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Biomedical subjects

F Muntoni

Publications and source records attributed to F Muntoni.

At least 37 records · Page 2Linked to original sources
PubMed2005

Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency.

General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed2005

Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy.

INTRODUCTION: Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures. UCMD is an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. METHODS: We developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes using single condition amplification/internal primer (SCAIP) sequencing. We have sequenced all three COL6 genes from genomic DNA in 79 patients with UCMD or BM. RESULTS: We found putative mutations in one of the COL6 genes in 62% of patients. This more than doubles the number of identified COL6 mutations. Most of these changes are consistent with straightforward autosomal dominant or recessive inheritance. However, some patients showed changes in more than one of the COL6 genes, and our results suggest that some UCMD patients may have dominantly acting mutations rather than recessive disease. DISCUSSION: Our findings may explain some or all of the cases of UCMD that are unlinked to the COL6 loci under a recessive model. The large number of single nucleotide polymorphisms which we generated in the course of this work may be of importance in determining the major phenotypic variability seen in this group of disorders.

Collagen Type VI↗
PubMed2005

The modulation of skeletal muscle glycosylation as a potential therapeutic intervention in muscular dystrophies.

Post-translational modification of proteins following glycosylation is a powerful tool to increase diversity of proteins and ligand interaction. alpha-Dystroglycan, a key muscle fibre receptor for various extracellular matrix ligands, is very heavily glycosylated. In addition heterogeneity of its glycosylation pattern has been described not only in different tissues and organs, but also in different regions of skeletal muscle, such as the sarcolemma and the neuromuscular junction. This review is focused on the potential of hyperglycosylation strategies as a means for therapeutic intervention in several forms of muscular dystrophy. Regarding Duchenne muscular dystrophy (DMD) overexpression of the synaptic CT GalNAc transferase in the sarcolemma of mdx animals was shown to induce the appearance of the CT antigen on the dystroglycan expressed at the sarcolemma. This was followed by the recruitment of utrophin at the sarcolemma and improved muscle pathology in mdx mice. A related strategy has also been used in preclinical models of "dystroglycanopathies". These conditions range in severity from severe and congenital onset to milder forms of limb girdle muscular dystrophy affecting the adult. The mechanism of disease in dystroglycanopathies is presumed to be the uncoupling of the cellular receptor alpha-dystroglycan from its extracellular matrix ligands of which laminin is the most important one. Recent work has demonstrated that the overexpression of 2 related glycosyltransferases, LARGE and LARGE L, results in the hyperglycosylation of alpha-dystroglycan. This hyperglycosylation can also be induced in cells from patients with a dystroglycanopathy, restoring normal dystroglycan ligand binding. LARGE and/or LARGE-L up regulation could therefore represent a therapeutic option for patients affected by dystroglycanopathies, regardless of their primary defect.

Dystroglycans↗
PubMed2004

The relationship between lean body mass and bone mineral content in paediatric health and disease.

INTRODUCTION: The correct interpretation of DXA data is critical to the diagnosis and management of children with suspected bone disease. This study examines the various influences on bone mineral content (BMC), as measured by dual-energy X-ray absorptiometry (DXA). MATERIALS AND METHODS: Six hundred and forty-six healthy school children and forty-three children with chronic diseases, aged 5-18 years, had their lumbar spine and whole body measured using a Lunar DPX-L DXA scanner. RESULTS: Stepwise linear regression identified lean body mass (LBM) as the strongest single predictor of BMC in the lumbar spine and the total body. A significant gender difference was observed in the relationship between BMC and LBM with girls having significantly more bone per unit LBM from 9 years of age in the spine and 13 years of age in the total body. To investigate the relationship between LBM and BMC in children with chronic disease, a two-stage algorithm based upon calculation of Z scores from the normative data was applied. Stage 1 assessed LBM for height and stage 2 assessed BMC for LBM. Ten children with spinal muscular atrophy had a mean LBM for height Z score of -1.8(1.4) but a mean BMC for LBM Z score of 1.2(1.3) indicating their primary abnormality was reduced muscle mass (sarcopenia) with no evidence of osteopenia. In contrast, 21 children with osteogenesis imperfecta had a mean LBM for height Z score of 0.4(1.7) but a mean BMC for LBM Z score of -2.5(1.8) indicating normal LBM for size but significantly reduced BMC for LBM (i.e. osteopenia) confirming a primary bone abnormality. A third group consisting of 12 children with low trauma fractures demonstrated little evidence of sarcopenia [mean LBM for height Z score -1.1(2.1)] but significant osteopenia [mean BMC for LBM Z score -1.9(1.5)]. CONCLUSION: The results from this study demonstrate how the relationship between height and lean body mass, and lean body mass and bone mineral content can be a useful method of diagnosing osteoporosis in children and how the relationships can be used to identify if the primary abnormality is in muscle or bone.

