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.