RARE DISEASE
Familial partial lipodystrophy
Familial partial lipodystrophy
Familial partial lipodystrophy
Synonyms: FPLD
Synonyms: FPLD
Synonyms: FPLD
Drug discovery
2
drugs
With orphan designations
Overview
Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by progressive subcutaneous fat loss in limbs/buttocks and ectopic fat deposition in the face, neck, or trunk. Associated with severe insulin resistance, hypertriglyceridemia, diabetes, hepatic steatosis, and cardiovascular complications. Most forms follow autosomal dominant inheritance, often linked to LMNA or PPARG mutations. Diagnosis is clinical and genetic, with management focusing on metabolic complications [1][10][14].
Burden
High rates of diabetes (∼80%), hypertriglyceridemia (60–90%), pancreatitis, and premature atherosclerosis [1][5][14].
Reduced quality of life due to body image concerns and psychiatric comorbidities (e.g., depression) [3][7].
Increased cardiovascular mortality; lifespan often reduced by 10–20 years [7][14][15].
Therapies
Lifestyle: Low-fat, high-fiber diets; structured exercise to reduce ectopic fat [3][16].
Pharmacologic: Metformin, fibrates, and insulin for metabolic control; metreleptin (leptin analog) for severe insulin resistance/hypertriglyceridemia [1][3][16].
PPARγ agonists (e.g., pioglitazone) may benefit PPARG mutation carriers [12][16].
Categories: rare endocrine diseases, rare genetic diseases, rare skin diseases
Research Papers
238 drug discovery papers about Familial partial lipodystrophy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
238 drug discovery papers about Familial partial lipodystrophy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-22 | First diagnosis of familial partial lipodystrophy syndrome type 3 during pregnancy associated with a novel heterozygous PPARG variant and a concurrent ABCC8 variant: a case report
Familial partial lipodystrophy (FPLD) is a rare genetic syndrome characterised by persistent, selective loss of adipose tissue and is closely associated with severe metabolic disturbances. Pregnancy in women with FPLD is associated with a high risk for both mother and foetus, while clinical experience remains very limited. Evidence from case reports and small series is essential for risk stratification, multidisciplinary management, and optimization of maternal and foetal health. Here, we report the case of a woman at 18 weeks of gestation with very severe hypertriglyceridaemia complicated by acute pancreatitis. The patient had a history of young-onset diabetes mellitus, hypertension, polycystic ovary syndrome (PCOS) and previously known hypertriglyceridaemia, accompanied by characteristic loss of gluteofemoral and lower limb adipose tissue, raising the clinical suspicion of FPLD. Molecular genetic analysis was performed using next-generation sequencing-based gene panel diagnostics. Variants were described according to Human Genome Variation Society (HGVS) nomenclature and classified according to the American College of Medical Genetics and genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. We made the initial diagnosis of severe FPLD3 syndrome and detected a novel heterozygous c.380A>C, p.(Glu127Ala) variant in the peroxisome proliferator-activated receptor gamma gene ( PPARG ), classified as likely pathogenic and considered causative for the patient´s phenotype. In addition, a heterozygous variant of uncertain significance c.328G>A, p.(Ala110Thr) in the ATP-binding cassette transporter sub-family C member 8 gene ( ABCC8 ), was detected. High-dose intensive insulin therapy in combination with metformin and omega-3 fatty acids resulted in a marked reduction in triglyceride levels, normalised blood glucose levels until delivery and avoided further episodes of pancreatitis. Early recognition of FPLD is crucial, particularly in high-risk settings such as pregnancy. Intensive, multidisciplinary metabolic management can stabilize severe metabolic complications and may enable favourable maternal and foetal outcomes.
2026-06-05 | Molecular insight into the activator and deactivator mutations of peroxisome proliferator-activated receptor gamma.
The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is essential for inflammation, lipid metabolism, glucose homeostasis, and adipogenesis. The function of PPARγ can be significantly impacted by mutations that either activate or deactivate the receptor. Deactivating variants can act as dominant-negative forms that sequester coactivators, impair ligand recognition, destabilize the activation function-2 (AF-2) surface, or favor corepressor binding. They are frequently found in the ligand-binding or DNA-binding domains. Metabolic disorders like severe insulin resistance and familial partial lipodystrophy type 3 are caused by these mutations. Activating mutations provide mechanistic insights into receptor overactivation by stabilizing helix 12 and the AF-2 surface, improving coactivator recruitment, and promoting ligand-independent transcription. These variations change the equilibrium between inactive and active states, modify coactivator binding, and reshape conformational ensembles, as demonstrated by molecular dynamics simulations. The design of selective modulators for precision therapy that target PPARγ is guided by an understanding of these molecular mechanisms, which also help classify mutations as dominant-negative or drug-rescuable.
