Seminars in Pediatric Neurology

Seminars in Pediatric Neurology

E L S E V I E R

Congenital Muscular Dystrophies: A Brief Review

Enrico Bertini, MD, Adele D'Amico, MD, PhD, [...], and Stefania Petrini, PhD

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Abstract

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments.

Congenital muscular dystrophies (CMDs) are overall clinically and genetically heterogeneous neuromuscular disorders1-3 with onset at birth or in infancy and in which the muscle biopsy is compatible with the presence of a dystrophic myopathy. In early stages the muscle biopsy may just reveal a myopathic picture without clear dystrophic features, but the clinical context and morphology are able to suggest a diagnosis different from that of a specific congenital myopathy, a metabolic myopathy, or a neurogenic disorder. During the past 10 years, our knowledge of neuromuscular disorders has increased dramatically, in particular with regard to the exponential boost in disclosing the genetic background of CMDs.

Information on incidence and prevalence of CMDs is scanty because of the lack of diagnostic genetic confirmation in the past 10 years. Few studies are limited to epidemiologic figures of prevalence ranging from 0.68 to 2.5 per 100,000, which are probably underestimated.4-5

Moreover, similarly to other rare autosomal recessive disorders, founder mutations are known to occur among CMDs, such as the founder mutation in fukutin (FKTN) reported in Japan in (FKTN-related) Fukuyama-type CMD (FCMD), representing the most common CMD in that country followed by collagen VI (COL6)–deficient CMD.6However, these epidemiologic data provide only a relative frequency of a diagnosed subtype of CMD in a given country rather than a real figure of incidence or prevalence.

The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have gained sufficient experience with the different CMD subtypes. Currently, the achievement of a molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments.

Common Clinical Aspects of CMD

Overall differential diagnosis of CMD has to take into account congenital myopathies, ie, myopathies with typical structural or ultrastructural features on the muscle biopsy, congenital myotonic dystrophy, congenital myasthenic syndromes, early-onset metabolic myopathies, Marinesco–Sjögren syndrome, and other subtypes of congenital ataxia, congenital disorders of the motor neuron and the peripheral nerve, and other genetic syndromes such as Prader–Willi syndrome,7 and the more frequently acquired conditions leading to profound hypotonia, such as acute hypoxic ischemic encephalopathy and neonatal sepsis.

The most important tools to address these differential diagnostic possibilities, beyond a careful family history and the physical examination, are creatine kinase (CK) determination searching for persistent increased CK in plasma, nerve conduction velocity (NCV) studies with repetitive stimulation to recognize neurogenic conditions and abnormalities of neuromuscular transmission, magnetic resonance imaging (MRI) of the brain, muscle biopsy, and specific genetic or metabolic testing. Physical examination will have to focus on clinical clues for subtyping CMDs, such as congenital contractures, hip dislocation, excessive laxity and externally visible malformations of the head, cleft lip and/or palate, as well as eye abnormalities (retinal dysplasia, anterior chamber malformation, Peter anomaly, and congenital cataract).

A great number of patients with CMD have onset of symptoms at birth or in infancy, manifesting hypotonia and weakness, and some of them show delay in walking unassistedly. The typical presentation of a “floppy baby” can be observed; however, in other patients with milder symptoms, antigravity movements of limbs may be preserved and axial muscles of the spine are more involved with pronounced head lag, as often happens in selenoprotein 1 (SEPN1)-and lamin A/C (LMNA)-related CMDs. Some symptoms are unlikely in CMD, such as marked facial weakness which is generally known to occur in patients with congenital myopathies, like nemaline myopathy, myotubular myopathy, centronuclear myopathy, or congenital myotonic dystrophy, as well as non-neuromuscular conditions, such as the Möbius syndrome. It is unlikely to observe ophthalmoplegia in CMD although it is a diagnostic clue in myotubular myopathy, centronuclear myopathy, or a congenital myasthenic syndrome.

Even though cardiomyopathy can develop during the course of disease in a patient with CMD, particularly in the second decade of life, due to FKTN-, fukutin-related protein (FKRP), and protein-O-mannosyl transferase 1 (POMT1)-related CMDs/limb-girdle muscular dystrophy (LGMD) phenotypes, the occurrence at birth is rather unlikely and should suggest the presence of another disorder, such as Pompe disease or a mitochondrial disorder, including cytochrome oxidase (COX) deficiency and the Barth syndrome. Sudden cardiac death has been reported almost exclusively in LMNA-related CMD.

While respiratory failure, particularly at night, is usually a common symptom in most CMDs during the advanced stages of the disease when the patient has lost his/her ability to walk, this symptom might unexpectedly become apparent when patients are still ambulant, particularly in SEPN1-related CMD and in COL6-deficient CMDs, thus resembling a congenital myasthenic syndrome or a juvenile/adult variant of acid maltase deficiency.

The α-dystroglycanopathies (aDGpathies) and, to a lesser degree, laminin-α2 (LAMA2)-related CMD can be associated with significant

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