Familial Partial Lipodystrophy

Mendelian MONDO:0020088 Pathograph 15 Show in embeddings browser partial lipodystrophy inherited lipodystrophy

Familial partial lipodystrophy (FPLD) is a group of rare, genetically heterogeneous Mendelian disorders of adipose tissue characterized by selective loss of subcutaneous fat from the limbs and gluteal region, usually beginning around puberty or early adulthood, with relative or excess fat accumulation in the face, neck, and intra-abdominal/visceral depots. The reduced capacity for safe triglyceride storage in subcutaneous adipose tissue drives ectopic lipid deposition, severe insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis, often accompanied by acanthosis nigricans, hypertension, early atherosclerotic cardiovascular disease, and (in women) polycystic ovary syndrome and hyperandrogenism. Multiple genes define the recognized subtypes, most prominently LMNA (FPLD2/Dunnigan) and PPARG (FPLD3), with rarer causes including PLIN1, CIDEC, LIPE, AKT2, CAV1, MFN2, and ADRA2A. FPLD1 (Köbberling) is defined clinically and lacks a consistently identified gene.

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Subtypes

FPLD1 (Köbberling type) MONDO:0012072

Köbberling-type familial partial lipodystrophy with subcutaneous fat loss confined predominantly to the limbs and sparing of the trunk; defined clinically, with no consistently identified causal gene to date. Associated with insulin resistance and metabolic complications.

FPLD2 (Dunnigan type, LMNA) MONDO:0007906

LMNA hgnc:6636

The most common genetic form, caused by autosomal dominant pathogenic variants in LMNA (commonly missense variants at codon 482, e.g., R482W/R482Q). Progressive loss of subcutaneous fat from limbs, buttocks, and trunk with relative accumulation in the face, neck, and intra-abdominal depots; muscular appearance and prominent veins are characteristic.

FPLD3 (PPARG) MONDO:0011448

PPARG hgnc:9236

Caused by loss-of-function pathogenic variants in PPARG (PPARgamma), the master regulator of adipogenesis. Often a severe insulin-resistant metabolic phenotype with high rates of hypertriglyceridemia, diabetes, hypertension, PCOS, and fatty liver disease; lipoatrophy may be less pronounced than FPLD2.

FPLD4 (PLIN1) MONDO:0013478

PLIN1 hgnc:9076

Caused by pathogenic variants in PLIN1 (perilipin-1), a key lipid-droplet coat protein. Impaired lipid-droplet biology leads to partial lipodystrophy with metabolic complications.

FPLD5 (CIDEC) MONDO:0014098

CIDEC hgnc:24229

Autosomal recessive partial lipodystrophy caused by biallelic CIDEC variants, affecting lipid-droplet formation and unilocular lipid storage in adipocytes.

FPLD6 (LIPE) MONDO:0014431

LIPE hgnc:6621

Autosomal recessive (biallelic) partial lipodystrophy caused by loss-of-function variants in LIPE (hormone-sensitive lipase), with a distinctive fat redistribution pattern and metabolic disturbances.

AKT2-related partial lipodystrophy MONDO:0019192

AKT2 hgnc:392

Partial lipodystrophy with severe insulin resistance and diabetes caused by dominant-negative variants in AKT2, a central kinase of the insulin/PI3K-AKT signaling pathway.

CAV1-related partial lipodystrophy (FPLD7) MONDO:0011714

CAV1 hgnc:1527

Partial lipodystrophy caused by heterozygous variants in CAV1 (caveolin-1), a structural protein of adipocyte caveolae important for lipid uptake and storage. Only two variants from a single report are known. The reported phenotype is broader than lipoatrophy alone: ClinGen's review records atypical partial lipodystrophy with severe type 5 hyperlipoproteinemia and recurrent pancreatitis, and congenital cataracts and neurological involvement in some affected individuals, which is the phenotype the bound MONDO class is named for.

Show evidence (1 reference)

CGGV:assertion_7278df5e-7003-4ff8-bcb6-f043cf2fcb60-2025-07-16T160000.000Z SUPPORT Other

"So far, only two variants (a frameshift and a 5’UTR variant) have been reported in association with atypical partial lipodystrophy, severe type 5 hyperlipoproteinemia, recurrent pancreatitis, and, in some affected individuals, congenital cataracts and neurological involvement"

ClinGen's phenotype summary for the dominant CAV1 relationship, which is both the description of this subtype and the reason the bound MONDO class is named for cataracts and neurodegeneration rather than for lipodystrophy alone.

ADRA2A-related partial lipodystrophy (FPLD8) MONDO:0958022

ADRA2A hgnc:281

Atypical autosomal dominant partial lipodystrophy reported in a single African-American pedigree with a heterozygous ADRA2A p.Leu68Phe variant. ADRA2A encodes the presynaptic inhibitory alpha-2A adrenergic receptor; activation normally suppresses adipocyte cAMP and lipolysis, and the mutant receptor loses that restraint, so the proposed mechanism is excessive depot-selective lipolysis rather than failed adipogenesis.

Show evidence (1 reference)

PMID:27376152 SUPPORT Human Clinical

"A heterozygous g.112837956C>T mutation on chromosome 10 (c.202C>T, p.Leu68Phe) affecting a highly conserved residue in adrenoceptor alpha 2A (ADRA2A) was found in all affected subjects but not in unaffected relatives."

Segregation of the ADRA2A p.Leu68Phe variant with the lipodystrophy phenotype in the founding pedigree is the genetic basis of this subtype.

FPLD9 (PLAAT3-related) MONDO:0958034

PLAAT3 hgnc:17825

Autosomal recessive lipodystrophy caused by homozygous loss-of-function variants in PLAAT3, a phospholipid-modifying enzyme expressed in neural tissue and white adipose tissue. Fat loss ranges from partial to generalized and is accompanied by variable neurological features (demyelinating neuropathy, intellectual disability), so the entity is broader than a purely adipose disorder; OMIM and MONDO nonetheless number it within the familial partial lipodystrophy series.

Show evidence (1 reference)

PMID:37919452 SUPPORT Human Clinical

"We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable..."

Establishes biallelic PLAAT3 loss of function as a cause of a lipodystrophy syndrome and records the partial-to-generalized fat loss and the neurological features this row describes.

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Pathophysiology

Impaired adipocyte differentiation and adipose storage capacity

The unifying defect across FPLD subtypes is failure of subcutaneous adipose tissue to develop and/or store triglycerides normally, owing to disruption of adipogenesis, lipid-droplet biology, or adipocyte maintenance. This produces selective loss of subcutaneous fat from the limbs and gluteal region.

Adipocyte CL:0000136

Fat cell differentiation (adipogenesis) GO:0045444 ↓ DECREASED Regulation of lipid storage GO:0010883 ↓ DECREASED

Subcutaneous adipose tissue UBERON:0002190

Downstream

Ectopic lipid deposition and systemic insulin resistance Reduced subcutaneous storage capacity diverts lipid to ectopic sites, driving systemic insulin resistance.

Show evidence (1 reference)

PMID:39398333 SUPPORT Human Clinical

"PPARγ plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy..."

Establishes impaired adipogenesis (via PPARgamma loss of function) as a core mechanism producing the lipodystrophy and metabolic phenotype.

LMNA nuclear-lamina dysfunction and adipocyte loss (FPLD2)

In FPLD2 (Dunnigan), pathogenic LMNA variants (commonly codon 482) perturb lamin A/C structure and lamin-chromatin (lamina-associated domain) interactions required for adipocyte differentiation and maintenance, with suppression of lipid-metabolism and mitochondrial programs and an intrinsic inflammatory transcriptional signature. (Adipocyte-specific Lmna-knockout mouse data supporting a cell-autonomous role for lamin A/C in adipocyte maintenance are summarized in the entry notes.)

Adipocyte CL:0000136

LMNA hgnc:6636

Chromatin organization GO:0006325 ⚠ ABNORMAL Lipid metabolic process GO:0006629 ↓ DECREASED Inflammatory response GO:0006954 ↑ INCREASED

Downstream

Ectopic lipid deposition and systemic insulin resistance LMNA-driven adipose dysfunction feeds the shared ectopic-lipid and insulin-resistance cascade.

Show evidence (1 reference)

PMID:39125589 SUPPORT Human Clinical

"Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions."

Supports LMNA-driven disruption of adipose tissue function and metabolic regulation as the FPLD2 mechanism.

Loss of PPARgamma-driven adipogenic transcription

PPARgamma is the master transcriptional regulator of preadipocyte-to-adipocyte differentiation. Two curated routes converge on reduced PPARgamma signaling: loss-of-function PPARG variants themselves (FPLD3), and biallelic PLAAT3 loss (FPLD9), which remodels white adipose membrane phospholipids and strongly lowers PPARgamma signaling without altering PPARG itself.

Adipocyte CL:0000136

PPARG hgnc:9236

PPARgamma nuclear receptor signaling GO:0141193 ↓ DECREASED

Downstream

Impaired adipocyte differentiation and adipose storage capacity Reduced PPARgamma transcriptional output blocks preadipocyte differentiation, limiting the subcutaneous adipose compartment that can be built and maintained.

Show evidence (1 reference)

PMID:39398333 SUPPORT Human Clinical

States both the adipogenic role of PPARgamma and the reduction of receptor activity by loss-of-function PPARG variants that this node asserts.

PLAAT3 loss and phospholipid remodeling of white adipose tissue

PLAAT3 is a phospholipid-modifying enzyme expressed in neural tissue and white adipose tissue. Biallelic loss of function enriches white adipose membranes in arachidonic-acid-containing phospholipids and strongly lowers PPARgamma signaling, so the lesion is upstream of the adipogenic transcriptional program rather than in it. This is the FPLD9 route.

Adipocyte CL:0000136

PLAAT3 hgnc:17825

membrane phospholipid metabolic process GO:0006644 ⚠ ABNORMAL

Downstream

Loss of PPARgamma-driven adipogenic transcription Phospholipid remodeling of white adipose membranes lowers PPARgamma signaling, joining the FPLD3 route at the adipogenic transcription node.

Show evidence (2 references)

PMID:37919452 SUPPORT Human Clinical

"Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation."

Patient-derived white adipose tissue shows both the phospholipid remodeling and the fall in PPARgamma signaling that this node and its downstream edge assert.

PMID:37919452 SUPPORT In Vitro

"CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ."

Directed inactivation in human adipose stem cells reproduces the differentiation defect, establishing the direction of the link rather than only its correlation.

Adipocyte lipid-droplet formation defect

CIDEC and PLIN1 act at the adipocyte lipid droplet itself. CIDEC is required for unilocular lipid droplet formation and for optimal energy storage in human fat; the truncating allele is mistargeted and fails to increase lipid droplet size, and the patient's white adipocytes are multiloculated (FPLD5). PLIN1 coats the droplet, and the FPLD4 frameshift alleles extend its C-terminus and act dominant-negatively rather than by haploinsufficiency.

Adipocyte CL:0000136

CIDEC hgnc:24229 PLIN1 hgnc:9076

Lipid droplet organization GO:0034389 ⚠ ABNORMAL

Downstream

Impaired adipocyte differentiation and adipose storage capacity Adipocytes that cannot build or coat a normal unilocular droplet store triglyceride inefficiently, reducing safe subcutaneous storage capacity.

Dysregulated adipocyte triglyceride lipolysis The same droplet-coat defect removes the perilipin-1 brake on lipase access to stored triglyceride.

Show evidence (2 references)

PMID:20049731 SUPPORT Human Clinical

"In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat."

Establishes the unilocular-droplet requirement whose failure is the CIDEC arm of this node.

CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z SUPPORT Other

"Mechanistic studies suggest that subcutaneous patients’ adipose tissues show reduced full-length perilipin-1 and an extended perilipin-1 form compatible with the predicted elongated C-terminal tail of the mutant proteins"

ClinGen's mechanistic review records the altered perilipin-1 protein on the droplet in patient adipose tissue, which is the PLIN1 arm of this node.

Dysregulated adipocyte triglyceride lipolysis

Three curated genes disturb the release of stored triglyceride from the adipocyte droplet, in opposite directions, which is why the node is tagged abnormal rather than increased or decreased. PLIN1 frameshift mutants fail to hold ABHD5, so adipose triglyceride lipase is constitutively activated and basal lipolysis runs unchecked (FPLD4). The reported ADRA2A variant removes the presynaptic alpha-2A adrenergic brake on adipocyte cAMP, again raising lipolysis, and is proposed to do so only in some depots (FPLD8). LIPE encodes hormone-sensitive lipase itself, so biallelic loss instead impairs triglyceride mobilization (FPLD6).

Adipocyte CL:0000136

PLIN1 hgnc:9076 LIPE hgnc:6621 ADRA2A hgnc:281

Adipocyte triglyceride lipolysis GO:0061725 ⚠ ABNORMAL

Downstream

Ectopic lipid deposition and systemic insulin resistance Triglyceride that cannot be retained in, or mobilized from, subcutaneous adipocytes reaches ectopic depots.

Show evidence (3 references)

CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z SUPPORT Other

"the p.(Val398Glyfs) and p.(Leu404Alafs) mutants fail to interact with ABHD5, leading to constitutive activation of adipocyte triglyceride lipase"

Gives the molecular route from the FPLD4 perilipin-1 alleles to unchecked lipolysis asserted in this node.

PMID:27376152 SUPPORT Human Clinical

"ADRA2A is the main presynaptic inhibitory feedback G protein-coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes."

States the normal restraining role of ADRA2A on adipocyte lipolysis that the reported loss-of-function variant removes.

PMID:27376152 SUPPORT In Vitro

"the mutant ADRA2A produced more cAMP and glycerol, which were resistant to the effects of the α2-adrenergic receptor agonist clonidine and the α2-adrenergic receptor antagonist yohimbine, suggesting loss of function."

Cell assays show the mutant receptor raises cAMP and glycerol release, the functional signature of increased lipolysis in this node.

Impaired adipose insulin and PI3K-AKT signaling

AKT2 is a kinase of the insulin/PI3K-AKT pathway, and ClinGen's review of the reported evidence records that AKT2 signaling is important for adipocyte differentiation. The reported FPLD allele has little or no kinase activity, so insulin signaling fails in the adipocyte itself rather than only downstream of an adipose deficit.

Adipocyte CL:0000136

AKT2 hgnc:392

Insulin receptor signaling pathway GO:0008286 ↓ DECREASED

Downstream

Impaired adipocyte differentiation and adipose storage capacity Loss of AKT2 kinase output impairs the insulin-driven differentiation and storage program of the adipocyte.

Ectopic lipid deposition and systemic insulin resistance A kinase-dead AKT2 also blocks insulin action directly, so the insulin resistance is not solely a consequence of reduced fat mass.

Show evidence (2 references)

CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z SUPPORT Other

"The mechanism of pathogenicity is reported to be loss of function, evidenced by in vitro functional assays showed that the AKT2 Arg274His allele has little or no kinase activity."

ClinGen's mechanistic review records the kinase-dead behaviour of the reported allele, the molecular basis of this node.

CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z SUPPORT Other

"AKT2 signaling is also important for adipocyte differentiation"

Links the signaling defect to the adipocyte differentiation failure this node feeds.

NOTCH3 gain of function and adipose senescence

Mechanism confidence: Provisional

Missense variants clustered in the heterodimerization domain of the NOTCH3 negative regulatory region were reported in three unrelated FPL families. Patient skin fibroblasts show raised NOTCH3 RNA and protein and activation of widespread senescence pathways, which the authors propose as the route from unrestrained NOTCH3 signaling to loss of adipose tissue. This node records a single-publication mechanism; see the notes on the NOTCH3 genetic record.

NOTCH3 hgnc:7883

Notch signaling pathway GO:0007219 ⇑ GAIN OF FUNCTION Cellular senescence GO:0090398 ↑ INCREASED

Downstream

Impaired adipocyte differentiation and adipose storage capacity Senescence activation is the proposed route by which unrestrained NOTCH3 signaling depletes the subcutaneous adipose compartment.

Show evidence (2 references)

PMID:39652711 SUPPORT Human Clinical

"All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3."

Localizes the reported variants to the domain that normally restrains receptor activation, which is the basis for calling the effect a gain of function rather than a quantitative increase.

PMID:39652711 SUPPORT Human Clinical

"RNA sequencing and proteomics analysis of skin fibroblasts revealed significantly higher RNA and protein expression of NOTCH3 and activation of widespread senescence pathways in the patients with FPL versus control study participants."

Patient-derived fibroblasts carry both halves of this node, raised NOTCH3 expression and activated senescence programs.

Ectopic lipid deposition and systemic insulin resistance

The limited subcutaneous storage capacity forces triglycerides into ectopic sites (liver, muscle, viscera), driving severe insulin resistance, hypertriglyceridemia, type 2 diabetes, hepatic steatosis, and downstream cardiometabolic disease.

Adipocyte CL:0000136

Lipid metabolic process GO:0006629 ⚠ ABNORMAL

Liver UBERON:0002107

Show evidence (1 reference)

PMID:39125589 SUPPORT Human Clinical

"their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes."

Supports the downstream cascade of insulin resistance, hypertriglyceridemia, hepatic steatosis, and cardiovascular risk arising from adipose dysfunction.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 2

Hypertension HP:0000822

Show evidence (1 reference)

PMID:39398333 SUPPORT Human Clinical

"hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension (59.5%), polycystic ovary syndrome (58.2% of women)"

Hypertension was present in 59.5% of FPLD3 (PPARG) patients in this review.

Atherosclerosis HP:0002621

Show evidence (1 reference)

PMID:38887266 SUPPORT Human Clinical

"cardiovascular disease in 10.4%. The overall mortality rate was 3.8%, due to cardiovascular events."

Cardiovascular disease affected 10.4% of patients and accounted for all deaths, underscoring atherosclerotic CVD as the principal cause of mortality.

