Congenital muscular dystrophy

Histomorphological and histochemical variability was studied in muscle specimens from 30 patients with congenital muscular dystrophy (CMD). We found involvement of the central nervous system in 8 patients (Fukuyama CMD, F-CMD), involvement of the brain and the eyes in 5 patients (muscle, eye and brain disease, MEB-D) and hypodense white matter on the CT scans of 2 patients with (sub)normal intelligence (occidentaltype cerebromuscular dystrophy, O-CMD). No morphological hallmarks were found to differentiate these subgroups. Only fat cell infiltration was found to be increased with increasing age in pure CMD (pure-CMD). The morphological data did not appear to be correlated with the clinical severity or type of dystrophy (pure-CMD, F-CMD, MEB-D and O-CMD). Immunohistochemistry with dystrophin, vimentin and desmin antibodies in 14 patients (6 pure-CMD, 5 F-CMD, 2 MEB-D and 1 O-CMD) showed a normal expression pattern.This investigation is part of the research program Disorders of the Neuromuscular System of the University of Nijmegen     

Congenital muscular dystrophy and cerebellar vermis agenesis in two brothers

Two brothers with motor retardation since the first months of life presented waddling ataxic-gait with lumbar lordosis, joint contractures and generalized muscle weakness. Both presented altered cerebellar tests and scanning speech. Creatine kinase, electromyography (EMG) and muscle biopsy pointed to muscular disease while CT scanning and NMR imaging showed cerebellar vermis agenesis. On this evidence we diagnosed the unusual association of vermian agenesis and congenital muscular dystrophy.

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Sommario Vengono riportati due fratelli con un ritardo motorio sin dai primi mesi di vita, andatura anserino-atassica, lordosi lombare, limitazioni articolari, debolezza muscolare diffusa, prove cerebellari alterate e parola scandita. La creatinchinasi, l'elettomiografia e la biopsia muscolare hanno evidenziato un coinvolgimento muscolare, mentre la tomografia computerizzata e la risonanza magnetica nucleare hanno mostrato una agenesia vermiana del cervelletto. Sulla base di questi dati abbiamo attribuito questa sintomatologia alla presenza simultanea di agenesia vermiana e di distrofia muscolare congenita.

     

Ullrich's congenital atonic sclerotic muscular dystrophy

Summary A 5-year old girl with Ullrich's atonic-sclerotic muscular dystrophy is reported and 16 previously reported cases are reviewed. The clinical features, in particular proximal contractures, distal hyperextensibility, mild dysmorphism and hyperhidrosis, allow recognition of this subtype of congenital muscular dystrophy, which has no specific pathological characteristics. There is evidence in favour of an autosomal recessive mode of inheritance.     

Congenital muscular dystrophy and severe central nervous system atrophy in two siblings

Severe degenerative features of the nervous system of a hitherto unknown kind, associated with a neuromuscular disorder with histopathological features of congenital muscular dystrophy, are reported in two female siblings. The clinical profile was characterized by generalized hypotonia followed by spastic tetraplegia, contractures, polyneuropathy, lack of cognitive development and progressive microcephaly. There was no involvement of the eyes. Neuropathological examination of the brain of one sibling, who died at the age of 30 months, revealed subtotal loss of neurons in the cerebral and cerebellar cortex and in the ventral pons, and secondary loss of myelin in the cerebral and cerebellar subcortical white matter. Sural nerve biopsy in the other sibling, who had a similar neurological affection, showed a lack of large myelinated fibers.This investigation is part of the research program Disorders of the Neuromuscular System of the University of Nijmegen     

FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort.     

Perioperative complications of scoliosis surgery in patients with Duchenne muscular dystrophy and spinal muscular atrophy,focussing on wound healing disorders

