Abstract Disclosure: M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. A. DillGomes: None. F. Grissi: None. S. Imam: None. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, receives payment, Ionis Pharmaceuticals Inc., Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Ionis Pharmaceuticals Inc., Aegerion Pharmaceuticals, Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GID Dynamics. Other; Self; Aegerion Pharmaceuticals. Multiple symmetric lipomatosis (MSL) is a rare disease characterized by symmetrical deposition of adipose tissue (AT) in the neck and upper body, associated with lipoatrophy in the distal segments of arms and legs and has been recently associated with biallelic mitofusin (MFN) 2 pathogenic variants. We are currently following multiple pedigrees, some with two affected siblings with MFN2-associated MSL. Homozygous MFN2 R707W (c.2119C>T) pathogenic variant was detected in all but one patient. Briefly, patient 1 is a 43-year-old female who first reported increased head and neck adiposity with increased muscularity of her extremities around 13 years old. Her sister is also affected (patient 2). The father was confirmed to be heterozygous for the pathogenic variant R707W. Patient 3 (20-year-old male) and patient 4 (17-year-old male) are siblings from another pedigree. The older sibling in this pedigree has evidence of axonal neuropathy and feet deformities. Both parents are heterozygous for R707W. Patient 5 () is a 54-year-old female reporting face and upper body fat tissue expansion starting when she was 15 years old; she also presented with distal axonal neuropathy. Her sister (patient 6) has clinical manifestations compatible with MSL (patient 6). Patient 7, who is a compound heterozygote with the R707W and D536T variants, is a 59-year-old woman who started noticing unusual body fat distribution at age 17 and progressively developed myopathy and neuropathy associated with Charcot-Marie-Tooth disease, and she also developed acromegalic features and severe macroglossia. All patients share the phenotypic features of the disease characterized by the accumulation of fat in the upper part of the body and lipoatrophic upper and lower limbs. Although variable, all patients have some degree of insulin resistance, but none of them has crossed the clinical threshold of diabetes so far. Triglyceride levels are elevated, ranging from around 200mg/dL-1300mg/dL. Remarkably, all patients have very low leptin levels and an enlarged liver with mildly impaired liver function. Obstructive sleep apnea is diagnosed in four patients due to the accumulation of AT in the neck. All patients have enlarged tongues. Patient 7 has an elevated IGF-1 level. Interestingly, all patients have been noted to have elevated GDF-15 levels (ranging from 1662-2813pg/mL). Affected patients have variable degrees of scoliosis, likely a secondary effect of adipose tissue overgrowth during adolescence. Although the mechanism of disease is not clear, R707 is in the carboxy-terminal coiled-coil domain HR2 of MFN2 and may regulate mitochondrial membrane fusion. A better understanding of the metabolic impact of MFN2 R707W in lipolysis and energy expenditure will provide new insights into patient care, hopefully improving these patients' quality of life. Presentation: Friday, June 16, 2023
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Apr 1, 2024
Rashid Shahid + 3
Open Access