Digestive 2

Pancreatitis HP:0001733

Show evidence (1 reference)

PMID:38887266 SUPPORT Human Clinical

"severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and pancreatitis in 8.5%."

Pancreatitis occurred in 8.5% of the cohort, linked to severe hypertriglyceridemia.

Hepatic steatosis FREQUENT HP:0001397

Show evidence (1 reference)

PMID:38887266 SUPPORT Human Clinical

"Metabolic-associated fatty liver disease (MAFLD) was observed in 56.6%,"

MAFLD (hepatic steatosis) was present in 56.6% of FPLD patients, supporting a FREQUENT frequency band.

Endocrine 1

Diabetes mellitus FREQUENT HP:0000819

Show evidence (1 reference)

PMID:38887266 SUPPORT Human Clinical

"Diabetes mellitus (DM) was highly prevalent (57.5%),"

Diabetes was present in 57.5% of a genetically confirmed FPLD cohort, supporting a FREQUENT frequency band.

Genitourinary 1

Polycystic ovaries HP:0000147

Show evidence (1 reference)

PMID:39398333 SUPPORT Human Clinical

"polycystic ovary syndrome (58.2% of women)"

PCOS occurred in 58.2% of women with FPLD3 (PPARG variants).

Integument 1

Acanthosis nigricans HP:0000956

Metabolism 3

Insulin resistance HP:0000855

Show evidence (1 reference)

PMID:39125589 SUPPORT Human Clinical

"their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome"

Lists insulin resistance among the core metabolic complications of FPLD.

Hypertriglyceridemia HP:0002155

Show evidence (1 reference)

PMID:38887266 SUPPORT Human Clinical

"severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and pancreatitis in 8.5%."

Documents severe hypertriglyceridemia and consequent pancreatitis in the FPLD cohort.

Decreased HDL cholesterol Decreased HDL cholesterol concentration HP:0003233

Show evidence (1 reference)

PMID:26775134 SUPPORT Human Clinical

"Metabolic abnormalities were observed as a form of insulin resistant diabetes, hypertriglyceridemia, low HDL cholesterol and hepatic steatosis."

Documents low HDL cholesterol as part of the metabolic abnormalities in an LMNA-confirmed FPLD2 family.

Musculoskeletal 1

Partial loss of subcutaneous fat Loss of subcutaneous adipose tissue in limbs HP:0003635

Show evidence (1 reference)

PMID:38887266 SUPPORT Human Clinical

"familial partial lipodystrophy (FPLD), a rare genetic disorder characterized by partial subcutaneous fat loss."

Defines the hallmark partial subcutaneous fat loss of FPLD in a genetically confirmed cohort.

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Genetic Associations

LMNA pathogenic variants (FPLD2/Dunnigan)

Gene: LMNA hgnc:6636 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (3 references)

PMID:38887266 SUPPORT Human Clinical

"LMNA pathogenic variants were identified in 85.8% of patients, PPARG in 10.4%, PLIN1 in 2.8%, and MFN2 in 0.9%."

Quantifies the relative contribution of LMNA, PPARG, PLIN1, and MFN2 in a genetically confirmed FPLD cohort.

CGGV:assertion_9a2725cf-2492-4f4d-8646-7a757cdac3dc-2024-10-09T160000.000Z SUPPORT Other

ClinGen rates the LMNA-lipodystrophy gene-disease relationship Definitive, which is the classification level the CAUSATIVE relationship_type on this record asserts.

CGGV:assertion_9a2725cf-2492-4f4d-8646-7a757cdac3dc-2024-10-09T160000.000Z SUPPORT Other

"In summary, LMNA is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults."

ClinGen records the inheritance as semidominant with most cases presenting as autosomal dominant familial partial lipodystrophy, which is the FPLD2 phenotype curated here.

PPARG loss-of-function variants (FPLD3)

Gene: PPARG hgnc:9236 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (3 references)

PMID:39398333 SUPPORT Human Clinical

"Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3)."

Establishes PPARG loss of function as the cause of FPLD3.

CGGV:assertion_b4c76c1c-7e8a-418f-ba62-b7eeb3c3d472-2024-08-14T160000.000Z SUPPORT Other

ClinGen rates the PPARG-lipodystrophy gene-disease relationship Definitive, supporting the CAUSATIVE relationship_type on this record.

CGGV:assertion_b4c76c1c-7e8a-418f-ba62-b7eeb3c3d472-2024-08-14T160000.000Z SUPPORT Other

"In summary, PPARG is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults."

ClinGen records semidominant inheritance with most cases presenting as autosomal dominant familial partial lipodystrophy, the FPLD3 phenotype curated here.

PLIN1 pathogenic variants (FPLD4)

Gene: PLIN1 hgnc:9076 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:38887266 SUPPORT Human Clinical

"PLIN1 in 2.8%, and MFN2 in 0.9%."

PLIN1 (FPLD4) and MFN2 were identified as rarer genetic causes in the cohort.

CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z SUPPORT Other

ClinGen rates the PLIN1-FPLD4 gene-disease relationship Definitive with autosomal dominant inheritance, supporting the CAUSATIVE relationship_type here.

CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z SUPPORT Other

"Instead, the disorder results specifically from dominant-negative effects of C-terminal elongating frameshift variants predicted to escape NMD."

ClinGen's allele review states the dominant-negative mechanism recorded in this record's notes and distinguishes it from haploinsufficiency.

CIDEC biallelic variants (FPLD5)

Gene: CIDEC hgnc:24229 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (1 reference)

PMID:20049731 SUPPORT Human Clinical

"we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet..."

The founding report of biallelic CIDEC loss of function in human partial lipodystrophy, including the multilocular-lipid-droplet adipocyte phenotype that distinguishes this subtype.

LIPE biallelic variants (FPLD6)

Gene: LIPE hgnc:6621 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (1 reference)

CGGV:assertion_05644df2-842b-45ef-a118-01994bdf07eb-2025-12-30T170000.000Z SUPPORT Other

ClinGen rates the LIPE-FPLD6 gene-disease relationship Definitive with autosomal recessive inheritance, supporting the CAUSATIVE relationship_type and the recessive inheritance recorded here.

AKT2 dominant-negative variants

Gene: AKT2 hgnc:392 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z SUPPORT Other

ClinGen classifies the AKT2-FPLD relationship as Limited, which is the evidence level this record reports.

CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z SUPPORT Other

"In summary, while the mechanistic link between AKT2 dysfunction and lipodystrophic insulin resistance is highly plausible and well evidenced, current genetic evidence supporting the human gene-disease relationship is limited."

Distinguishes the strong mechanistic case for AKT2 from the limited human genetic evidence, which is why relationship_type is left UNKNOWN here.

CAV1 variants (FPLD7)

Gene: CAV1 hgnc:1527 gene page relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

CGGV:assertion_7278df5e-7003-4ff8-bcb6-f043cf2fcb60-2025-07-16T160000.000Z SUPPORT Other

ClinGen classifies the autosomal dominant CAV1-lipodystrophy relationship as Limited, the evidence level this record reports.

CGGV:assertion_7278df5e-7003-4ff8-bcb6-f043cf2fcb60-2025-07-16T160000.000Z SUPPORT Other

"Evidence supporting this gene-disease relationship includes limited case-level data, with no segregation data or experimental data available."

States what the CAV1 partial-lipodystrophy claim rests on, supporting the caution recorded in this record's notes.

MFN2 variants

Gene: MFN2 hgnc:16877 gene page variant_origin: GERMLINE

Show evidence (3 references)

PMID:38887266 SUPPORT Human Clinical

"PLIN1 in 2.8%, and MFN2 in 0.9%."

MFN2 was a rare cause identified in the genetically confirmed cohort.

CGGV:assertion_9322bddb-bcdb-466b-acae-058f4a368e01-2025-09-10T160000.000Z SUPPORT Other

ClinGen curates MFN2 against a separate autosomal recessive disease term, not against a familial partial lipodystrophy term, which is the basis for not making MFN2 a subtype of this entry.

CGGV:assertion_9322bddb-bcdb-466b-acae-058f4a368e01-2025-09-10T160000.000Z SUPPORT Other

"One specific MFN2 variant, p.Arg707Trp, has been reported in all multiple symmetric lipomatosis with partial lipodystrophy cases to date."

The single recurrent allele behind every reported case is part of what distinguishes this entity from the allelically heterogeneous FPLD subtypes.

NOTCH3 gain-of-function variants

Gene: NOTCH3 hgnc:7883 gene page relationship_type: UNKNOWN variant_origin: GERMLINE

Autosomal dominant

Show evidence (2 references)

PMID:39652711 SUPPORT Human Clinical

"Further analysis of WES data of 222 patients with unexplained FPL identified two unrelated patients with FPL with novel heterozygous (p.Cys1600Tyr and p.Gln1552Pro) NOTCH3 variants."

Two further unrelated probands beyond the index pedigree are the human genetic evidence for this gene-disease relationship, and also show how narrow it still is.

PMID:39652711 SUPPORT Human Clinical

"We conclude that gain-of-function missense variants in the negative regulatory region of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways."

The authors' own conclusion, which describes the entity as a novel subtype of familial partial lipodystrophy rather than as the Koebberling type that OMIM and MONDO attach the gene to.

PLAAT3 biallelic loss-of-function variants (FPLD9)

Gene: PLAAT3 hgnc:17825 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (1 reference)

PMID:37919452 SUPPORT Human Clinical

"These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function."

The report's own conclusion establishing the gene-disease relationship and naming the PPARgamma-dependent mechanism wired on the pathophysiology graph.

ADRA2A variants (FPLD8)

Gene: ADRA2A hgnc:281 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (2 references)

PMID:27376152 SUPPORT Human Clinical

"We conclude that heterozygous p.Leu68Phe ADRA2A mutation causes a rare atypical FPLD, most likely by inducing excessive lipolysis in some adipose tissue depots."

The founding report's own conclusion, giving both the allele and the proposed excessive-lipolysis mechanism curated on the pathophysiology node.

PMID:42681552 SUPPORT REVIEW SYNTHESIS Other

"Conversely, increasing use of next-generation sequencing has led to proliferation of proposed new genetic causes of lipodystrophy with variable supporting evidence."

The ECLip consensus states the field-level reason this single-pedigree association is recorded with an UNKNOWN relationship_type rather than as causative.

💊

Medical Actions

Dietary intervention

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Balanced calorie-controlled diet (typically ~50-60% carbohydrate, 20-30% fat, ~20% protein) with reduced simple sugars and alcohol abstinence to reduce metabolic stress on limited adipose storage capacity and lower triglyceride/pancreatitis risk.

Aerobic exercise

Action: aerobic exercise therapy Ontology label: Physical Therapy NCIT:C15302

Regular aerobic exercise (after cardiac evaluation) to improve insulin sensitivity and cardiometabolic risk.

Metformin

Action: Pharmacotherapy NCIT:C15986

Agent: metformin CHEBI:6801

Platform: Small molecule

First-line pharmacotherapy for hyperglycemia and insulin resistance in FPLD.

Statin therapy

Action: Pharmacotherapy NCIT:C15986

Agent: atorvastatin CHEBI:39548

Platform: Small molecule

First-line lipid-lowering therapy (e.g., atorvastatin) for dyslipidemia.

Fibrate therapy

Action: Pharmacotherapy NCIT:C15986

Agent: fenofibrate CHEBI:5001

Platform: Small molecule

Fibrates (e.g., fenofibrate), often with omega-3 fatty acids, for severe hypertriglyceridemia (TG > 500 mg/dL) to reduce pancreatitis risk.

Metreleptin

Action: Pharmacotherapy NCIT:C15986

Agent: metreleptin NCIT:C170171

Platform: Protein replacement

Recombinant leptin analog (leptin replacement therapy); a major advance for generalized lipodystrophy, with more variable benefit in partial forms, associated with reductions in triglycerides and HbA1c in hypoleptinemic patients.

GLP-1 receptor agonist therapy

Action: Pharmacotherapy NCIT:C15986

Agent: liraglutide NCIT:C82239

Platform: Peptide

Glucagon-like peptide 1 receptor agonists (GLP-1RA) improve weight, BMI, HbA1c, fasting glucose, and triglycerides in FPLD; acute pancreatitis has been reported with longer therapy, warranting caution in patients with prior pancreatitis.

Show evidence (1 reference)

PMID:38300898 SUPPORT Human Clinical

"Our study demonstrates the relative safety and effectiveness of GLP-1RA in patients with FPLD."

Retrospective study supporting GLP-1RA efficacy and relative safety in FPLD, with a noted pancreatitis signal on longer therapy.

Volanesorsen

Action: Pharmacotherapy NCIT:C15986

Agent: volanesorsen NCIT:C152904

Platform: Antisense oligonucleotide RNase H knockdown

RNA target: APOC3 hgnc:610 APOC3 mRNA

ApoC-III antisense oligonucleotide investigated for severe hypertriglyceridemia in FPLD (BROADEN trial); produces large triglyceride reductions.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling and cascade genetic testing of relatives are recommended for affected families.

📊

Related Datasets

NOTCH3 missense variants cause familial partial lipodystrophy massive:MSV000096235

Molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We identified novel NOTCH3 heterozygous variants in familial partial lipodystrophy (FPL) pedigrees. All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3. Proteomics of skin fibroblasts revealed significantly higher RNA expression of NOTCH3 and activation of widespread senescence pathways in the FPL patients versus controls.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Familial Partial Lipodystrophy"). Retrieved 2026-08-02.

🔬

Clinical Trials

NCT02527343 PHASE_III TERMINATED

The BROADEN Study: a randomized, double-blind, placebo-controlled trial of volanesorsen (ApoC-III antisense oligonucleotide) in participants with familial partial lipodystrophy, with triglyceride lowering as the primary endpoint.

Target Phenotypes: Hypertriglyceridemia HP:0002155

Show evidence (1 reference)

clinicaltrials:NCT02527343 SUPPORT

"The purpose of this study is to evaluate the efficacy and safety of volanesorsen given for 52 weeks in a randomized treatment (RT) period in participants with familial partial lipodystrophy (FPL)."

The BROADEN trial tested volanesorsen specifically in FPLD, targeting the severe hypertriglyceridemia that drives pancreatitis risk.

NCT02262806 NOT_APPLICABLE COMPLETED

Compassionate use of metreleptin in previously treated people with partial lipodystrophy (NIDDK).

Target Phenotypes: Insulin resistance HP:0000855

Show evidence (1 reference)

clinicaltrials:NCT02262806 SUPPORT

"Partial lipodystrophy can cause high blood fat levels and resistance to insulin."

This NIDDK trial provides metreleptin to partial lipodystrophy patients who benefited previously, addressing insulin resistance and dyslipidemia.