Adolescent↗
PubMed2004

Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study.

We describe clinical and muscle magnetic resonance imaging (MRI) findings in 11 cases (three familial and eight sporadic) with the form of spinal muscular atrophy characterised by predominant involvement of the lower limbs with weakness of the proximal and distal muscles and marked atrophy of the distal leg and foot muscles. All patients presented at birth with talipes, which were in extension in seven of the 11. Arm muscle and function were preserved and lower limbs appeared to be disproportionately shorter compared to trunk and upper limbs. Functional abilities were markedly affected and only one of the 11 is able to walk independently for long distances, while six require support of crutches and two use callipers for walking. One child lost ambulation following a fall. The course of the disease is relatively stable and the progression of disability appeared to be related mostly to increased contractures rather than to loss of muscle strength. Respiratory and cardiac function were well preserved. A neurogenic disorder was suggested by electromyography and/or muscle biopsy in all patients, while motor nerve conduction was consistently normal. Muscle MRI of the thighs revealed diffuse atrophic appearance with relative hypertrophy of the adductor longus and of the semitendinosus. Genetic studies excluded the involvement of the survival motor neuron gene but none of these families was sufficiently informative to study linkage to the locus on chromosome 12q23-q24 previously found to be involved in patients with similar phenotype. In our experience this form of spinal muscular atrophy affecting predominantly the lower limbs is a relatively common form and should be considered in the differential diagnosis of infants with talipes and weakness in the lower limbs. The identical clinical and imaging features of the sporadic and familial cases suggest that these cases are likely to be affected by the same condition.

Adolescent↗
PubMed2004

Expanding the phenotype of potassium channelopathy: severe neuromyotonia and skeletal deformities without prominent Episodic Ataxia.

We report an unusual family in which the same point mutation in the voltage-gated potassium channel gene KCNA1 resulted in markedly different clinical phenotypes. The propositus presented in infancy with marked muscle stiffness, motor developmental delay, short stature, skeletal deformities, muscle hypertrophy and muscle rippling on percussion. He did not experience episodic ataxia. His mother presented some years later with typical features of Episodic Ataxia type 1 (EA1), with episodes of ataxia lasting a few minutes provoked by exercise. On examination she had myokymia, joint contractures and mild skeletal deformities. A heterozygous point mutation in the voltage-gated K(+) channel (KCNA1) gene (ACG-AGG, Thr226Arg) was found in both. We conclude that mutations in the potassium channel gene (KCNA1) can cause severe neuromyotonia resulting in marked skeletal deformities even if episodic ataxia is not prominent.

Adult↗
PubMed2004

A case of severe congenital chronic inflammatory demyelinating polyneuropathy with complete spontaneous remission.

Chronic inflammatory demyelinating polyneuropathy (CIPD) is characterised by progressive weakness, hyporeflexia and electrophysiological evidence of demyelination with maximal neurological deficit reached after at least 8 weeks progression. CIPD rarely affects children. We present a neonate with clinical features compatible with congenital CIPD. A term male infant of non-consanguineous parents was referred to us at birth with weakness and contractures affecting his legs, suggesting a prenatal onset of immobility. He also had evidence of bulbar dysfunction with poor suck, recurrent aspiration and requiring nasogastric feeding. He had no antigravity movements in the legs, bilateral wrist drop, distal joint contractures and absent deep tendon reflexes. Electromyography showed neurogenic changes, with nerve conduction velocities markedly reduced, increased distal motor latency and dispersed compound muscle action potentials. Cerebrospinal fluid protein was raised. Sural nerve biopsy demonstrated decreased numbers of myelinated fibres and inflammatory cell infiltrates. Muscle biopsy showed denervation. He only received supportive treatment and by 6 months he had fully recovered, and all electrophysiological parameters had normalised.

