Non limb girdle pattern muscular dystrophies with involvement of cranial musculature - 2

Dystrophic myotonias
Myotonic dystrophy  is  the  most  common  inherited  neuromuscular  disease;  the  prevalence  is  about  5/100,000.  The characteristic  phenotype  includes,  in  addition  to  grip  and percussion myotonia: progressive muscular weakness and wasting, starting distally, bilateral ptosis and facial muscle weakness, sternomastoid wasting, cataracts, endocrinopathy, notably insulin resistance, cardiac conduction defects which can lead to sudden death, bulbar and respiratory muscle weakness, dysphagia and gut dysfunction, frontal balding and calcifying epithelioma of Malherbe and in severe cases mental retardation. Gene expression can vary from asymptomatic cases with no clinical signs, to severe congenital onset disease. The disease is associated with a CTG triplet expansion at 19q13.3, from 5–37 repeats in normal individuals to 50 to more than 1000 repeats in disease. The mutation involves the 3' untranslated region of the myotonin-protein kinase gene and the 5' untranslated region of  Six5 (myotonic dystrophy associated homeobox protein), which is involved in the regulation of eye formation (and might  therefore  explain  the  prominence  of  cataract  in  the phenotype). There is a broad correlation between the size of the expansion and disease severity, individuals in successive generations usually inherit larger expansions and thus have more severe and earlier onset disease (genetic anticipation). A second, clinically identical form of myotonic dystrophy has been described recently, linked to chromosome 3q.

Proximal myotonic myopathy is clinically and genetically distinct from myotonic dystrophy but shares a number of phenotypic features. Weakness starts in and is mainly confined to proximal muscles, and cramps and myalgia are common. Non-dystrophic myotonias and periodic paralyses and number of familial muscle diseases have recently been shown to result from mutations of genes encoding muscle ion channels. The defects can lead to a phenotype in which myotonia is the major  manifestation, as in myotonia congenita (chloride channelopathy), or to episodic weakness, as in hypokalaemic periodic paralysis (calcium channelopathy). Sodium channel mutations lead to a complex mixture of phenotypes in which myotonic stiffness (as in potassium aggravated myotonia)  or periodic weakness  (as  in  hyperkalaemic  periodic paralysis and paramyotonia congenita) can occur under various conditions (eg. exercise, exposure to cold). Patients with myotonia congenita may not come to medical attention, unless ‘cramp’ caused by the myotonia is very troublesome. Gross muscular hypertrophy is typically found on examination. Periodic paralyses present with episodic, profound muscular weakness, not involving breathing and with normal consciousness, with appropriate abnormal serum K+. Hyperkalaemic periodic paralysis is associated with myotonia; the hypokalaemic form is not.

Genetically  determined  metabolic  myopathies
Disorders of intermediary metabolism Certain genetic disorders of intermediary metabolism can affect  muscle  particularly or exclusively. Such diseases may cause progressive myopathic weakness as a result of storage of glycogen (e.g. acid maltase deficiency – Pompe’s disease) or lipids (e.g. carnitine deficiency), or may cause exercise-related myalgia, and sometimes muscle contracture, with swelling and rhabdomyolysis, leading to myoglobinuria with a risk of acute renal failure.

McArdle’s disease is the most common of these disorders. Deficiency of myophosphorylase results in failure to break down glycogen to glucose in muscle. Severe myalgia with ‘cramp’ (which is in fact electrically silent muscle contracture) develops soon after the start of exercise, but the patient may notice easing of symptoms as exercise continues (‘second-wind’ phenomenon), as alternative energy sources are mobilized. The disease can be diagnosed simply and rapidly by demonstrating absent phosphorylase on muscle histochemistry. McArdle’s disease and other rarer forms of glycolytic disorder may also be suggested by the finding of a much reduced increase in plasma lactate following ischemic forearm exercise.

Mitochondrial disorders
Mitochondrial disorders can affect muscle specifically or as part of a multisystem disease, typically involving the central nervous system. Large  deletions  of  mitochondrial  DNA  commonly  underlie Kearns–Sayre syndrome and chronic progressive external ophthalmoplegia. Point mutations cause a wide variety of syndromes, including mitochondrial encephalopathy, lactic acidosis and strokes  (MELAS)  and  myoclonus, epilepsy and ragged red fibres (MERRF). Diagnosis of a mitochondrial disease is suggested by the demonstration of: increased basal plasma lactate and cerebrospinal fluid lactate, an inappropriately large increase in plasma lactate on exercise testing, typical histochemical features (e.g. ragged red fibres and cytochrome oxidase-negative fibres on muscle biopsy). Ultrastructural studies usually demonstrate accumulations of large, bizarrely structured mitochondria, though biochemical features of mitochondrial cytopathy can usually be demonstrated before structural changes can be found.

Other disorders
Metabolic myopathy resulting from myoadenylate deaminase deficiency (involved in purine metabolism) and Brody’s disease (sarcoplasmic reticulum Ca2+ATPase deficiency) are rare, and present with exertional myalgia and ‘cramps’. Malignant hyperthermia, characterized by hyperpyrexia, rhabdomyolysis and severe acidosis induced by anaesthetic agents, is relatively common and genetically heterogeneous. Mutations at one malignant hyperthermia locus on 19q13.1 (ryanodine receptor) also determines a congenital myopathy (central core disease).