MYOTONIC DISORDERS

Myotonic Muscular Dystrophy 1 (DM1)

Myotonic muscular dystrophy 1 (DM1) is an autosomal-dominant multisystem muscular dystrophy with an incidence of 1 per 7,500 to 8,000 (7,104). It represents the most common inherited NMD of adults and may be the most common disorder of skeletal muscle. The disorder affects multiple systems including skeletal muscle, smooth muscle, myocardium, brain, and ocular structures. Associated findings include baldness and gonadal atrophy (in males), cataracts, and cardiac dysrhythmias. Insulin insensitivity may be present. DM1 is caused by expansion of a cytosine-thymine-guanine (CTG) triplet repeat in the 3' noncoding region of myotonin protein kinase, the gene encoding the DM protein kinase (DMPK). The gene has been localized to chromosome 19ql3.3. Patients demonstrate expansion of an unstable CTG trinucleotide repeat within the region. Molecular genetic testing is available for diagnosis. Normal individuals generally have less than 37 repeats which are transmitted from generation to generation. DM1 patients may have 50 to several thousand CTG repeats with remarkable instability. The age of onset is inversely correlated by the repeat links (105). Mild, late onset DM1 usually is associated with 50 to 150 repeats, classic adolescent or young adult onset

(A) Typical facial characteristics in myotonic muscular dystrophy 1 (DM1) and congenital DM1. The symptomatic mother has 660 trinucleotide CTG repeats at the DM protein kinase (DMPK) gene loci in chromosome 19q13.3, while the child has 1,560 repeats. (B) Temporal wasting and myopathic facies with tent-shaped mouth in children with DM1.

FIGURE 18.9 (A) Typical facial characteristics in myotonic muscular dystrophy 1 (DM1) and congenital DM1. The symptomatic mother has 660 trinucleotide CTG repeats at the DM protein kinase (DMPK) gene loci in chromosome 19q13.3, while the child has 1,560 repeats. (B) Temporal wasting and myopathic facies with tent-shaped mouth in children with DM1.

DM1 shows 100 to 1,000 repeats and congenital DM1 patients show greater than 1,000 repeats. The expanded CTG repeat further expands as it is transmitted to successive generations, providing a molecular basis for genetic anticipation. Both maternal to child and paternal to child transmission occurs. Repeat size in offspring exceeding 1,000 CTG repeats is generally seen in maternal rather than paternal transmission. Affected fathers seldom transmit alleles larger than 1,000 copies to offspring owing to a lack of sperm containing such alleles.

Several characteristic facial features of DM1 may be noted on inspection (Figure 18.9). The adult with long-standing DM1 often has characteristic facial features. The long thin face with temporal and masseter wasting is drawn and has been described by some as "lugubrious." Adult males often exhibit frontal balding. Children with congenital myotonic muscular dystrophy often exhibit a triangular or "tent-shaped mouth" (Figure 18.9).

Myotonia. Myotonia is a state of delayed relaxation or sustained contraction of skeletal muscle is easily identified in school-age children, adolescents, and adults with DM1. Grip myotonia may be demonstrated by delayed opening of the hand with difficult extension of the fingers following tight grip. Percussion myotonia may be elicited by percussion of thenar eminence with a reflex hammer, giving an adduction and flexion of the thumb with slow return (Figure 18.10). Symptomatic myotonia may be treated with agents such as mexiletine, or membrane stabilizers such as carbamazepine or Dilantin, which have been shown to impact the symptoms; however, patients treated have shown little functional gain (106). A randomized placebo-controlled crossover study of mexiletine showed reduction of grip myotonia by up to 50% in DM1 patients after 7 weeks of treatment (107).

DM1 is one of the few dystrophic myopathies with greater distal weakness than proximal weakness, although neck flexors, shoulder girdle musculature, and pelvic girdle musculature may become significantly involved over decades, weakness initially is often most predominant in the ankle dorsiflexors, ankle everters and inverters, and hand muscles (108). As with other dystrophic myopathies, significant muscle wasting may occur over time. In DM1 patients with infantile onset, a congenital club foot or talipes equinovarus is a fairly common deformity (Figure 18.11). In patients with noncongenital DM1, contractures at the wrist, ankle, and elbows are relatively uncommon and mild (108). Patients with congenital onset DM1 may develop spinal deformity requiring surgical spinal arthrodesis (108).

Hyper somnolence. Excessive daytime sleepiness is commonly seen in DM1 (109) and it is thought to be related to the loss of serotonergic neurons in the dorsal raphe and superior central nucleus of the brainstem. Treatment of the hypersomnolence with modafinil has been helpful.

Cardiac involvement. The cardiac impact of DM1 falls mainly on the conduction system. Abnormalities on ECG and echocardiography are demonstrated in approximately 70% to 75% of patients (110). Prolongation of the PR interval, abnormal axis, and intranodal conduction abnormalities are all suggestive of conduction system disease which may explain the occurrence of sudden death which is a risk in adult DM1 patients (111). Ventricular tachycardia may also contribute to the syncope and sudden death associated with DM1. Cardiac dysrhythmia,

A-C, Percussion myotonia of the thenar eminence.

FIGURE 18.10 A-C, Percussion myotonia of the thenar eminence.

particularly heart block, is the second leading cause of death after respiratory failure (112). In a prospective study, the risk of sudden death in a clinic population was 1.1% per year (113). Sixty-five percent of patients show prolongation of the PR interval or QRS duration. The conduction defects are progressive and may lead to severe bradycardia or asystole due to atrioventricular block.

Talipes equinus in congenital myotonic muscular dystrophy 1 (DM1).

FIGURE 18.11 Talipes equinus in congenital myotonic muscular dystrophy 1 (DM1).