Disease Progression↗
PubMed2004

OCTN2 mutation (R254X) found in Saudi Arabian kindred: recurrent mutation or ancient founder mutation?

The truncating R254X mutation in the OCTN2 gene results in defective high-affinity carnitine transport and has been previously described as a founder mutation in the Chinese population. We now report a Saudi Arabian kindred with this same mutation, suggesting that it may be a recurrent mutation or a very ancient founder mutation. Western blot analysis of skin fibroblast lysates from the proband with our specific anti-murine OCTN2 antibody revealed the absence of the OCTN2 protein.

Blotting, Western↗
PubMed2004

Congenital muscular dystrophy with short stature, proximal contractures and distal laxity.

We report 5 cases (2 familial and 3 sporadic) who share a diagnosis of congenital muscular dystrophy (CMD) in association with short stature, proximal contractures, rigidity of the spine and distal joint laxity as well as early respiratory failure and mild to moderate mental retardation. The expression of collagen VI was confirmed to be normal on muscle biopsies of all 5 patients and in the informative family linkage to any of the three COL6 A loci was excluded. These findings extend the phenotypes within the CMD classification.

Adolescent↗
PubMed2004

Pilot trial of salbutamol in central core and multi-minicore diseases.

Several studies have documented positive effects of beta-adrenergic agonists on human skeletal muscle with regard to muscle mass and strength. The aim of this pilot study was to evaluate the effect of the beta2-agonist salbutamol (albuterol) in a group of children with central core disease and multi-minicore disease. Thirteen patients, 8 with central core disease (mean age 17.5 years) and 5 with minicore disease (mean age 13.6 years) received oral salbutamol at a dose of 2 mg four times a day. Measures of efficacy were the change from baseline at 3 and 6 months in muscle strength, assessed by MRC score, myometry, functional measures and forced vital capacity. Statistical analysis was performed using repeated measures ANOVA (significance level < 0.05). Two patients with central core disease stopped the medication after one month because they did not notice any improvement and another one with minicore disease after 4 months because of increased tremors and palpitations. The remaining ten (6 with central core and 4 with minicore disease) completed the course of salbutamol without any significant adverse effects. There were significant increases in myometry, MRC scores and forced vital capacity between baseline and the six-month assessments. For both myometry and MRC the difference was already significant at 3 months and this was associated with a significant increase in functional abilities assessed with a structured functional scale. Our results suggest that salbutamol was overall well tolerated and might be beneficial in both central core and minicore patients. Larger prospective randomised, double-blind, placebo-controlled trials with salbutamol will be needed to confirm these preliminary findings.

Adolescent↗
PubMed2004

Bone mineral density in a paediatric spinal muscular atrophy population.

BACKGROUND/OBJECTIVE: Reduced bone mineral density is a feature of patients with reduced mobility. The aim of this study was to assess bone mineral density in children with spinal muscular atrophy (SMA) and to evaluate bone mineral density in relation to age and motor disability. PATIENTS AND METHODS: We analysed bone mineral density measurements on twelve patients (4 with SMA type II, mean age 8.2 years [range 6.2 - 11.8]; 8 with SMA type III, mean age 11.8 years [range 5.5 - 20]). Dual-energy X-ray absorptiometry (DXA) was used to determine total body bone mineral density. The results were matched with published normative data for age and sex for a white Caucasian population. RESULTS: The total body bone mineral density values were in the normal range in 10 out of the 12 SMA patients studied, all below the age of 17 (mean age 8.8 years [range 5.5 - 16.33]). Four of them had SMA II and six had had SMA III and were still ambulant. Total body bone mineral density was, however, below 2 SD in the remaining 2 patients aged 19.7 and 20 years, respectively. Both had SMA III but had lost independent ambulation for a period of 3.5 years. CONCLUSION: Our results suggest that bone mineral density was surprisingly normal in most of the young SMA children studied. This is in contrast to what is reported in other conditions characterised by reduced mobility such as Duchenne muscular dystrophy. However, there was a tendency to decreasing bone mineral density with increasing age, not always related to the ability to walk, with the two eldest patients having the lowest values in spite of a relatively good mobility. These findings suggest that factors other than mobility are likely to have an effect on SMA bone mineral density.