{ }

Source YAML

click to show

name: Familial Partial Lipodystrophy
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
  Familial partial lipodystrophy (FPLD) is a group of rare, genetically
  heterogeneous Mendelian disorders of adipose tissue characterized by selective
  loss of subcutaneous fat from the limbs and gluteal region, usually beginning
  around puberty or early adulthood, with relative or excess fat accumulation in
  the face, neck, and intra-abdominal/visceral depots. The reduced capacity for
  safe triglyceride storage in subcutaneous adipose tissue drives ectopic lipid
  deposition, severe insulin resistance, diabetes mellitus, hypertriglyceridemia,
  and hepatic steatosis, often accompanied by acanthosis nigricans, hypertension,
  early atherosclerotic cardiovascular disease, and (in women) polycystic ovary
  syndrome and hyperandrogenism. Multiple genes define the recognized subtypes,
  most prominently LMNA (FPLD2/Dunnigan) and PPARG (FPLD3), with rarer causes
  including PLIN1, CIDEC, LIPE, AKT2, CAV1, MFN2, and ADRA2A. FPLD1
  (Köbberling) is defined clinically and lacks a consistently identified gene.
disease_term:
  preferred_term: Familial Partial Lipodystrophy
  term:
    id: MONDO:0020088
    label: familial partial lipodystrophy
parents:
- partial lipodystrophy
- inherited lipodystrophy
synonyms:
- FPLD
- familial partial lipodystrophy
- familial lipodystrophy, partial
- partial lipodystrophy, familial
has_subtypes:
- name: FPLD1
  display_name: FPLD1 (Köbberling type)
  description: >-
    Köbberling-type familial partial lipodystrophy with subcutaneous fat loss
    confined predominantly to the limbs and sparing of the trunk; defined
    clinically, with no consistently identified causal gene to date. Associated
    with insulin resistance and metabolic complications.
  subtype_term:
    preferred_term: FPLD1 (Köbberling type)
    term:
      id: MONDO:0012072
      label: familial partial lipodystrophy, Kobberling type
  review_notes: >-
    No genes list is attached to this row, and that is a deliberate
    disagreement with MONDO. MONDO records NOTCH3 (hgnc:7883) as the causal
    gene of MONDO:0012072 via RO:0004003. That assignment traces to OMIM:
    MONDO:0012072 cross-references OMIM:608600, and NCBI's mim2gene_medgen
    table (retrieved 2026-09-19) maps phenotype MIM 608600 to GeneID 4854
    (NOTCH3) through OMIM's GeneMap. The primary report behind that mapping,
    Garg et al. Diabetes 2025 (PMID:39652711), describes its gain-of-function
    NOTCH3 variants as causing "a novel subtype of FPL" and nowhere equates
    the affected families with the Koebberling phenotype. MONDO's own text
    definition of this class still reads "of unknown etiology". Koebberling-type
    FPLD1 is a clinical description (limb-confined lipoatrophy with normal or
    increased truncal fat), so this entry keeps the row clinical and curates
    NOTCH3 separately in the genetic list rather than asserting that the two
    are the same disorder. A synonym-inclusive OLS search of MONDO for
    "lipodystrophy" (2026-09-19) returns no separate class for NOTCH3-related
    familial partial lipodystrophy, so MONDO:0012072 is the only place MONDO
    has to put the gene. Note also that PMID:39652711 carries a published
    erratum (PMID:41147879) whose content could not be retrieved: PubMed
    returns the erratum record with no abstract text, and Crossref returns no
    abstract for its DOI 10.2337/db26-er01a (both checked 2026-09-19). What the
    erratum corrects is therefore unknown here, and no reference cache for it
    is committed.
- name: FPLD2
  display_name: FPLD2 (Dunnigan type, LMNA)
  description: >-
    The most common genetic form, caused by autosomal dominant pathogenic
    variants in LMNA (commonly missense variants at codon 482, e.g., R482W/R482Q).
    Progressive loss of subcutaneous fat from limbs, buttocks, and trunk with
    relative accumulation in the face, neck, and intra-abdominal depots; muscular
    appearance and prominent veins are characteristic.
  subtype_term:
    preferred_term: FPLD2 (Dunnigan type)
    term:
      id: MONDO:0007906
      label: familial partial lipodystrophy, Dunnigan type
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
- name: FPLD3
  display_name: FPLD3 (PPARG)
  description: >-
    Caused by loss-of-function pathogenic variants in PPARG (PPARgamma), the
    master regulator of adipogenesis. Often a severe insulin-resistant metabolic
    phenotype with high rates of hypertriglyceridemia, diabetes, hypertension,
    PCOS, and fatty liver disease; lipoatrophy may be less pronounced than FPLD2.
  subtype_term:
    preferred_term: FPLD3 (PPARG-related)
    term:
      id: MONDO:0011448
      label: PPARG-related familial partial lipodystrophy
  genes:
  - preferred_term: PPARG
    term:
      id: hgnc:9236
      label: PPARG
- name: FPLD4
  display_name: FPLD4 (PLIN1)
  description: >-
    Caused by pathogenic variants in PLIN1 (perilipin-1), a key lipid-droplet
    coat protein. Impaired lipid-droplet biology leads to partial lipodystrophy
    with metabolic complications.
  subtype_term:
    preferred_term: FPLD4 (PLIN1-related)
    term:
      id: MONDO:0013478
      label: PLIN1-related familial partial lipodystrophy
  genes:
  - preferred_term: PLIN1
    term:
      id: hgnc:9076
      label: PLIN1
- name: FPLD5
  display_name: FPLD5 (CIDEC)
  description: >-
    Autosomal recessive partial lipodystrophy caused by biallelic CIDEC variants,
    affecting lipid-droplet formation and unilocular lipid storage in adipocytes.
  subtype_term:
    preferred_term: FPLD5 (CIDEC-related)
    term:
      id: MONDO:0014098
      label: CIDEC-related familial partial lipodystrophy
  genes:
  - preferred_term: CIDEC
    term:
      id: hgnc:24229
      label: CIDEC
- name: FPLD6
  display_name: FPLD6 (LIPE)
  description: >-
    Autosomal recessive (biallelic) partial lipodystrophy caused by
    loss-of-function variants in LIPE (hormone-sensitive lipase), with a
    distinctive fat redistribution pattern and metabolic disturbances.
  subtype_term:
    preferred_term: FPLD6 (LIPE-related)
    term:
      id: MONDO:0014431
      label: LIPE-related familial partial lipodystrophy
  genes:
  - preferred_term: LIPE
    term:
      id: hgnc:6621
      label: LIPE
- name: AKT2
  display_name: AKT2-related partial lipodystrophy
  description: >-
    Partial lipodystrophy with severe insulin resistance and diabetes caused by
    dominant-negative variants in AKT2, a central kinase of the insulin/PI3K-AKT
    signaling pathway.
  subtype_term:
    preferred_term: AKT2-related familial partial lipodystrophy
    term:
      id: MONDO:0019192
      label: AKT2-related familial partial lipodystrophy
  genes:
  - preferred_term: AKT2
    term:
      id: hgnc:392
      label: AKT2
- name: CAV1
  display_name: CAV1-related partial lipodystrophy (FPLD7)
  subtype_term:
    preferred_term: FPLD7 (CAV1-related)
    term:
      id: MONDO:0011714
      label: partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome
  description: >-
    Partial lipodystrophy caused by heterozygous variants in CAV1
    (caveolin-1), a structural protein of adipocyte caveolae important for
    lipid uptake and storage. Only two variants from a single report are known.
    The reported phenotype is broader than lipoatrophy alone: ClinGen's review
    records atypical partial lipodystrophy with severe type 5
    hyperlipoproteinemia and recurrent pancreatitis, and congenital cataracts
    and neurological involvement in some affected individuals, which is the
    phenotype the bound MONDO class is named for.
  genes:
  - preferred_term: CAV1
    term:
      id: hgnc:1527
      label: CAV1
  review_notes: >-
    subtype_term added 2026-09-19, and the reason it was nearly missed is worth
    recording. MONDO:0011714 is the class for OMIM:606721, the phenotype number
    ClinGen names as the disease it split the dominant CAV1 lipodystrophy
    curation against, and it carries "lipodystrophy, familial partial, type 7"
    as an exact synonym. Its primary label names the fuller syndrome instead, so
    a label search (runoak -i ols:mondo search "l~familial partial
    lipodystrophy") does not return it; a synonym-inclusive OLS search for
    "lipodystrophy" does. An earlier draft of this row asserted that MONDO had
    no class for CAV1-related partial lipodystrophy, which was wrong.
    Note that MONDO places MONDO:0011714 directly under MONDO:0003847
    "hereditary disease" rather than under this entry's disease term
    MONDO:0020088, unlike every other numbered FPLD class, so the parent
    relationship here is a curation judgement rather than an ontology one.
  evidence:
  - reference: CGGV:assertion_7278df5e-7003-4ff8-bcb6-f043cf2fcb60-2025-07-16T160000.000Z
    reference_title: "CAV1 / lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      So far, only two variants (a frameshift and a 5’UTR variant) have been reported in association with atypical partial lipodystrophy, severe type 5 hyperlipoproteinemia, recurrent pancreatitis, and, in some affected individuals, congenital cataracts and neurological involvement
    explanation: >-
      ClinGen's phenotype summary for the dominant CAV1 relationship, which is
      both the description of this subtype and the reason the bound MONDO class
      is named for cataracts and neurodegeneration rather than for lipodystrophy
      alone.
- name: ADRA2A
  display_name: ADRA2A-related partial lipodystrophy (FPLD8)
  subtype_term:
    preferred_term: FPLD8 (ADRA2A-related)
    term:
      id: MONDO:0958022
      label: lipodystrophy, familial partial, type 8
  genes:
  - preferred_term: ADRA2A
    term:
      id: hgnc:281
      label: ADRA2A
  description: >-
    Atypical autosomal dominant partial lipodystrophy reported in a single
    African-American pedigree with a heterozygous ADRA2A p.Leu68Phe variant.
    ADRA2A encodes the presynaptic inhibitory alpha-2A adrenergic receptor;
    activation normally suppresses adipocyte cAMP and lipolysis, and the mutant
    receptor loses that restraint, so the proposed mechanism is excessive
    depot-selective lipolysis rather than failed adipogenesis.
  review_notes: >-
    subtype_term added 2026-09-19. MONDO:0958022 "lipodystrophy, familial
    partial, type 8" is a direct child of this entry's disease term
    MONDO:0020088 (checked via the OLS MONDO parents endpoint) and
    cross-references OMIM:620679, which NCBI's mim2gene_medgen table maps to
    GeneID 150 (ADRA2A). The row previously carried neither a term nor a gene.
  evidence:
  - reference: PMID:27376152
    reference_title: Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A heterozygous g.112837956C>T mutation on chromosome 10 (c.202C>T, p.Leu68Phe) affecting a highly conserved residue in adrenoceptor alpha 2A (ADRA2A) was found in all affected subjects but not in unaffected relatives.
    explanation: >-
      Segregation of the ADRA2A p.Leu68Phe variant with the lipodystrophy
      phenotype in the founding pedigree is the genetic basis of this subtype.
- name: FPLD9
  display_name: FPLD9 (PLAAT3-related)
  subtype_term:
    preferred_term: FPLD9 (PLAAT3-related)
    term:
      id: MONDO:0958034
      label: lipodystrophy, familial partial, type 9
  genes:
  - preferred_term: PLAAT3
    term:
      id: hgnc:17825
      label: PLAAT3
  description: >-
    Autosomal recessive lipodystrophy caused by homozygous loss-of-function
    variants in PLAAT3, a phospholipid-modifying enzyme expressed in neural
    tissue and white adipose tissue. Fat loss ranges from partial to
    generalized and is accompanied by variable neurological features
    (demyelinating neuropathy, intellectual disability), so the entity is
    broader than a purely adipose disorder; OMIM and MONDO nonetheless number
    it within the familial partial lipodystrophy series.
  review_notes: >-
    Added 2026-09-19. MONDO:0958034 is a direct child of MONDO:0020088 (OLS
    MONDO parents endpoint) and cross-references OMIM:620683, which NCBI's
    mim2gene_medgen maps to GeneID 11145 (PLAAT3). The neurological component
    means this row is a syndromic member of the series rather than an isolated
    partial lipodystrophy; it is kept here because MONDO places it under this
    entry's disease term, and the caveat is recorded in the description rather
    than being silently dropped.
  evidence:
  - reference: PMID:37919452
    reference_title: Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability.
    explanation: >-
      Establishes biallelic PLAAT3 loss of function as a cause of a lipodystrophy
      syndrome and records the partial-to-generalized fat loss and the
      neurological features this row describes.
pathophysiology:
- name: Impaired adipocyte differentiation and adipose storage capacity
  description: >-
    The unifying defect across FPLD subtypes is failure of subcutaneous adipose
    tissue to develop and/or store triglycerides normally, owing to disruption of
    adipogenesis, lipid-droplet biology, or adipocyte maintenance. This produces
    selective loss of subcutaneous fat from the limbs and gluteal region.
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Fat cell differentiation (adipogenesis)
    term:
      id: GO:0045444
      label: fat cell differentiation
    modifier: DECREASED
  - preferred_term: Regulation of lipid storage
    term:
      id: GO:0010883
      label: regulation of lipid storage
    modifier: DECREASED
  locations:
  - preferred_term: Subcutaneous adipose tissue
    term:
      id: UBERON:0002190
      label: subcutaneous adipose tissue
  evidence:
  - reference: PMID:39398333
    reference_title: "Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PPARγ plays an essential role in adipogenesis, stimulating the
      differentiation of preadipocytes into adipocytes. Loss-of-function
      pathogenic variants in PPARG reduce the activity of the PPARγ receptor and
      can lead to severe metabolic consequences associated with familial partial
      lipodystrophy type 3 (FPLD3).
    explanation: >-
      Establishes impaired adipogenesis (via PPARgamma loss of function) as a
      core mechanism producing the lipodystrophy and metabolic phenotype.
  downstream:
  - target: Ectopic lipid deposition and systemic insulin resistance
    description: >-
      Reduced subcutaneous storage capacity diverts lipid to ectopic sites,
      driving systemic insulin resistance.
- name: LMNA nuclear-lamina dysfunction and adipocyte loss (FPLD2)
  description: >-
    In FPLD2 (Dunnigan), pathogenic LMNA variants (commonly codon 482) perturb
    lamin A/C structure and lamin-chromatin (lamina-associated domain)
    interactions required for adipocyte differentiation and maintenance, with
    suppression of lipid-metabolism and mitochondrial programs and an intrinsic
    inflammatory transcriptional signature. (Adipocyte-specific Lmna-knockout
    mouse data supporting a cell-autonomous role for lamin A/C in adipocyte
    maintenance are summarized in the entry notes.)
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  - preferred_term: Lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: DECREASED
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:39125589
    reference_title: "Navigating Lipodystrophy: Insights from Laminopathies and Beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Research on laminopathies has highlighted how LMNA mutations disrupt
      adipose tissue function and metabolic regulation, leading to altered fat
      distribution and metabolic pathway dysfunctions.
    explanation: >-
      Supports LMNA-driven disruption of adipose tissue function and metabolic
      regulation as the FPLD2 mechanism.
  downstream:
  - target: Ectopic lipid deposition and systemic insulin resistance
    description: >-
      LMNA-driven adipose dysfunction feeds the shared ectopic-lipid and
      insulin-resistance cascade.
- name: Loss of PPARgamma-driven adipogenic transcription
  biological_scale: MOLECULAR
  description: >-
    PPARgamma is the master transcriptional regulator of preadipocyte-to-adipocyte
    differentiation. Two curated routes converge on reduced PPARgamma signaling:
    loss-of-function PPARG variants themselves (FPLD3), and biallelic PLAAT3 loss
    (FPLD9), which remodels white adipose membrane phospholipids and strongly
    lowers PPARgamma signaling without altering PPARG itself.
  genes:
  - preferred_term: PPARG
    term:
      id: hgnc:9236
      label: PPARG
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: PPARgamma nuclear receptor signaling
    term:
      id: GO:0141193
      label: nuclear receptor-mediated signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:39398333
    reference_title: "Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PPARγ plays an essential role in adipogenesis, stimulating the
      differentiation of preadipocytes into adipocytes. Loss-of-function
      pathogenic variants in PPARG reduce the activity of the PPARγ receptor and
      can lead to severe metabolic consequences associated with familial partial
      lipodystrophy type 3 (FPLD3).
    explanation: >-
      States both the adipogenic role of PPARgamma and the reduction of receptor
      activity by loss-of-function PPARG variants that this node asserts.
  downstream:
  - target: Impaired adipocyte differentiation and adipose storage capacity
    description: >-
      Reduced PPARgamma transcriptional output blocks preadipocyte
      differentiation, limiting the subcutaneous adipose compartment that can be
      built and maintained.
- name: PLAAT3 loss and phospholipid remodeling of white adipose tissue
  biological_scale: MOLECULAR
  description: >-
    PLAAT3 is a phospholipid-modifying enzyme expressed in neural tissue and
    white adipose tissue. Biallelic loss of function enriches white adipose
    membranes in arachidonic-acid-containing phospholipids and strongly lowers
    PPARgamma signaling, so the lesion is upstream of the adipogenic
    transcriptional program rather than in it. This is the FPLD9 route.
  genes:
  - preferred_term: PLAAT3
    term:
      id: hgnc:17825
      label: PLAAT3
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: membrane phospholipid metabolic process
    term:
      id: GO:0006644
      label: phospholipid metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37919452
    reference_title: Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation.
    explanation: >-
      Patient-derived white adipose tissue shows both the phospholipid
      remodeling and the fall in PPARgamma signaling that this node and its
      downstream edge assert.
  - reference: PMID:37919452
    reference_title: Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ.
    explanation: >-
      Directed inactivation in human adipose stem cells reproduces the
      differentiation defect, establishing the direction of the link rather than
      only its correlation.
  downstream:
  - target: Loss of PPARgamma-driven adipogenic transcription
    description: >-
      Phospholipid remodeling of white adipose membranes lowers PPARgamma
      signaling, joining the FPLD3 route at the adipogenic transcription node.
- name: Adipocyte lipid-droplet formation defect
  biological_scale: CELLULAR
  description: >-
    CIDEC and PLIN1 act at the adipocyte lipid droplet itself. CIDEC is required
    for unilocular lipid droplet formation and for optimal energy storage in
    human fat; the truncating allele is mistargeted and fails to increase lipid
    droplet size, and the patient's white adipocytes are multiloculated (FPLD5).
    PLIN1 coats the droplet, and the FPLD4 frameshift alleles extend its
    C-terminus and act dominant-negatively rather than by haploinsufficiency.
  genes:
  - preferred_term: CIDEC
    term:
      id: hgnc:24229
      label: CIDEC
  - preferred_term: PLIN1
    term:
      id: hgnc:9076
      label: PLIN1
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Lipid droplet organization
    term:
      id: GO:0034389
      label: lipid droplet organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20049731
    reference_title: Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
    explanation: >-
      Establishes the unilocular-droplet requirement whose failure is the CIDEC
      arm of this node.
  - reference: CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z
    reference_title: "PLIN1 / PLIN1-related familial partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mechanistic studies suggest that subcutaneous patients’ adipose tissues show reduced full-length perilipin-1 and an extended perilipin-1 form compatible with the predicted elongated C-terminal tail of the mutant proteins
    explanation: >-
      ClinGen's mechanistic review records the altered perilipin-1 protein on the
      droplet in patient adipose tissue, which is the PLIN1 arm of this node.
  downstream:
  - target: Impaired adipocyte differentiation and adipose storage capacity
    description: >-
      Adipocytes that cannot build or coat a normal unilocular droplet store
      triglyceride inefficiently, reducing safe subcutaneous storage capacity.
  - target: Dysregulated adipocyte triglyceride lipolysis
    description: >-
      The same droplet-coat defect removes the perilipin-1 brake on lipase
      access to stored triglyceride.
- name: Dysregulated adipocyte triglyceride lipolysis
  biological_scale: CELLULAR
  description: >-
    Three curated genes disturb the release of stored triglyceride from the
    adipocyte droplet, in opposite directions, which is why the node is tagged
    abnormal rather than increased or decreased. PLIN1 frameshift mutants fail to
    hold ABHD5, so adipose triglyceride lipase is constitutively activated and
    basal lipolysis runs unchecked (FPLD4). The reported ADRA2A variant removes
    the presynaptic alpha-2A adrenergic brake on adipocyte cAMP, again raising
    lipolysis, and is proposed to do so only in some depots (FPLD8). LIPE encodes
    hormone-sensitive lipase itself, so biallelic loss instead impairs
    triglyceride mobilization (FPLD6).
  genes:
  - preferred_term: PLIN1
    term:
      id: hgnc:9076
      label: PLIN1
  - preferred_term: LIPE
    term:
      id: hgnc:6621
      label: LIPE
  - preferred_term: ADRA2A
    term:
      id: hgnc:281
      label: ADRA2A
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Adipocyte triglyceride lipolysis
    term:
      id: GO:0061725
      label: cytosolic lipolysis
    modifier: ABNORMAL
  evidence:
  - reference: CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z
    reference_title: "PLIN1 / PLIN1-related familial partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the p.(Val398Glyfs) and p.(Leu404Alafs) mutants fail to interact with ABHD5, leading to constitutive activation of adipocyte triglyceride lipase
    explanation: >-
      Gives the molecular route from the FPLD4 perilipin-1 alleles to unchecked
      lipolysis asserted in this node.
  - reference: PMID:27376152
    reference_title: Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADRA2A is the main presynaptic inhibitory feedback G protein-coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes.
    explanation: >-
      States the normal restraining role of ADRA2A on adipocyte lipolysis that
      the reported loss-of-function variant removes.
  - reference: PMID:27376152
    reference_title: Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the mutant ADRA2A produced more cAMP and glycerol, which were resistant to the effects of the α2-adrenergic receptor agonist clonidine and the α2-adrenergic receptor antagonist yohimbine, suggesting loss of function.
    explanation: >-
      Cell assays show the mutant receptor raises cAMP and glycerol release,
      the functional signature of increased lipolysis in this node.
  downstream:
  - target: Ectopic lipid deposition and systemic insulin resistance
    description: >-
      Triglyceride that cannot be retained in, or mobilized from, subcutaneous
      adipocytes reaches ectopic depots.
- name: Impaired adipose insulin and PI3K-AKT signaling
  biological_scale: MOLECULAR
  description: >-
    AKT2 is a kinase of the insulin/PI3K-AKT pathway, and ClinGen's review of
    the reported evidence records that AKT2 signaling is important for adipocyte
    differentiation. The reported FPLD allele has little or no kinase activity,
    so insulin signaling fails in the adipocyte itself rather than only
    downstream of an adipose deficit.
  genes:
  - preferred_term: AKT2
    term:
      id: hgnc:392
      label: AKT2
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Insulin receptor signaling pathway
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z
    reference_title: "AKT2 / AKT2-related familial partial lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism of pathogenicity is reported to be loss of function, evidenced by in vitro functional assays showed that the AKT2 Arg274His allele has little or no kinase activity.
    explanation: >-
      ClinGen's mechanistic review records the kinase-dead behaviour of the
      reported allele, the molecular basis of this node.
  - reference: CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z
    reference_title: "AKT2 / AKT2-related familial partial lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AKT2 signaling is also important for adipocyte differentiation"
    explanation: >-
      Links the signaling defect to the adipocyte differentiation failure this
      node feeds.
  downstream:
  - target: Impaired adipocyte differentiation and adipose storage capacity
    description: >-
      Loss of AKT2 kinase output impairs the insulin-driven differentiation and
      storage program of the adipocyte.
  - target: Ectopic lipid deposition and systemic insulin resistance
    description: >-
      A kinase-dead AKT2 also blocks insulin action directly, so the insulin
      resistance is not solely a consequence of reduced fat mass.
- name: NOTCH3 gain of function and adipose senescence
  biological_scale: CELLULAR
  description: >-
    Missense variants clustered in the heterodimerization domain of the NOTCH3
    negative regulatory region were reported in three unrelated FPL families.
    Patient skin fibroblasts show raised NOTCH3 RNA and protein and activation of
    widespread senescence pathways, which the authors propose as the route from
    unrestrained NOTCH3 signaling to loss of adipose tissue. This node records a
    single-publication mechanism; see the notes on the NOTCH3 genetic record.
  genes:
  - preferred_term: NOTCH3
    term:
      id: hgnc:7883
      label: NOTCH3
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: GAIN_OF_FUNCTION
  - preferred_term: Cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:39652711
    reference_title: Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3.
    explanation: >-
      Localizes the reported variants to the domain that normally restrains
      receptor activation, which is the basis for calling the effect a gain of
      function rather than a quantitative increase.
  - reference: PMID:39652711
    reference_title: Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA sequencing and proteomics analysis of skin fibroblasts revealed significantly higher RNA and protein expression of NOTCH3 and activation of widespread senescence pathways in the patients with FPL versus control study participants.
    explanation: >-
      Patient-derived fibroblasts carry both halves of this node, raised NOTCH3
      expression and activated senescence programs.
  downstream:
  - target: Impaired adipocyte differentiation and adipose storage capacity
    description: >-
      Senescence activation is the proposed route by which unrestrained NOTCH3
      signaling depletes the subcutaneous adipose compartment.
- name: Ectopic lipid deposition and systemic insulin resistance
  description: >-
    The limited subcutaneous storage capacity forces triglycerides into ectopic
    sites (liver, muscle, viscera), driving severe insulin resistance,
    hypertriglyceridemia, type 2 diabetes, hepatic steatosis, and downstream
    cardiometabolic disease.
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: ABNORMAL
  locations:
  - preferred_term: Liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:39125589
    reference_title: "Navigating Lipodystrophy: Insights from Laminopathies and Beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      their associated metabolic complications, such as insulin resistance,
      hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of
      which elevate the risk of cardiovascular disease, stroke, and diabetes.
    explanation: >-
      Supports the downstream cascade of insulin resistance, hypertriglyceridemia,
      hepatic steatosis, and cardiovascular risk arising from adipose dysfunction.
phenotypes:
- name: Partial loss of subcutaneous fat
  category: Physical
  description: >-
    Selective loss of subcutaneous adipose tissue from the limbs and gluteal
    region with relative accumulation in face, neck, and abdomen; muscular
    appearance and prominent veins are common, especially in FPLD2.
  phenotype_term:
    preferred_term: Loss of subcutaneous adipose tissue in limbs
    term:
      id: HP:0003635
      label: Loss of subcutaneous adipose tissue in limbs
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      familial partial lipodystrophy (FPLD), a rare genetic disorder
      characterized by partial subcutaneous fat loss.
    explanation: >-
      Defines the hallmark partial subcutaneous fat loss of FPLD in a
      genetically confirmed cohort.
- name: Insulin resistance
  category: Laboratory
  phenotype_term:
    preferred_term: Insulin resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: PMID:39125589
    reference_title: "Navigating Lipodystrophy: Insights from Laminopathies and Beyond."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      their associated metabolic complications, such as insulin resistance,
      hypertriglyceridemia, hepatic steatosis, and metabolic syndrome
    explanation: >-
      Lists insulin resistance among the core metabolic complications of FPLD.
- name: Diabetes mellitus
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diabetes mellitus (DM) was highly prevalent (57.5%),"
    explanation: >-
      Diabetes was present in 57.5% of a genetically confirmed FPLD cohort,
      supporting a FREQUENT frequency band.
- name: Hypertriglyceridemia
  category: Laboratory
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and
      pancreatitis in 8.5%.
    explanation: >-
      Documents severe hypertriglyceridemia and consequent pancreatitis in the
      FPLD cohort.
- name: Decreased HDL cholesterol
  category: Laboratory
  description: >-
    Low HDL cholesterol is part of the characteristic dyslipidemia of FPLD and a
    core component of the metabolic syndrome that accompanies the lipodystrophic
    phenotype; it is used as a diagnostic criterion alongside hypertriglyceridemia.
  phenotype_term:
    preferred_term: Decreased HDL cholesterol concentration
    term:
      id: HP:0003233
      label: Decreased HDL cholesterol concentration
  evidence:
  - reference: PMID:26775134
    reference_title: "A case of familial partial lipodystrophy caused by a novel lamin A/C (LMNA) mutation in exon 1 (D47N)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic abnormalities were observed as a form of insulin resistant
      diabetes, hypertriglyceridemia, low HDL cholesterol and hepatic steatosis.
    explanation: >-
      Documents low HDL cholesterol as part of the metabolic abnormalities in an
      LMNA-confirmed FPLD2 family.
- name: Pancreatitis
  category: Physical
  description: >-
    Acute pancreatitis can result from severe hypertriglyceridemia.
  phenotype_term:
    preferred_term: Pancreatitis
    term:
      id: HP:0001733
      label: Pancreatitis
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and
      pancreatitis in 8.5%.
    explanation: >-
      Pancreatitis occurred in 8.5% of the cohort, linked to severe
      hypertriglyceridemia.
- name: Hepatic steatosis
  category: Physical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic-associated fatty liver disease (MAFLD) was observed in 56.6%,"
    explanation: >-
      MAFLD (hepatic steatosis) was present in 56.6% of FPLD patients,
      supporting a FREQUENT frequency band.
- name: Hypertension
  category: Physical
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:39398333
    reference_title: "Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension
      (59.5%), polycystic ovary syndrome (58.2% of women)
    explanation: >-
      Hypertension was present in 59.5% of FPLD3 (PPARG) patients in this review.
- name: Acanthosis nigricans
  category: Physical
  description: >-
    Skin manifestation of severe insulin resistance, recognized among the
    FPLD-associated conditions in clinical consensus criteria.
  phenotype_term:
    preferred_term: Acanthosis nigricans
    term:
      id: HP:0000956
      label: Acanthosis nigricans
- name: Polycystic ovaries
  category: Physical
  subtype: FPLD3
  description: >-
    Polycystic ovary syndrome and hyperandrogenism are frequent in women,
    particularly in PPARG-related FPLD3.
  phenotype_term:
    preferred_term: Polycystic ovaries
    term:
      id: HP:0000147
      label: Polycystic ovaries
  evidence:
  - reference: PMID:39398333
    reference_title: "Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "polycystic ovary syndrome (58.2% of women)"
    explanation: >-
      PCOS occurred in 58.2% of women with FPLD3 (PPARG variants).
- name: Atherosclerosis
  category: Physical
  description: >-
    Premature/early atherosclerotic cardiovascular disease is a major
    complication and the leading cause of death in FPLD cohorts.
  phenotype_term:
    preferred_term: Atherosclerosis
    term:
      id: HP:0002621
      label: Atherosclerosis
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cardiovascular disease in 10.4%. The overall mortality rate was 3.8%, due
      to cardiovascular events.
    explanation: >-
      Cardiovascular disease affected 10.4% of patients and accounted for all
      deaths, underscoring atherosclerotic CVD as the principal cause of
      mortality.
genetic:
- name: LMNA pathogenic variants (FPLD2/Dunnigan)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FPLD2
  notes: >-
    Autosomal dominant pathogenic variants in LMNA cause FPLD2 (Dunnigan), the
    most common genetic form, frequently missense variants at codon 482. LMNA was
    the most common genetic cause in a Brazilian cohort (85.8%).
  gene_term:
    preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LMNA \npathogenic variants were identified in 85.8% of patients, PPARG in 10.4%, PLIN1 \nin 2.8%, and MFN2 in 0.9%."
    explanation: >-
      Quantifies the relative contribution of LMNA, PPARG, PLIN1, and MFN2 in a
      genetically confirmed FPLD cohort.
  - reference: CGGV:assertion_9a2725cf-2492-4f4d-8646-7a757cdac3dc-2024-10-09T160000.000Z
    reference_title: "LMNA / lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMNA | HGNC:6636 | lipodystrophy | MONDO:0006573 | SD | Definitive"
    explanation: >-
      ClinGen rates the LMNA-lipodystrophy gene-disease relationship Definitive, which is the classification level the CAUSATIVE relationship_type on this record asserts.
  - reference: CGGV:assertion_9a2725cf-2492-4f4d-8646-7a757cdac3dc-2024-10-09T160000.000Z
    reference_title: "LMNA / lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, LMNA is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults.
    explanation: >-
      ClinGen records the inheritance as semidominant with most cases presenting as autosomal dominant familial partial lipodystrophy, which is the FPLD2 phenotype curated here.
- name: PPARG loss-of-function variants (FPLD3)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FPLD3
  notes: >-
    Loss-of-function pathogenic variants in PPARG (PPARgamma) cause FPLD3 by
    reducing activity of the master regulator of adipogenesis.
  gene_term:
    preferred_term: PPARG
    term:
      id: hgnc:9236
      label: PPARG
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39398333
    reference_title: "Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss-of-function pathogenic variants in PPARG reduce the activity of the
      PPARγ receptor and can lead to severe metabolic consequences associated
      with familial partial lipodystrophy type 3 (FPLD3).
    explanation: >-
      Establishes PPARG loss of function as the cause of FPLD3.
  - reference: CGGV:assertion_b4c76c1c-7e8a-418f-ba62-b7eeb3c3d472-2024-08-14T160000.000Z
    reference_title: "PPARG / lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PPARG | HGNC:9236 | lipodystrophy | MONDO:0006573 | SD | Definitive"
    explanation: >-
      ClinGen rates the PPARG-lipodystrophy gene-disease relationship Definitive, supporting the CAUSATIVE relationship_type on this record.
  - reference: CGGV:assertion_b4c76c1c-7e8a-418f-ba62-b7eeb3c3d472-2024-08-14T160000.000Z
    reference_title: "PPARG / lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, PPARG is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults.
    explanation: >-
      ClinGen records semidominant inheritance with most cases presenting as autosomal dominant familial partial lipodystrophy, the FPLD3 phenotype curated here.
- name: PLIN1 pathogenic variants (FPLD4)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FPLD4
  notes: >-
    Pathogenic variants in PLIN1 (perilipin-1) cause FPLD4; PLIN1 accounted for
    2.8% of a genetically confirmed Brazilian FPLD cohort. The mechanism is
    dominant-negative rather than haploinsufficient: ClinGen's review of the
    reported alleles records that only frameshift variants extending the
    perilipin-1 C-terminus have been implicated in humans, and that
    heterozygous null variants predicted to undergo nonsense-mediated decay
    are not associated with FPLD4.
  gene_term:
    preferred_term: PLIN1
    term:
      id: hgnc:9076
      label: PLIN1
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLIN1 \nin 2.8%, and MFN2 in 0.9%."
    explanation: >-
      PLIN1 (FPLD4) and MFN2 were identified as rarer genetic causes in the
      cohort.
  - reference: CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z
    reference_title: "PLIN1 / PLIN1-related familial partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLIN1 | HGNC:9076 | PLIN1-related familial partial lipodystrophy | MONDO:0013478 | AD | Definitive"
    explanation: >-
      ClinGen rates the PLIN1-FPLD4 gene-disease relationship Definitive with autosomal dominant inheritance, supporting the CAUSATIVE relationship_type here.
  - reference: CGGV:assertion_dcba327c-dc89-4e78-ae7b-84b23db5429e-2025-09-10T160000.000Z
    reference_title: "PLIN1 / PLIN1-related familial partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Instead, the disorder results specifically from dominant-negative effects of C-terminal elongating frameshift variants predicted to escape NMD.
    explanation: >-
      ClinGen's allele review states the dominant-negative mechanism recorded in
      this record's notes and distinguishes it from haploinsufficiency.
- name: CIDEC biallelic variants (FPLD5)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FPLD5
  notes: >-
    Biallelic CIDEC variants cause autosomal recessive FPLD5, impairing
    lipid-droplet formation and lipid storage. The founding report is a single
    homozygous proband with supporting cell and mouse work. No ClinGen
    gene-disease validity curation exists for CIDEC: the ClinGen validity table
    committed in this repository (cache/clingen/gene_validity.csv) contains no
    CIDEC row, so the CAUSATIVE relationship_type rests on the primary report
    and on OMIM/MONDO recognition of the locus rather than on a ClinGen
    classification.
  gene_term:
    preferred_term: CIDEC
    term:
      id: hgnc:24229
      label: CIDEC
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:20049731
    reference_title: Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X).
    explanation: >-
      The founding report of biallelic CIDEC loss of function in human partial
      lipodystrophy, including the multilocular-lipid-droplet adipocyte phenotype
      that distinguishes this subtype.
- name: LIPE biallelic variants (FPLD6)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FPLD6
  notes: >-
    Biallelic loss-of-function variants in LIPE (hormone-sensitive lipase) cause
    autosomal recessive FPLD6.
  gene_term:
    preferred_term: LIPE
    term:
      id: hgnc:6621
      label: LIPE
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: CGGV:assertion_05644df2-842b-45ef-a118-01994bdf07eb-2025-12-30T170000.000Z
    reference_title: "LIPE / LIPE-related familial partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LIPE | HGNC:6621 | LIPE-related familial partial lipodystrophy | MONDO:0014431 | AR | Definitive"
    explanation: >-
      ClinGen rates the LIPE-FPLD6 gene-disease relationship Definitive with autosomal recessive inheritance, supporting the CAUSATIVE relationship_type and the recessive inheritance recorded here.

