Discussion
The patientpresented to our facility for the first time in 2016 for lipodystrophy with a history of diabetes mellitus and menstrual cramps. She was on oral contraceptives. She was noted to have fat maldistribution with a protuberant abdomen and skinny legs and arms. Her mandible was hypoplastic, and she also had sensorineural hearing loss. POLD 1 (DNA Polymerase Delta 1) mutation was suspected given a positive family history: Her mother had lipodystrophy and died at age 68 due to a myocardial infarction but no information about her father, a visiting Austrian.Twoout of her four maternal brothers have lipodystrophy and one also has crowded teeth. One brother also has 2 children with lipodystrophy with no genetic evaluation. Her grandmother had similar features and died at age of 80. She also has two maternal uncles with lipodystrophy.She has a mixed European and Native Indian ancestry with no Jewish heritage and consanguinity. Her cousin and nephew also had a history of Mandibular Hypoplasia, Deafness, progeroid features, and lipodystrophy syndrome (MDLP).
She was tested for POLD1 gene mutation, which revealed the presence of a variant of uncertain significance (UVUS), c.1519C>T (p.Arg507Cys) in POLD1, prompting further evaluation of her condition. Researchers, particularly a metabolic disease expert and a lipidologist interested in her case, were contacted [what was their contribution?]. This sequence change replaces arginine with cysteine at codon 507 of the POLD1 protein. The arginine residue is highly conserved, and there is a sizeable physiochemical difference between arginine and cysteine. This variant was not found to be in the population databases at that time.
Lipodystrophies include a heterogeneous group of disorders that share certain features, particularly fat loss in a generalized or partial pattern associated with hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Lipodystrophies are classified as either genetic or acquired. Acquired forms are usually caused due to various infections, autoimmune diseases, and drugs such as protease inhibitors and reverse transcriptase inhibitors. There is a growing consensus amongst the medical community to elucidate the genetic causes of lipodystrophies. Research in the area is yielding results, but a lot remains to be comprehended. A brief overview of currently known genetic lipodystrophies is presented in the discussion.
According to a literature review, about 1000 patients have been found to have genetic lipodystrophies5. Congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL) are two important forms. CGL presents withovert features of lipodystrophy and can be diagnosed at birth. However, FPL is commonly misdiagnosed as metabolic syndrome in adult life due to overlapping common clinical features noticed in the two conditions.