCSP/NG2 expression is detectable in the sarcolemma, and in the neuromuscular junction of human postnatal skeletal muscle, and it gradually reduces with advancing age. In human and murine myogenic cell lines, we found no clear differences in MCSP/NG2 expression between myoblasts and myotubes. Reduced levels of the core protein were found in merosin-negative congenital muscular dystrophy (MDC1A). Duchenne muscular dystrophy patients muscles exhibited an overexpression of the MCSP/NG2 core protein. In γ-sarcoglycanopathy and calpainopathy, MCSP/NG2 upregulation was restricted to regenerating myofibers. We demonstrate that MCSP/NG2 is expressed in differentiated myofibers, and appears to have a role in the pathogenesis of MDC1A and severe dystrophinopathies.

Congenital muscular dystrophy in Israeli families.

Twelve patients from 11 Israeli families with congenital muscular dystrophy were evaluated between 1991 and 2001. There were six males and six females, of whom six were merosin negative and six were merosin positive. Serum creatine kinase levels were highly elevated in the merosin-negative group. Four of the children were cognitively normal but nonambulant. Two had unusual clinical findings of severe cognitive and motor developmental dysfunction. Four infants in the merosin-positive group who had normal serum creatine kinase levels had early-onset severe motor weakness and died within the first year of life owing to ventilatory insufficiency. The other two were ambulant and had normal cognitive development and elevated serum creatine kinase levels. Noteworthy, two of the six children with merosin-negative congenital muscular dystrophy had cognitive impairment, and four of the six children with merosin-positive congenital muscular dystrophy had a severe form of the disease with ventilatory insufficiency and death during infancy.

Nonmuscular involvement in merosin-negative congenital muscular dystrophy

The spectrum of nonmuscular involvement in six children with merosin-negative congenital muscular dystrophy is described. In all children, biochemical, neuroradiologic, cardiac, and neurophysiologic studies were performed. Cerebral structures that were myelinated at gestation, including internal capsule, corpus callosum, brainstem, and cerebellar white matter, demonstrated no abnormalities, whereas the periventricular and subcortical white matter, which were myelinated in the first postnatal year, demonstrated signs of leukoencephalopathy. Cerebrospinal fluid analysis revealed an elevated albumin cerebrospinal fluid to serum ratio in the younger children. Electroencephalogram results were abnormal in the two elder children. One child suffered from congestive cardiomyopathy. The increase in nerve conduction velocity in these children over the years lagged behind those of healthy patients, pointing to a demyelinating neuropathy. We conclude that in merosin-negative congenital muscular dystrophy patients, nonmuscular involvement includes the central and peripheral nervous system and the heart. The pattern of myelination of the brain and nerve conduction slowing suggests a myelination arrest. Merosin deficiency can give rise to a congestive cardiomyopathy, which is of no clinical relevance in the majority of children.

Expression of Laminin α1, α2, α4, and α5 Chains, Fibronectin, and Tenascin-C in Skeletal Muscle of Dystrophic 129ReJdy/dyMice

Thedy/dymouse is an animal model for human merosin-negative congenital muscular dystrophy (CMD), which has been reported to have reduced or no expression of the basement membrane protein laminin α2. We here investigate various myogenic and nonmyogenic tissues of maturedy/dyand control 129ReJ mice histologically and for laminin α2 expression. In addition, expression patterns of laminin α1, α2, α4, and α5 chains, the interstitial proteins fibronectin and tenascin-C, and the adhesion molecules VCAM-1, ICAM-1, and α4 integrin were characterized in skeletal muscle of 1- and 7-day and mature (>6 weeks old)dy/dyand control 129ReJ mice. The laminin α2 chain remained detectable in myogenic tissues ofdy/dymice by immunofluorescence using two different monoclonal antibodies and by Northern blot analysis. However, laminin α2 expression was significantly reduced or not detectable in nonmyogenic tissues ofdy/dymice, including skin, lung, kidney, brain, thymus, and eye. Focal lesions were observed in mature skeletal muscle only, characterized by necrotic tissue, isolated VCAM-1- and ICAM-1-positive cells indicative of inflammatory processes, and regenerating muscle fibers surrounded by intense tenascin-C and fibronectin expression. In contrast to studies on human CMD muscle, laminin α1 was not detectable in eitherdy/dyor control skeletal muscle using immunofluorescence or Northern blot analysis. Immunofluorescence localized laminin α4 to basement membranes of blood vessels, the endoneurium of the intramuscular nerves, and the neuromuscular junction in skeletal muscle of 1- and 7-day-olddy/dyand control mice. In mature muscle, laminin α4 expression shifted to the perineurium of intramuscular nerves in bothdy/dyand control mice. Furthermore, strong upregulation of laminin α4 in the basement membranes of blood vessels, the perineurium of intramuscular nerves, and of isolated regenerating muscle fibers in thedy/dymice was apparent. Investigation of 1-day-old animals revealed expression of laminin α5 in skeletal muscle fiber basement membranes ofdy/dybut not control animals. This difference betweendy/dyand control animals was no longer apparent at 7 days after birth, indicating a temporary shift in expression pattern of laminin α5 indy/dyanimals. Analysis of the extracellular matrix components of 1- and 7-day-olddy/dyand control skeletal muscle revealed an early onset of the dystrophy, even before histopathological features of the disease were evident. Our data confirm the absence of laminin α1 chain in myogenic tissues of bothdy/dyand control mice and suggest compensation for reduced laminin α2 indy/dyskeletal muscle by laminin α4 and, in early development, also laminin α5. These results have significant ramifications in the diagnosis of human merosin-negative CMD.