2026-04-27 | Familial partial lipodystrophy type 2 associated with a novel LMNA variant (c.604G>C; p.Glu202Gln): a Colombian family case series.
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant laminopathy caused by LMNA gene variants. It is characterized by progressive gluteofemoral lipoatrophy and severe metabolic derangements, including insulin resistance and metabolic dysfunction-associated steatotic liver disease. Three Colombian women (two sisters and a daughter) underwent standardized clinical phenotyping, dual-energy X-ray absorptiometry (DXA), cardiometabolic laboratory testing, and next-generation sequencing-based testing for lipodystrophy-related genes with copy-number variant analysis. All patients carried the heterozygous LMNA variant c.604G>C (p.Glu202Gln). Patients 1 and 2 exhibited classic Dunnigan phenotypes with diabetes and severe hypertriglyceridemia (up to 1,471 mg/dL), as well as imaging evidence of metabolic dysfunction-associated steatotic liver disease. Patient 3 (age 27) presented an evolving phenotype with central adiposity, clinically reported lower-limb fat loss, and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR], 4), without hepatic steatosis on abdominal ultrasound. Management optimization in Patients 1 and 2 using contemporary combination therapy, including glucagon-like peptide-1 receptor agonist-based treatment and sodium-glucose cotransporter-2 inhibitors, was followed by sustained improvement in glycemia (HbA1c 11.1% to 7.6% in Patient 1) and triglycerides. In Patient 3, liraglutide was discontinued due to poor tolerability and limited weight response, and she was transitioned to semaglutide in February 2026. This case series expands the phenotypic spectrum of LMNA-associated FPLD2 and supports a disease association for the p.Glu202Gln variant despite its current classification as a variant of uncertain significance. It demonstrates that modern cardiometabolic therapies can be implemented in middle-income settings; however, the absence of functional data, population frequency metrics, and genetic testing in unaffected relatives limits the strength of variant interpretation.
2026-03-23 | Evaluating the therapeutic impact of tirzepatide in people with partial lipodystrophy.
Lipodystrophy syndromes (LD) are a group of rare conditions characterized by the generalized or partial absence and/or dysfunction of adipocytes. Due to the lack of fat storage capacity, excess lipid accumulates in other tissues, leading to severe insulin resistance. At present, effective therapeutic options remain limited, with metreleptin currently the only specific licensed treatment. To this end, we evaluated the therapeutic impact of tirzepatide in people with partial lipodystrophy (PLD). This was a single-center, retrospective, observational study, including all patients with PLD treated with tirzepatide between January 2022 and September 2025. Forty patients with PLD were included FPLD1 like = 26 (65%), FPLD2 = 4 (10%), FPLD3 = 7 (17.5%), FPLD7 = 1 (2.5%), APLD = 1 (2.5%), unclassified = 1 (2.5%). 87.5% (n = 35) were female with a median age of 47 years (IQR 39-59) and a median BMI of 31.5 kg/m2 (IQR 27.3 to 35.5). After a median 9.5 month follow-up (IQR 7 to 11), marked reductions were seen in body weight from 91.0 kg (IQR 75.0 to 106.0) to 82.8 kg (IQR 69.0 to 93.4; P < .0001), in HbA1c from 65 mmol/mol (IQR 54.5 to 85) to 52 mmol/mol (IQR 39 to 62; P < .0001) and in serum triglycerides from 2.80 mmol/L (IQR 1.6 to 3.7) to 1.83 mmol/L (IQR 1.0 to 2.9; P = .0005). Daily insulin requirements fell from 177.5 IU (IQR 101.3 to 213.8) to 58.0 IU (IQR 0 to 112.5; P = .0028). In patients with partial lipodystrophy, tirzepatide use resulted in substantial statistically significant reductions in weight, glycemic control, serum triglycerides, and daily insulin requirement. We recommend further prospective studies to support these findings and to evaluate its impact earlier in the course of the disorder.
2026-03-19 | Lamin A/C in health, laminopathies, and familial partial lipodystrophy 2.