Absorptiometry, Photon↗
PubMed2004

Short-chain acyl-CoA dehydrogenase deficiency associated with early onset severe axonal neuropathy.

Two unusual cases of axonal neuropathy associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency are described. These two unrelated infants presented with profound generalised weakness, particularly affecting the upper limbs. Clinical examination revealed generalised peripheral hypotonia and weakness, with absent deep tendon reflexes. An axonal polyneuropathy was confirmed on electromyogram (EMG) and nerve conduction studies (NCS) and, following an extensive metabolic screen, an acylcarnitine and organic acid profile consistent with a short-chain fatty acid beta-oxidation defect was found. In both cases, SCAD deficiency was confirmed by enzyme analysis. Genetic analysis showed the presence of common gene variations in the SCAD gene. SCAD deficiency is a rare disorder with a wide clinical phenotype. SCAD deficiency associated with axonal neuropathy has not previously been reported. As highlighted in these cases, it may be necessary to include axonal neuropathy as a presenting feature of SCAD.

Age of Onset↗
PubMed2004

Absence of neuronal nitric oxide synthase (nNOS) as a pathological marker for the diagnosis of Becker muscular dystrophy with rod domain deletions.

Immunohistochemistry using antibodies to dystrophin is the pathological basis for the diagnosis of Duchenne and Becker muscular dystrophy (DMD and BMD). While the sarcolemma of DMD muscle is negative, BMD muscle generally shows variable labelling because of the translation of a partially functional dystrophin that is localized to the sarcolemma. In rare cases, however, this labelling is equivocal and similar to that observed in controls making diagnosis difficult. We report here that in such instances immunolabelling with antibodies to the neuronal form of nitric oxide synthase (nNOS) can be useful in suspecting a dystrophinopathy with a mutation in the 'hot-spot' rod domain and help to direct molecular analysis. nNOS localizes to the sarcolemma of mature muscle fibres via several components of the dystrophin-associated protein complex (DAPC) including dystrophin but sarcolemmal nNOS is lost when dystrophin levels are very low or absent because of deletions in critical regions of the rod domain. We report three cases who presented with only mild or no muscle weakness but had elevated serum creatine kinase activity and dystrophin immunolabelling indistinguishable from normal, making a pathological diagnosis difficult. All three cases had a complete absence of sarcolemmal nNOS and were subsequently found to have an in-frame deletion in the common rod domain exons (in these cases 48, 45-51, 47-53) compatible with a BMD. In addition, we observed that nNOS appears to be developmentally regulated with the antibody used and was often absent from the sarcolemma of immature fibres. These findings demonstrate the value of including antibodies to nNOS in routine immunohistochemical studies and that absence of nNOS can be a more sensitive marker than up-regulation of utrophin for diagnosis of BMD. Immaturity of fibres, however, needs to be taken into account, especially in neonates.

Biomarkers↗
PubMed2004

Multiple pathogenetic mechanisms in X linked dilated cardiomyopathy.

X linked dilated cardiomyopathy is a familial disease that is allelic to Duchenne and Becker muscular dystrophies and caused by mutations in the dystrophin gene. In several families with X linked dilated cardiomyopathy, the pattern of expression of dystrophin mutations in cardiac muscle differs from that in skeletal muscle. A number of these mutations affect transcription and splicing of the dystrophin gene in a tissue specific manner; others may affect regions of dystrophin that are presumed to have a more important role in cardiac than in skeletal muscle. These mutations are important because they highlight the fundamental differences in processing of the dystrophin gene between skeletal and cardiac tissues, as well as differences in the functional domains more relevant for one tissue or the other. This review focuses on the major mechanisms that have been proposed to explain this disorder.

Cardiomyopathy, Dilated↗