Myotubular Myopathy

Congenital muscle disease characterized by generalized hypotonia, muscle weakness, and central nuclei on muscle biopsy (myotube-like aspect).

XMTM; X-Linked Myotubular Myopathy; XLMTM; Centronuclear Myopathy.

1:50,000 males births.

Three types of myotubular myopathy are recognized based on the mode of inheritance: X-linked, autosomal recessive, and autosomal dominant. For the neonatal form, the gene has been localized on chromosome Xq28.

The myotubular or centronuclear myopathies are a group of inherited myopathies defined by the presence of central nuclei in affected skeletal muscle. Males with XLMTM with identifiable mutations in MTM1 can be said to have MTM1. Typically, X-linked myotubular myopathy is the most severe form, presenting with hypotonia and respiratory distress in affected newborn males. It is associated with high neonatal mortality. Surviving patients typically have prolonged ventilator dependence and grossly delayed motor milestones. Female carriers of XLMTM are generally asymptomatic, although rare manifesting heterozygotes have been described. The autosomal dominant (or adult) form has a later onset and a milder course. The course and severity of the autosomal recessive (or infantile) form is intermediate between the X-linked and the autosomal dominant form. Intelligence is usually within the normal range.

Creatine kinase level is normal or slightly increased. The diagnosis of XLMTM has traditionally relied upon the presence of characteristic pathology in muscle samples: atrophy predominantly of type I muscle fibers, which have centrally placed myofiber nuclei. The central areas of muscle fibers are devoid of myofibrils, with aggregation of mitochondria. Resemblance to fetal myotubes is thought to reflect an arrest in morphogenesis of the muscle fibers. The diagnosis of XLMTM should be considered in any male with significant neonatal hypotonia and/or muscle weakness. A positive family history suggestive of X-linked inheritance, found in approximately 30% of reported cases, provides further evidence for XLMTM. Although clinical features such as a length and head circumference greater than 90th percentile, cryptorchidism, and/or long fingers and toes are common, none is diagnostic of XLMTM. With the advent of molecular genetic testing, males with milder clinical phenotypes have been found to have mutations in the MTM1 gene.

Neonatal Form: In males with the classic, severe, neonatal presentation, polyhydramnios with decreased fetal movement is often present. Hypotonia in the neonatal period appears to be a universal finding and, in the US series of Herman et al. (1999), 80% of patients required endotracheal intubation and ventilatory support at birth. Patients often have typical myopathic facies with dolichocephaly, a high forehead, long face with midface hypoplasia, and a narrow, high-arched palate with subsequent severe malocclusion. Additional features in the US series included length greater than 90th percentile with a proportionately lower weight (60%), long fingers and/or toes (43%), cryptorchidism (>50%), contractures including clubfeet (30%), and areflexia (60%). Many patients succumb during infancy to complications of the disorder or as a result of withdrawal of life support. For surviving patients in the United States, the average length of initial hospitalization is approximately 90 days. Most surviving males in the United States are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy (G-tube) feedings. With the isolation of the MTM1 gene in 1996, it became apparent that some males with a much milder phenotype have mutations in MTM1. A clinical classification for this broader phenotype (termed MTM1) was described by Herman et al. (1999). Neonates were classified as severe, moderate, or mild:

Severe (Classic): Characteristic facies, chronic ventilator dependence, grossly delayed motor milestones, nonambulatory, or death in infancy.

Moderate: More rapid achievement of motor milestones than patients with the severe form; prolonged periods of decreased ventilatory support.

Mild: Ambulatory with minimally delayed motor milestones, lack of chronic ventilatory support beyond the newborn period, lack of typical myopathic facies.