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by selective adipose tissue loss, expansion, and dysfunction, caused by pathogenic variants in LMNA encoding nuclear lamins A and C. Here, we synthesize current evidence on how nuclear shape abnormalities, impaired mechanosensing, blocked adipogenesis, chromatin remodeling, and altered lamin-binding partner interactions may contribute to FPLD2 pathology. Emerging data highlight chromatin and transcriptional dysregulation of lipogenic, mitochondrial, and inflammatory genes as central drivers, with other mechanisms acting in complementary ways. We also discuss depot-specific transcriptional remodeling that may explain differential adipose loss and expansion in FPLD2. Understanding how these mechanistic pathways converge across FPLD2 and other laminopathies may reveal new therapeutic targets to preserve adipose function.
2026-06-22 | First diagnosis of familial partial lipodystrophy syndrome type 3 during pregnancy associated with a novel heterozygous PPARG variant and a concurrent ABCC8 variant: a case report
Familial partial lipodystrophy (FPLD) is a rare genetic syndrome characterised by persistent, selective loss of adipose tissue and is closely associated with severe metabolic disturbances. Pregnancy in women with FPLD is associated with a high risk for both mother and foetus, while clinical experience remains very limited. Evidence from case reports and small series is essential for risk stratification, multidisciplinary management, and optimization of maternal and foetal health. Here, we report the case of a woman at 18 weeks of gestation with very severe hypertriglyceridaemia complicated by acute pancreatitis. The patient had a history of young-onset diabetes mellitus, hypertension, polycystic ovary syndrome (PCOS) and previously known hypertriglyceridaemia, accompanied by characteristic loss of gluteofemoral and lower limb adipose tissue, raising the clinical suspicion of FPLD. Molecular genetic analysis was performed using next-generation sequencing-based gene panel diagnostics. Variants were described according to Human Genome Variation Society (HGVS) nomenclature and classified according to the American College of Medical Genetics and genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. We made the initial diagnosis of severe FPLD3 syndrome and detected a novel heterozygous c.380A>C, p.(Glu127Ala) variant in the peroxisome proliferator-activated receptor gamma gene ( PPARG ), classified as likely pathogenic and considered causative for the patient´s phenotype. In addition, a heterozygous variant of uncertain significance c.328G>A, p.(Ala110Thr) in the ATP-binding cassette transporter sub-family C member 8 gene ( ABCC8 ), was detected. High-dose intensive insulin therapy in combination with metformin and omega-3 fatty acids resulted in a marked reduction in triglyceride levels, normalised blood glucose levels until delivery and avoided further episodes of pancreatitis. Early recognition of FPLD is crucial, particularly in high-risk settings such as pregnancy. Intensive, multidisciplinary metabolic management can stabilize severe metabolic complications and may enable favourable maternal and foetal outcomes.
2026-06-05 | Molecular insight into the activator and deactivator mutations of peroxisome proliferator-activated receptor gamma.
The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is essential for inflammation, lipid metabolism, glucose homeostasis, and adipogenesis. The function of PPARγ can be significantly impacted by mutations that either activate or deactivate the receptor. Deactivating variants can act as dominant-negative forms that sequester coactivators, impair ligand recognition, destabilize the activation function-2 (AF-2) surface, or favor corepressor binding. They are frequently found in the ligand-binding or DNA-binding domains. Metabolic disorders like severe insulin resistance and familial partial lipodystrophy type 3 are caused by these mutations. Activating mutations provide mechanistic insights into receptor overactivation by stabilizing helix 12 and the AF-2 surface, improving coactivator recruitment, and promoting ligand-independent transcription. These variations change the equilibrium between inactive and active states, modify coactivator binding, and reshape conformational ensembles, as demonstrated by molecular dynamics simulations. The design of selective modulators for precision therapy that target PPARγ is guided by an understanding of these molecular mechanisms, which also help classify mutations as dominant-negative or drug-rescuable.
2026-04-27 | Familial partial lipodystrophy type 2 associated with a novel LMNA variant (c.604G>C; p.Glu202Gln): a Colombian family case series.
Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant laminopathy caused by LMNA gene variants. It is characterized by progressive gluteofemoral lipoatrophy and severe metabolic derangements, including insulin resistance and metabolic dysfunction-associated steatotic liver disease. Three Colombian women (two sisters and a daughter) underwent standardized clinical phenotyping, dual-energy X-ray absorptiometry (DXA), cardiometabolic laboratory testing, and next-generation sequencing-based testing for lipodystrophy-related genes with copy-number variant analysis. All patients carried the heterozygous LMNA variant c.604G>C (p.Glu202Gln). Patients 1 and 2 exhibited classic Dunnigan phenotypes with diabetes and severe hypertriglyceridemia (up to 1,471 mg/dL), as well as imaging evidence of metabolic dysfunction-associated steatotic liver disease. Patient 3 (age 27) presented an evolving phenotype with central adiposity, clinically reported lower-limb fat loss, and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR], 4), without hepatic steatosis on abdominal ultrasound. Management optimization in Patients 1 and 2 using contemporary combination therapy, including glucagon-like peptide-1 receptor agonist-based treatment and sodium-glucose cotransporter-2 inhibitors, was followed by sustained improvement in glycemia (HbA1c 11.1% to 7.6% in Patient 1) and triglycerides. In Patient 3, liraglutide was discontinued due to poor tolerability and limited weight response, and she was transitioned to semaglutide in February 2026. This case series expands the phenotypic spectrum of LMNA-associated FPLD2 and supports a disease association for the p.Glu202Gln variant despite its current classification as a variant of uncertain significance. It demonstrates that modern cardiometabolic therapies can be implemented in middle-income settings; however, the absence of functional data, population frequency metrics, and genetic testing in unaffected relatives limits the strength of variant interpretation.
2026-03-23 | Evaluating the therapeutic impact of tirzepatide in people with partial lipodystrophy.
Lipodystrophy syndromes (LD) are a group of rare conditions characterized by the generalized or partial absence and/or dysfunction of adipocytes. Due to the lack of fat storage capacity, excess lipid accumulates in other tissues, leading to severe insulin resistance. At present, effective therapeutic options remain limited, with metreleptin currently the only specific licensed treatment. To this end, we evaluated the therapeutic impact of tirzepatide in people with partial lipodystrophy (PLD). This was a single-center, retrospective, observational study, including all patients with PLD treated with tirzepatide between January 2022 and September 2025. Forty patients with PLD were included FPLD1 like = 26 (65%), FPLD2 = 4 (10%), FPLD3 = 7 (17.5%), FPLD7 = 1 (2.5%), APLD = 1 (2.5%), unclassified = 1 (2.5%). 87.5% (n = 35) were female with a median age of 47 years (IQR 39-59) and a median BMI of 31.5 kg/m2 (IQR 27.3 to 35.5). After a median 9.5 month follow-up (IQR 7 to 11), marked reductions were seen in body weight from 91.0 kg (IQR 75.0 to 106.0) to 82.8 kg (IQR 69.0 to 93.4; P < .0001), in HbA1c from 65 mmol/mol (IQR 54.5 to 85) to 52 mmol/mol (IQR 39 to 62; P < .0001) and in serum triglycerides from 2.80 mmol/L (IQR 1.6 to 3.7) to 1.83 mmol/L (IQR 1.0 to 2.9; P = .0005). Daily insulin requirements fell from 177.5 IU (IQR 101.3 to 213.8) to 58.0 IU (IQR 0 to 112.5; P = .0028). In patients with partial lipodystrophy, tirzepatide use resulted in substantial statistically significant reductions in weight, glycemic control, serum triglycerides, and daily insulin requirement. We recommend further prospective studies to support these findings and to evaluate its impact earlier in the course of the disorder.
2026-03-19 | Lamin A/C in health, laminopathies, and familial partial lipodystrophy 2.
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by selective adipose tissue loss, expansion, and dysfunction, caused by pathogenic variants in LMNA encoding nuclear lamins A and C. Here, we synthesize current evidence on how nuclear shape abnormalities, impaired mechanosensing, blocked adipogenesis, chromatin remodeling, and altered lamin-binding partner interactions may contribute to FPLD2 pathology. Emerging data highlight chromatin and transcriptional dysregulation of lipogenic, mitochondrial, and inflammatory genes as central drivers, with other mechanisms acting in complementary ways. We also discuss depot-specific transcriptional remodeling that may explain differential adipose loss and expansion in FPLD2. Understanding how these mechanistic pathways converge across FPLD2 and other laminopathies may reveal new therapeutic targets to preserve adipose function.
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Drug Discovery Landscape
2 orphan drug designations for Familial partial lipodystrophy, including 1 approved therapy.
2 orphan drug designations for Familial partial lipodystrophy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Volanesorsen sodium | oligonucleotides | EMA | 2016-07-14 | — | Akcea Therapeutics Ireland Limited |
Metreleptin [Myalepta] | proteins | EMA | 2012-07-17 | 2018-08-01 | Chiesi Farmaceutici S.p.A. |
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