The Second Congress of the European Paediatric Neurology Society: Maastricht 8-11 October 1997.
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Humans↗
Biomedical subjects
F Muntoni
Publications and source records attributed to F Muntoni.
Evidence of left ventricular dysfunction in children with merosin-deficient congenital muscular dystrophy.
BACKGROUND: Deficiency of the sarcolemmal protein dystrophin has been linked to dilated cardiomyopathy. Some children with congenital muscular dystrophy have a deficiency of the laminin alpha2 chain of merosin, an extracellular matrix protein linked to dystrophin through a group of glycoproteins. It has been shown that deficiency in one of these glycoproteins is responsible for muscular dystrophy and dilated cardiomyopathy. Children with laminin alpha2 deficiency may be at risk for development of cardiomyopathy. METHODS AND RESULTS: We studied the cardiac function of a cohort of 16 children with congenital muscular dystrophy by using 2-dimensional echocardiography. The expression of the laminin alpha2 of merosin in the patients was determined on a skin or muscle biopsy. Two of 6 merosin-deficient children had an ejection fraction <40%. The average ejection fraction of the merosin-deficient children was 43%+/-11%, which was significantly lower than the merosin-positive children (53%+/-5%, P=.03). CONCLUSIONS: This study suggests that a deficiency of laminin alpha2 can give rise to dilated cardiomyopathy, supporting the idea that defects of dystrophin, or of associated proteins, can cause dilated cardiomyopathy in addition to muscular dystrophy.
Adolescent↗
Visual function in children with merosin-deficient and merosin-positive congenital muscular dystrophy.
This study evaluates whether abnormalities of visual function are present in children with congenital muscular dystrophy and whether these, if present, are associated with merosin status or magnetic resonance imaging (MRI) findings. Twenty children (age range 5-17 years) with a diagnosis of classical congenital muscular dystrophy were assessed on visual acuity, stereopsis, and visual fields and the results compared with merosin status and MRI findings. Visual-evoked potential results were available for 14 of 20 children. All 20 children revealed normal results on all the clinical tests assessing visual function, irrespective of their merosin status or of MRI findings. Visual-evoked potentials were normal in the children with merosin-positive congenital muscular dystrophy but were abnormal in those with merosin deficiency. Unlike the other forms of congenital muscular dystrophy, which are associated with structural brain changes and eye involvement, visual function was always normal in the classical form of congenital muscular dystrophy. Interestingly, visual function was normal also in the group of children with merosin-deficient congenital muscular dystrophy who manifested white matter changes involving the occipital lobes on MRI and abnormal visual evoked potentials. Further studies are needed to specify the nature of the white matter changes observed with MRI and the reason for the dissociation between clinical and neurophysiologic findings.
Adolescent↗
Early presentation of X-linked Emery-Dreifuss muscular dystrophy resembling limb-girdle muscular dystrophy.
Emery-Dreifuss muscular dystrophy is an X-linked neuromuscular disorder caused by defects in the STA gene on Xq28, which codes for a nuclear protein named emerin. Affected patients usually present in early adolescence with scapulo-peroneal muscle weakness and wasting, and contractures of the tendo Achilles, elbows and paraspinal muscles, resulting in spine rigidity. We present here a case of Emery-Dreifuss muscular dystrophy with an unusually severe, early presentation. He presented at 2.5 years with predominantly proximal weakness and mild equinovarus deformity of the right foot. Serum creatine kinase activity was elevated (1994 IU/I) and a muscle biopsy at the age of 4 years showed marked dystrophic abnormalities. Normal expression of dystrophin, and no detectable deletion in the corresponding gene, excluded a diagnosis of Duchenne muscular dystrophy. Similarly, normal expression of alpha-sarcoglycan made a limb-girdle muscular dystrophy caused by a defect in a sarcoglycan unlikely. Several years later, examination of the proband's maternal cousin, aged 14 years, suggested Emery-Dreifuss muscular dystrophy. This was confirmed in both affected boys by the absence of emerin in muscle and leucocytes, and identification of a mutation in exon 4 of the STA gene. Carrier status in both mothers was also confirmed by mutational and protein analysis. Emery-Dreifuss muscular dystrophy should therefore be considered in the differential diagnosis of cases of early onset muscular dystrophy, even in the absence of the typical clinical features.
Age of Onset↗
A severe clinical and pathological variant of central core disease with possible autosomal recessive inheritance.