Despite having a chronic illness and prolonged ventilator dependence, many patients with MTM1 have linear growth above the 50th percentile; some patients in the US series achieved greater than 90th percentile for height. An advanced bone age and/or premature adrenarche have been documented in several boys, suggesting some disturbance of endocrine regulation; however, results of endocrinologic studies performed in several patients have been normal. Puberty has occurred normally in the few patients who have reached adulthood, although reproduction by an affected male has not been documented. Cognitive development in the majority of patients is normal if no significant hypoxic episodes have occurred. The muscle disease is not progressive, and muscle strength improves slowly over time. Medical complications related to the underlying myopathy are ophthalmoplegia, ptosis, severe myopia, dental malocclusion (requiring orthodontic care), and scoliosis. Scoliosis often develops in later childhood and may require surgical intervention. Scoliosis can exacerbate respiratory insufficiency and can cause some ventilator-independent boys to become ventilator dependent again as the condition progresses. With more aggressive supportive care and longer survival of some patients with MTM1, medical complications unrelated to the muscle disorder have occurred; these complications include pyloric stenosis, a mild form of spherocytosis, gallstones, kidney stones, nephrocalcinosis, a vitamin K-responsive bleeding diathesis, and liver dysfunction manifested by pruritus and elevated serum transaminases. Several patients have died following prolonged liver hemorrhage or hemorrhage into the peritoneal cavity. In three patients, peliosis hepatis, a rare vascular lesion characterized by the presence of multiple blood-filled cysts within the liver, was noted. Authors are aware of several additional unreported cases of boys with MTM1 and liver dysfunction, peliosis, or hemorrhage into the peritoneum. The pathogenetic mechanisms for these complications are not understood, but their lack of occurrence in other congenital myopathies and neuromuscular disorders, such as spinal muscular atrophy, strongly suggests that they are related to abnormal function of or absence of myotubularin.

Infantile Form: Delayed walking and mild proximal nonprogressive muscles weakness—most patients die or are wheelchair-bound by the second or third decade of life; the myocardium is often involved; scoliosis with restrictive lung disease. Seizures or some degree of mental retardation may be observed.

Adult Form: Stable and slow course; pregnancy worsens the muscle weakness; muscle disease usually becomes apparent by the third decade of life; patients often are wheelchair-bound by the sixth decade of life; cardiomyopathy not unusual.

As in any child presenting with a muscular disorder, thorough cardiac evaluation (ECG, echocardiography) is mandatory. Note respiratory status, arterial blood gases where indicated, chest radiograph (scoliosis, infection), and pulmonary function tests where possible. Ensure optimal hydration. Order chest physiotherapy before anesthesia and postoperatively. Postoperative mechanical ventilation might be needed in patients who are not already ventilator dependent. Check blood clotting profile and liver profile, and consider liver scan. Prophylactic vitamin K may be indicated preoperatively.

Tracheal intubation, where necessary, is likely to be complicated by the facies, high-arched palate, and dental defects. Wherever possible, use local or regional anesthesia and aim for early postoperative emergence from anesthesia. Total intravenous anesthesia has been successfully used in some cases. Regional anesthesia for postoperative pain relief if possible. Although there are no reports of malignant hyperthermia in patients affected with this disorder, inhalational anesthesia agents should be used with caution or avoided.

Malnutrition and underweight for age are common as a result of chronic infection or malabsorption; consequently, drug dosages should be reduced accordingly. By analogy with central core disease, it is probably safer to avoid malignant hyperthermia-triggering agents and succinylcholine. If possible, avoid neuromuscular blocking agents because they produce unreliable effects and may potentiate muscle weakness.

Central Core Disease: Congenital myopathy with a specific histologic pattern and high susceptibility to malignant hyperthermia.

Congenital Myopathy with Fiber-Type Disproportion: Rare genetic myopathy presenting at birth with hypotonia, muscle weakness, and high-arched palate. Findings occurring later include short stature, progressive scoliosis, hip dislocation, and deformities of the feet.

Nemaline Rod Myopathy: Rare congenital and slowly progressive inherited neuromuscular disease usually apparent at birth and characterized by extreme hypotonia.