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F Muntoni

Publications and source records attributed to F Muntoni.

At least 109 records · Page 6Linked to original sources
PubMed2000

An unusual case of hyperekplexia.

Hyperekplexia is a rare paroxysmal disorder characterized by exaggerated startle response, hypertonia during infancy and a transient increase in tone following startle attacks. We report an unusual case of hyperekplexia in a young man. In addition to common symptoms of the condition, we found generalized spasticity persisting beyond infancy, and facial and skeletal dysmorphism. Because of an unsteady gait with frequent falls and raised serum creatine kinase levels, a congenital myopathy had been suspected in the past and an abnormal muscle biopsy had been documented. We diagnosed hyperekplexia at the age of 21 years on clinical grounds and following the response to pharmacological treatment. A mutation in the alpha1 subunit of the glycine receptor confirmed the diagnosis. A repeated needle muscle biopsy demonstrated mild myopathic changes, which we considered to be secondary to increased muscle tone. This case highlights the diagnostic difficulties of hyperekplexia, particularly in sporadic cases with unusual presentation.

Adult↗
PubMed2000

Velocardiofacial syndrome associated with atrophy of the shoulder girdle muscles and cervicomedullary narrowing.

Velocardiofacial syndrome is the most common microdeletion syndrome in humans. It is secondary to a chromosome 22q11 rearrangement and is characterized by craniofacial abnormalities, heart defects and learning disability. We report a case of a 10-year-old girl with a chromosome 22q11 deletion who, in addition to learning difficulties, hypernasal speech and mild dysmorphic features, had weakness and wasting of the shoulder girdle muscles but no cardiac involvement. Brain magnetic resonance imaging revealed narrowing of the cervicomedullary junction. The clinical features of this patient with velocardiofacial syndrome further expand the spectrum of abnormalities associated with this condition.

Brachial Plexus Neuritis↗
PubMed2000

Brain magnetic resonance imaging abnormalities in merosin-positive congenital muscular dystrophy.

We report the brain magnetic resonance imaging (MRI) findings in 23 patients with merosin-positive congenital muscular dystrophy (CMD). Twelve patients had normal scans. Eight other children had essentially normal scans but showed mild non-specific periventricular white matter changes. Three children had structural abnormalities on imaging. The first patient, a 15-month-old boy with hypotonia, muscle weakness and global development delay, had moderate cerebellar atrophy and mild dilatation of the lateral ventricles. The second child, a 3-year-old ambulant girl with subtle learning problems, had mild cerebellar hypoplasia and a large subarachnoid space when scanned at 16 months. The third patient, a 15-year-old ambulant male with normal intelligence and complex partial seizures, had polymicrogyria of both temporoparietal lobes on brain MRI. The clinical features and motor ability of children with merosin-positive CMD are variable, although usually milder than merosin-deficient CMD. Our findings confirm that central nervous system involvement can occur in some merosin-positive cases. We suggest performing brain MRI in children with merosin-positive CMD, as this may help in our understanding of this very heterogeneous disease.

Atrophy↗
PubMed2000

Congenital muscular dystrophy with secondary merosin deficiency and normal brain MRI: a novel entity?

We describe two Scottish siblings affected by a form of congenital muscular dystrophy characterised by a severe clinical phenotype, similar to that observed in the 6q-linked merosin-deficient CMD but in whom brain MRI and cognitive development were normal. The maximal function achieved in the 2 siblings was sitting independently. Serum CK were grossly elevated and the skin and muscle biopsies showed a severe reduction of merosin in both. The normal brain MRI and normal cognitive development distinguish this form from Fukuyama congenital muscular dystrophy, muscle-eye-brain disease or other forms of CMD with secondary partial merosin deficiency and abnormal brain MRI and/or mental retardation. Linkage analysis excluded all the known loci for CMD. We propose that this may represent a novel variant of CMD.

Biopsy↗
PubMed2000

Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42.

We have previously reported an autosomal recessive form of congenital muscular dystrophy, characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the tendo Achilles, in a consanguineous family from the United Arab Emirates. Early respiratory failure resulting from severe diaphragmatic involvement was present. Intellect and the results of brain imaging were normal. Serum creatine kinase levels were grossly elevated, and muscle-biopsy samples showed dystrophic changes. The expression of the laminin-alpha2 chain of merosin was reduced on several fibers, but linkage analysis excluded the LAMA2 locus on chromosome 6q22-23. Here, we report the results of genomewide linkage analysis of this family, by use of homozygosity mapping. In all four affected children, an identical homozygous region was identified on chromosome 1q42, spanning 6-15 cM between flanking markers D1S2860 and D1S2800. We have identified a second German family with two affected children having similar clinical and histopathological features; they are consistent with linkage to the same locus. The cumulative LOD score was 3.57 (straight theta=.00) at marker D1S213. This represents a novel locus for congenital muscular dystrophy. We suggest calling this disorder "CMD1B." The expression of three functional candidate genes in the CMD1B critical region was investigated, and no detectable changes in their level of expression were observed. The secondary reduction in laminin-alpha2 chain in these families suggests that the primary genetic defect resides in a gene coding for a protein involved in basal lamina assembly.

