Congenital muscular dystrophies

The congenital muscular dystrophies are a group of genetic myopathies characterized by hypotonia, weakness, or arthrogryposis at birth. Classification is inadequate and based entirely upon phenotypic expression, because a genetic marker has not been identified in any of these disorders. Some have only muscle disease, whereas others have cerebral disturbances (hypomyelination and/or disturbances of neuronal migration) as well. Ocular malformation may also be present. The outcome is variable, and it is difficult to provide an accurate prognosis soon after birth.     

Congenital muscular dystrophies

The number of new syndromes, loci, and genes responsible for CMD forms has dramatically increased in the last few years, and it has become increasingly evident that the classification of the different forms of CMD is a difficult task. A recent classification separated the forms of CMD that have been mapped (CMD diseases) from the ones with clearly defined clinical and pathologic features that have not been mapped yet (CMD syndromes). Eight CMD forms have been mapped up to now, and the genes responsible for three of them have been identified. This review describes an update of clinical, pathologic, and genetic findings in the different CMD forms.     

Dystrophin-related muscular dystrophies

The gene for the locus involved in Duchenne and Becker muscular dystrophies has been cloned and subject to intense analysis. The protein product of the locus is called dystrophin, and it has been shown to be associated with the muscle fiber membrane. The new knowledge of the molecular genetics of these disorders is being applied rapidly in clinical practice. Carrier detection and prenatal diagnosis have been revolutionized by the use of probes for the gene. These probes are also being employed to clarify cases where conventional clinical examination results in equivocal diagnoses. It is suggested that the disorders characterized by dystrophin abnormalities should be called dystrophin-related muscular dystrophies (DRMD). There are mouse and dog models for DRMD and these are being used to explore therapeutic strategies for treating DRMD patients.     

Deformed erythrocytes in muscular dystrophies

Because of previous reports of a possible correlation between echinocytogenesis and muscular dystrophies, we investigated the time-dependent development of echinocytes in the blood of normal subjects, patients, and healthy carries of Duchenne dystrophy. There was a quantitatively significant increase of echinocytes in patients and carriers.     

Lymphocyte capping in muscular dystrophies

Since reports of lymphocyte capping in muscular dystrophies of various authors revealed controversial results, we investigated 47 patients and carriers with Duchenne or Becker-Kiener muscular dystrophy according to different methods. There was no significant reduction of cap formation compared to 64 healthy controls, both groups showing a mean of about 75% caps. Reduced numbers of caps, however, could be demonstrated in three otherwise healthy probands aged 70 years or more, two patients under interferon treatment, four patients under high dose methotrexate therapy as well as one patient with untreated chronic myeloic leukemia. Thus lymphocyte capping in our experience is far from being a valid method for carrier detection or prenatal diagnosis of muscular dystrophies.     

Genetic treatments in muscular dystrophies

PURPOSE OF REVIEW: The search for a cure for Duchenne muscular dystrophy and other muscular dystrophies is progressing rapidly despite significant challenges posed by some genes and the complexity of targeting all skeletal muscles. This review focuses on three areas in which experimental clinical studies are in progress. RECENT FINDINGS: Two Phase I/IIa gene-therapy trials using adeno-associated viral vectors have recently started, one in limb-girdle muscular dystrophy and one in Duchenne muscular dystrophy. They will assess the safety of the intramuscular administration of the relevant adeno-associated viral vectors, and local efficacy. Two more Phase I/IIa studies are underway in Duchenne muscular dystrophy, focused on the intramuscular administration of antisense oligonucleotides to induce exon skipping. A third study is evaluating efficacy and tolerability of a drug which induces read-through of stop codons in Duchenne muscular dystrophy patients carrying nonsense mutations. SUMMARY: These studies should provide proof of principle of these experimental approaches in humans. It is likely that further refinement will be required before extending their use to the wider community of patients with muscular dystrophy. In the meantime it is important to prepare accurate registries of molecularly characterized patients to facilitate their recruitment in future studies.     