Central core disease (CCD) is a well recognized, relatively mild, non- or slowly progressive, dominantly inherited, congenital myopathy due, at least in some families, to mutations in the ryanodine receptor gene on chromosome 19q13.1. We report two unrelated cases with an unusual, early onset congenital myopathy with severe contractures, delayed motor milestones, proximal muscle weakness, normal serum creatine kinase (CK), a non-progressive course, with muscle biopsy findings of central cores and in addition, marked proliferation of connective and adipose tissue, and variation in fibre size. Muscle biopsies from the parents, who were non-consanguineous and healthy, showed minor myopathic changes and uneven staining with oxidative enzymes, but no central cores. The marked histological muscle changes, the distribution of weakness and the non-progressive course of the disease suggest that this is a severe variant of central core disease with secondary dystrophy-like change. The presence of mild changes in the histochemical reactions of biopsies of both parents of these two children supports the hypothesis that they are carriers of a recessive disease gene mutation responsible for this unusually severe form of central core disease.
Biopsy↗
Laminin alpha 2-chain gene mutations in two siblings presenting with limb-girdle muscular dystrophy.
We report two siblings, an 11-year-old boy and his 7-year-old sister, referred to us with a diagnosis of muscular dystrophy. The boy presented at 22 months with delay in walking. A very high serum creatine kinase (CK) level and a dystrophic muscle biopsy lead to a diagnosis of Duchenne muscular dystrophy prior to the identification of the dystrophin gene. Two years later his sister presented with similar problems. A diagnosis of limb-girdle muscular dystrophy was made when they were shown to have inherited different X-chromosomes and normal expression of dystrophin and all sarcoglycans. Their conditions remained static. Recently a slowing of the peripheral motor nerve conduction velocities and T2-weighted brain magnetic resonance imaging showed increased signal of the white matter, both of which are features of merosin-deficient congenital muscular dystrophy. Immunolabelling using a C-terminal laminin alpha 2 chain antibody showed a reduction in expression, while labelling with another antibody that recognises a 300-kDa fragment showed a very significant reduction. Mutational analysis of the LAMA2 gene showed two mutations: one was a G-->C point mutation at position -1 of intron 28 acceptor splicing site. This mutation induced activation of a cryptic splice at nucleotide 4429 of exon 29 and partial skipping of this exon, with conservation of the open reading frame. The other was a nonsense mutation due to a C_T transition at position 5525 of the cDNA sequence (exon 37), resulting in a stop codon. These data confirm that mutations of the LAMA2 gene that do not completely disrupt the production of the protein can give rise to phenotypes considerably milder than classical merosin-deficient congenital muscular dystrophy. Partial laminin alpha 2 deficiency should be considered in the differential diagnosis of limb-girdle muscular dystrophy.
Base Sequence↗
Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families.
This study reports three children from three unrelated families, aged from 9 to 12 years, who were investigated because of the incidental finding of elevated serum creatine kinase (CK) levels and were found to have a dystrophinopathy. The molecular defect consisted of a deletion of variable extent within the central rod domain of the dystrophin gene, involving either exons 32-44 or 48-51 or 48-53. In each family we found the same deletion in at least one adult male relative aged from 40 to 77 years, who was either completely asymptomatic or had very mild muscle involvement (thin muscles and/or mild scoliosis), with normal or borderline CK levels. This study suggests once again that deletions of the central rod domain of dystrophin may be associated with elevation of serum CK as the only manifestation and that prediction of the clinical severity based solely on the molecular findings should be interpreted with caution.
Adult↗
Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36.
Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin alpha2 chain (or merosin), has been identified in these disorders. Mutations in LAMA2 cause CMD with complete or partial merosin deficiency, detectable by immunocytochemistry on muscle biopsies, and account for approximately 50% of CMD cases. In a large consanguineous family (11 siblings) comprising three children affected by CMD without merosin deficiency, we undertook a genomewide search by homozygosity mapping and analyzed 380 microsatellite markers. The affected children were homozygous for several markers on chromosome 1p35-36. We identified two additional consanguineous families with affected children who also showed linkage to this locus. A maximum cumulative LOD score of 4.48, at a recombination fraction of .00, was obtained with D1S2885. A consistent feature in these three families was the presence of early rigidity of the spine, scoliosis, and reduced vital capacity, as found in rigid-spine syndrome (RSS). This study is the first description of a locus for a merosin-positive CMD and will help to better define the nosology of RSS.
Adolescent↗
A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy.