Antigens, CD↗
PubMed2000

Mutations in the laminin alpha2-chain gene in two children with early-onset muscular dystrophy.

We investigated two children who presented with delayed motor milestones. The first was a girl who was referred at 20 months because of developmental delay. She walked at 28 months and currently, aged 5 years, is independently mobile but has difficulty rising from the floor or going upstairs. The second was also a girl who presented at 6 weeks of age with hypotonia. Her motor milestones were delayed and she walked at the age of 2 years and 8 months and is currently independently mobile at the age of 3 years. Serum creatine kinase was elevated and a muscle biopsy showed dystrophic changes in both children. Immunohistochemistry of the laminin alpha2 chain of merosin was very similar in both cases: using a C-terminal antibody that recognizes an 80 kDa fragment, there was a mild reduction in expression on most fibres, while the staining with another antibody that recognizes a 300 kDa fragment showed a very marked reduction. Mutational analysis of the laminin alpha2 chain gene in the first patient showed that one of the two alleles had a de novo single nucleotide deletion at position 5702, causing a frameshift. In the other allele, we identified two point mutations present in cis; one was a G-->C transition at position +5 while the second was a T-->C transition at position +6 of the conserved donor splicing consensus sequence of introns 37 and 63, respectively. Transcription analysis of the corresponding cDNA region did not show any alternative splicing occurring as a result of these splice site mutations. Therefore, these mutations probably affect the splicing efficiency. Interestingly, the second child carried in both alleles the same two splicing consensus sequence mutations found in cis in the first patient. Our data provide further evidence that mutations in the laminin alpha2 chain gene are responsible not only for the severe form of congenital muscular dystrophy with onset at birth, but also for milder phenotypes, with later onset, in which the synthesis of a partially functional protein, or of a normal protein but in reduced quantity, is possible. The finding that these two unrelated patients had the same unusual mutation in common might suggest that this is a relatively commonly allele responsible for partial merosin deficiency in the UK.

Age of Onset↗
PubMed2000

X-linked vacuolar myopathies: two separate loci and refined genetic mapping.

X-linked vacuolar myopathies can be divided into two forms: one that is associated with cardiomyopathy and mental retardation (XVCM-MR) and a second form, termed X-linked myopathy with excessive autophagy (XMEA), that spares cardiac muscle and has no central nervous system involvement. In this article, we demonstrate linkage between XMEA and markers on chromosome Xq28 and assign the XMEA gene locus to the most telomeric 10.5 cM of chromosome X. We also show that XVCM-MR is not allelic to XMEA.

Adolescent↗
PubMed2000

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease. In conclusion, the high proportion of de novo mutations together with the large spectrum of both LMNA mutations and the expression of the disease should now prompt screening for LMNA in familial and sporadic cases of both EDMD and dilated cardiomyopathy associated with conduction system disease.

Adolescent↗
PubMed1999

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

BACKGROUND: Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood. METHODS: We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained. RESULTS: Five novel missense mutations were identified: four in the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C. CONCLUSIONS: Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility.

Adolescent↗
PubMed1999

Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the alpha-tropomyosin gene TPM3. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3' end of the 20. 8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.

Australia↗
PubMed1999

Cardiomyopathy in duchenne, becker, and sarcoglycanopathies: a role for coronary dysfunction?

Dilated cardiomyopathy is a feature of Duchenne and Becker muscular dystrophies and occasionally of sarcoglycanopathies. Its pathogenesis is unknown. Patients with myotonic dystrophy have an impairment of coronary smooth muscle and this could contribute to their cardiomyopathy. We used positron emission tomography (PET) to study myocardial blood flow and coronary vasodilator reserve at baseline and during hyperemia in 7 Duchenne, 8 Becker, and 5 sarcoglycanopathy patients. The study was normal in all Becker patients. In contrast, baseline myocardial blood flow was increased and coronary vasodilator reserve blunted in Duchenne and sarcoglycanopathy patients despite normal hyperemic myocardial blood flow. The reduction of coronary vasodilator reserve was due to an increased baseline myocardial blood flow. In Duchenne dystrophy, but not in sarcoglycanopathies, correction for cardiac workload normalized the coronary vasodilator reserve. In the latter patients, abnormal baseline myocardial blood flow could be due to vascular smooth muscle dysfunction.