Purpose: Patients with Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA), both neuromuscular diseases, sustain spinal scoliosis in the course of their disease. To reduce the concomitant major morbidity and to improve their quality of life, patients require surgical spine stabilization. This can lead to complications like respiratory, cardiac or neurological complications or wound healing disorders (WHD). To find out the different complexities and risk factors increasing the chance to develop a WHD, the inpatient database was analyzed. Methods: We performed a retrospective statistical study. Therefore, we analyzed the inpatient database of 180 patients (142 DMD and 38 SMA patients). The focus was on WHD. To figure out the risk factors leading to WHD, we conducted a logistic regression. Results: Cardiac complications occurred most frequently, followed by pulmonary complications and neurological lesions. Fifty-seven out of 180 patients developed a WHD. In 23 cases the WHD was aseptic, in the other 34 cases dermal organisms, Pseudomonas species and intestinal organisms were responsible. By means of the logistic regression, we were able to identify two more risk factors, in addition to diagnosis and gender, for developing a WHD in our patients: the year of surgery and the direction of pelvic tilt. Conclusions: Most common complications following scoliosis surgery are respiratory and cardiac complications. WHD is a severe complication that implies a prolonged therapy. Some risk factors for developing WHD could be identified in this analysis. Specifically, these were the date of surgery and the direction of pelvic tilt.     

The most severe form of LMNA-associated congenital muscular dystrophy

Alterations in the LMNA gene cause a wide spectrum of diseases collectively called laminopathies. LMNA-associated congenital muscular dystrophy is a form of laminopathy, which usually causes infantile onset of muscle weakness, predominantly in the cervical-axial muscles, and motor developmental retardation. Cardiac symptoms during the first decade of life are rare. We report a case of LMNA-associated congenital muscular dystrophy in which the patient did not achieve head control and experienced facial muscle weakness. Cardiac dysrhythmias were observed at 5 years with development of dilated cardiomyopathy and ischemic strokes at 7 years. Despite intensive medical intervention, he died suddenly at 9 years. This report broadens the spectrum of phenotypes of this disorder with the most severe symptoms during the first decade of life. Our case underscores the need for early genetic testing for LMNA in patients with congenital muscular dystrophy to screen for cardiac manifestations and intervene as necessary.     

A scapular onset muscular dystrophy without facial involvement: Possible allelism with facioscapulohumeral muscular dystrophy

A dominantly inherited muscular dystrophy with onset in the shoulder girdle and later progression to the lower limbs is described. The disorder was clinically distinguishable from known facioscapulohumeral, scapulohumeral and limb girdle syndromes. A 38 kb allele detected by probe p13E-11 (D4F104S1) segregated with the disease. Linkage analysis gave a maximum lod score of z = 1.61 at θ = 0.01 with the 4q35 marker D4S184 (affected only analysis z = 1.20 at θ = 0.01) suggesting probable allelism with facioscapulohumeral muscular dystrophy.     

Congenital muscular dystrophy,brain and eye abnormalities: one or more clinical entities?

Four children with congenital muscular dystrophy (CMD), eye and brain abnormalities are described. Their clinical and neuroradiological features are compatible with a diagnosis of Walker-Warburg syndrome (WWS), according to the criteria proposed by Dobyns et al. (i.e., presence of type II lissencephaly, typical cerebellar and retinal malformations, CMD), who also conclude that WWS is indistinguishable from the muscleeye-brain disease (MEBD) described by Santavuori. On the basis of our own experience and two recently published series, we emphasize certain features that are different in patients with WWS and patients with MEBD, which make their inclusion in the same syndrome dubious.     

Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy

Background

One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited.

Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome

We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest in their surroundings. In addition, all patients had a striking enlargement of the calf and quadriceps muscles. Ophthalmologic examination revealed no structural ocular abnormalities in any of the children; one patient had severe myopia. In all cases a magnetic resonance imaging of the brain showed an abnormal posterior cranial fossa with enlargement of the cisterna magna and variable hypoplasia of the vermis of the cerebellum. Abnormality of the white matter was also present in all patients, in the form of patchy signal most evident in the periventricular areas. Serum CK was grossly elevated in all. The muscle biopsy from all cases showed dystrophic changes compatible with congenital muscular dystrophy. Immunofluorescence studies showed mild to moderate partial deficiency of laminin 2 chain. Linkage analysis in the only informative family excluded the known loci for congenital muscular dystrophy, including laminin 2 chain on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3 and the muscle-eye-brain disease on chromosome 1p3. We propose that this represent a novel severe variant of congenital muscular dystrophy, with associated central nervous system involvement.     

