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

doi:10.1016/0960-8966(96)00359-8

Neuromuscular Disorders

Volume 6, Issue 5, October 1996, Pages 377-381

https://doi.org/10.1016/0960-8966(96)00359-8 Get rights and content

Abstract

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.

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Mutation in the laminin of α2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy
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There are more references available in the full text version of this article.

Cited by (51)

Cardiac involvement in two rare neuromuscular diseases: LAMA2-related muscular dystrophy and SELENON-related myopathy
2022, Neuromuscular Disorders
LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related myopathy (SELENON-RM) are rare neuromuscular diseases caused by mutations in the LAMA2 and SELENON (SEPN1) gene, respectively. Systematic reviews on cardiac features in both neuromuscular diseases are lacking. This scoping review aims to elucidate the cardiac involvement in LAMA2-MD or SELENON-RM. Three electronic databases (PubMed, Embase and Cochrane) were searched. All studies, case reports and case series with information on cardiac features in LAMA2-MD or SELENON-RM patients were included. Study selection and data extraction were performed by two independent reviewers. 31 Articles on LAMA2-MD and 17 articles on SELENON-RM met the inclusion criteria, resulting in the inclusion of 131 LAMA2-MD and 192 SELENON-RM cases. In 41% of LAMA2-RM cases, a cardiac abnormality was present. Left ventricular systolic dysfunction and arrhythmia were most frequently described. In 15% of SELENON-RM cases, a cardiac abnormality was reported, of which pulmonary hypertension, including right ventricular dysfunction secondary to pulmonary failure, was most prevalent. We conclude that in LAMA2-MD primary left ventricular dysfunction and in SELENON-RM secondary right ventricular dysfunction are frequently reported. Optimal cardiorespiratory surveillance by screening of asymptomatic patients every two years with ECG, Holter and echocardiography is necessary for early detection and/or treatment of cardiac manifestations.
Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina
2016, Human Pathology: Case Reports
Citation Excerpt :
The present report aims to characterize the pathologic features of a nerve biopsy obtained from the cauda equina, which shows clear evidence of an ongoing segmental demyelination and remyelination. MDC1A and the severity of its clinical presentation are dependent on the amount of merosin found in the musculature, as complete absence correlates with the most severe phenotype [6,7]. Individuals with absent merosin rarely achieve the ability to walk independently [6,8].
Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.
Limb girdle muscular dystrophy due to LAMA2 mutations: Diagnostic difficulties due to associated peripheral neuropathy
2014, Neuromuscular Disorders
Citation Excerpt :
Normal brain MRI is rare in merosin deficient CMD, and thus far only one MDC1A patient with normal brain imaging has been reported [9]. Peripheral nerve involvement in merosin deficient CMD can manifest with decreased motor nerve conduction velocities [4–7], or decreased sensory nerve action potentials as well as absent merosin expression seen in sural nerve biopsies [8,18] and sensory nerves and the epidermal/dermal junction of the skin [19,20]. Our patient’s electrophysiological findings are compatible with a sensorimotor demyelinating polyneuropathy.
We report an eleven year old girl with early motor difficulties initially diagnosed with a peripheral neuropathy in another hospital based on abnormal electrophysiological findings. Our clinical assessment did not highlight obvious clinical features supporting a peripheral neuropathy but evidence of mild proximal weakness. Electrophysiological studies performed at our hospital revealed evidence of a sensorimotor demyelinating polyneuropathy with possible axonal involvement. Brain magnetic resonance imaging (MRI) revealed subtle white matter signal abnormalities, interpreted as nonspecific. Given the patient’s proximal weakness and a mildly elevated serum creatine kinase, we performed a muscle biopsy. The muscle had mildly dystrophic features and subtly depleted laminin α2 expression. There was diffusely upregulated laminin α5 expression, and depletion of laminin α2 in intramuscular motor nerves, which made us suspect a partial laminin α2 (merosin) deficiency. Muscle MRI showed predominant posterior and medial compartments involvement. The patient was found to have autosomal recessively inherited double heterozygous LAMA2 mutations. This case illustrates the mild end of the partial merosin deficiency phenotypic spectrum, and highlights how careful assessment of laminin α2 expression in intramuscular motor nerves can be a helpful diagnostic clue in partial merosin deficiency.
Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations
2010, Neuromuscular Disorders
Citation Excerpt :
Subsequently we and others reported that merosin may be only partially reduced on skeletal muscle biopsy and that often these cases with residual staining have a more variable phenotype compared to MDC1A. Case reports have highlighted this variability with regard to age of presentation, pattern of weakness, CK levels, and brain MRI findings [5–7,13–23]. Laminins are a family of large extra-cellular basement membrane glycoproteins, with a heterotrimeric cruciform structure composed of three subunits, a heavy α chain and two light chains, β and γ.
Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7 days) (P = 0.0073), were more likely to lack independent ambulation (P = 0.0215), or require enteral feeding (P = 0.0099) and ventilatory support (P = 0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.
The value of elecromyography in the aetiological diagnosis of hypotonia in infants and toddlers
2009, Annals of Physical and Rehabilitation Medicine
During the first two years of life, hypotonia may be the only symptom of a central or peripheral nervous system disorder. We propose to assess the sensitivity of electroneuromyography (ENMG) in the aetiological diagnosis of hypotonia of neuromuscular origin in infants and toddlers.
This is a retrospective, single-centre study with revision of the files of the 37 children aged between zero and 24 months who, between 1994 and 2006, underwent an ENMG in the etiological approach of their hypotonia and had a final diagnosis of neuromuscular disease.
All the 13 patients with spinal muscular atrophy or Charcot Marie-Tooth disease displayed neurogenic alterations on the electromyography (EMG). Among the 24 children ultimately diagnosed with myopathies, five only displayed myogenic alterations when tested before the age of two. Sixteen had normal EMG results and three showed neurogenic alterations.
In infants presenting with hypotonia, ENMG is useful for the diagnosis of peripheral neuropathy. Normal ENMG is relatively common for confirmed muscle disorders in infants whereas myogenic alterations seem more unusual, so that muscle biopsy appears unquestionable. In a few cases, early onset myopathies may present with a neurogenic ENMG pattern. Such a result should not invalidate the clinically presumed diagnosis of myopathy and would indicate on the contrary the need for a muscle biopsy.
Le tonus musculaire poursuit sa maturation jusqu’à l’âge de 24 mois. Pendant cette période, l’hypotonie peut être le seul symptôme d’une maladie du système nerveux central ou périphérique. Nous nous sommes proposés d’évaluer la sensibilité de l’électroneuromyographie (ENMG) dans le diagnostic étiologique des hypotonies d’origine périphérique chez les nourrissons.
Il s’agit d’une étude rétrospective, monocentrique, avec révision des dossiers des 37 enfants de zéro à 24 mois qui, entre 1994 et 2006, ont bénéficié d’un ENMG dans le cadre du bilan étiologique de leur hypotonie et ont obtenu un diagnostic final de maladie neuromusculaire.
Les 13 patients avec une amyotrophie spinale ou une maladie de Charcot Marie-Tooth présentaient tous des anomalies neurogènes à l’électromyogramme. Parmi les 24 enfants qui ont finalement reçu un diagnostic de maladie neuromusculaire, cinq seulement avaient des anomalies myogènes à l’électromyogramme. Seize avaient un ENMG normal et trois présentaient des anomalies neurogènes.
Chez les nourrissons avec une hypotonie, l’ENMG est utile pour le diagnostic des atteintes du neurone périphérique. Un ENMG normal est une éventualité relativement commune dans les maladies musculaires du nourrisson alors que des anomalies myogènes semblent plus inhabituelles. La biopsie musculaire paraît donc indispensable. Dans quelques cas, des myopathies à début précoce peuvent présenter un aspect neurogène à l’ENMG. Un tel résultat ne devrait pas remettre en cause le diagnostic de myopathie évoqué cliniquement et devrait conduire au contraire à la réalisation d’une biopsie musculaire.
Merosin-deficient congenital muscular dystrophy in Korea
2009, Brain and Development
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of muscle disorders, presenting at birth or early infancy with hypotonia, muscle weakness, joint contractures, and dystrophic changes in the muscles. Merosin-deficient CMD (MDCMD) is rare in Asian populations, but more common in Caucasians, comprising about 50% of CMDs. We report, for the first time in Korea, eight patients with merosin-deficient CMD, confirmed by immunohistochemical staining of muscle or skin samples. We also describe their wide spectrum of clinical features and neuroimaging findings. Among 35 patients diagnosed as CMD, almost 23% of them were proved to have MDCMD with typical phenotypic presentation. We infer that prevalence of MDCMD in Korea may not be as low as expected. One of the patients was diagnosed by skin biopsy, which is good alternative for diagnosis of MDCMD.

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Neuromuscular Disorders

Abstract

References (10)

Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle

Neuromusc Disord

Expression of laminin subunits in congenital muscular dystrophy

Neuromusc Disord

Congenital muscular dystrophy with merosin deficiency

C R Acad Sci Paris, Life Science

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

Hum Mol Genet

Mutation in the laminin of α2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy

Nature Genet

Cited by (51)

Cardiac involvement in two rare neuromuscular diseases: LAMA2-related muscular dystrophy and SELENON-related myopathy

Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

Limb girdle muscular dystrophy due to LAMA2 mutations: Diagnostic difficulties due to associated peripheral neuropathy

Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations

The value of elecromyography in the aetiological diagnosis of hypotonia in infants and toddlers

Merosin-deficient congenital muscular dystrophy in Korea

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

Abstract

Neuromusc Disord

Neuromusc Disord

Congenital muscular dystrophy with merosin deficiency

C R Acad Sci Paris, Life Science

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

Hum Mol Genet

Mutation in the laminin of α2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy

Nature Genet

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