Myopathology in congenital myopathies.

Congenital myopathies are clinically and genetically a heterogeneous group of early onset neuromuscular disorders, characterized by hypotonia and muscle weakness. Clinical severity and age of onset are variable. Many patients are severely affected at birth while others have a milder, moderately progressive or nonprogressive phenotype. Respiratory weakness is a major clinical aspect that requires regular monitoring. Causative mutations in several genes have been identified that are inherited in a dominant, recessive or X-linked manner, or arise de novo. Muscle biopsies show characteristic pathological features such as nemaline rods/bodies, cores, central nuclei or caps. Small type 1 fibres expressing slow myosin are a common feature and may sometimes be the only abnormality. Small cores (minicores) devoid of mitochondria and areas showing variable myofibrillar disruption occur in several neuromuscular disorders including several forms of congenital myopathy. Muscle biopsies can also show more than one structural defect. There is considerable clinical, pathological and genetic overlap with mutations in one gene resulting in more than one pathological feature, and the same pathological feature being associated with defects in more than one gene. Increasing application of whole exome sequencing is broadening the clinical and pathological spectra in congenital myopathies, but pathology still has a role in clarifying the pathogenicity of gene variants as well as directing molecular analysis.

Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.

OBJECTIVES: Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations. PATIENTS: Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated. METHODS: The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes. RESULTS: Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown. CONCLUSIONS: Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.

RYR1 mutations are a common cause of congenital myopathies with central nuclei.

OBJECTIVE: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. METHODS: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. RESULTS: The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. INTERPRETATION: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies.

Importance of immunohistochemical evaluation of developmentally regulated myosin heavy chains in human muscle biopsies.

Our retrospective immunohistochemical study of normal quadriceps muscle biopsies shows that embryonic myosin heavy chains are down-regulated by, or soon after, birth. Fetal myosin heavy chains are down-regulated by 4-6 months. Thus the presence of an appreciable number of fibres with embryonic myosin heavy chains at birth or of fetal myosin heavy chains after 6 months of age suggests a delay in maturation or an underlying abnormality. Regenerating fibres in dystrophic muscle often co-express both embryonic and fetal myosin heavy chains but more fibres with fetal than embryonic myosin heavy chains can occur. Embryonic myosin heavy chains are a useful marker of regeneration but effects of denervation, stress, disuse, and fibre maintenance also have to be taken into account. In neurogenic disorders fibres with embryonic myosin heavy chains are rare but fetal myosin heavy chain expression is common, particularly in 5q spinal muscle atrophy. Nuclear clumps in denervated muscle show fetal and sometimes embryonic myosin heavy chains. Developmentally regulated myosins are useful for highlighting the perifascicular atrophy in juvenile dermatomyositis. Our studies highlight the importance of baseline data for embryonic and fetal myosin heavy chains in human muscle biopsies and the importance of assessing them in a spectrum of neuromuscular disorders.

A congenital myopathy with diaphragmatic weakness not linked to the SMARD1 locus.

Severe diaphragmatic weakness in infancy is rare. Common causes include structural myopathies, neuromuscular transmission defects, or anterior horn cell dysfunction (spinal muscular atrophy with respiratory distress, SMARD1). We describe a form of infantile diaphragmatic weakness without mutations in the SMARD1 gene, in which pathological and clinical features differ from known conditions, and investigations suggest a myopathy. We identified seven cases in four families. All presented soon after birth with feeding and breathing difficulties, marked head lag, facial weakness, and preserved antigravity movements in the limbs, with arms weaker than legs. All had paradoxical breathing and paralysis of at least one hemi-diaphragm. All required gastrostomy feeding, and all became ventilator-dependent. Investigations included myopathic EMG, muscle biopsy showing myopathic changes, normal electrophysiology and no mutations in SMN1 or IGHMBP2. These seven infants are affected by a myopathic condition clinically resembling SMARD1. However, its pathogenesis appears to be a myopathy affecting predominantly the diaphragm.

Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins.

Individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. We identified two patients with genetically proven Emery-Dreifuss muscular dystrophy (EDMD) who followed an unusual course and had uncommon clinicopathological findings. We hypothesized digenic inheritance and looked for additional molecular explanations. Mutations in additional separate genes were identified in both patients. The first patient was a member of a family with molecularly proven X-linked EDMD. However, the clinical features were unusually severe for this condition in the propositus: he presented at 2.5 years with severe proximal weakness and markedly elevated serum creatine kinase. Muscle weakness rapidly progressed, leading to loss of independent ambulation by the age of 12. In addition, the patient developed cardiac conduction system disease requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early teens. Despite pacing, he had several syncopal episodes attributed to ventricular dysrhythmias. As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus. The second patient had a cardioskeletal myopathy, similar to his mother who had died more than 20 years previously. Because of the dominant family history, a laminopathy was suspected and a mutation in exon 11 of the LMNA gene was identified. This mutation, however, was not present in his mother, but instead, surprisingly, was identified in his virtually asymptomatic father. Unusual accumulations of desmin found in the cardiac muscle of the propositus prompted us to examine the desmin gene in this patient, and in so doing, we identified a desmin mutation, in addition to the LMNA mutation in the propositus. These cases suggest that separate mutations in related proteins that are believed to interact, or that represent different parts of a presumed functional pathway, may synergistically contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic inheritance may well contribute to the clinical severity of many other neuromuscular disorders.

Muscular dystrophies due to defective glycosylation of dystroglycan.

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders. Until recently most of the proteins associated with muscular dystrophies were believed to be proteins of the sarcolemma associated with reinforcing the plasma membrane or in facilitating its re-sealing following injury. In the last few years a novel and frequent pathogenic mechanism has been identified that involves the abnormal glycosylation of alpha-dystroglycan (ADG). This peripheral membrane protein undergoes complex and crucial glycosylation steps that enable it to interact with LG domain containing extracellular matrix proteins such as laminins, agrin and perlecan. Mutations in six genes (POMT1, POMT2, POMGnT1, fukutin, FKRP and LARGE) have been identified in patients with reduced glycosylation of ADG. While initially a clear correlation between gene defect and phenotype was observed for each of these 6 genes (for example, Walker Warburg syndrome was associated with mutations in POMT1 and POMT2, Fukuyama congenital muscular dystrophy associated with fukutin mutations, and Muscle Eye Brain disease associated with POMGnT1 mutations), we have recently demonstrated that allelic mutations in each of these 6 genes can result in a much wider spectrum of clinical conditions. Thus, the crucial aspect in determining the phenotypic severity is not which gene is primarily mutated, but how severely the mutation affects the glycosylation of ADG. Systematic mutation analysis of these 6 glycosyltransferases in patients with a dystroglycan glycosylation disorder identifies mutations in approximately 65% suggesting that more genes have yet to be identified.

A comparative analysis of collagen VI production in muscle, skin and fibroblasts from 14 Ullrich congenital muscular dystrophy patients with dominant and recessive COL6A mutations.

Ullrich congenital muscular dystrophy (UCMD) is caused by recessive and dominant mutations in COL6A genes. We have analysed collagen VI expression in 14 UCMD patients. Sequencing of COL6A genes had identified homozygous and heterozygous mutations in 12 cases. Analysis of collagen VI in fibroblast cultures derived from eight of these patients showed reduced extracellular deposition in all cases and intracellular collagen VI staining in seven cases. This was observed even in cases that showed normal collagen VI labelling in skin biopsies. Collagen VI immunolabelling was reduced in all the available muscle biopsies. When comparisons were possible no correlation was seen between the extent of the reduction in the muscle and fibroblast cultures, the mode of inheritance or the severity of the clinical phenotype. Mutations affecting glycine substitutions in the conserved triple helical domain were common and all resulted in reduced collagen VI. This study expands the spectrum of collagen VI defects and shows that analysis of skin fibroblasts may be a useful technique for the detection of collagen VI abnormalities. In contrast, immunohistochemical analysis of skin biopsies may not always reveal an underlying collagen VI defect.