- name: AKT2 dominant-negative variants
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: AKT2
  notes: >-
    Dominant-negative variants in AKT2, a kinase in the insulin/PI3K-AKT pathway,
    cause partial lipodystrophy with severe insulin resistance. ClinGen rates
    this gene-disease relationship Limited: the mechanism is well evidenced but
    the human genetic evidence still rests on one kindred. relationship_type is
    UNKNOWN rather than CAUSATIVE because GeneDiseaseRelationshipEnum defines
    CAUSATIVE as ClinGen Definitive or Strong and has no Limited value; it is
    not DISPUTED, because nothing contradicts the association.
  gene_term:
    preferred_term: AKT2
    term:
      id: hgnc:392
      label: AKT2
  evidence:
  - reference: CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z
    reference_title: "AKT2 / AKT2-related familial partial lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AKT2 | HGNC:392 | AKT2-related familial partial lipodystrophy | MONDO:0019192 | AD | Limited"
    explanation: >-
      ClinGen classifies the AKT2-FPLD relationship as Limited, which is the
      evidence level this record reports.
  - reference: CGGV:assertion_77eff07e-5764-4161-86b7-ac8289cc5461-2026-01-21T170000.000Z
    reference_title: "AKT2 / AKT2-related familial partial lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, while the mechanistic link between AKT2 dysfunction and lipodystrophic insulin resistance is highly plausible and well evidenced, current genetic evidence supporting the human gene-disease relationship is limited.
    explanation: >-
      Distinguishes the strong mechanistic case for AKT2 from the limited human
      genetic evidence, which is why relationship_type is left UNKNOWN here.
- name: CAV1 variants (FPLD7)
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: CAV1
  notes: >-
    Variants in CAV1 (caveolin-1) are associated with partial lipodystrophy
    (FPLD7, OMIM 606721), affecting adipocyte caveolae and lipid storage.
    ClinGen rates this Limited: only two variants from a single 2008
    publication have been reported, with no segregation or experimental data.
    ClinGen split CAV1 into three curations - the autosomal dominant partial
    and/or progeroid lipodystrophy curated here, autosomal recessive congenital
    generalized lipodystrophy type 3 (OMIM 612526, rated Definitive; curated in
    dismech as the CGL3 subtype of
    kb/disorders/Berardinelli_Seip_Congenital_Lipodystrophy.yaml), and
    autosomal dominant pulmonary
    arterial hypertension - so a CAV1 result must be read against the right one
    of the three. relationship_type is UNKNOWN for the same enum reason given
    on the AKT2 record.
  gene_term:
    preferred_term: CAV1
    term:
      id: hgnc:1527
      label: CAV1
  evidence:
  - reference: CGGV:assertion_7278df5e-7003-4ff8-bcb6-f043cf2fcb60-2025-07-16T160000.000Z
    reference_title: "CAV1 / lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CAV1 | HGNC:1527 | lipodystrophy | MONDO:0006573 | AD | Limited"
    explanation: >-
      ClinGen classifies the autosomal dominant CAV1-lipodystrophy relationship as
      Limited, the evidence level this record reports.
  - reference: CGGV:assertion_7278df5e-7003-4ff8-bcb6-f043cf2fcb60-2025-07-16T160000.000Z
    reference_title: "CAV1 / lipodystrophy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Evidence supporting this gene-disease relationship includes limited case-level data, with no segregation data or experimental data available.
    explanation: >-
      States what the CAV1 partial-lipodystrophy claim rests on, supporting the
      caution recorded in this record's notes.
- name: MFN2 variants
  variant_origin: GERMLINE
  notes: >-
    Rare cases of partial lipodystrophy are associated with MFN2; identified in
    0.9% of a genetically confirmed FPLD cohort. No subtype is assigned and
    relationship_type is left unset, because the entity ClinGen curates for
    MFN2 is not familial partial lipodystrophy: it is autosomal recessive
    multiple symmetric lipomatosis with partial lipodystrophy
    (MONDO:1060153, OMIM 151800), rated Definitive, in which every reported
    patient carries at least one p.Arg707Trp allele and upper-body adipose
    overgrowth accompanies the limb lipodystrophy. The inheritance also differs
    from the dominant FPLD forms curated above. MFN2 is retained on this entry
    because MFN2 carriers turn up in genetically screened FPLD cohorts and a
    curator reading an MFN2 result needs to find this disposition; it is a
    candidate for a separate dismech entry rather than an FPLD subtype.
  gene_term:
    preferred_term: MFN2
    term:
      id: hgnc:16877
      label: MFN2
  evidence:
  - reference: PMID:38887266
    reference_title: "Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLIN1 \nin 2.8%, and MFN2 in 0.9%."
    explanation: >-
      MFN2 was a rare cause identified in the genetically confirmed cohort.
  - reference: CGGV:assertion_9322bddb-bcdb-466b-acae-058f4a368e01-2025-09-10T160000.000Z
    reference_title: "MFN2 / multiple symmetric lipomatosis with partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MFN2 | HGNC:16877 | multiple symmetric lipomatosis with partial lipodystrophy | MONDO:1060153 | AR | Definitive"
    explanation: >-
      ClinGen curates MFN2 against a separate autosomal recessive disease term,
      not against a familial partial lipodystrophy term, which is the basis for
      not making MFN2 a subtype of this entry.
  - reference: CGGV:assertion_9322bddb-bcdb-466b-acae-058f4a368e01-2025-09-10T160000.000Z
    reference_title: "MFN2 / multiple symmetric lipomatosis with partial lipodystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One specific MFN2 variant, p.Arg707Trp, has been reported in all multiple symmetric lipomatosis with partial lipodystrophy cases to date.
    explanation: >-
      The single recurrent allele behind every reported case is part of what
      distinguishes this entity from the allelically heterogeneous FPLD subtypes.
- name: NOTCH3 gain-of-function variants
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  notes: >-
    Heterozygous missense variants clustered in the heterodimerization domain of
    the NOTCH3 negative regulatory region were reported in three unrelated
    families with familial partial lipodystrophy, with patient fibroblasts
    showing raised NOTCH3 expression and activation of senescence pathways. No
    subtype is assigned. OMIM has folded this gene-disease relationship into
    phenotype MIM 608600 (familial partial lipodystrophy type 1, the Koebberling
    type), and MONDO therefore records NOTCH3 as the causal gene of
    MONDO:0012072; the source report instead describes its families as a novel
    subtype of FPL and does not call them Koebberling, so this entry curates the
    gene without asserting that equivalence (see the review_notes on the FPLD1
    subtype). relationship_type is UNKNOWN: the evidence is a single 2025
    publication, the ClinGen validity table committed in this repository has no
    NOTCH3 row for any lipodystrophy (its only NOTCH3 row is a Disputed
    pulmonary arterial hypertension curation), and that publication carries an
    erratum (PMID:41147879) whose content could not be retrieved - see the
    FPLD1 review_notes.
  gene_term:
    preferred_term: NOTCH3
    term:
      id: hgnc:7883
      label: NOTCH3
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:39652711
    reference_title: Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further analysis of WES data of 222 patients with unexplained FPL identified two unrelated patients with FPL with novel heterozygous (p.Cys1600Tyr and p.Gln1552Pro) NOTCH3 variants.
    explanation: >-
      Two further unrelated probands beyond the index pedigree are the human
      genetic evidence for this gene-disease relationship, and also show how
      narrow it still is.
  - reference: PMID:39652711
    reference_title: Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that gain-of-function missense variants in the negative regulatory region of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways.
    explanation: >-
      The authors' own conclusion, which describes the entity as a novel subtype
      of familial partial lipodystrophy rather than as the Koebberling type that
      OMIM and MONDO attach the gene to.
- name: PLAAT3 biallelic loss-of-function variants (FPLD9)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: FPLD9
  notes: >-
    Homozygous loss-of-function PLAAT3 variants were identified in seven
    patients from four unrelated consanguineous families with a lipodystrophy
    syndrome, with variable neurological involvement. The ClinGen validity table
    committed in this repository contains no PLAAT3 row, so the CAUSATIVE
    relationship_type rests on the primary report - multiple unrelated
    consanguineous families, a concordant mouse knockout, and CRISPR
    inactivation in human adipose stem cells - together with OMIM and MONDO
    recognition of the locus as FPLD9.
  gene_term:
    preferred_term: PLAAT3
    term:
      id: hgnc:17825
      label: PLAAT3
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:37919452
    reference_title: Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.
    explanation: >-
      The report's own conclusion establishing the gene-disease relationship and
      naming the PPARgamma-dependent mechanism wired on the pathophysiology
      graph.
- name: ADRA2A variants (FPLD8)
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  subtype: ADRA2A
  notes: >-
    A heterozygous ADRA2A p.Leu68Phe variant segregated with atypical familial
    partial lipodystrophy in a single African-American pedigree; functional work
    in the same report showed the mutant receptor produced more cAMP and
    glycerol and was resistant to alpha-2 agonist and antagonist, consistent
    with loss of the receptor's normal restraint on adipocyte lipolysis. OMIM
    numbers this FPLD8 (620679) and MONDO carries it as MONDO:0958022.
    relationship_type is UNKNOWN: the evidence is one pedigree, the ClinGen
    validity table committed in this repository contains no ADRA2A row, and the
    European Consortium for Lipodystrophies consensus warns that next-generation
    sequencing has produced a proliferation of proposed new genetic causes of
    lipodystrophy with variable supporting evidence.
  gene_term:
    preferred_term: ADRA2A
    term:
      id: hgnc:281
      label: ADRA2A
  evidence:
  - reference: PMID:27376152
    reference_title: Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that heterozygous p.Leu68Phe ADRA2A mutation causes a rare atypical FPLD, most likely by inducing excessive lipolysis in some adipose tissue depots.
    explanation: >-
      The founding report's own conclusion, giving both the allele and the
      proposed excessive-lipolysis mechanism curated on the pathophysiology node.
  - reference: PMID:42681552
    reference_title: European Consortium for Lipodystrophies consensus definition and classification framework for monogenic lipodystrophy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Conversely, increasing use of next-generation sequencing has led to proliferation of proposed new genetic causes of lipodystrophy with variable supporting evidence.
    explanation: >-
      The ECLip consensus states the field-level reason this single-pedigree
      association is recorded with an UNKNOWN relationship_type rather than as
      causative.
treatments:
- name: Dietary intervention
  description: >-
    Balanced calorie-controlled diet (typically ~50-60% carbohydrate, 20-30%
    fat, ~20% protein) with reduced simple sugars and alcohol abstinence to
    reduce metabolic stress on limited adipose storage capacity and lower
    triglyceride/pancreatitis risk.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
- name: Aerobic exercise
  description: >-
    Regular aerobic exercise (after cardiac evaluation) to improve insulin
    sensitivity and cardiometabolic risk.
  treatment_term:
    preferred_term: aerobic exercise therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Metformin
  description: >-
    First-line pharmacotherapy for hyperglycemia and insulin resistance in FPLD.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metformin
      term:
        id: CHEBI:6801
        label: metformin
- name: Statin therapy
  description: >-
    First-line lipid-lowering therapy (e.g., atorvastatin) for dyslipidemia.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atorvastatin
      term:
        id: CHEBI:39548
        label: atorvastatin
- name: Fibrate therapy
  description: >-
    Fibrates (e.g., fenofibrate), often with omega-3 fatty acids, for severe
    hypertriglyceridemia (TG > 500 mg/dL) to reduce pancreatitis risk.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fenofibrate
      term:
        id: CHEBI:5001
        label: fenofibrate
- name: Metreleptin
  description: >-
    Recombinant leptin analog (leptin replacement therapy); a major advance for
    generalized lipodystrophy, with more variable benefit in partial forms,
    associated with reductions in triglycerides and HbA1c in hypoleptinemic
    patients.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metreleptin
      term:
        id: NCIT:C170171
        label: Metreleptin
- name: GLP-1 receptor agonist therapy
  description: >-
    Glucagon-like peptide 1 receptor agonists (GLP-1RA) improve weight, BMI,
    HbA1c, fasting glucose, and triglycerides in FPLD; acute pancreatitis has
    been reported with longer therapy, warranting caution in patients with prior
    pancreatitis.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: liraglutide
      term:
        id: NCIT:C82239
        label: Liraglutide
  evidence:
  - reference: PMID:38300898
    reference_title: "Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study demonstrates the relative safety and effectiveness of GLP-1RA in
      patients with FPLD.
    explanation: >-
      Retrospective study supporting GLP-1RA efficacy and relative safety in FPLD,
      with a noted pancreatitis signal on longer therapy.
- name: Volanesorsen
  description: >-
    ApoC-III antisense oligonucleotide investigated for severe
    hypertriglyceridemia in FPLD (BROADEN trial); produces large triglyceride
    reductions.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: APOC3
      term:
        id: hgnc:610
        label: APOC3
    target_transcript: APOC3 mRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: volanesorsen
      term:
        id: NCIT:C152904
        label: Volanesorsen
- name: Genetic counseling
  description: >-
    Genetic counseling and cascade genetic testing of relatives are recommended
    for affected families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
clinical_trials:
- name: NCT02527343
  phase: PHASE_III
  status: TERMINATED
  description: >-
    The BROADEN Study: a randomized, double-blind, placebo-controlled trial of
    volanesorsen (ApoC-III antisense oligonucleotide) in participants with
    familial partial lipodystrophy, with triglyceride lowering as the primary
    endpoint.
  target_phenotypes:
  - preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: clinicaltrials:NCT02527343
    reference_title: "A Randomized, Double-Blind, Placebo-Controlled, With an Open Label Extension, Phase 2/3 Study of ISIS 304801 Administered Subcutaneously to Patients With Familial Partial Lipodystrophy"
    supports: SUPPORT
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of
      volanesorsen given for 52 weeks in a randomized treatment (RT) period in
      participants with familial partial lipodystrophy (FPL).
    explanation: >-
      The BROADEN trial tested volanesorsen specifically in FPLD, targeting the
      severe hypertriglyceridemia that drives pancreatitis risk.
- name: NCT02262806
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Compassionate use of metreleptin in previously treated people with partial
    lipodystrophy (NIDDK).
  target_phenotypes:
  - preferred_term: Insulin resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: clinicaltrials:NCT02262806
    reference_title: "Compassionate Use of Metreleptin in Previously-Treated Patients With Partial Lipodystrophy"
    supports: SUPPORT
    snippet: >-
      Partial lipodystrophy can cause high blood fat levels and resistance to
      insulin.
    explanation: >-
      This NIDDK trial provides metreleptin to partial lipodystrophy patients
      who benefited previously, addressing insulin resistance and dyslipidemia.
notes: >-
  FPLD is typically autosomal dominant for the common forms (LMNA, PPARG), while
  CIDEC (FPLD5) and LIPE (FPLD6) are autosomal recessive. FPLD1 (Köbberling) is
  defined clinically with no consistently identified gene. Partial lipodystrophy
  prevalence is estimated at roughly 1.7-2.8 per million, and diagnostic delay is
  substantial (median ~10.5 years for FPLD2 in a French reference-center cohort).
  An adipocyte-specific Lmna-knockout mouse recapitulates adipocyte loss,
  supporting a cell-autonomous role for lamin A/C. This entry is distinct from
  acquired partial lipodystrophy (Barraquer-Simons syndrome, MONDO:0012104),
  which is immune/complement-mediated rather than Mendelian. Note: no dedicated
  GeneReviews chapter exists for familial partial lipodystrophy (PubMed has no
  GeneReviews[Book] record for this condition as of 2026-06); the Fernandez-Pombo
  et al. 2023 systematic review is used as the authoritative baseline reference
  instead.