We have identified and characterized a genomic sequence with some features typical of Alu-like mobile elements rearranged into the dystrophin gene in a family affected by X-linked dilated cardiomyopathy. The Alu-like sequence rearrangement occurred 2.4 kb downstream from the 5' end of intron 11 of the dystrophin gene. This rearrangement activated one cryptic splice site in intron 11 and produced an alternative transcript containing the Alu-like sequence and part of the adjacent intron 11, spliced between exons 11 and 12. Translation of this alternative transcript is truncated because of the numerous stop codons present in every frame of the Alu-like sequence. Only the mutant mRNA was detected in the heart muscle, but in the skeletal muscle it coexisted with the normal one. This result is supported by the immunocytochemical findings, which failed to detect dystrophin in the patient's cardiac muscle but showed expression of a reduced level of protein in the skeletal muscle. Comparative analysis of the Alu-like sequence showed high homology with other repeated-element-containing regions and with several expressed sequence tags. We suggest that this Alu-like sequence could represent a novel class of repetitive elements, reiterated and clustered with some known mobile elements and capable of transposition. Our report underlines the complexity of the pathogenic mechanism leading to X-linked dilated cardiomyopathy but suggests that differences in tissue-specific expression of dystrophin mutations may be a common feature in this condition.
Adult↗
Abnormal merosin in adults. A new form of late onset muscular dystrophy not linked to chromosome 6q2.
We have identified seven patients (including two sib pairs) with a predominantly late onset limb-girdle muscular dystrophy in whom an absence of merosin was noted on immunoblotting. Merosin immunocytochemistry was normal, and no abnormalities were detected on immunostaining for the various proteins known to be involved in the limb-girdle muscular dystrophies (alpha, beta, gamma, delta sarcoglycan and calpain 3). Apart from one patient, where muscle problems began in childhood, reported age at onset of muscle weakness involving initially the proximal muscles of the lower limbs ranged from 17 to 40 years. The pattern of muscle involvement was similar from patient to patient, with hypertrophy of at least the calf muscles, absence of scapular winging and predominant involvement of hip flexors and adductors and hamstrings more than quadriceps. Serum creatine kinase in all patients was at least 10 times normal, and muscle biopsies showed non-specific dystrophic features. We believe that the patients described here may represent a genetically distinct subset within the limb-girdle muscular dystrophy group.
Adolescent↗
Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression.
Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been studied both by DNA sequencing and by emerin protein expression. Fourteen had mutations in the X-linked emerin gene, while three showed evidence of autosomal inheritance. Twelve of the 14 emerin mutations caused early termination of translation. An in-frame deletion of six amino acids from the C-terminal transmembrane helix caused almost complete absence of emerin from muscle with no localization to the nuclear membrane, although mRNA levels were normal. This shows that mutant emerin proteins are unstable if they are unable to integrate into a membrane. A 22 bp deletion in the promoter region was expected to result in reduced emerin production, but normal amounts of emerin of normal size were found in leucocytes and lymphoblastoid cell lines. This shows that DNA analysis is necessary to exclude emerin mutations in suspected X-linked EDMD. Emerin levels in female carriers often deviated from the expected 50% and this was due, in at least two families, to skewed emerin mRNA expression from the normal and mutated alleles. In one family with a novel deletion of the last three exons of the emerin gene, a carrier had a cardiomyopathy and very low emerin levels (<5% of normal) due to skewed X-inactivation. In the three autosomal cases of EDMD, emerin was normal on western blots of blood cells, which suggests that autosomal EDMD is not caused by indirect reduction of emerin levels.
Adolescent↗
DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population.
Multiple sclerosis (MS) is a common neurological disease caused by genetic and environmental factors. Previous genetic analyses have suggested that theMHC/HLA region on chromosome 6p21 contains an MS-predisposing component. Which of the many genes present in this region is primarily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the Mediterranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition. Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian-specific DRB1*0405(DR4)- DQA1*0501-DQB1*0301 haplotype and the DRB1* 0301(DR3)-DQA1*0501-DQB1*0201 haplotype. Detailed comparative analysis of the DRB1-DQA1- DQB1 haplotypes present in this data set did not identify an individual locus that could explain MS susceptibility. The predisposing effect is haplotype specific, in that it is confined to specific combinations of alleles at the DRB1, DQA1 and DQB1 loci. Cross-ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These results suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsible for genetic susceptibility to MS. Alternatively, the presence of complex interactions between different HLA haplotypes, other non-HLA predisposing genes and environmental factors may explain different associations in different populations.
Adolescent↗
Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy.