A and B utrophin in human muscle and sarcolemmal A-utrophin associated with tumours.

Utrophin is an autosomal homologue of dystrophin, abnormal expression of which is responsible for X-linked Duchenne and Becker muscular dystrophy. In normal mature muscle utrophin is confined to blood vessels, nerves and myotendinous and neuromuscular junctions. When dystrophin is absent utrophin is abundant on the sarcolemma. This has raised the possibility that up-regulation of utrophin may be of therapeutic benefit. Two full-length transcripts of utrophin, A and B, have been identified, which are regulated by alternatively spliced 5' promoters. In dystrophic mouse muscle, the A isoform is present on the sarcolemma, whereas the B form is confined to blood vessels. We show here using immunohistochemistry and human isoform-specific antibodies that A- and B-utrophin localisation is the same in human muscle. The A isoform is present on the sarcolemma of foetal human muscle fibres, regenerating fibres, fibres deficient in dystrophin and on blood vessels and neuromuscular junctions. B-utrophin is only detected on blood vessels. We also show that muscle adjacent to some soft tissue tumours shows increased sarcolemmal utrophin-A, showing that utrophin and dystrophin can simultaneously localise to the sarcolemma and raising the possibility that factor(s) from the tumour cells or accompanying inflammatory cells may have a role in regulating utrophin.

Zebra body myopathy is caused by a mutation in the skeletal muscle actin gene (ACTA1).

We present follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame.

Non-sarcolemmal muscular dystrophies.

The muscular dystrophies are characterised by progressive muscle weakness and wasting. Pathologically the hallmarks are muscle fibre degeneration and fibrosis. Several recessive forms of muscular dystrophy are caused by defects in proteins localised to the sarcolemma. However, it is now apparent that others are due to defects in a wide range of proteins including those which are either nuclear-related (Emery-Dreifuss type muscular dystrophies, oculopharyngeal muscular dystrophy), enzymatic (limb-girdle muscular dystrophy 2A, myotonic dystrophy) or sarcomeric (limb-girdle muscular dystrophies 1A and 2G). Although the clinical and molecular basis of these disorders is heterogeneous all display myopathic morphological features. These include variation in fibre size, an increase in internal nuclei, and some myofibrillar distortion. Degeneration and fibrosis occur, but usually not to the same extent as in muscular dystrophies associated with sarcolemmal protein defects. This review outlines the genetic basis of these "non-sarcolemmal" forms of dystrophy and discusses current ideas on their pathogenesis.

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.

Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study.

BACKGROUND: Ullrich congenital muscular dystrophy (UCMD) is a form of merosin-positive congenital muscular dystrophy characterized by proximal contractures, distal laxity, rigidity of the spine, and respiratory complications. Recently, a deficiency of collagen VI on muscle and skin biopsy together with recessive mutations in the collagen 6A2 gene were reported in three families with UCMD. However, the clinical spectrum, frequency, and level of heterogeneity of this disorder are not known. SUBJECTS AND METHODS: The authors studied 15 patients (aged 3 to 23.6 years) with a clinical diagnosis of UCMD. Linkage analysis to the three collagen VI genes was performed in all informative families (n = 7), whereas immunohistochemical analysis of collagen VI expression in muscle was performed in the remaining cases. RESULTS: An immunocytochemical reduction of collagen VI was observed in six patients. Three of the six patients belonged to informative families, and haplotype analysis clearly suggested linkage to the COL6A1/2 locus in two cases and to the COL6A3 loci in the third case. In the remaining nine patients, primary collagen VI involvement was excluded based on either the linkage analysis (four families) or considered unlikely based on normal immunolabeling of collagen VI. Age and presentation at onset, the distribution and severity of weakness and contractures, and the frequency of nonambulant patients were similar in the patients with and without collagen VI involvement. Distal laxity, rigidity of the spine, scoliosis, failure to thrive, and early and severe respiratory impairment were found in all patients by the end of the first decade of life, irrespective of their maximum motor functional ability or their collagen status. CONCLUSIONS: These results suggest that collagen VI involvement is relatively common in UCMD (40%); however, the role of this molecule was excluded in a number of cases, suggesting genetic heterogeneity of this condition.

Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores.

Central core disease (CCD) is a congenital myopathy due to dominant mutations in the skeletal muscle ryanodine receptor gene (RYR1). The authors report three patients from two consanguineous families with symptoms of a congenital myopathy, cores on muscle biopsy, and confirmed linkage to the RYR1 locus. Molecular genetic studies in one family identified a V4849I homozygous missense mutation in the RYR1 gene. This report suggests a congenital myopathy associated with recessive RYR1 mutations.

The role of immunocytochemistry in congenital myopathies.

Immunocytochemistry is playing an increasingly important role in the field of congenital myopathies. It is not yet the diagnostic tool that it is for the muscular dystrophies, but nevertheless it provides useful information on the nature of the structural defects that define each congenital myopathy, and on the additional secondary changes that accompany them. Immunocytochemistry may have a role in identifying primary protein defects but this may be dependent on the effect of a mutation on protein expression. Mutations affecting function, rather than expression, of a protein may not be detected by immunocytochemistry. Studies of candidate proteins, such as nebulin in nemaline myopathy, and the ryanodine receptor in central core disease, are, however, in progress, and as more defective genes are identified, and antibodies become available, immunocytochemistry will have an increasingly important role. Myofibrillar components are frequently affected in congenital myopathies and immunocytochemical localisation of their isoforms can reveal the nature of the structural abnormalities, such as rods, cores, and a variety of inclusions. Developmentally regulated proteins such as myosin heavy chains and intermediate filaments are also relevant to the understanding of the maturational process, in particular in myotubular/centronuclear myopathies, and also to the plasticity of muscle fibre types. Immunocytochemistry will continue to play an active role in studies of congenital myopathies and provide insight into their pathogenesis.

Notechis scutatus venom increases the yield of proliferating muscle cells from biopsies of normal and dystrophic canine muscle--a possible source for myoblast transfer studies.

The injection of 1 micrograms Notechis scutatus (Australian tiger snake) venom (notexin) induces localized necrosis in the muscles of normal and dystrophic dogs. Biopsies taken from the muscles on the second day of postnecrotic regeneration provide about 8-16 x 10(6) cells capable of proliferation per g tissue, about 100 fold more than the untreated adult dog muscles. Muscle specific markers, such as the capacity of the cells to fuse, surface labelling with N-CAM antibodies (Leu-19 and 5.1.H11), and immunostaining with desmin, indicated that over 90% of the cultivated cells are indeed myogenic. The method is a safe and cost effective way to generate large amounts of proliferating muscle cells from biopsies of adult animals, which could provide a useful step in the therapeutic efforts in inherited muscle diseases by the implantation of normal myoblasts or genetically corrected myoblasts.

Expression of dystrophin-associated glycoproteins and utrophin in carriers of Duchenne muscular dystrophy.