  GeneReviews, rechecked 2026-09-19. The absence claim above is now checkable
  offline: the committed Bookshelf index (cache/bookshelf/genereviews.csv,
  snapshot 2026-09-10, 958 chapters) contains no chapter for familial partial
  lipodystrophy, and `just check-genereviews` on this file reports NO_CHAPTER.
  The nearest chapters in that index are LMNA-Related Dilated Cardiomyopathy,
  INSR-Related Severe Insulin Resistance Syndrome, and a retired
  Berardinelli-Seip Congenital Lipodystrophy chapter, none of which covers this
  disease.

  Gene scope and dispositions, 2026-09-19. Every gene-defined has_subtypes row
  now carries a genes list, and every genetic record now carries a subtype
  foreign key except the two that deliberately have none: NOTCH3 (see the
  FPLD1 review_notes) and MFN2 (see below). Two MONDO leaf classes that were missing were added as subtype rows:
  MONDO:0958022 (FPLD8), bound to the pre-existing ADRA2A row, and
  MONDO:0958034 (FPLD9, PLAAT3), added new. Both are direct children of this
  entry's disease term MONDO:0020088. FPLD9 is syndromic - fat loss with
  variable demyelinating neuropathy and intellectual disability - and is kept
  here because MONDO places it under this term, with the caveat recorded on the
  row rather than dropped.

  MFN2 is kept in the genetic list but is not a subtype of this disease.
  ClinGen curates MFN2 against autosomal recessive multiple symmetric
  lipomatosis with partial lipodystrophy (MONDO:1060153, OMIM 151800), a
  distinct entity with a different inheritance pattern in which every reported
  patient carries at least one p.Arg707Trp allele. It is a candidate for a
  separate dismech entry.

  CAV1 has no pathophysiology node. ClinGen's Limited curation for the
  autosomal dominant CAV1 partial-lipodystrophy relationship records that no
  experimental data are available for it, so there is no mechanism to cite, and
  a node was not invented. The gene remains curated with its subtype row, its
  gene binding and its ClinGen evidence. The row is bound to MONDO:0011714,
  whose exact synonym is "lipodystrophy, familial partial, type 7"; MONDO
  places that class under hereditary disease rather than under MONDO:0020088,
  unlike the other numbered FPLD classes.

  Unverified legacy prose. The prevalence figure (roughly 1.7-2.8 per million)
  and the diagnostic-delay figure (median about 10.5 years for FPLD2 in a
  French reference-center cohort) in the first paragraph predate this pass and
  carry no citation anywhere in the entry. They were not re-derived here and
  should be sourced or removed.
references:
- reference: PMID:36899861
  title: "Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review."
  findings: []
datasets:
- accession: massive:MSV000096235
  title: NOTCH3 missense variants cause familial partial lipodystrophy
  description: Molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We identified novel NOTCH3 heterozygous variants in familial partial lipodystrophy (FPL) pedigrees. All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3. Proteomics of skin fibroblasts revealed significantly higher RNA expression of NOTCH3 and activation of widespread senescence pathways in the FPL patients versus controls.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Familial Partial Lipodystrophy"). Retrieved 2026-08-02.

📚

References & Deep Research

References

PMID:36899861

Clinical Spectrum of LMNA-Associated Type 2 Familial Partial Lipodystrophy: A Systematic Review.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 67 citations 2026-06-05T14:48:32.689131

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Familial Partial Lipodystrophy
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Familial Partial Lipodystrophy covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: Familial Partial Lipodystrophy (FPLD)

Target disease: Familial Partial Lipodystrophy (Mendelian, genetically heterogeneous)

Evidence scope note: This report is based on retrieved primary/review literature and clinical-trial registry records available in the current tool context. Some requested identifiers (e.g., MONDO/MeSH) were not explicitly present in retrieved full-text excerpts and are therefore marked as not available from the retrieved sources.