Respiratory management in muscular dystrophies

Respiratory failure is a major contributor to immobility and mortality in progressive muscular dystrophies. The severity of pulmonary impairment and the stage at which it develops differ according to the type of muscular dystrophy. Appropriate respiratory management for each type should be considered. In Duchenne muscular dystrophy (DMD), respiratory impairment manifests in the late teens, and assisted mechanical ventilation is administered. Noninvasive positive-pressure ventilation (NIPPV) has increased the median survival of patients with DMD by 10 year and improved quality of life. In myotonic dystrophy (MyD), the causes of respiratory failure can involve both the central and the peripheral nervous systems in addition to respiratory muscles. Nocturnal desaturation is more severe in MyD than in other muscular dystrophies with similar degrees of respiratory muscle weakness. Cognitive impairment should be taken into account in the management of MyD patients. NIPPV does not appear to improve survival of MyD. Guidelines for DMD have been published. Respiratory function should be assessed serially by measuring forced vital capacity, oxyhemoglobin saturation, peak cough flow, and end-tidal CO₂ level. A respiratory action plan should be enacted with increasing disease severity. Therapeutic measures comprise airway clearance, respiratory muscle training, noninvasive nocturnal ventilation, daytime noninvasive ventilation, and continuous invasive ventilation. At the advanced stage of respiratory failure, attention should be paid to complications related to long-term mechanical ventilation, such as pneumothorax and tracheal hemorrhage. Discussing about end-of-life care among the patient, family, and physician is important before mechanical ventilatory support is required.     

Glycosylation defects in muscular dystrophies

PURPOSE OF REVIEW: Congenital disorders of glycosylation are caused by defects in the synthesis of the glycan moiety of glycoproteins or other glycoconjugates. There has been a great explosion in the number of neuromuscular diseases caused by mutations in genes that affect carbohydrate metabolism or protein glycosylation. A common defect in these disorders is the defective processing of alpha-dystroglycan. RECENT FINDINGS: Recent advances demonstrating mutations in glycosyltransferases and dysfunction of the alpha-beta dystroglycan axis causing different forms of muscular dystrophy, especially with brain involvement, shows clearly that muscle integrity is dependent on glycosylation. We first review the newly identified muscular dystrophies, with a focus on the hypoglycosylation of alpha-dystroglycan, from a clinical, biochemical and genetic standpoint, and second hereditary inclusion body myopathies caused by mutations in the gene that encodes an enzyme responsible for the protein's posttranslational modification that cause sialidation defects. It is shown very recently that molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan. Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores alpha-dystroglycan function. SUMMARY: The clinical spectrum of congenital disorders of glycosylation is becoming increasingly broad. A demonstration of mutations in glycosyltransferases will further help to design diagnostic tools and therapeutic approaches. Recent findings which show that molecular recognition by LARGE is essential for expression of functional dystroglycan and LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies, indicate a new therapeutic strategy.     

Intellectual function in muscular dystrophies

Summary Intellectual function was studied in 28 boys with Duchenne dystrophy, 12 patients with facioscapulohumeral-type and 10 patients with limb-girdle-type muscular dystrophy. A definite relationship between intelligence level and the type of muscle disease was found. The more severe the genetic damage manifested by the rapidity of progression of muscular dystrophy the more definite the affection of the CNS manifesting as mental deficit. The factors influencing the level and structure of intelligence seem to exert their effect before the manifestation of muscle lesions.     

The nuclear muscular dystrophies

Nuclear muscular dystrophies are referred to as inherited muscular dystrophies caused by mutations in genes--(STA) or lamina (LMNA)--encoding components of the nuclear envelope. Phenotypically, they present as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscle dystrophy 1B (LGMD1B), or dilated cardiomyopathy with conduction defects (DCM-CD). Genetically related are the Dunnigan-type of familial partial lipodystrophy (FPLD) and Charcot-Marie-Tooth neuropathy type 2 (CMT2B). Until now, approximately 70 unique STA mutations, leading to X-linked EDMD or DCM-CD, have resulted mostly in a complete lack of emerin. Further 50 mostly missense mutations in LMNA result in autosomal-dominant EDMD, autosomal-recessive EDMD, LGMD1B, DCM-CD, FPLD, or CMT2B. Independent of type or location of the mutations, emerinopathies and laminopathies show wide clinical intrafamilial and interfamilial variability. Although structural abnormalities of nuclei in animal and cell models have been observed, the molecular pathology of the nuclear muscular dystrophies needs still to be elucidated.     

