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Congenital Myopathies and Muscular Dystrophies

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Congenital Myopathies and Muscular Dystrophies ManagementSectionSection Topic Congenital myopathies and muscular dystrophies ongenital myopathies are a distinct group of Author Laboratory investigations can be non-specific (mild- Cinherited disorders of skeletal muscle which (1) ly raised serum creatine kinase) or difficult to inter- present predominantly in the perinatal period; (2) are pret (EMG in a neonate). In the absence of a fami- non-progressive or only very slowly progressive; (3) ly history, muscle biopsy is necessary for diagnosis. share some clinical features and (4) have characteris- Supportive medical intervention is limited to tic structural abnormalities on muscle immunohisto- monitoring respiratory function, cardiac function chemistry. ‘Congenital’ myopathies can present later (core pulmonale) and spinal scoliosis. In addition, in childhood and these children may have a milder individuals with central core disease have to be course. Occasionally, adults presenting with limb-gir- screened for susceptibility to malignant hyperther- dle weakness or exercise intolerance have the same mia and warned of the risks of anaesthetic agents. histological findings. Multiple gene defects can give rise to similar clinical and ultrastructural phenotypes Dr Wojtek Rakowicz is a Congenital myopathies so the congenital myopathies remain defined by Specialist Registrar in Neurology. CENTRAL CORE DISEASE After training in Norwich and Central core disease was the first congenital muscle immunohistochemistry. Cambridge he worked in the Congenital muscular dystrophies (CMDs) are dis- Neuromuscular Division at myopathy to be described and many of its clinical tinguished by the immunohistochemical finding of Washington University in St features are characteristic of this group of disorders. prominent ‘dystrophic’ changes: muscle fibre necro- Louis. He is currently at the Infants present at or shortly after birth with hypoto- National Hospital for Neurology sis and regeneration, increased endomysial connec- and Neurosurgery. nia, areflexia, delayed motor milestones, proximal tive tissue, and replacement of muscle with fat tissue. limb weakness and often mild facial weakness. Classical CMDs are clinically confined to the muscu- Accompanying skeletal abnormalities include short loskeletal system but other CMDs are characterised by signifi- stature, kyphoscoliosis, pes cavus and congenital dislocation of cant cerebral neuronal migration defects and eye abnormalities. the hips. The condition is usually non-progressive with affected Classical CMDs are further subdivided according to the pres- children remaining ambulatory into adult life. Central core dis- ence or absence of merosin (laminin-2). ease can present in adulthood with muscle cramps or limb-gir- dle weakness but may also be asymptomatic. An important Presentations and management additional part of the phenotype, specific to central core dis- Congenital myopathies are most commonly evident at birth with ease, is the co-existence of susceptibility to anaesthesia-related infants exhibiting a loss of axial and appendicular tone malignant hyperthermia in one third of patients. Individuals (‘floppy infant’), decreased spontaneous movement and, later, within the same family may exhibit one or both phenotypes. At- delayed acquisition of motor milestones. However, congenital risk individuals can be screened with an in vitro contracture test muscle disease has to be distinguished from more common performed on a fresh muscle sample. causes of the same presentation, especially systemic disease or Central core disease is inherited in an autosomal dominant global developmental delay (Table 1). fashion with mutations in the ryanodine receptor gene (RYR1) In utero weakness from any cause can result in skeletal accounting for up to 50% of cases. The gene encodes a sar- deformities and contractures. Recognised skeletal deformi- coplasmic reticulum calcium channel that releases intracellular ties include congenital dislocation of the hips, kyphoscoliosis calcium as a step in excitation-contraction coupling. The char- and pes cavus. Contractures are particularly common in, but not acteristic immunohistochemical finding is the presence of specific to, CMDs. Arthrogryposis is the term used to describe densely packed disorganised myofibrils (‘cores’) in the centre of multiple severe bony deformities and contractures in the new- the majority of type 1 muscle fibres. These cores extend along born. the length of the fibres, excluding mitochondria and many mus- Facial weakness and respiratory insufficiency are more cle enzymes (cytochrome oxidase, NADH), giving rise to a char- common in congenital myopathies (Table 2) but no single clin- acteristic central pallor (Fig. 1a.). ical finding is diagnostic. These features may also be present in congenital myasthenia or congenital myasthenic syndrome. NEMALINE MYOPATHY Typical nemaline myopathy presents sporadically at birth Table 1. Causes of hypotonia in infants with severe floppiness and weakness. Feeding difficulties are common and respiratory muscle involvement can be a cause of anatomical localisation pathological processes early death but improvement and weaning are usually achieved. central nervous system deep tendon reflexes typically preserved Childhood presentations, characterised by weakness and brain/systemic disease hypoxic-ischaemic encephalopathy delayed motor milestones, are relatively benign and individuals sepsis usually remain ambulant. Affected children typically have an congestive cardiac failure elongated, weak face, tent-shaped mouth due to facial weak- ness, a high-arched palate and a nasal voice. Limb weakness is brainstem Down's syndrome diffuse and initially greater in proximal muscles but distal weak- Prader-Willi syndrome ness is also a feature of some of the nemaline myopathy syn- craniocervical junction congenital malformations dromes. perinatal cord injury The inheritance of nemaline myopathy is most commonly motor unit autosomal recessive but can be autosomal dominant. The dis- ease has been linked to mutations in three very different genes anterior horn cell spinal muscular atrophy (encoding α-actin, tropomyosin-3 and nebulin) but it is unclear peripheral nerve hereditary motor-sensory neuropathy how these bring about a common phenotype. Careful exami- nation of the parents, possibly combined with muscle biopsy, is neuromuscular junction myasthenia myasthenic syndromes needed to confirm the mode of inheritance. The name of nema- line myopathy is derived from the histological hallmark of gran- muscle congenital myopathies ules or rods of filamentous material (nema = thread in Greek) metabolic myopathies which tend to aggregate under the sarcolemma (Fig.1b). muscular dystrophies Nemaline rods are accumulations of disorganised Z-disk mater- ACNR • VOLUME 2 NUMBER 6 JANUARY/FEBRUARY 2003 11 Management Topic Section Table 2. The major clinical features of the congenital myopathies and congenital muscular dystrophies Main Clinical Features hypotonia limb facial respiratory clinical CNS eye additional weakness weakness insufficiency involvement involvement features Congenital Myopathies Central Core Disease • • (•) ± malignant hyperthermia Nemaline Myopathy •••• Centronuclear Myopathy •••• ptosis severe course (usu.); ophthalmoplegia Congenital muscular dystrophies Merosin-positive CMD • • (•) Merosin-deficient CMD •• • white matter changes on MRI Fukuyama CMD ••••• severe course; seen in Japan Muscle-Eye-Brain Disease •• ••• Walker-Warburg Syndrome • (•) • • • severe course; blind at birth ial, best seen in sections stained with the modified Gomori nism of weakness in these individuals remains a puzzle. Small trichrome technique. Rods can also be seen in denervated mus- type 1 fibres are also seen in other congenital myopathies such cle and in HIV myopathy. as nemaline and centronuclear myopathies. Multicore (mini- core) disease is a mild non-progressive disorder in which mus- CENTRONUCLEAR (MYOTUBULAR) MYOPATHY cle fibres contain multiple cores that share many of the features Centronuclear myopathy most commonly presents in boys of those seen in central core disease but are smaller in size (X-linked) at birth with severe hypotonia and weakness. (minicores) and not confined to the centre of the fibre. Facial Ventilatory insufficiency and feeding difficulties may lead to weakness, ptosis and ophthalmoplegia are also commonly seen. death over days to weeks though longer survival occurs in a Multicore disease can be caused by mutations in RYR1, the gene subset of infants. Evidence for the condition starting in utero responsible for central core disease. comes from a maternal history of polyhydramnios or of miscar- riages/perinatal death of male infants. As with nemaline myopa- Congenital muscular dystrophies (CMDs) thy, affected infants have an elongated, expressionless face, CLASSICAL CMDs tent-shaped mouth and a high-arched palate. Kyphoscoliosis Merosin-deficient CMD accounts for around a half of classical and pes cavus may be present. Autosomal recessive and domi- CMD and has a consistently severe phenotype with multiple nant forms that are more mild have onsets later in childhood or contractures and joint deformities (arthrogryposis) at birth. early adulthood. Facial weakness remains a prominent feature, Infants can succumb to respiratory failure and death but, if ade- usually accompanied by ophthalmoplegia and ptosis and prox- quately supported, they can often be weaned off ventilatory imal muscle weakness. support. A proportion will achieve independent sitting but The
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