1. Disease information

1.1 Definition and overview

Familial partial lipodystrophy (FPLD) refers to inherited lipodystrophy syndromes characterized by selective loss of subcutaneous adipose tissue (SAT) in specific body regions, often with relative/ectopic fat accumulation in others, and associated metabolic complications driven by insulin resistance (diabetes, dyslipidemia/hypertriglyceridemia, fatty liver disease, cardiovascular and reproductive complications). (soares2024familialpartiallipodystrophy pages 1-2, fernandezpombo2023clinicalspectrumof pages 3-5, fossfreitas2025lipodystrophysyndromesone pages 7-8)

FPLD2 (Dunnigan disease/syndrome) is the most prevalent monogenic form and is described in a recent review as involving loss of fat from trunk/buttocks/limbs with fat accumulation in face/neck/supraclavicular regions (a “Cushingoid appearance”), with frequent insulin-resistance manifestations. (fernandezpombo2023clinicalspectrumof pages 3-5, diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3)

Abstract support (direct quote): A systematic review summarized FPLD2 as a disorder where adipose dysfunction “conditions the development of metabolic complications associated with insulin resistance, such as diabetes, dyslipidaemia, fatty liver disease, cardiovascular disease, and reproductive disorders.” (Fernandez‑Pombo et al., 2023; Cells; 2023‑02; https://doi.org/10.3390/cells12050725) (fernandezpombo2023clinicalspectrumof pages 7-9)

1.2 Key identifiers and coding (from retrieved sources)

Because FPLD comprises multiple subtypes, identifiers may be subtype-specific.

FPLD2 / Dunnigan syndrome - OMIM (MIM): 151660 (explicitly stated as “MIM#151660”). (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3) - Orphanet (ORPHA): ORPHA:2348 (“FPLD2; ORPHA 2348”). (mosbah2022dunniganlipodystrophysyndrome pages 1-2) - ICD-10/ICD-9 codes used for lipodystrophy case capture: ICD‑10 E88.1, ICD‑9 272.6 (broad lipodystrophy/lipoatrophy coding used in EHR-based prevalence work; not specific to FPLD2). (gonzagajauregui2020clinicalandmolecular pages 1-2)

FPLD3 / PPARG-related familial partial lipodystrophy - OMIM (MIM): 604367 was shown in a subtype table linking FPLD3 to PPARG. (kruger2024navigatinglipodystrophyinsights pages 8-9)

MONDO, MeSH, ICD-11: Not explicitly present in retrieved excerpts; therefore not reliably reportable here from tool evidence.

1.3 Synonyms and alternative names

“Familial partial lipodystrophy” (FPLD) (soares2024familialpartiallipodystrophy pages 1-2)
“Familial partial lipodystrophy type 2” (FPLD2) (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3)
“Dunnigan disease/syndrome” (synonymous with FPLD2) (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3, mosbah2022dunniganlipodystrophysyndrome pages 1-2)

1.4 Evidence sources: patient-level vs aggregated

Evidence used here includes: - Aggregated reviews (systematic review of FPLD2; review of PPARG/FPLD3). (fernandezpombo2023clinicalspectrumof pages 7-9, soares2024familialpartiallipodystrophy pages 1-2) - Multicenter cohort study (Brazil, 106 genetically confirmed cases). (guidorizzi2024comprehensiveanalysisof pages 1-2, guidorizzi2024comprehensiveanalysisof pages 3-5) - National reference-center registry analysis (France PRISIS/BNDMR, 292 patients across syndromes; includes FPLD subsets). (donadille2024diagnosticandreferral pages 1-2) - International registry cross-sectional analysis (ECLip registry). (ceccarini2025epidemiologicalandclinical pages 1-2, ceccarini2025epidemiologicalandclinical pages 9-10) - ClinicalTrials.gov registry records for interventional studies. (NCT02527343 chunk 1, NCT02262806 chunk 2)

2. Etiology

2.1 Primary causes

FPLD is primarily a genetic disorder of adipose biology (adipogenesis, lipid storage/lipid droplet biology, nuclear lamina/chromatin regulation), leading to reduced capacity for safe triglyceride storage in subcutaneous depots and promoting ectopic fat deposition and insulin resistance. (soares2024familialpartiallipodystrophy pages 1-2, kruger2024navigatinglipodystrophyinsights pages 12-14, brown2025theclinicalapproach pages 3-5)

2.2 Genetic risk factors (causal genes)

FPLD is genetically heterogeneous, with subtype-defining genes including LMNA (FPLD2) and PPARG (FPLD3), as well as rarer causes (e.g., PLIN1, CIDEC, LIPE, CAV1). (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, fossfreitas2025lipodystrophysyndromesone pages 7-8)

In a Brazilian multicenter cohort (n=106) with genetic confirmation: - LMNA: 85.8% - PPARG: 10.4% - PLIN1: 2.8% - MFN2: 0.9% (guidorizzi2024comprehensiveanalysisof pages 1-2)

The same cohort states genetic FPLD forms “typically follow autosomal dominant inheritance” and highlights Köbberling (FPLD1) as an exception without an identified mutation. (guidorizzi2024comprehensiveanalysisof pages 1-2)

2.3 Pathogenic variant types/classes (examples from retrieved sources)

LMNA codon 482 missense variants are repeatedly emphasized as common in classic FPLD2 (e.g., R482W/R482Q). (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3, tirthani2024mon045acase pages 1-1)
LIPE biallelic loss-of-function can cause FPLD6; a case series reports a homozygous frameshift variant (p.Val1068GlyfsTer102). (magno2026casereportfamilial pages 5-7)

2.4 Environmental risk factors / protective factors

For familial (Mendelian) FPLD, environmental exposures do not cause the disorder, but lifestyle factors modify severity of metabolic complications. Dietary composition and caloric excess are discussed as key modifiable contributors to metabolic burden in lipodystrophy care. (fernandezpombo2023clinicalspectrumof pages 13-14, gilio2025clinicalguidancefor pages 8-10)

Evidence for true “protective” genetic variants within FPLD-specific genes was not identified in the retrieved FPLD-focused excerpts.

2.5 Gene–environment interactions

Direct gene–environment interaction studies in FPLD were not identified in the retrieved texts. Available guidance emphasizes that caloric reduction and macronutrient management may reduce metabolic stress on limited adipose storage capacity across forms of lipodystrophy. (gilio2025clinicalguidancefor pages 8-10)

3. Phenotypes (with suggested HPO terms)

3.1 Core adipose distribution phenotype

Phenotype: Selective regional lipoatrophy with relative fat accumulation in face/neck/trunk/intra-abdominal depots; muscular appearance and prominent veins are common in FPLD2. (fernandezpombo2023clinicalspectrumof pages 3-5, diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3, fernandezpombo2023clinicalspectrumof pages 7-9)

Onset: FPLD2 typically emerges progressively around puberty in women; later in men. (fernandezpombo2023clinicalspectrumof pages 3-5)

Suggested HPO terms: - Abnormality of body fat distribution (HP:0009126) - Partial lipodystrophy (HP:0009124) - Lipoatrophy (HP:0009121) - Increased subcutaneous fat in face/neck (map to regional fat accumulation; consider HP terms for increased neck adipose)

3.2 Metabolic complications (frequency data)

Diabetes / insulin resistance

FPLD2 systematic review reports diabetes prevalence 28–51%, higher in women (54% women vs 17% men). (fernandezpombo2023clinicalspectrumof pages 10-11)

In the Brazilian cohort (n=106): diabetes was 57.5% overall; by gene group diabetes was ~55% in LMNA and 73% in PPARG. (guidorizzi2024comprehensiveanalysisof pages 3-5)

Suggested HPO terms: - Insulin resistance (HP:0000855) - Diabetes mellitus (HP:0000819)

Dyslipidemia / hypertriglyceridemia / pancreatitis

FPLD2 review reports dyslipidemia prevalence 59–89%, with marked hypertriglyceridemia and low HDL; severe hypertriglyceridemia may cause acute pancreatitis, with pancreatitis events “up to 29% in affected women” in one series. (fernandezpombo2023clinicalspectrumof pages 10-11)

In the Brazilian cohort: severe hypertriglyceridemia (≥500 mg/dL) occurred in 34.9%, and pancreatitis in 8.5%. (guidorizzi2024comprehensiveanalysisof pages 1-2)

Suggested HPO terms: - Hypertriglyceridemia (HP:0002155) - Low HDL cholesterol (HP:0003563) - Acute pancreatitis (HP:0001733)

Fatty liver disease

In the Brazilian cohort: metabolic-associated fatty liver disease (MAFLD) was 56.6%. (guidorizzi2024comprehensiveanalysisof pages 1-2)

Suggested HPO terms: - Hepatic steatosis (HP:0001397)

Cardiovascular disease and arrhythmia

FPLD2 review notes early atherosclerosis (reported before age 45), and arrhythmias more frequent with an odds ratio OR 3.77. (fernandezpombo2023clinicalspectrumof pages 10-11)

In the Brazilian cohort: cardiovascular disease (CVD) was 10.4%, and mortality was attributed to cardiovascular events. (guidorizzi2024comprehensiveanalysisof pages 1-2)

Suggested HPO terms: - Atherosclerosis (HP:0002633) - Arrhythmia (HP:0011675) - Hypertension (HP:0000822)

3.3 Reproductive/endocrine features

FPLD3 review reports PCOS in 58.2% of women among PPARG variant carriers. (soares2024familialpartiallipodystrophy pages 1-2)

Suggested HPO terms: - Polycystic ovary syndrome (HP:0000130) - Hyperandrogenism (HP:0000847) - Hirsutism (HP:0001007)

3.4 Pregnancy outcomes (FPLD2)

A retrospective study of pregnancies in women with FPLD2 (n=8 women; 17 pregnancies) reported: gestational diabetes 25%, preeclampsia 12.5%, miscarriages 11.8%, macrosomia 29.4%, plus prematurity and neonatal complications including two neonatal deaths (case-level). (tirthani2024mon045acase pages 1-1)

3.5 Quality of life impact

The prospective QuaLip study (lipodystrophy broadly) found psychiatric disorders diagnosed in 27.69% of adults (18/65 assessed), and clinically significant depressive symptoms (BDI >17) in 37.3% at baseline and 44.6% at final visit; >1/4 reported significant hunger, and physical appearance, fatigue, and pain were major contributors to burden. (demir2024impactoflipodystrophy pages 1-2, demir2024impactoflipodystrophy pages 5-8)

A registry analysis also reports psychosocial impact prevalence around 27% in partial and generalized lipodystrophy groups (27.3% vs 26.3%). (ceccarini2025epidemiologicalandclinical pages 13-13)

Suggested HPO terms: - Depressed mood (HP:0000716) - Anxiety (HP:0000739) - Hyperphagia (HP:0002591) - Fatigue (HP:0012378) - Pain (HP:0012531)

4. Genetic / molecular information

4.1 Causal genes (non-exhaustive from retrieved sources)

LMNA → FPLD2 (Dunnigan). (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3, mosbah2022dunniganlipodystrophysyndrome pages 1-2)
PPARG → FPLD3. (soares2024familialpartiallipodystrophy pages 1-2, kruger2024navigatinglipodystrophyinsights pages 8-9)
PLIN1 → FPLD4. (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7)
CIDEC → FPLD5. (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7)
LIPE → FPLD6. (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, magno2026casereportfamilial pages 5-7)
CAV1 → FPLD7. (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7)
MFN2 can be associated with partial lipodystrophy (rare). (guidorizzi2024comprehensiveanalysisof pages 1-2, brown2025theclinicalapproach pages 3-5)

4.2 Mechanistic genotype–phenotype anchors

FPLD2: classic forms frequently involve LMNA exon 8 codon 482 variants (e.g., R482W/R482Q). (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3)
In the Brazilian cohort, 58.2% of LMNA variants involved codon 482, and all deaths occurred among those with codon-482 variants (suggesting higher-risk subgroup, though causality cannot be established from a cross-sectional design). (guidorizzi2024comprehensiveanalysisof pages 3-5)

4.3 Modifier/protective genes and epigenetics

LMNA-driven disease is explicitly linked to chromatin/epigenetic regulation through disruption of lamina-associated chromatin domains and altered chromatin accessibility programs relevant to lipid metabolism and inflammatory signaling (see Mechanisms). (kruger2024navigatinglipodystrophyinsights pages 1-2, maung2026alteredlipidmetabolism pages 1-6)

Specific modifier genes affecting clinical expressivity were not explicitly identified in the retrieved excerpts.

5. Environmental information

No infectious etiology is implicated for familial partial lipodystrophy. Lifestyle factors are relevant primarily for management of metabolic consequences (diet, exercise, alcohol avoidance for pancreatitis risk) rather than disease causation. (fernandezpombo2023clinicalspectrumof pages 13-14)

6. Mechanism / pathophysiology (with causal chain, GO/CL suggestions)

6.1 Unifying pathophysiologic concept

Across FPLD subtypes, the core downstream problem is adipose tissue dysfunction and reduced capacity to store triglycerides in subcutaneous depots, promoting ectopic lipid deposition, insulin resistance, and multi-organ metabolic disease. This is emphasized in reviews of FPLD and lipodystrophic laminopathies. (fernandezpombo2023clinicalspectrumof pages 7-9, kruger2024navigatinglipodystrophyinsights pages 4-5)

6.2 LMNA-associated FPLD2 (Dunnigan): nuclear lamina → adipocyte loss → metabolic disease

Upstream trigger: LMNA pathogenic variants (commonly codon 482) affecting lamin A/C biology. (diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3, kruger2024navigatinglipodystrophyinsights pages 1-2)

Proposed chain: 1) LMNA mutations can cause toxic accumulation of permanently farnesylated prelamin A and disrupt nuclear lamina structure. (kruger2024navigatinglipodystrophyinsights pages 12-14) 2) Lamin A/C normally binds large lamina-associated domains (LADs); variants (e.g., R482W) perturb lamin–chromatin interactions essential for differentiation (including adipogenesis), leading to altered gene regulation. (kruger2024navigatinglipodystrophyinsights pages 1-2) 3) Multi-omics data in FPLD2 adipose tissue and models identify suppression of lipid metabolism and mitochondrial pathways with increased inflammation, and show adipocytes that “shrank and disappeared” in adipocyte-specific Lmna knockout mice, supporting a cell-autonomous requirement for lamin A/C in adipocyte maintenance. (maung2026alteredlipidmetabolism pages 6-11, maung2026alteredlipidmetabolism pages 1-6) 4) Downstream systemic effects include insulin resistance, hypertriglyceridemia, fatty liver disease, and cardiovascular risk. (fernandezpombo2023clinicalspectrumof pages 10-11, guidorizzi2024comprehensiveanalysisof pages 1-2)

Key molecular programs: - Chromatin organization / enhancer accessibility (maung2026alteredlipidmetabolism pages 1-6) - Lipogenesis impairment (reduced ChREBP and lipogenic enzymes) and mitochondrial OXPHOS dysfunction (maung2026alteredlipidmetabolism pages 15-19) - Intrinsic inflammatory transcription (Il6, Il1b, Nlrp3, Tnfa) without early macrophage expansion in some models (maung2026alteredlipidmetabolism pages 15-19)

Suggested GO Biological Process terms (examples): - Chromatin organization (GO:0006325) - Regulation of transcription, DNA-templated (GO:0006355) - Adipocyte differentiation (GO:0045444) - Lipid metabolic process (GO:0006629) - Mitochondrial respiratory chain complex I biogenesis / oxidative phosphorylation (GO:0006119) - Inflammatory response (GO:0006954) - Extracellular matrix organization / fibrosis programs (based on ECM/fibrosis signals) (maung2026alteredlipidmetabolism pages 6-11)

Suggested Cell Ontology (CL) terms: - Adipocyte (CL:0000136) - Adipose stromal cell / adipose stem and progenitor cell (ASPC; as described in single-nucleus RNA-seq) (maung2026alteredlipidmetabolism pages 6-11) - Fibroblast (CL:0000057) (maung2026alteredlipidmetabolism pages 6-11) - Macrophage (CL:0000235) (kruger2024navigatinglipodystrophyinsights pages 4-5)

6.3 PPARG-associated FPLD3: impaired adipogenesis and lipid storage

PPARG encodes PPARγ, described as a master regulator of adipogenesis; loss-of-function pathogenic PPARG variants reduce PPARγ activity, leading to defective adipocyte differentiation and a severe metabolic phenotype. (soares2024familialpartiallipodystrophy pages 1-2)

Abstract support (direct quote): “Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3).” (Soares et al., 2024; Frontiers in Endocrinology; 2024‑09; https://doi.org/10.3389/fendo.2024.1394102) (soares2024familialpartiallipodystrophy pages 1-2)

Suggested GO terms: - Fat cell differentiation / adipogenesis (GO:0045444) - Regulation of lipid storage (GO:0010883) - Regulation of insulin secretion / insulin sensitivity pathways (downstream phenotype)

7. Anatomical structures affected (UBERON suggestions)

Primary tissues/organs: - Subcutaneous adipose tissue depots (limbs, gluteofemoral) and visceral/neck depots (relative accumulation). (fernandezpombo2023clinicalspectrumof pages 3-5, fossfreitas2025lipodystrophysyndromesone pages 7-8) - Liver (steatosis/MAFLD). (guidorizzi2024comprehensiveanalysisof pages 1-2) - Cardiovascular system (early atherosclerosis, arrhythmias). (fernandezpombo2023clinicalspectrumof pages 10-11) - Pancreas (pancreatitis from severe hypertriglyceridemia). (fernandezpombo2023clinicalspectrumof pages 10-11) - Reproductive organs/endocrine axis (PCOS/hyperandrogenism). (soares2024familialpartiallipodystrophy pages 1-2)

