MON-571 Unusual presentation of mitochondrial disease with diabetes, lipomatosis, and metabolic dyslipidemia: clinical lessons to recognize phenotype for the endocrinologist

Abstract Disclosure: O. Besci: None. C.D. Uwandu: None. M.C. Foss de Freitas: None. C.L. Chase: None. K.N. Lee: None. E.A. Oral: Regeneron Pharmaceuticals, Rejuvenate Bio., Novo Nordisk, Morphic Medical, Marea Therapeutics, Ionis Pharmaceuticals Inc., Amryt Pharmaceuticals, Fractyl Laboratories. Introduction: MT-TK-related mitochondrial disease is a rare mitochondrial DNA disorder caused by pathogenic variants in the MT-TK gene. Clinical presentations are widely variable and can include lactic acidosis, myopathy, exercise intolerance, hearing loss, diabetes, short stature, and dysautonomia. Other features, including lipomatosis and additional endocrine abnormalities (e.g., dyslipidemia with refractory hypertriglyceridemia, hypothyroidism, hypoparathyroidism, hypogonadism, osteoporosis, and metabolic kidney disease), have also been reported. Clinical Cases: A 32-year-old female presented with shortness of breath, palpitations, and significant weight loss. Evaluation revealed severe metabolic acidosis (pH 7.04, bicarbonate 5 mmol/L), persistent lactate elevations (16 mmol/L), and ketonemia. Past medical history included short stature, irregular periods and anovulation, exercise intolerance, and frequent exhaustion during physical activity. Further examination revealed multiple lipomas on the left thigh and back of the neck, bilateral sensorineural hearing loss, dysautonomia with tachycardia, and metabolic dyslipidemia requiring fibrates and niacinamide. Trio exome sequencing via blood sample confirmed a heteroplasmic (38%) pathogenic variant in the MT-TK gene (m.8363G>A), with elevated heteroplasmy in urine sediment (83%) and buccal cells (80%), consistent with a primary mitochondrial disorder. Management included a personalized mitochondrial cocktail and sodium bicarbonate for acidosis. The same pathogenic MT-TK variant was detected in the patient’s 68-year-old mother (heteroplasmy >75% in blood). Her past medical history included diabetes, hearing loss, macular degeneration with progressive visual loss, cystic kidney disease, hypothyroidism, hypoparathyroidism, osteoporosis, exercise intolerance and statin intolerance, and multiple lipomas around the face and neck, upper back, and extremities. Suspicion for a genetic disorder had not been raised prior to her daughter’s evaluation and identification of the MT-TK variant. Despite treatment with a similar cocktail regimen, her symptoms continued to progress with increasing weakness, fatigue, and tremors. Further clinical evaluations demonstrated severe coronary and peripheral macrovascular diseases thought to be due to years of inadequately treated dyslipidemia. Conclusion: These cases illustrate the variable presentation and multisystem complexity of MT-TK-related mitochondrial disease across two generations, with characteristic features including severe lactic acidosis and dysautonomia along with lipomatosis, diabetes, metabolic dyslipidemia, and progressive fatigue, which may be overlooked given their relative prevalence. Early recognition of these constellations of features and multidisciplinary care can make a difference in outcomes. Presentation: Monday, July 14, 2025