Limb girdle muscular dystrophies in India

The recent years have seen remarkable progress in the field of limb girdle muscular dystrophies (LGMDs) with the advances in immunocytochemistry and genetics. Based on this, many subgroups have emerged. Protein products and genes are getting defined and newer mechanisms of disease are being recognized. Limb girdle muscular dystrophies are common in India. The clinical material is plentiful, and from various centers in the country, phenotypes have been studied. With the help of immunocytochemistry, sarcoglycanopathies and dysferlinopathies have been studied. Genetic information on these subgroups is now beginning to emerge. The laboratory facilities are limited and available in select centers in large institutes. Establishment of genetic laboratories and sophisticated muscle pathology techniques will further elucidate the LGMDs in India.     

Respiratory function in the muscular dystrophies

The purpose of this investigation was to compare the respiratory function of patients with different clinical types of muscular dystrophy (MD). A total of 190 patients representing facioscapulohumeral MD (n = 20), limb-girdle MD (n = 50), Becker MD (n = 20), Duchenne MD (n = 90), and the “intermediate” type of MD (n = 10) were studied using simple spirometric respiratory function tests. The respiratory modifications observed in the 3 adult forms indicate that pulmonary function was almost normal. Respiratory function in Duchenne muscular dystrophy (DMD) was always characterized by a restrictive syndrome which severely impaired pulmonary function. The vital capacity (VC) underwent ascending, plateau, and descending phases during the course of the disease. The VC at the plateau stage may be used as an estimate of life span. The most interesting finding was the high degree of variability in the restrictive syndrome associated with DMD. In the DMD group 30% presented a severe restrictive respiratory syndrome associated with a life span of less than 20 years (Type 1), 40% had a serious restrictive syndrome and variable mortality (Type 2), and the remaining 30% had a moderate restrictive respiratory syndrome (Type 3).     

Defective glycosylation in congenital muscular dystrophies

PURPOSE OF REVIEW: The recent identification of mutations in five genes coding for proteins with putative or demonstrated glycosyltransferase activity has shed light on a novel mechanism responsible for muscular dystrophy. Abnormal glycosylation of alpha-dystroglycan appears to be a common finding in all these conditions. Surprisingly, the disease severity due to mutations in several of these genes is extremely variable. This article provides an overview of the clinical, biochemical and genetic advances that have been made over the last year in this field. RECENT FINDINGS: Mutations in the human LARGE gene, a putative glycosyltransferase mutated in the myodystrophy mouse, have now been identified in a form of human muscular dystrophy. In addition, the clinical variability of patients with mutations in the genes encoding fukutin, protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 and the fukutin-related protein has been significantly expanded. Disease severity in patients with mutations in the gene encoding the fukutin-related protein varies from a severe prenatal form of congenital muscular dystrophy with cobblestone lissencephaly and structural eye defects to a mild form of limb-girdle muscular dystrophy with onset in adult life and neither brain nor eye involvement. SUMMARY: Glycosylation disorders represent a rapidly growing and common group of muscular dystrophies. Accurate genetic diagnosis can now be made for five forms, and it is anticipated that several other variants will eventually fall into these categories.     

Cardiac involvement in the muscular dystrophies

Cardiac disease is a common clinical manifestation present in a variety of neuromuscular disorders, most notably the muscular dystrophies. Heart disease may produce the presenting or predominant symptoms in these disorders but more often not does not result in clinical features at the time of initial presentation. Cardiac involvement in the muscular dystrophies results from pathologic changes in the myocardium and the cardiac conduction system, leading to cardiomyopathy and/or rhythm disturbances including supraventricular arrhythmias, life‐threatening ventricular arrhythmias, and sudden cardiac death. This Review covers the spectrum of cardiac dysfunction in these inherited muscle disorders and proposes practical recommendations for monitoring and management. Muscle Nerve 57 : 707–715, 2018