The expression of dystrophin, the dystrophin-associated proteins and utrophin has been studied immunocytochemically in three young, manifesting carriers of Duchenne muscular dystrophy, aged 3, 5 and 12 yrs, one adult manifesting carrier, aged 60 yrs, and one presumptive carrier with a raised serum creatine kinase, aged 24 yrs, the mother of the 5-yr-old manifesting carrier. The manifesting carriers had variable degrees of weakness; the presumptive carrier had no weakness. Morphological abnormalities were also variable and were most marked in the young manifesting carriers. The three young manifesting carriers and the presumptive carrier had a mosaic pattern of dystrophin-positive and dystrophin-negative fibres. All the dystrophin-associated proteins were reduced in the dystrophin-deficient fibres, giving a similar mosaic pattern to dystrophin. Expression of dystrophin and the dystrophin-associated proteins was normal in the adult manifesting carrier. Utrophin was detected on the sarcolemma of fibres both with and without dystrophin and the dystrophin-associated proteins. Thus, dystrophin and utrophin are co-expressed in several fibres in carriers. The results emphasize the close association between dystrophin and the glycoprotein complex and their role in the pathogenesis of muscle damage. In addition, the presence of utrophin in fibres with greatly reduced glycoproteins suggests that very little of the glycoprotein complex may be required to anchor the amount of utrophin expressed at the sarcolemma in these particular cases.

The muscle-specific marker desmin is expressed in a proportion of human dermal fibroblasts after their exposure to galectin-1.

We have previously shown that galectin-1 is a factor capable of converting mouse dermal fibroblasts to the myogenic lineage [Cell Transplant 2000;9:519]. Here, we report that human dermal fibroblasts are also capable of expressing the myogenic marker, desmin, when grown in muscle-cell-conditioned media. Furthermore, the human foetal skin cells also express this marker when grown in the presence of galectin-1. These results highlight the importance of galectin-1 in the conversion of both human and murine skin cells to a myogenic lineage. Thus galectin-1 could be an important tool for use in autologous cell therapies for the treatment of human muscular dystrophies.

Experimental regeneration in canine muscular dystrophy--2. Expression of myosin heavy chain isoforms.

The sequential expression of neonatal, fast and slow myosin heavy chain isoforms was examined during the regeneration of normal and dystrophic dog muscle from 1 to 56 days, following necrosis induced by the venom of Notechis scutatis, to assess the regenerative potential of dystrophic muscle. Regeneration was equally rapid in normal and dystrophic dogs but morphological and immunocytochemical abnormalities were more apparent in the dystrophic fibres. New myotubes were formed by 3 days, and by 4 days all myosin isoforms were expressed. Neonatal myosin persisted in normal dogs after morphological restoration of the muscle and after dystrophin and beta-spectrin expression had returned to normal. Neonatal myosin was considerably reduced by 21 days in normal dogs, but persisted beyond 28 days in dystrophic dogs, suggesting a delay in maturation. At 42 and 56 days, dystrophic dogs showed a population of small fibres expressing neonatal myosin, which may represent a second cycle of degeneration and regeneration. The reciprocal pattern of fast and slow myosin was not fully restored in normal or dystrophic regenerating muscle, and co-expression persisted. Thus, dystrophic muscle retains its potential to regenerate, but maturation is slower than normal. The persistent co-expression of isoforms has implications for the long-term function of fibres formed after myoblast therapy, but the results imply that a stable state can be achieved if dystrophin expression is restored by gene or myoblast transfer therapy.

Deficiency of the 50 kDa dystrophin-associated glycoprotein and abnormal expression of utrophin in two south Asian cousins with variable expression of severe childhood autosomal recessive muscular dystrophy.

Two male cousins with severe childhood, autosomal recessive, Duchenne-like, muscular dystrophy (SCARMD) have been identified with a deficiency of the 50 kDa dystrophin-associated glycoprotein but normal expression of dystrophin. Both boys were from consanguineous marriages and were Asian, having originated from Pakistan. This is in contrast to all previously reported cases from North Africa. Clinical severity varied and the patients were still able to walk at 13 and 12 yr, respectively. Neither had calf hypertrophy, a feature reported to be almost consistent in the North African patients. Abnormal expression of utrophin, the dystrophin-related protein, was observed on the surface of several non-regenerating muscle fibres, with less intense immunolabelling in the clinically more affected child. This family shows that SCARMD is not confined to North Africa and illustrates a hitherto unreported expression of utrophin in this condition.