Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center

Familial partial lipodystrophy (FPLD) is a rare syndrome in which a patient’s phenotype is not merely dependent on the specific genetic mutation, but it is also defined by a combination of other demographic, environmental and genetic factors. In this prospective observational study in a Greek referral center, we enrolled 39 patients who fulfilled the clinical criteria of FPLD. A genetic analysis was conducted, which included sequence and deletion/duplication analyses of the LMNA and PPRARG genes, along with anthropometric and metabolic parameters. The treatment responses of patients who were eligible for treatment with metreleptin were evaluated at 3 and 12 months. In most of the patients, no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. On the contrary, various changes were detected at the intron level, especially in introns 7 and 10, whose clinical significance is considered unknown. In addition, treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, an effect which was sustained at the 12-month follow-up. More large-scale studies are necessary to clarify the genetic and allelic heterogeneity of the disease, along with other parameters which could predict treatment response.

[1]  E. Renard,et al.  Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real‐life experience from a national reference network , 2022, Diabetes, obesity & metabolism.

[2]  Rebecca J. Brown,et al.  Effects of metreleptin in patients with lipodystrophy with and without baseline concomitant medication use , 2021, Current medical research and opinion.

[3]  F. Karpe,et al.  Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance , 2021, Frontiers in Endocrinology.

[4]  A. Bargiota,et al.  Familial Partial Lipodystrophy (FPLD): Recent Insights , 2020, Diabetes, metabolic syndrome and obesity : targets and therapy.

[5]  Rebecca J. Brown,et al.  Comorbidities and Survival in Patients with Lipodystrophy: An International Chart Review Study. , 2019, The Journal of clinical endocrinology and metabolism.

[6]  A. Garg,et al.  Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants. , 2019, The Journal of clinical endocrinology and metabolism.

[7]  E. Kalkhoven,et al.  Gene-gene and gene-environment interactions in lipodystrophy: Lessons learned from natural PPARγ mutants. , 2019, Biochimica et biophysica acta. Molecular and cell biology of lipids.

[8]  C. López-Otín,et al.  Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome , 2018, Journal of Medical Genetics.

[9]  Ş. Savaş-Erdeve,et al.  Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy. , 2017, Metabolism: clinical and experimental.

[10]  C. Vigouroux,et al.  Clinical Utility Gene Card for: Familial partial lipodystrophy , 2017, European Journal of Human Genetics.

[11]  F. Hisama,et al.  High incidence of BSCL2 intragenic recombinational mutation in Peruvian type 2 Berardinelli–Seip syndrome , 2017, American journal of medical genetics. Part A.

[12]  D. Dunger,et al.  The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline , 2016, The Journal of clinical endocrinology and metabolism.

[13]  F. Travert,et al.  One‐year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes , 2016, Diabetes, obesity & metabolism.

[14]  E. Oral,et al.  Efficacy and Safety of Metreleptin in Patients with Partial Lipodystrophy: Lessons from an Expanded Access Program , 2016, Journal of diabetes & metabolism.

[15]  P. Gorden,et al.  Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. , 2015, The Journal of clinical endocrinology and metabolism.

[16]  J. Santos,et al.  Divergent Metabolic Phenotype between Two Sisters with Congenital Generalized Lipodystrophy Due to Double AGPAT2 Homozygous Mutations. A Clinical, Genetic and In Silico Study , 2014, PloS one.

[17]  J. Chan,et al.  The clinical approach to the detection of lipodystrophy - an AACE consensus statement. , 2013, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[18]  C. Quittner,et al.  Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. , 2012, The Journal of clinical endocrinology and metabolism.

[19]  P. Robinson,et al.  Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene , 2011, American journal of medical genetics. Part A.

[20]  P. Gorden,et al.  Long-term efficacy of leptin replacement in patients with Dunnigan-type familial partial lipodystrophy. , 2007, Metabolism: clinical and experimental.

[21]  R. Hegele,et al.  A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. , 2004, The Journal of clinical endocrinology and metabolism.

[22]  P. Gorden,et al.  Long-term effectiveness and safety of metreleptin in the treatment of patients with partial lipodystrophy , 2019, Endocrine.