Atrial tachycardias (flutter, fibrillation, or sinus tachycardia) are relatively common, and risk of ventricular tachycardia is also elevated. Although the cardiac contractility is relatively preserved, heart failure may occur at later ages. Ten percent of patients in a large study had clinical or echocardiographic evidence of LVSD (113). LVSD was rare before 40 years of age, but after this age the frequency steadily increased, reaching a high of 30% by the age of 70 years. Some patients have required implantation of cardiac pacemakers. Q-waves have been reported on screening ECGs in DM1 patients and this abnormality may reflect myocardial fibrosis (111,114). Occasionally teenagers may present with atrial arrhythmias. Any DM1 patient with dyspnea, chest pain, syncope, or other cardiac symptoms should receive thorough cardiac evaluation. Care should be taken during general anesthesia in DM1 due to risk of cardiac arrhythmias and malignant hyperthermia.

Ocular involvement. Cataracts before the age of 55 years, or family history of premature cataracts, suggest the diagnosis of DM1 or DM2 in patients with muscle symptoms. By direct ophthalmoscopy, the cataracts of DM are nonspecific and appear as punctate opacities. By slit lamp examination, they have a multicolored iridescent appearance and are located in the posterior lens capsule, findings that are highly suggestive of DM1 or DM2. Premature cataracts may also occur in mitochondrial, centronuclear, or myofibrillar (aB-crystallin) myopathies.

CNS involvement. Congenital DM1 show severe cognitive impairment and mental retardation is common. In noncongenital DM1, there is evidence for a generally lower intelligence of a mild degree (full-scale IQs have been reported in the 86-92 range) (110). There is a wide range of IQ values found in this population with many subjects scoring in the above-average range. Cognitive functioning also appears to be related to the size of the CTG expansion at the DM1 gene locus. The most common CNS symptom, affecting around 80% of patients, is daytime hypersomnolence. In some individuals this is coupled with a global disorganization of sleep habits and diurnal rhythm. Studies have shown sleep-onset rapid eye movement in 26% to 54% of patients (115,116). DM1 is also associated with a variable constellation of behavioral and cognitive changes, which may include anxiety, avoidant behavior, apathy, memory impairment, executive dysfunction, and problems with visuospatial processing.

Endocrinopathies. Endocrine disorders are frequently found in DM1. Hypothyroidism is common as is insulin resistance and type 2 diabetes. DM1 patients should be screened regularly with thyroid stimulating hormone (TSH) levels and a fasting insulin, fasting glucose, and HgbAlC. There is often reduced insulin-like growth factor-1 (IGF-1) levels, and pituitary deficiency with reduced growth hormone release and increased FSH levels. In males there is hypogonadism with testicular atrophy, reduced testosterone levels, oligospermia, reduced fertility, and erectile dysfunction.

Pulmonary disorders. Individuals with congenital and noncongenital DM1 have a very high incidence of restrictive lung disease (110). Involvement of respiratory muscles is a major cause of respiratory distress and mortality in affected infants with DM1. Early ventilator support may be required but children frequently wean from the ventilator over the first few years of life. Swallowing difficulties that produce aspiration of material into the trachea and bronchial tree, along with weakened respiratory muscles and a weak cough have been reported as factors that may result in pulmonary complications in DM1 patients.

Gastrointestinal disorders. Gastrointestinal symptoms are highly prevalent in DM1 (117). The frequency of cholelithiasis is increased, which may reflect involvement of smooth muscle in the gallbladder (118). Intestinal dysmotility is common, producing symptoms of bowel urgency and diarrhea, often alternating with constipation. Whether these symptoms result from involvement of smooth muscle, enteric neurons, or both has not been determined.

Hair loss. Male pattern balding can occur in men and women with DM1. It rarely occurs in children with DM1.

Metabolic disorders. DM1 patients often show increased cholesterol and hypertriglyceridemia (119,120).

Abnormal liver function tests are common in DM1 and DM2 (120,121). Modest elevations of alanine and aspartate aminotransferase levels, gamma-glutamyltransferase, and alkaline phosphatase may occur. Generally these abnormalities are nonprogressive and do not require liver biopsy unless there is corollary evidence of another disease process. It is unknown whether these changes represent a primary effect of DM on hepatocytes or a secondary consequence of metabolic derangements, biliary stasis, or fatty liver.

Congenital DM1. Twenty-five percent of infants born to myotonic mothers have congenital DM1 and 10% to 15% of all DM1 patients have congenital presentations. CTG repeats in these cases may range from 1,000 to over 4,000 repeats. Obstetric problems are inversely related to the age of presentation of the mother with DM1 and they include polyhydramnios, decreased fetal movements, breech presentation, and preterm labor. Infants show hypotonia, failure to thrive due to an inability to suck, bilateral facial and jaw muscle weakness, craniofacial changes including a tented upper lip and high-arched palate, neonatal respiratory distress (50%), delayed motor milestones, and delayed speech. Equinovarus deformities are common. Most children are weaned from the ventilator and walk independently. Clinically children with congenital DM1 usually show no myotonia over the first five years of life. Those with congenital DM1 usually show significantly reduced IQ, often in the mentally retarded range (108,122). The cognitive impairment is nonprogressive. Behavioral abnormalities include attention deficit hyperactivity and autistic behavior. Hydrocephalus may be seen in nearly half of patients with congenital DM1. MRI may show hypoplasia of corpus callosum and cerebral white matter changes, and diffuse cerebral atrophy. Diagnosis of congenital DM1 is made by molecular genetic studies as EMG shows no myotonia and CK is usually normal. Muscle biopsy is normal or nonspecific.

 
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