Clinical Guidance

X-MTM is most frequently caused by nonsense, frameshift, and splice site variants that predict loss of function. Pathogenic variants are found throughout the gene with no concentration in any specific domain.

Source: GeneReviews — "X-Linked Myotubular Myopathy"

Penetrance

Penetrance is thought to be 100% in males with a pathogenic variant in MTM1, as all have shown findings of the disease. However, disease severity can range from mild to severe. Carrier females are generally asymptomatic, though an increasing number of manifesting heterozygotes are being identified .

Source: GeneReviews — "X-Linked Myotubular Myopathy"

Diagnostic Criteria

Suggestive Findings

The diagnosis of X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), should be suspected in any male with the following clinical and histopathologic features.

Clinical features

• Neonatal hypotonia

• Neonatal respiratory failure

• Significant and diffuse muscle weakness

• Diminished muscle bulk

• A family history suggestive of X-linked inheritance

• Length and head circumference 90th centile

• Cryptorchidism

• Long fingers and toes

• Involvement of the extraocular muscles (i.e., ophthalmoparesis)

Histopathologic

features on muscle biopsy

Source: GeneReviews — "X-Linked Myotubular Myopathy"

Differential Diagnosis

Table 2. Disorders to Consider in the Differential Diagnosis of X-Linked Myotubular Myopathy

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked myotubular myopathy (X-MTM), the following evaluations are recommended if they have not already been completed:

• Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established.

• Feeding/swallowing assessment, as performed by a qualified occupational therapist or equivalent allied health professional

• Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established

• In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis

• In the presence of infantile vomiting, investigation for pyloric stenosis

• Consultation with a clinical geneticist and/or genetic counselor

• In older children, evaluation for orthopedic complications, including examination for scoliosis

Treatment of Manifestations

Management of individuals with X-MTM is based on supportive care measures and in large part is similar to that for other congenital myopathies . Management optimally involves a team of specialists with expertise in the long-term care of individuals with neuromuscular disorders. Such teams often include a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, and clinical geneticist.

Clinical Guidance

It is generally agreed that neuromuscular paralytics such as succinylcholine should be avoided as part of anesthesia for patients with X-MTM. However, it is important to note that individuals with X-MTM are NOT susceptible to malignant hyperthermia .

Source: GeneReviews — "X-Linked Myotubular Myopathy"

Therapies Under Investigation

Gene replacement therapy is a promising treatment strategy for X-MTM. AAV-mediated delivery of MTM1 is associated with significant improvement in strength, histopathology, and survival in both murine and canine models of the disease . A Phase I/II clinical trial (ASPIRO) is currently under way testing the safety and efficacy of this treatment in X-MTM in boys under age four years. Several other strategies have shown promise in preclinical models of X-MTM. Lowering of DNM2, a key disease modifier, using either genetic or antisense oligonucleotide-mediated gene knockdown, resulted in increased strength and prolonged survival in a murine model of X-MTM .

Source: GeneReviews — "X-Linked Myotubular Myopathy"

Surveillance Guidelines

Appropriate surveillance includes the following:

• Annual pulmonary assessment, including pulmonary function testing if able to be performed

• Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history

• Spinal examination for signs of scoliosis, particularly in late childhood and adolescence

• Annual ophthalmologic exams for ophthalmoplegia, ptosis, myopia, and for protective assessment of the effect of impaired eyelid closure

• Assessment for dental malocclusion, with referral for orthodontia if indicated

Currently, the risk for non-neurologic events including bleeding diatheses and gastrointestinal complications is uncertain. Furthermore, the benefit of screening for such abnormalities has yet to be determined. Potential screening tests may include the following, though these studies have not been found to reliably identify actionable abnormalities:

• Annual blood counts

• Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis

Note: No advanced screening has been found to be useful for detecting hepatic peliosis prior to the development of clinically significant hemorrhage.

Source: GeneReviews — "X-Linked Myotubular Myopathy"