Prednisolone therapy in Duchenne muscular dystrophy prolongs ambulation and prevents scoliosis

Steroids may have a beneficial effect on the course of Duchenne muscular dystrophy (DMD). However, results vary in different studies. This study consisted of 66 DMD boys who were in the therapy group and 22 DMD boys in the control group. The mean ages were 6.8 +/- 2.1 years (range 2.5-12.5) and 7.0 +/- 1.3 years (range 5.0-9.0), respectively. We assessed muscle strength, 10-m walking, ankle contracture, and loss of independent walking ability age and onset of scoliosis. Treatment regimen was oral prednisolone 0.75 mg/kg on alternate days, plus vitamin D 600-1200 units/day and a calcium-enriched diet. After a follow-up period of 2.75 +/- 1.1 years (range 1.5-5) and when compared with controls, there was a statistically significant change in muscle strength between the two groups after 12 months (P < 0.05). Although 10-m walking time decreased in therapy group (P < 0.05), there was not significance between the groups in the end. Boys in the control group developed significantly less ankle contractures (P < 0.05). None of the therapy group had scoliosis during the follow-up period (mean age 10.8 +/- 1.2 years), whereas seven boys of the control group had scoliosis at a mean age of 11.7 +/- 2 years. Loss of walking ability age was statistically different between groups (P < 0.05). Our results indicate that, alternate-day prednisolone regimen may prolong ambulation and scoliosis can be delayed or prevented.     

Erythrocyte flexibility, ATPase activities and Ca efflux in patients with Duchenne muscular dystrophy, myotonic muscular dystrophy and congenital myotonia

Erythrocyte flexibility measured by a polycarbonate membrane filtration method showed increased fragility (265 +/- 163 Hb mg/l vs. controls 86 +/- 72 Hb mg/l; mean +/- SD; P less than 0.0025) and increased rigidity (123 +/- 96 mm Hg vs. 79 +/- 19 mm Hg; P less than 0.05) in patients with congenital myotonia, while both parameters were normal in patients with Duchenne muscular dystrophy or with myotonic dystrophy. Erythrocyte ghosts obtained from patients with MyD displayed highly significant increases in both (Na+ + K+)-ATPase and (Ca2+ + Mg2+)-ATPase activities (P less than 0.005) and to a lesser extent in Mg2+-ATPase activity (P less than 0.05), while no difference was seen between patients with DMD and age-matched controls. The efflux of Ca2+ was increased from erythrocytes of patients with DMD as compared to age-matched controls (82 +/- 2% vs. 70 +/- 4%; P less than 0.005), while no difference was detected between patients with MyD and age-matched controls.     

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations

Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker–Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker–Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.     

Infantile facioscapulohumeral muscular dystrophy: new observations

Clinical, electrodiagnostic, and biopsy findings in a family with infantile facioscapulohumeral muscular dystrophy are reported. Four of eight family members having the disorder, all with onset in infancy, developed severe weakness leading to death in adolescence. The clinical course and prognosis of infantile facioscapulohumeral muscular dystrophy may, therefore, be as devastating as that of Duchenne muscular dystrophy. The unusual infantile presentation and high mortality in our affected family members suggest that the gene coding for this disorder may be different from that responsible for conventional facioscapulohumeral muscular dystrophy.     

Intrafamilial variability of X-linked progressive muscular dystrophy

Summary Four of five afflicted boys in the family K. suffer from the Becker type of dystrophy and one from a more severe type. All affected boys and their mothers, who are three sisters, have undergone clinical, electromyographic, electrocardiographic and biochemical examination; muscle biopsy was performed in some boys. This family is a rare example of the intrafamilial variability of X-linked progressive muscular dystrophy. The possible explanation of the variability observed is discussed.This work was supported by PLO grant No. 05-002 N of N.I.H., Bethesda, Ma., USA     

Becker and limb-girdle muscular dystrophy associated with pituitary dwarfism

Summary In 1981 a report appeared of a patient with Duchenne muscular dystrophy associated with dwarfism caused by growth hormone deficiency, in whom the muscular disease was unusually benign. The authors suggested that the benign course might be related to the growth hormone deficiency and dwarfism. Other authors later supported this idea, having observed that in dystrophic mice and hamsters with congenital and experimentally induced pituitary dwarfism, respectively, pathological expressions of the dystrophy were markedly reduced. In this paper one case of Becker and one of limb-girdle dystrophy, each associated with short stature and growth hormone deficiency are described. In these cases the disease did not have a particularly benign course. It is concluded that caution is necessary, at least in certain cases, before an association between reduced muscular growth and the dystrophic process can be assumed.