Tk2-Related Mitochondrial Dna Maintenance Defect, Myopathic Form

Clinical characteristics.

TK2-related mitochondrial DNA (mtDNA) maintenance defect is a phenotypic continuum that ranges from severe to mild. To date, approximately 107 individuals with a molecularly confirmed diagnosis have been reported.

Three main subtypes of presentation have been described:

• Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared.
• Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years
• Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria.

Diagnosis/testing.

The diagnosis of TK2-related mtDNA maintenance defect is established in a proband with infantile onset of disease with severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle. The diagnosis of TK2-related mtDNA maintenance defect is established in a proband older than age two years with reduced mtDNA content or multiple mtDNA deletions, ragged red fibers and/or COX-deficient fibers in skeletal muscle. The diagnosis is confirmed by the identification of biallelic pathogenic variants in TK2 by molecular genetic testing.

Management.

Treatment of manifestations: Management should involve a multidisciplinary team. Feeding difficulties should be managed aggressively, including use of a nasogastric tube or gastrostomy tube when the risk for aspiration is high. Physical therapy can help maintain muscle function; a physical medicine and rehabilitation (PM&R) specialist can help those who have difficulty walking. A pulmonologist can oversee chest physiotherapy to improve pulmonary function, reduce the risk of pulmonary infection, and manage respiratory insufficiency, if present. Hearing loss and seizures are managed in a standard manner.

Prevention of secondary complications: Chest physiotherapy can help reduce the risk of pulmonary infection; physical therapy can help prevent joint contractures.

Surveillance: No clinical guidelines are available. Treating physicians should consider: routine evaluation of growth and weight, pulmonary function tests with consideration of blood gases, neurodevelopmental assessments at each visit, and at least annual audiology evaluations in those with infantile-onset disease.

Genetic counseling.

TK2-related mtDNA maintenance defect is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

TK2-related mtDNA maintenance defect should be suspected in individuals with the following clinical features (by age), supportive laboratory findings, electromyography results, skeletal muscle pathology, mtDNA content (copy number) analysis, and electron transport chain activity in skeletal muscle.

Establishing the Diagnosis

The diagnosis of TK2-related mitochondrial DNA maintenance defect is established in:

• A proband with infantile onset of disease with:
  • Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
  • Biallelic pathogenic variants in TK2 identified by molecular genetic testing (see Table 1).
• A proband older than age two years with:
  • Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
  • Biallelic pathogenic variants in TK2 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of TK2-related mitochondrial DNA maintenance defect is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other mitochondrial myopathies are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, approximately 107 individuals with molecularly confirmed TK2-related mtDNA maintenance defect have been reported [Pons et al 1996, Galbiati et al 2006, Oskoui et al 2006, Blakely et al 2008, Götz et al 2008, Collins et al 2009, Lesko et al 2010, Martí et al 2010, Zhang et al 2010, Béhin et al 2012, Garone et al 2018, Wang et al 2018].

The clinical presentation of TK2-related mtDNA maintenance defect is variable; as understanding of the disorder increases, the phenotype continues to broaden (Table 2).

Infantile onset (<2 years). The prenatal and perinatal histories are usually unremarkable; onset is typically in the first two years of life.

• Initial development is normal, followed by gradual onset of hypotonia:
  • A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
  • Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
    Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [Zhang et al 2010].
• Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop.
• Muscle atrophy becomes evident [Martí et al 2010].
• Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.
• Sensorineural hearing loss develops.
• Cognitive function is typically spared.

Muscle weakness rapidly progresses leading to respiratory failure and death within a few years after onset. Most children succumb to complications of respiratory muscle weakness; several are ventilator dependent before age six years. The most common cause of death is pulmonary infection.

Juvenile-/childhood-onset (ages 2-18 years) disease is characterized by distinct disease progression:

• Moderate-to-severe progression of generalized weakness
  • The severity of muscle weakness can vary widely among affected individuals.
  • In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• Survival to at least age 13 years, with respiratory failure as the primary cause of death

Adult-onset (>18 years) disease is characterized by:

• Mild proximal limb muscle weakness due to progressive mitochondrial myopathy;
• Slow progression to respiratory failure in some affected individuals;
• Involvement of the facial and extraocular muscles with manifestations including chronic progressive external ophthalmoplegia, ptosis, dysphagia, and dysarthria.

Genotype-Phenotype Correlations

It is possible that the range of phenotypes observed may be explained by the variability in the amount of residual activity of mutated enzymes [Poulton et al 2009].

The small number of individuals reported to date precludes identification of genotype-phenotype correlations; however, the following have been observed:

• The pathogenic variant p.Arg130Trp appears to be associated with the most severe phenotype, with CNS involvement (i.e., seizures and loss of previously acquired motor skills) during the first months of life [Lesko et al 2010].
• Homozygosity for p.Arg183Trp is associated with myopathy and severe mtDNA depletion restricted to skeletal muscle [Götz et al 2008].
• Homozygosity for p.Lys202del has only been found in individuals with adult-onset TK2-related mtDNA maintenance defect [Wang et al 2018].
• When the p.Arg192Lys pathogenic variant is found in trans with other variants (p.Thr108Met and p.Lys202del), childhood onset of symptoms with prolonged survival is typical [Wang et al 2018].

Prevalence

The prevalence of TK2-related mtDNA maintenance defect is unknown; the disorder appears to be rare, with only approximately 107 affected individuals reported to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with TK2-related mitochondrial DNA maintenance defect, myopathic form, the following evaluations are recommended, if not completed as part of the diagnostic evaluation.

Treatment of Manifestations

Treatment is primarily supportive; management should involve a multidisciplinary team.