Mitochondrial DNA-Associated Leigh Syndrome Spectrum

CLINICAL CHARACTERISTICS

Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation, which includes the overlapping phenotypes mtDNA-associated Leigh syndrome and mtDNA-associated Leigh-like syndrome. Mitochondrial DNA-LSS is characterized by onset of manifestations typically between ages three and 12 months, often following an intercurrent illness (usually viral) or metabolic challenge (vaccinations, surgery, prolonged fasting). Decompensation (often with elevated lactate levels in blood and/or cerebrospinal fluid) is typically associated with developmental delay and/or regression. Neurologic features include hypotonia, spasticity, seizures, movement disorders, cerebellar ataxia, and peripheral neuropathy. Brain stem dysfunction may manifest with respiratory symptoms, swallowing difficulties, ophthalmoparesis, and abnormalities in thermoregulation. Extraneurologic manifestations may include poor weight gain, cardiomyopathy, and conduction defects. Up to 50% of individuals die by age three years, most often from respiratory or cardiac failure.

DIAGNOSIS/TESTING: The diagnosis of mtDNA-LSS is established in a proband fulfilling clinical diagnostic criteria for LSS by identification of a heteroplasmic or homoplasmic pathogenic variant in one of the 15 mtDNA genes known to be involved in mtDNA-LSS.

MANAGEMENT

Treatment is supportive. Sodium bicarbonate or sodium citrate for significant acidosis (THAM may be used if there is hypernatraemia); anti-seizure medication for seizures; dystonia therapy with benzhexol, baclofen, tetrabenazine, or gabapentin alone or in combination, or by botulinum toxin injection; treatment of respiratory compromise per pulmonologist; caloric and nutritional supplementation and feeding therapy as needed; developmental and educational support; physical therapy and occupational therapy; standard treatment of eye movement disorders; medical management of cardiomyopathy; treatment of constipation as needed; treatment of liver failure per hepatologist; treatment of electrolyte abnormalities per nephrologist; hearing aids or cochlear implants for sensorineural hearing loss; speech therapy and hearing support services as needed; management of diabetes mellitus and adrenal insufficiency per endocrinologist; standard treatments for anxiety and/or depression; psychological support and care coordination for the affected individual and family. Affected individuals should be followed at regular intervals to monitor for progression of disease and associated complications. Neurologic assessment for ataxia and seizures at each visit along with an assessment of pulmonary issues, growth, nutrition, and gastrointestinal manifestations. Development, educational, and cognitive assessment and assessment of mobility and self-help skills at least annually. Ophthalmology assessment every six to 12 months or as advised by ophthalmologist. Annual blood pressure, EKG, and echocardiogram or as advised by cardiologist. Liver function tests, urinalysis, urine albumin-to-creatinine ratio, urine amino acids, serum electrolytes, blood urea nitrogen, creatinine, complete blood count, and fasting glucose annually. Annual audiology assessment. Assessment of care coordination and family psychosocial needs at each visit. Sodium valproate, medications that cause acidosis, and dichloroacetate should be avoided or used with caution; administration of anesthesia requires careful consideration to avoid aggravation of respiratory symptoms and precipitation of respiratory failure.

GENETIC COUNSELING

Mitochondrial DNA-LSS is transmitted by maternal inheritance. The mother of a proband may have the mtDNA pathogenic variant and may exhibit mild clinical manifestations of mtDNA-LSS. Many affected individuals have no known family history of mtDNA-LSS or other mitochondrial disorder. The explanation for apparently simplex cases may be absence of a comprehensive and/or reliable family history, a maternal heteroplasmy level below the disease threshold (i.e., the minimum level of heteroplasmy expected to result in mitochondrial disease), or a mtDNA pathogenic variant in the proband. If the mother of the proband has the mtDNA pathogenic variant identified in the proband, all sibs of the proband are at risk of inheriting the pathogenic variant. Sibs may inherit the pathogenic variant at varying heteroplasmy levels due to the bottleneck effect and variant-specific segregation patterns. The risk to a sib of developing clinical manifestations is difficult to determine and depends on heteroplasmy level, the variation in heteroplasmy levels among different tissues, and the disease threshold for the specific variant. Recurrence risk assessment and prenatal testing for disorders caused by pathogenic variants in mtDNA is challenging due to the intricacies of mtDNA transmission and the inherent challenge in using prenatal genetic test results to predict clinical outcome. Reproductive options for the family members of a proband with an mtDNA pathogenic variant may include prenatal testing, preimplantation genetic testing, and oocyte donation.