Adolescent↗
PubMed1999

Is there selection in favour of heterozygotes in families with merosin-deficient congenital muscular dystrophy?

Merosin-deficient congenital muscular dystrophy is an autosomal recessive neuromuscular disorder caused by partial or total absence of laminin-2 (merosin) in the skeletal muscle. Affected children have severe weakness, hypotonia at birth, high creatine kinase (CK) levels (more than 10 times normal) and are not able to walk or stand unsupported. Linkage and mutation analysis demonstrated that the gene encoding for the laminin-alpha2 chain, mapped on chromosome 6q22-23, is invariably responsible for this form of congenital muscular dystrophy. We investigated the pattern of inheritance of the haplotypes associated with the mutated allele in 29 informative merosin-deficient families, using tightly linked informative polymorphic microsatellite markers. This allowed us to identify heterozygous individuals from normal homozygotes, who are clinically, pathologically and biochemically indistinguishable. By linkage analysis, we found a statistically significant increase in the number of heterozygous individuals carrying either the paternal or the maternal haplotypes associated with the mutated allele. This could suggest a selection in favour of the alleles carrying mutations at the laminin alpha2-chain locus.

Female↗
PubMed1999

Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group.

OBJECTIVES: This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND: A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS: Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS: Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS: Familial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.

Adolescent↗
PubMed1999

Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging.

Children with merosin-deficient congenital muscular dystrophy (CMD) have striking white matter changes on T-2 weighted brain magnetic resonance imaging (MRI). There have been occasional cases with structural abnormalities, mainly involving the occipital cortex. We report our brain imaging findings in 14 children with merosin-deficient CMD. Ten cases had a severe reduction or absence of merosin on immunocytochemistry and four cases had partial reduction. All 14 cases had white matter changes, which appeared after the first 6 months of life and persisted with time. The changes were diffuse and the oldest child scanned (14 years) also showed involvement of the U fibres. Five children with total absence of merosin also had structural abnormalities. One child had moderate mental retardation and epilepsy, mainly characterised by complex partial seizures, with atypical absences, which had been difficult to treat. Brain MRI showed marked occipital agyria and pontocerebellar hypoplasia. The gyral pattern of the rest of the brain looked normal. The four other cases, all with normal intelligence, also had cerebellar hypoplasia with variable involvement of the pons. They did not, however, have neuronal migration defects. It is recognised that several forms of congenital muscular dystrophy, namely Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, have structural brain abnormalities and associated severe mental retardation. Our cases demonstrate that a range of structural malformations can also be found in a significant number of children with merosin-deficient CMD.

Adolescent↗
PubMed1999

X-linked dilated cardiomyopathy and the dystrophin gene.

X-linked dilated cardiomyopathy (XLDC) represents a well known genetic disease, allelic to Duchenne and Becker muscular dystrophies and caused by dystrophin gene mutations. XLDC is a rare disease and only few families have been fully characterised. In several of them, the dystrophin mutations show a different pattern of expression in cardiac compared to skeletal muscle. In the families with the most severe cardiac phenotype, the cardiac muscle is usually unable to produce dystrophin, due to a specific effect that the mutation(s) have on the gene transcription in this tissue. The skeletal muscle escapes the dystrophic changes by maintaining dystrophin synthesis via exon skipping or alternative splicing that the heart is not able to put in place. In this paper we have reviewed the families with X-linked dilated cardiomyopathy reported so far; in addition we provided novel transcription data on two families we previously described. The aim of this review is to attempt a genotype-phenotype correlation and speculate on common pathogenic mechanisms underlying this disease.

Adolescent↗
PubMed1999

Cognitive abilities in children with congenital muscular dystrophy: correlation with brain MRI and merosin status.

The aim of the study was to evaluate whether children with merosin-positive or merosin-deficient congenital muscular dystrophy (CMD) show any cognitive impairment and whether this is related to brain abnormalities on magnetic resonance imaging (MRI). Twenty-two patients (age range: 5.8-15.3 years) were assessed by the Wechsler Intelligence Scales. Twelve were merosin-positive and ten merosin-deficient. One child had severe mental retardation and could not be tested. The full scale IQ in the remaining 21 ranged from 51 to 134, the verbal IQ ranged from 78 to 136 and the performance from 51 to 136. Of the twelve children with normal merosin one had a mild delay (IQ < 75) and two were borderline (IQ 75-95). Of the ten children with merosin-deficiency, one showed severe mental retardation and could not be tested, one showed a mild delay and two had borderline results. While the children with merosin deficiency with the typical diffuse white matter changes on MRI had normal scores, the children who in addition had cerebellar hypoplasia had lower performance IQ. The child with cortical dysplasia had severe mental retardation. Our results suggest that the spectrum of cognitive abilities in CMD is very wide even within genetically homogeneous conditions.

Adolescent↗