Dunnigan-type familial partial lipodystrophy associated with the heterozygous R482W mutation in LMNA gene — case study of three women from one family

Abstract

Lipodystrophies are a heterogeneous group of diseases affecting adipose tissue distribution. Familial partial lipodystrophy of the Dunnigan type (FPLD) is a rare autosomal, dominant disorder caused by missense mutations in lamin A/C (LMNA) gene where selective loss of subcutaneous adipose tissue from the limbs and trunk, and accumulation of fat in the neck and face, is usually associated with a variety of metabolic disorders including insulin resistance, diabetes mellitus, dyslipidemia, hepatic steatosis and high blood pressure. In this report we present clinical and molecular features of three Polish women with FLPD phenotype coming from one family (a mother and her two daughters). FPLD was recognised under the circumstances of diabetes treatment, where sequencing of LMNA gene revealed heterozygous R482W mutation. In order to be able to recognise monogenic diabetes associated with lipodystrophy, it is important to be very precise in physical examination while diagnosing diabetes and to be aware of the necessity of performing genetic testing. Diabetesappropriate differential diagnosis is essential for the treatment strategy, anticipation of the disease progression, and determination of the prognosis. It is necessary for an individual mutation carrier to look carefully at the patient's family. StreszczenieLipodystrofie są heterogenną grupą chorób dotyczących rozmieszczenia tkanki tłuszczowej w organizmie. Rodzinna częściowa lipodystrofia typu Dunnigana (FPLD, familial partial lipodystrophy of the Dunnigan type) jest rzadkim autosomalnie dominującym schorzeniem, którego przyczyną jest mutacja braku sensu w genie laminy A/C (gen LMNA). W chorobie tej dochodzi do selektywnej utraty podskórnej tkanki tłuszczowej kończyn i tułowia oraz jej kumulacji w okolicy karku i twarzy, co zwykle jest związane z występowaniem różnych schorzeń metabolicznych, w tym insulinooporności, cukrzycy, dyslipidemii, stłuszczenia wątroby i nadciśnienia tętniczego. W przedstawionym raporcie opisujemy kliniczne i molekularne cechy trzech polskich kobiet pochodzących z jednej rodziny charakteryzujących się fenotypem FLPD (matka i jej dwie córki). Obecność FLPD rozpoznano w trakcie leczenia cukrzycy na podstawie sekwencjonowania genu LMNA i ujawnienia heterozygotycznej mutacji R482W. W celu rozpoznania cukrzycy monogenowej związanej z lipodystrofią ważne jest przeprowadzenie szczegółowego badania fizykalnego w toku diagnostyki cukrzycy oraz świadomość konieczności diagnostyki genetycznej wątpliwych przypadków. Prawidłowa diagnostyka różnicowa cukrzycy jest niezbędna w celu ustalenia strategii leczenia, przewidywania progresji choroby, określenia rokowania, a także jest potrzebna w celu wzmożenia czujności diagnostycznej w odniesieniu do rodziny osoby będącej nosicielem mutacji. (Endokrynol Pol 2013; 64 (4): 306-310)

Effectiveness of Insulin Pump Therapy in a Patient with Familial Partial Lipodystrophy of Dunnigan Type

“…We present a case of a 24 year old Caucasian female diagnosed with FPLD at the age 21 based on physical examination, positive family history (her mother and sister were diagnosed with FLPD) and genetic studies. Direct DNA sequencing revealed a heterozygous missense mutation at codon 482 (c.1444C>T; R482W) located in exon 8 of the LMNA gene what was described in detail elsewhere [4]. Since diagnosis she has been treated with multiple daily injections (MDIs) of insulin analogue (insulin aspart before meals and insulin detemir at night) and 3000 mg of metformin.…”

Familial partial lipodystrophy, Dunnigan variety - challenges for patient care during pregnancy: a case report

“…Lack of fertility and obstetrical complications are frequent with FPLD2. Vantyghem et al reported a prevalence of polycystic ovarian syndrome of more than 50%, of infertility close to 30%, miscarriages of 50%, gestational diabetes of at least 30%, and preeclampsia and foetal death of over 10% [ 25 , 32 ]. Contrary to these previous reports, our patient had no history of polycystic ovarian syndrome, nor any signs of hyperandrogenism, and presented no difficulties in conceiving.…”

“…The mutant gene products may disrupt interaction with chromatin or other nuclear lamina proteins, resulting in abnormal differentiation and the premature death of adipocytes [ 17 - 19 ]. Most mutations cluster in the carboxy-terminal immunoglobulin domain of lamin A/C [ 3 ], and the majority of patients have heterozygous missense mutations, affecting codon 482 on exon 8 [ 20 - 25 ]. FPLD2 patients are born with normal fat distribution and after puberty they lose subcutaneous fat from their extremities, trunk and gluteal regions.…”

Atomic force microscopy and lamins: A review study towards future, combined investigations

“…Besides the recent findings relating LMNA mutations to the fibro‐fatty replacement typical of ARVC, the connection among aberrant lamins and adipose tissues had already been widely investigated over the years, as in the case of Dunnigan type familial partial lipodystrophy. Nowadays it is well‐known that the majority of LMNA mutations causing FPLD leads to aminoacid substitutions within the immunoglobulin‐type domain of lamin A/C (Nabrdalik et al, ), and the LMNA R482W mutation is the most frequent genotype related to familial partial lipodystrophy of the Dunnigan type (Vantyghem et al, ).…”

“…Nowadays it is well-known that the majority of LMNA mutations causing FPLD leads to aminoacid substitutions within the immunoglobulintype domain of lamin A/C (Nabrdalik et al, 2013), and the LMNA R482W mutation is the most frequent genotype related to familial partial lipodystrophy of the Dunnigan type (Vantyghem et al, 2004).…”