Changes of laminin β2 chain expression in congenital muscular dystrophy

We studied the distribution of laminin β2 chain in the skeletal muscle basement membrane of 16 patients with congenital muscular dystrophy (CMD) by immunohistochemistry. A dramatic reduction in the laminin β2 staining was observed in four patients with classical merosin-negative CMD. A moderate reduction of laminin β2 labelling was observed in four patients with partial merosin deficiency and two patients with merosin-positive CMD. Two patients with merosin-positive CMD had no apparent changes in the expression of laminin β2. In three patients and one fetus diagnosed as Walker-Warburg syndrome (WWS) the laminin β2 pattern was similar to normal controls. We conclude that a primary deficiency in the laminin α2 chain may lead to a vast or moderate reduction in the laminin β2 chain in the skeletal muscle membrane.

Immunohistochemical study of merosin-negative congenital muscular dystrophy: laminin alpha 2 deficiency in skin biopsy.

We studied the immunohistochemical expression of laminin subunits alpha 2, alpha 1, beta 1 in muscle and skin biopsy samples from three patients with congenital muscular dystrophy (CMD), and from ten control patients investigated for various neuromuscular disorders. Merosin alpha 2 chain was not detectable in the basement membrane of muscle fibers, or in the nerve endings, cutaneous nerves, and corium in the skin of the CMD patients, whereas it was clearly expressed in the skin biopsy samples from control patients, especially in the nerve endings of the arrector pili muscles. Laminin alpha 1 chain was expressed in the corium, in the muscle fiber membranes of arrector pili muscles and in cutaneous nerve fibers, perineurium and blood vessels in controls and in CMD patients. Laminin beta 1 chain was faintly expressed in the corium, and a diffuse labeling was detected on arrector pili muscle with enhanced expression at nerve endings, intracutaneous nerves and capillaries, with similar findings in all biopsy specimens. For merosin-negative CMD patients, skin biopsy may provide a diagnostic alternative to muscle biopsy since merosin deficiency can be demonstrated in the skin neural structures, and in particular in the nerve endings of the arrector pili smooth muscles.

Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cerebral white matter

A girl born from consanguineous Turkish parents had marked hypotonia from birth and delayed milestones. She was able to stand unaided by 3 years of age with then progressive worsening of motor abilities. She had a severe non-progressive mental deficiency. Epilepsy occurred by 6 years of age. Ophthalmological investigation was normal. A marked white matter high signal was seen on magnetic resonance imaging without cortical dysplasia. Dystrophic changes were seen on muscle biopsy. Two brothers had had a similar history with early death. Muscular immunocytochemical studies showed a normal staining for dystrophin and all dystrophin related glycoproteins (including 43 and 50 DAG). Merosin staining was normal. This case differs from Fukuyama's congenital dystrophy, from merosin negative congenital muscular dystrophy, or from other congenital muscular dystrophy with CNS dysfunction. It underlines the heterogeneity of congenital muscular dystrophy and the non-specific aspect of white matter changes on neuro-imaging.

Mild clinical phenotype in a 12-year-old boy with partial merosin deficiency and central and peripheral nervous system abnormalities

We found partial merosin deficiency in a boy presenting at 12 yr with marked limb weakness and a waddling gait. Magnetic resonance imaging (MRI) showed the characteristic white matter abnormalities of merosin-negative congenital muscular dystrophy. There were also peripheral demyelinating polyneuropathy and evoked potential abnormalities. Unlike classic merosin-negative congenital muscular dystrophy, however, our patient was less hypotonic and weak and was able to achieve independent walking. Both by immunohistochemistry and Western blot merosin was shown to be moderately reduced. By immunostaining the α1 laminin chain was overexpressed and the β1 laminin chain was reduced. A spectrum of clinical phenotypes is likely to become evident in merosin-deficient patients in relation to the discovery of a range of molecular defects in, and variable expression of, this protein.

Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families

We report clinical, EEG and neuroimaging findings of three patients in two Italian families with merosin-negative congenital muscular dystrophy (CMD), drug-resistant occipital epilepsy, diffuse persistent cerebral white matter changes and focal cortical dysplasia. Clinical and epilepsy histories, EEG and neuroimaging findings were very similar in all patients. Seizures started in childhood and mainly consisted of periodic spasms, a particular type of partial seizure characterized by clusters of epileptic spasms. The motor expression of the spasms was very mild so that they had been frequently missed or misinterpreted as non-convulsive generalized absence seizures. Interictal EEG showed occipital spike-waves and bilateral synchronous slow spike-wave discharges. Ictal EEG showed prolonged periodic sequences of slow waves with associated fast rhythm complexes, characteristic of periodic spasms. Two patients had normal intelligence, one patient presented moderate mental retardation. Focal cortical dysplasia in the posterior areas of the brain, in addition to marked diffuse white matter alterations, was detected in the magnetic resonance images of all patients. Findings in these patients indicate that in merosin-negative CMD brain involvement can include cortical dysplasia, in addition to white matter changes. In such cases the brain damage can lead to a childhood-onset localization-related symptomatic occipital epilepsy. Epileptic seizures and cortical dysplasia can be, however, difficult to detect in CMD. The clinical semiology of epileptic seizures may in fact be modified because of muscular weakness. This implies that epilepsy may be misdiagnosed or even missed and EEG-polymyographic recordings may be necessary to identify it. Similarly, cortical dysplasia may be very localized and visible by neuroimaging only if it is carefully investigated on the basis of epileptological and EEG-polymyographic findings.

Basement membrane abnormality in merosin-negative congenital muscular dystrophy.

In muscle biopsy specimens from three patients with merosin-negative congenital muscular dystrophy (CMD), there was marked variation in fiber size with evidence of necrotic and regenerating processes and with marked interstitial fibrosis. No muscle fibers or intramuscular nerves stained with merosin antibody. On electron microscopy, the basement membrane of all the muscle fibers was very poorly discernible and there were occasional disruptions, while the basement membrane of the Schwann cells was well preserved. On the other hand, the sarcolemmal basement membrane in merosin-positive CMD was well preserved even in patient with severe interstitial fibrosis. It remains to be determined how the defective basement membrane in merosin-negative CMD induces defective sarcolemma and eventual fiber necrosis.

Merosin-negative congenital muscular dystrophy, cortical dysplasia and epilepsy: An association to investigate

Merosin-negative congenital muscular dystrophy, cortical dysplasia and epilepsy: An association to investigate

Merosin-negative non-Fukuyama-type congenital muscular dystrophy: a case report

We report a female infant with non-Fukuyama-type congenital muscular dystrophy with merosin deficiency. She manifested marked hypotonia and muscle weakness from the neonatal period, with an elevated creatine kinase concentration. Her motor developmental milestones were markedly delayed; however, her intellectual development was normal. Although cranial computed tomography (CT) at 3 months of age was normal, subsequent CT at 16 months of age demonstrated diffuse, abnormal white matter lucencies. Muscle biopsy findings at 16 months of age were compatible with those of congenital muscular dystrophy. In addition, no muscle fibers were immunostained by the merosin antibody. The patient died of pneumonia at 23 months of age. These clinical symptoms and CT findings are similar to those described in patients with merosin-negative congenital muscular dystrophy in European countries.

Deficiency of laminin alpha 2-chain mRNA in muscle in a patient with merosin-negative congenital muscular dystrophy.

Deficiency of laminin alpha 2-chain mRNA in muscle in a patient with merosin-negative congenital muscular dystrophy.

WS-13-2 EMG monitoring of the hemiplegic patient

We studied the distribution of laminin β2 chain in the skeletal muscle basement membrane of 16 patients with congenital muscular dystrophy (CMD) by immunohistochemistry. A dramatic reduction in the laminin β2 staining was observed in four patients with classical merosin-negative CMD. A moderate reduction of laminin β2 labelling was observed in four patients with partial merosin deficiency and two patients with merosin-positive CMD. Two patients with merosin-positive CMD had no apparent changes in the expression of laminin β2. In three patients and one fetus diagnosed as Walker-Warburg syndrome (WWS) the laminin β2 pattern was similar to normal controls. We conclude that a primary deficiency in the laminin α2 chain may lead to a vast or moderate reduction in the laminin β2 chain in the skeletal muscle membrane.