Suggested UBERON terms (examples): - Subcutaneous adipose tissue (UBERON:0002190) - Visceral adipose tissue (UBERON:0010414) - Liver (UBERON:0002107) - Pancreas (UBERON:0001264) - Heart (UBERON:0000948) - Ovary (UBERON:0000992)

8. Temporal development

FPLD2: onset typically around puberty in women; later in men. (fernandezpombo2023clinicalspectrumof pages 3-5)
In a national French reference-center analysis (FPLD2 subgroup), first signs occurred at median age 19.3 years (IQR 14.4–27.8) with a median diagnostic delay 10.5 years (IQR 1.8–27.0). (donadille2024diagnosticandreferral pages 1-2)

9. Inheritance and population

9.1 Inheritance

FPLD genetic forms are typically autosomal dominant (LMNA, PPARG, PLIN1, etc.), while some subtypes are autosomal recessive (CIDEC/FPLD5; LIPE/FPLD6). (guidorizzi2024comprehensiveanalysisof pages 1-2, brown2025theclinicalapproach pages 3-5)

9.2 Epidemiology and underdiagnosis

Prevalence estimates (non-HIV lipodystrophy; partial lipodystrophy): - A systematic review reports partial lipodystrophy prevalence around 1.7–2.8 per million and gives a genomic estimate of pathogenic variant carrier prevalence for autosomal dominant FPLD of ~1 in 7588. (fernandezpombo2023clinicalspectrumof pages 3-5) - Spain cohort estimated prevalence of all (non-HIV) lipodystrophies in Spain (excluding Köbberling) at 2.78 per million. (fernandezpombo2023naturalhistoryand pages 1-2)

Registry/care-pathway evidence of diagnostic delay (recent): - France PRISIS reference-center: median diagnostic delay across syndromes 6.4 years; for FPLD2 specifically 10.5 years. (donadille2024diagnosticandreferral pages 1-2)

ECLip registry (2025): - FPLD was the most common subtype 57.4%; FPLD2 comprised 37.9% of the whole registry. (ceccarini2025epidemiologicalandclinical pages 1-2) - Metabolic complications were common: dyslipidemia 59.0%, diabetes 48.4% (all lipodystrophy). (ceccarini2025epidemiologicalandclinical pages 1-2)

10. Diagnostics

10.1 Clinical suspicion criteria (Brazilian expert consensus, 2025)

A Brazilian expert consensus proposes clinical suspicion requiring: - Mandatory criterion: “lipoatrophy in the lower limbs” - plus ≥1 associated condition: “hypertriglyceridemia and/or low HDL, diabetes mellitus, impaired fasting glucose or glucose intolerance, metabolic-associated steatosis liver disease, early coronary atherosclerotic disease, acanthosis nigricans, and polycystic ovary syndrome.” (valerio2025brazilianexpertconsensus pages 1-2)

For diagnosis confirmation, the consensus suggests combinations of the mandatory criterion plus major/minor criteria or a positive genetic test together with the mandatory criterion. (valerio2025brazilianexpertconsensus pages 1-2)

10.2 Anthropometry and imaging aids

Suggested supportive thresholds include: - Anterior thigh skinfold: <22 mm (women) and <10 mm (men) (proposed as diagnostic/supportive). (valerio2025brazilianexpertconsensus pages 2-4, gilio2025clinicalguidancefor pages 3-4) - DXA: lower-limb fat ≤1st percentile (women) and diagnostic performance reports including sensitivity 1.0 and specificity 0.995 in one study; fat mass ratio (FMR = trunk/lower-limb fat) cut-off ~1.2 suggested. (fernandezpombo2023clinicalspectrumof pages 7-9)

10.3 Laboratory evaluation and exclusion of secondary causes

Brazilian consensus recommends metabolic characterization and exclusion testing including lipid profile, fasting glucose/HbA1c (±OGTT), CBC/platelets, liver tests with fibrosis risk stratification (FIB-4), and evaluation for secondary causes such as HIV and complement testing (C3, C4, CH50), plus endocrine tests when indicated (Cushing’s testing; IGF-1 for acromegaly). (valerio2025brazilianexpertconsensus pages 4-5, valerio2025brazilianexpertconsensus pages 2-4)

10.4 Genetic testing strategy

A 2025 clinical guidance review emphasizes that diagnosis uses history/phenotype plus metabolic complications and imaging, and that genetic testing via multi-gene panels (LMNA, PPARG, PLIN1, CIDEC, MFN2, etc.) and WES/WGS can be efficient in undiagnosed/complex cases; cascade testing is recommended for relatives. (gilio2025clinicalguidancefor pages 3-4, valerio2025brazilianexpertconsensus pages 4-5)

Clinical resource note (France): A national protocol (PNDS) exists for Dunnigan/FPLD2 and states that “molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations” (abstract). (mosbah2022dunniganlipodystrophysyndrome pages 1-2)

11. Outcome / prognosis

11.1 Complications and mortality (recent cohort)

In the Brazilian cohort (n=106 genetically confirmed FPLD): - CVD: 10.4% - Pancreatitis: 8.5% - MAFLD: 56.6% - Overall mortality: 3.8%, attributed to cardiovascular events - LMNA codon-482 variants: 58.2% of LMNA variants; all deaths were in codon‑482 carriers (guidorizzi2024comprehensiveanalysisof pages 1-2, guidorizzi2024comprehensiveanalysisof pages 3-5)

11.2 Registry-level survival differences

In the ECLip registry, 34 deaths were documented; generalized forms had earlier death than partial forms (median age at death 27.0 vs 72.0 years). (ceccarini2025epidemiologicalandclinical pages 1-2)

12. Treatment

12.1 Standard metabolic management (real-world practice)

A systematic review of FPLD2 summarizes typical management including diet and exercise, metformin as first-line therapy for hyperglycemia, statins first-line for dyslipidemia, and fibrates/omega‑3 for TG >500 mg/dL. (fernandezpombo2023clinicalspectrumof pages 13-14)

Dietary macronutrient guidance (from review summarizing multisociety guidance): 50–60% carbohydrate, 20–30% fat, ~20% protein; reduced simple sugars/fat and alcohol abstinence may help, and exercise is encouraged after cardiac evaluation. (fernandezpombo2023clinicalspectrumof pages 13-14)

Suggested MAXO terms (examples): - Dietary modification therapy (MAXO:0000082) - Exercise therapy (MAXO:0000064) - Metformin therapy (MAXO term for metformin administration) - Statin therapy (MAXO term) - Fibrate therapy (MAXO term)

12.2 Leptin replacement: metreleptin

Metreleptin is described as a major breakthrough for generalized lipodystrophy, with more variable efficacy in partial forms; early trials enrolled hypoleptinemic subjects (females <4 ng/dL, males <3 ng/mL). (gilio2025clinicalguidancefor pages 7-8)

A systematic review reports metreleptin associated with lower triglycerides and HbA1c in aggregated lipodystrophy and partial lipodystrophy (n=71 in partial). (semple2023systematicreviewof pages 1-5)

A review of FPLD2 reports, in small numbers of Dunnigan patients, triglyceride reductions (e.g., 65% at 4 months in six patients) and improvements in insulin sensitivity, but inconsistent HbA1c effects across studies; predictive biomarkers for response are not established. (fernandezpombo2023clinicalspectrumof pages 13-14)

Clinical trial / program implementation (registry): Compassionate use of metreleptin in partial lipodystrophy is registered as NCT02262806. (NCT02262806 chunk 2)

Suggested MAXO terms: leptin replacement therapy; metreleptin administration.

12.3 GLP-1 receptor agonists (notable 2024 development)

A 2024 Diabetes Care retrospective study in 14 FPLD patients reported at 6 months after GLP‑1RA initiation: - Weight: 95 ± 23 → 91 ± 22 kg (P=0.002) - BMI: 33 ± 6 → 31 ± 6 kg/m² (P=0.001) - HbA1c: 8.2 ± 1.4% → 7.7 ± 1.4% (P≈0.02) - Fasting glucose: 186 ± 64 → 166 ± 53 mg/dL (P≈0.04) - Triglycerides: 334.1 ± 170 → 256 ± 81 mg/dL (16.7% reduction) - Safety: no pancreatitis during the initial 6‑month observation, but two patients developed acute pancreatitis within the following 12 months on longer therapy; both had prior pancreatitis history. (fossfreitas2024efficacyandsafety pages 1-3, fossfreitas2024efficacyandsafety pages 3-4)

Suggested MAXO terms: GLP‑1 receptor agonist therapy.

12.4 Targeting severe hypertriglyceridemia: ApoC-III and ANGPTL3 pathways

Volanesorsen (ApoC-III antisense): Reviews report large triglyceride reductions in FPLD, including ~88% TG reduction at 3 months and hepatic fat reduction in a 40-subject FPLD study context. (fernandezpombo2023clinicalspectrumof pages 13-14, gilio2025clinicalguidancefor pages 8-10)

BROADEN trial registry record: NCT02527343 (Phase 2/3; randomized, double-blind, placebo-controlled with open-label extension) tested weekly 300 mg SC volanesorsen for 52 weeks; primary endpoint was percent TG change at month 3; study terminated early after sufficient data were collected; enrollment 40; results posted 2021‑10‑18. (NCT02527343 chunk 1)

Vupanorsen (ANGPTL3 inhibition): A review reports a 59.9% fasting triglyceride reduction in four FPLD patients. (fernandezpombo2023clinicalspectrumof pages 13-14)

Suggested MAXO terms: antisense oligonucleotide therapy; triglyceride-lowering therapy.

12.5 Investigational leptin receptor agonism

A clinical guidance review summarizes a leptin-receptor agonist antibody program (REGN4461) with good tolerability and “promising results” in leptin-deficient patients, with a partial lipodystrophy trial listed as NCT05088460 (terminated) and additional programs noted. (gilio2025clinicalguidancefor pages 7-8)

13. Prevention

13.1 Primary prevention

Primary prevention of germline FPLD is not generally feasible without reproductive planning, but family-based risk reduction strategies apply.

13.2 Secondary/tertiary prevention (complication prevention)

Cascade screening/testing: Brazilian consensus recommends genetic testing for individuals meeting suspicion criteria and relatives of clinically/genetically affected patients (cascade screening). (valerio2025brazilianexpertconsensus pages 4-5)
Early cardiometabolic surveillance: Given high rates of diabetes, severe hypertriglyceridemia, fatty liver and cardiovascular disease in cohorts, systematic screening for these complications is essential. (guidorizzi2024comprehensiveanalysisof pages 1-2, valerio2025brazilianexpertconsensus pages 4-5)
Reproductive counseling: FPLD2 pregnancy series highlighted fetal complications and emphasized effective contraception to plan pregnancies when metabolic comorbidities are optimized. (tirthani2024mon045acase pages 1-1)

Suggested MAXO terms: genetic counseling; cascade genetic testing; cardiovascular risk monitoring; liver disease screening.

14. Other species / natural disease

No naturally occurring veterinary FPLD analogs were identified in the retrieved sources. (Not available from current evidence.)

15. Model organisms

A multi-omics mechanistic study reports that adipocyte loss/inflammation/lipid metabolic suppression signatures in human FPLD2 adipose were mirrored in tamoxifen-inducible adipocyte-specific Lmna-knockout mice, where lamin A/C–deficient adipocytes “shrank and disappeared,” supporting a causal role for LMNA in adipocyte maintenance and providing an experimental disease model. (maung2026alteredlipidmetabolism pages 6-11)

Model limitations: The extent to which mouse depots and endocrine phenotypes replicate the sex-specific and puberty-linked onset in human FPLD2 is not established in the retrieved excerpt.

Visual evidence from a key 2023 systematic review

A 2023 systematic review includes a table and figures summarizing FPLD2 clinical spectrum and diagnostic imaging features (DXA-based patterns). (fernandezpombo2023clinicalspectrumof media da405135, fernandezpombo2023clinicalspectrumof media 983292a0, fernandezpombo2023clinicalspectrumof media 6e575424)

Summary table (subtypes, genes, complications)

FPLD subtype	Main gene(s)	Usual inheritance	Typical onset	Hallmark fat distribution	Key metabolic/systemic complications	Quantitative data from available evidence	Main citation IDs
FPLD2 (Dunnigan disease)	LMNA	Usually autosomal dominant	During or around puberty; sometimes before puberty; later in men in some series	Progressive loss of subcutaneous fat from limbs, buttocks, and trunk with relative accumulation in face, neck/supraclavicular region, mons pubis, and intra-abdominal depots; muscular appearance; prominent veins; “Dunnigan sign” may be present	Insulin resistance, diabetes, hypertriglyceridemia/dyslipidemia, pancreatitis, MASLD/MAFLD, hypertension, early atherosclerotic CVD/arrhythmias, hyperandrogenism/PCOS in women	In Brazilian FPLD cohort, LMNA accounted for 85.8% of genetically confirmed cases; overall cohort: diabetes 57.5%, severe hypertriglyceridemia 34.9%, pancreatitis 8.5%, MAFLD 56.6%, CVD 10.4%, mortality 3.8%; in FPLD2 review, diabetes 28–51% overall, 54% in women vs 17% in men; dyslipidemia 59–89%; lipomas about 20%; lower-limb fat ≤1st percentile on DXA in women had sensitivity 1.0 and specificity 0.995 in one diagnostic study (guidorizzi2024comprehensiveanalysisof pages 3-5, fernandezpombo2023clinicalspectrumof pages 10-11, fernandezpombo2023clinicalspectrumof pages 3-5, fernandezpombo2023clinicalspectrumof pages 7-9)	(diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3, guidorizzi2024comprehensiveanalysisof pages 3-5, fernandezpombo2023clinicalspectrumof pages 10-11, fernandezpombo2023clinicalspectrumof pages 3-5, fernandezpombo2023clinicalspectrumof pages 7-9)
FPLD3	PPARG	Usually autosomal dominant (loss-of-function)	Early adulthood; mean lipoatrophy onset about 21 y, diagnosis about 33 y	Selective fat loss, often less pronounced than FPLD2; typically buttocks/lower limbs with relative accumulation in abdomen/neck	Severe insulin resistance phenotype with hypertriglyceridemia, diabetes, hypertension, PCOS, fatty liver/MASLD	Review of 91 patients / 41 PPARG variants: hypertriglyceridemia 91.9%, diabetes 77%, hypertension 59.5%, PCOS 58.2% of women, MASLD 87.5%; in Brazilian FPLD cohort, PPARG accounted for 10.4% of cases and diabetes was reported in about 73% of PPARG cases (soares2024familialpartiallipodystrophy pages 1-2, guidorizzi2024comprehensiveanalysisof pages 3-5)	(soares2024familialpartiallipodystrophy pages 1-2, guidorizzi2024comprehensiveanalysisof pages 3-5)
FPLD4	PLIN1	Monogenic; inheritance not detailed in provided evidence	Childhood in review-level summary	Partial lipodystrophy; detailed depot pattern not provided in retrieved evidence	Metabolic complications can occur, but subtype-specific profile is not detailed in provided evidence	In Brazilian cohort, PLIN1 accounted for 2.8% (3/106) of genetically confirmed FPLD; diabetes reported in 67% of these few cases, but sample size is very small (guidorizzi2024comprehensiveanalysisof pages 3-5, guidorizzi2024comprehensiveanalysisof pages 1-2)	(diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, fossfreitas2025lipodystrophysyndromesone pages 7-8, guidorizzi2024comprehensiveanalysisof pages 3-5, guidorizzi2024comprehensiveanalysisof pages 1-2)
FPLD5	CIDEC	Autosomal recessive	Childhood in review-level summary	Partial lipodystrophy; specific fat-loss pattern not detailed in provided evidence	Metabolic complications expected in lipodystrophy, but subtype-specific frequencies not available here	No quantitative subtype-specific clinical series retrieved in the provided evidence; gene–subtype association established (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, fossfreitas2025lipodystrophysyndromesone pages 7-8, brown2025theclinicalapproach pages 3-5)	(diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, fossfreitas2025lipodystrophysyndromesone pages 7-8, brown2025theclinicalapproach pages 3-5)
FPLD6	LIPE	Autosomal recessive / biallelic	Early adulthood in review-level summary	Partial lipodystrophy with distinctive redistribution pattern in reported cases; full canonical depot pattern not well quantified in provided evidence	Metabolic disturbances reported; some cases with distinctive non-LMNA phenotype	Evidence in provided set is limited mainly to case-level data; one reported patient had homozygous LIPE frameshift p.Val1068GlyfsTer102; broader frequency estimates unavailable (magno2026casereportfamilial pages 1-2, magno2026casereportfamilial pages 5-7)	(magno2026casereportfamilial pages 1-2, fossfreitas2025lipodystrophysyndromesone pages 7-8, brown2025theclinicalapproach pages 3-5, magno2026casereportfamilial pages 5-7)
FPLD7	CAV1	Monogenic; inheritance not detailed in provided evidence	Not available from provided evidence	Partial lipodystrophy; detailed depot pattern not provided in retrieved evidence	Limited subtype-specific data in provided evidence	Gene–subtype mapping available, but no quantitative cohort or phenotype-frequency data retrieved (diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, fossfreitas2025lipodystrophysyndromesone pages 7-8)	(diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7, fossfreitas2025lipodystrophysyndromesone pages 7-8)
MFN2-associated partial lipodystrophy	MFN2	Not detailed in provided evidence	Not available from provided evidence	Partial lipodystrophy reported in rare cases; specific depot pattern not detailed here	Diabetes/metabolic disease may occur	Brazilian cohort identified 1/106 (0.9%) with MFN2; that single case had diabetes mellitus; broader phenotype/frequency data not available (guidorizzi2024comprehensiveanalysisof pages 3-5, guidorizzi2024comprehensiveanalysisof pages 1-2)	(guidorizzi2024comprehensiveanalysisof pages 3-5, guidorizzi2024comprehensiveanalysisof pages 1-2, brown2025theclinicalapproach pages 3-5)

Table: This table summarizes the major familial partial lipodystrophy subtypes, their genes, onset patterns, fat-distribution phenotypes, and key complications. It highlights where quantitative evidence is available and where current evidence remains limited for rarer subtypes.