BACKGROUND: Respiratory failure is the commonest cause of death in patients with Duchenne muscular dystrophy (DMD). Life expectancy is less than one year once diurnal hypercapnia develops. This study examines the effects of nasal intermittent positive pressure ventilation (NIPPV) on survival in symptomatic Duchenne patients with established ventilatory failure. METHODS: Nocturnal NIPPV was applied in 23 consecutive patients with DMD of mean (SD) age 20.3 (3.4) years who presented with diurnal and nocturnal hypercapnia. RESULTS: One year and five year survival rates were 85% (95% CI 69 to 100) and 73% (95% CI 53 to 94), respectively. Early changes in arterial blood gas tensions following NIPPV occurred with mean (SD) PO2 increasing from 7.6 (2.1) kPa to 10.8 (1.3) kPa and mean (SD) PCO2 falling from 10.3 (4.5) kPa to 6.1 (1.0) kPa. Improvements in arterial blood gas tensions were maintained over five years. Health perception and social aspects of SF-36 health related quality of life index were reported as equivalent to other groups with nonprogressive disorders using NIPPV. CONCLUSIONS: Nasal ventilation is likely to increase survival in hypercapnic patients with Duchenne muscular dystrophy and should be considered as a treatment option when ventilatory failure develops.
Adolescent↗
Intraventricular alpha-interferon in subacute sclerosing panencephalitis.
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Antineoplastic Agents↗
Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene.
Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Dejerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q (CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.
Adult↗
Congenital muscular dystrophy: from rags to riches.
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Humans↗
Early onset, autosomal recessive muscular dystrophy with Emery-Dreifuss phenotype and normal emerin expression.
OBJECTIVE: To describe the clinical and histopathologic picture of a childhood-onset, severe variant of scapuloperoneal MD with rigidity of the spine. BACKGROUND: Rigidity of the spine is a feature of numerous syndromes, including X-linked Emery-Dreifuss MD, Bethlem myopathy, and the rigid spine syndrome. These are, however, relatively static or very slowly progressive neuromuscular disorders, usually associated with preserved ambulation into adult life. PATIENTS AND METHODS: Five unrelated children (three boys and two girls) presented in the first 2 years of life with poor neck control, waddling gait, and frequent falls. Early wasting of the distal leg muscles, biceps, triceps, and neck muscles was noted in all patients, and all had contractures and severe rigidity of the spine. The condition progressed rapidly, and all patients lost ambulation before the age of 8 years. Cardiac function was normal in all. RESULTS: Creatine kinase was moderately elevated in all, and muscle biopsy specimens showed nonspecific dystrophic changes with normal expression of dystrophin, the sarcoglycans, and laminin alpha2, alpha5, beta1, and gamma1 chains. Emerin expression was normal in two of the boys whose tissue was available for study. CONCLUSIONS: The distribution of weakness, wasting, and contractures of the patients described resembled Emery-Dreifuss MD, but the rapid progression of weakness and contractures and the involvement of both sexes together with normal emerin expression suggest that this form is not X-linked Emery-Dreifuss MD. We suggest that these patients represent a severe MD characterized by early onset distal wasting and severe rigidity of the spine, with probable autosomal recessive inheritance.
Age of Onset↗
Localization of laminin alpha 2 chain in normal human central nervous system: an immunofluorescence and ultrastructural study.
Recently, a rare form of congenital muscular dystrophy has been shown to be associated with a deficiency of laminin alpha 2 chain, a tissue-specific component of the basal lamina. Besides muscular dystrophy, children affected with this disorder also show electrophysiological and magnetic resonance imaging evidence of white matter involvement in the central nervous system (CNS). We have studied the precise localization of laminin alpha 2 chain in normal human brain, using specific electron microscopic techniques including thin-section fracture labeling and cryoultramicrotomy, in parallel with immunohistochemical techniques. We found that this laminin chain was localized to the basal lamina of all cerebral blood vessels, whereas blood vessels of the choroid plexus did not show any reaction. No positive reaction was found in meningeal blood vessels either. We hypothesize that in normal brain, laminin alpha 2 may be important for the selective filtration capability of the blood-brain barrier. The lack of laminin alpha 2 in cerebral vessels of children with laminin alpha 2-deficient congenital muscular dystrophy may cause impaired selective filtration, leading to leakage of plasma components and damage to the CNS. Further studies should be performed on patients affected by congenital muscular dystrophy associated with laminin alpha 2 deficiency to test this hypothesis.
Adult↗