High-priority 2023–2024 developments highlighted

1) Large contemporary cohort data on genetically confirmed FPLD (Brazil, 2024; n=106) quantifying complication burden and gene distribution. (guidorizzi2024comprehensiveanalysisof pages 1-2, guidorizzi2024comprehensiveanalysisof pages 3-5) 2) GLP‑1 receptor agonists in FPLD: quantitative 6‑month improvements and pancreatitis safety signal in longer follow-up. (fossfreitas2024efficacyandsafety pages 1-3, fossfreitas2024efficacyandsafety pages 3-4) 3) Care-pathway evidence of diagnostic delay (France national reference center, 2024) reinforcing need for earlier recognition and cascade testing. (donadille2024diagnosticandreferral pages 1-2) 4) Quality-of-life/psychiatric burden quantified prospectively (QuaLip, 2024). (demir2024impactoflipodystrophy pages 1-2, demir2024impactoflipodystrophy pages 5-8)

URLs and publication dates (selected key sources)

Fernandez‑Pombo et al. Cells (Systematic review of FPLD2). 2023‑02. https://doi.org/10.3390/cells12050725 (fernandezpombo2023clinicalspectrumof pages 7-9)
Soares et al. Frontiers in Endocrinology (PPARG/FPLD3 review). 2024‑09. https://doi.org/10.3389/fendo.2024.1394102 (soares2024familialpartiallipodystrophy pages 1-2)
Guidorizzi et al. Frontiers in Endocrinology (Brazilian cohort). 2024‑06. https://doi.org/10.3389/fendo.2024.1359211 (guidorizzi2024comprehensiveanalysisof pages 1-2)
Foss‑Freitas et al. Diabetes Care (GLP‑1RA in FPLD). 2024‑02. https://doi.org/10.2337/dc23-1614 (fossfreitas2024efficacyandsafety pages 1-3)
Donadille et al. Orphanet Journal of Rare Diseases (France PRISIS referral pathways). 2024‑04. https://doi.org/10.1186/s13023-024-03173-2 (donadille2024diagnosticandreferral pages 1-2)
Demir et al. Orphanet Journal of Rare Diseases (QuaLip). 2024‑01. https://doi.org/10.1186/s13023-023-03004-w (demir2024impactoflipodystrophy pages 1-2)
Mosbah et al. Orphanet Journal of Rare Diseases (FPLD2 PNDS). 2022‑04. https://doi.org/10.1186/s13023-022-02308-7 (mosbah2022dunniganlipodystrophysyndrome pages 1-2)
ClinicalTrials.gov: Volanesorsen BROADEN NCT02527343 (record created 2015; results posted 2021‑10‑18). https://clinicaltrials.gov/study/NCT02527343 (NCT02527343 chunk 1)
ClinicalTrials.gov: Metreleptin compassionate use NCT02262806 (record created 2014). https://clinicaltrials.gov/study/NCT02262806 (NCT02262806 chunk 2)

Key gaps (from retrieved evidence)

MONDO and MeSH identifiers for FPLD were not explicitly present in retrieved excerpts; confirm via MONDO/MeSH/Orphanet/OMIM database queries in a follow-on curation pass.
Variant-level penetrance, founder effects, and carrier frequencies by ancestry were limited in retrieved excerpts; additional population-genetic studies (e.g., biobank-based genotype-first analyses) would strengthen these sections.
Rarer FPLD subtypes (PLIN1/CAV1/CIDEC/LIPE): limited quantitative natural history data were available in the retrieved corpus.

References

(soares2024familialpartiallipodystrophy pages 1-2): Reivla Marques Vasconcelos Soares, Monique Alvares da Silva, Julliane Tamara Araújo de Melo Campos, and Josivan Gomes Lima. Familial partial lipodystrophy resulting from loss-of-function pparγ pathogenic variants: phenotypic, clinical, and genetic features. Frontiers in Endocrinology, Sep 2024. URL: https://doi.org/10.3389/fendo.2024.1394102, doi:10.3389/fendo.2024.1394102. This article has 14 citations.
(fernandezpombo2023clinicalspectrumof pages 3-5): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(fossfreitas2025lipodystrophysyndromesone pages 7-8): Maria Foss-Freitas, Donatella Gilio, and Elif A. Oral. Lipodystrophy syndromes: one name but many diseases highlighting the importance of adipose tissue in metabolism. Current Diabetes Reports, Aug 2025. URL: https://doi.org/10.1007/s11892-025-01602-5, doi:10.1007/s11892-025-01602-5. This article has 6 citations and is from a peer-reviewed journal.
(diazlopez2024lipodystrophiclaminopathiesfrom pages 2-3): Everardo Josué Díaz-López, Sofía Sánchez-Iglesias, Ana I. Castro, Silvia Cobelo-Gómez, Teresa Prado-Moraña, David Araújo-Vilar, and Antia Fernandez-Pombo. Lipodystrophic laminopathies: from dunnigan disease to progeroid syndromes. International Journal of Molecular Sciences, 25:9324, Aug 2024. URL: https://doi.org/10.3390/ijms25179324, doi:10.3390/ijms25179324. This article has 3 citations.
(fernandezpombo2023clinicalspectrumof pages 7-9): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(mosbah2022dunniganlipodystrophysyndrome pages 1-2): H. Mosbah, B. Donadille, C. Vatier, S. Janmaat, M. Atlan, C. Badens, P. Barat, S. Béliard, J. Beltrand, R. Ben Yaou, E. Bismuth, F. Boccara, B. Cariou, M. Chaouat, G. Charriot, S. Christin-Maitre, M. De Kerdanet, B. Delemer, E. Disse, N. Dubois, B. Eymard, B. Fève, O. Lascols, P. Mathurin, E. Nobécourt, A. Poujol-Robert, G. Prevost, P. Richard, J. Sellam, I. Tauveron, D. Treboz, B. Vergès, V. Vermot-Desroches, K. Wahbi, I. Jéru, M. C. Vantyghem, and C. Vigouroux. Dunnigan lipodystrophy syndrome: french national diagnosis and care protocol (pnds; protocole national de diagnostic et de soins). Orphanet Journal of Rare Diseases, Apr 2022. URL: https://doi.org/10.1186/s13023-022-02308-7, doi:10.1186/s13023-022-02308-7. This article has 35 citations and is from a peer-reviewed journal.
(gonzagajauregui2020clinicalandmolecular pages 1-2): Claudia Gonzaga-Jauregui, Wenzhen Ge, Jeffrey Staples, Cristopher Van Hout, Ashish Yadav, Ryan Colonie, Joseph B. Leader, H. Lester Kirchner, Michael F. Murray, Jeffrey G. Reid, David J. Carey, John D. Overton, Alan R. Shuldiner, Omri Gottesman, Steve Gao, Jesper Gromada, Aris Baras, and Judith Altarejos. Clinical and molecular prevalence of lipodystrophy in an unascertained large clinical care cohort. Diabetes, 69:249-258, Dec 2020. URL: https://doi.org/10.2337/db19-0447, doi:10.2337/db19-0447. This article has 109 citations and is from a highest quality peer-reviewed journal.
(kruger2024navigatinglipodystrophyinsights pages 8-9): Peter Krüger, Ramona Hartinger, and Karima Djabali. Navigating lipodystrophy: insights from laminopathies and beyond. International Journal of Molecular Sciences, 25:8020, Jul 2024. URL: https://doi.org/10.3390/ijms25158020, doi:10.3390/ijms25158020. This article has 14 citations.
(guidorizzi2024comprehensiveanalysisof pages 1-2): Natália Rossin Guidorizzi, Cynthia M. Valerio, Luiz F. Viola, Victor Rezende Veras, Virgínia Oliveira Fernandes, Grayce Ellen da Cruz Paiva Lima, Amanda Caboclo Flor, Jessica Silveira Araújo, Raquel Beatriz Gonçalves Muniz, Rodrigo Oliveira Moreira, Francisco José Albuquerque De Paula, Lenita Zajdenverg, Joana R. Dantas, Amélio F. Godoy-Matos, Renan Magalhães Montenegro Júnior, and Maria Cristina Foss-Freitas. Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study. Frontiers in Endocrinology, Jun 2024. URL: https://doi.org/10.3389/fendo.2024.1359211, doi:10.3389/fendo.2024.1359211. This article has 17 citations.
(guidorizzi2024comprehensiveanalysisof pages 3-5): Natália Rossin Guidorizzi, Cynthia M. Valerio, Luiz F. Viola, Victor Rezende Veras, Virgínia Oliveira Fernandes, Grayce Ellen da Cruz Paiva Lima, Amanda Caboclo Flor, Jessica Silveira Araújo, Raquel Beatriz Gonçalves Muniz, Rodrigo Oliveira Moreira, Francisco José Albuquerque De Paula, Lenita Zajdenverg, Joana R. Dantas, Amélio F. Godoy-Matos, Renan Magalhães Montenegro Júnior, and Maria Cristina Foss-Freitas. Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study. Frontiers in Endocrinology, Jun 2024. URL: https://doi.org/10.3389/fendo.2024.1359211, doi:10.3389/fendo.2024.1359211. This article has 17 citations.
(donadille2024diagnosticandreferral pages 1-2): Bruno Donadille, Sonja Janmaat, Héléna Mosbah, Inès Belalem, Sophie Lamothe, Mariana Nedelcu, Anne-Sophie Jannot, Sophie Christin-Maitre, Bruno Fève, Camille Vatier, and Corinne Vigouroux. Diagnostic and referral pathways in patients with rare lipodystrophy and insulin-resistance syndromes: key milestones assessed from a national reference center. Orphanet Journal of Rare Diseases, 19:1-10, Apr 2024. URL: https://doi.org/10.1186/s13023-024-03173-2, doi:10.1186/s13023-024-03173-2. This article has 9 citations and is from a peer-reviewed journal.
(ceccarini2025epidemiologicalandclinical pages 1-2): Giovanni Ceccarini, Camille Vatier, Baris Akinci, Ines Belalem, Marjoleine Broekema, Eva Csajbok, Maria Rosaria D'Apice, Alessandra Gambineri, Kathrin Heldt, Martin Heni, Lotte Kleinendorst, Kerstin Krause, Giovanna Lattanzi, Konstanze Miehle, Lavinia Palladino, Flavia Prodam, Ferruccio Santini, Ermelinda Santos Silva, David B Savage, Paolo Sbraccia, Thomas Scherer, Ekaterina Sorkina, Iztok Štotl, Marie-Christine Vantyghem, Corinne Vigouroux, Elena Vorona, David Araújo-Vilar, Martin Wabitsch, Gabriele Nagel, Julia von Schnurbein, Carolina Cerchetti, Laura Rotolo, Roza Sabia, Gisa Ufer, Marianna Beghini, Hippolyte Dupuis, Elaine Withers, Anna Stears, Héléna Mosbah, Sophie Lamothe, Bruno Donadille, Sonja Janmaat, Martina Romanisio, Silvia Magno, Donatella Gilio, and Giuseppe Novelli. Epidemiological and clinical data from the european lipodystrophy registry. European Journal of Endocrinology, 193:585-603, Oct 2025. URL: https://doi.org/10.1093/ejendo/lvaf214, doi:10.1093/ejendo/lvaf214. This article has 2 citations and is from a highest quality peer-reviewed journal.
(ceccarini2025epidemiologicalandclinical pages 9-10): Giovanni Ceccarini, Camille Vatier, Baris Akinci, Ines Belalem, Marjoleine Broekema, Eva Csajbok, Maria Rosaria D'Apice, Alessandra Gambineri, Kathrin Heldt, Martin Heni, Lotte Kleinendorst, Kerstin Krause, Giovanna Lattanzi, Konstanze Miehle, Lavinia Palladino, Flavia Prodam, Ferruccio Santini, Ermelinda Santos Silva, David B Savage, Paolo Sbraccia, Thomas Scherer, Ekaterina Sorkina, Iztok Štotl, Marie-Christine Vantyghem, Corinne Vigouroux, Elena Vorona, David Araújo-Vilar, Martin Wabitsch, Gabriele Nagel, Julia von Schnurbein, Carolina Cerchetti, Laura Rotolo, Roza Sabia, Gisa Ufer, Marianna Beghini, Hippolyte Dupuis, Elaine Withers, Anna Stears, Héléna Mosbah, Sophie Lamothe, Bruno Donadille, Sonja Janmaat, Martina Romanisio, Silvia Magno, Donatella Gilio, and Giuseppe Novelli. Epidemiological and clinical data from the european lipodystrophy registry. European Journal of Endocrinology, 193:585-603, Oct 2025. URL: https://doi.org/10.1093/ejendo/lvaf214, doi:10.1093/ejendo/lvaf214. This article has 2 citations and is from a highest quality peer-reviewed journal.
(NCT02527343 chunk 1): The BROADEN Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Partial Lipodystrophy. Akcea Therapeutics. 2015. ClinicalTrials.gov Identifier: NCT02527343
(NCT02262806 chunk 2): Compassionate Use of Metreleptin in Previously Treated People With Partial Lipodystrophy. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). 2014. ClinicalTrials.gov Identifier: NCT02262806
(kruger2024navigatinglipodystrophyinsights pages 12-14): Peter Krüger, Ramona Hartinger, and Karima Djabali. Navigating lipodystrophy: insights from laminopathies and beyond. International Journal of Molecular Sciences, 25:8020, Jul 2024. URL: https://doi.org/10.3390/ijms25158020, doi:10.3390/ijms25158020. This article has 14 citations.
(brown2025theclinicalapproach pages 3-5): Rebecca J. Brown, B. Akıncı, Saif Al Yaarubi, Elise Bismuth, Marco Cappa, Asma Deeb, Clemens Kamrath, Carla Musso, N. Patni, Flavia Prodam, Rachel Williams, and Martin Wabitsch. The clinical approach to child and adolescent patients with lipodystrophy: a series of international case discussions. Frontiers in Endocrinology, Aug 2025. URL: https://doi.org/10.3389/fendo.2025.1597053, doi:10.3389/fendo.2025.1597053. This article has 2 citations.
(diazlopez2024lipodystrophiclaminopathiesfrom pages 6-7): Everardo Josué Díaz-López, Sofía Sánchez-Iglesias, Ana I. Castro, Silvia Cobelo-Gómez, Teresa Prado-Moraña, David Araújo-Vilar, and Antia Fernandez-Pombo. Lipodystrophic laminopathies: from dunnigan disease to progeroid syndromes. International Journal of Molecular Sciences, 25:9324, Aug 2024. URL: https://doi.org/10.3390/ijms25179324, doi:10.3390/ijms25179324. This article has 3 citations.
(tirthani2024mon045acase pages 1-1): Ekta Tirthani and Richard D Siegel. Mon-045 a case of familial partial lipodystrophy type 2 with isolated hepatic steatosis. Journal of the Endocrine Society, Oct 2024. URL: https://doi.org/10.1210/jendso/bvae163.2293, doi:10.1210/jendso/bvae163.2293. This article has 0 citations and is from a peer-reviewed journal.
(magno2026casereportfamilial pages 5-7): Silvia Magno, Caterina Pelosini, Melania Paoli, Donatella Gilio, Lavinia Palladino, Francesca Menconi, Andrea Barison, Giancarlo Todiere, Simona Ortori, Barbara Coco, Giordano Paolucci, Guido Salvetti, Maria Rita Sessa, Giovanni Ceccarini, and Ferruccio Santini. Case report: familial partial lipodystrophy, description of novel and ultrarare variants with distinct phenotypic spectrum. Frontiers in Endocrinology, Mar 2026. URL: https://doi.org/10.3389/fendo.2026.1725771, doi:10.3389/fendo.2026.1725771. This article has 0 citations.
(fernandezpombo2023clinicalspectrumof pages 13-14): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(gilio2025clinicalguidancefor pages 8-10): Donatella Gilio, Maria Foss-Freitas, and Elif A. Oral. Clinical guidance for lipodystrophy syndromes: from diagnosis and work-up to treatment. Current Diabetes Reports, Sep 2025. URL: https://doi.org/10.1007/s11892-025-01603-4, doi:10.1007/s11892-025-01603-4. This article has 8 citations and is from a peer-reviewed journal.
(fernandezpombo2023clinicalspectrumof pages 10-11): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(demir2024impactoflipodystrophy pages 1-2): Tevfik Demir, Ilgin Yildirim Simsir, Ozlem Kuman Tuncel, Burcu Ozbaran, Ilker Yildirim, Sebnem Pirildar, Samim Ozen, and Baris Akinci. Impact of lipodystrophy on health-related quality of life: the qualip study. Orphanet Journal of Rare Diseases, Jan 2024. URL: https://doi.org/10.1186/s13023-023-03004-w, doi:10.1186/s13023-023-03004-w. This article has 11 citations and is from a peer-reviewed journal.
(demir2024impactoflipodystrophy pages 5-8): Tevfik Demir, Ilgin Yildirim Simsir, Ozlem Kuman Tuncel, Burcu Ozbaran, Ilker Yildirim, Sebnem Pirildar, Samim Ozen, and Baris Akinci. Impact of lipodystrophy on health-related quality of life: the qualip study. Orphanet Journal of Rare Diseases, Jan 2024. URL: https://doi.org/10.1186/s13023-023-03004-w, doi:10.1186/s13023-023-03004-w. This article has 11 citations and is from a peer-reviewed journal.
(ceccarini2025epidemiologicalandclinical pages 13-13): Giovanni Ceccarini, Camille Vatier, Baris Akinci, Ines Belalem, Marjoleine Broekema, Eva Csajbok, Maria Rosaria D'Apice, Alessandra Gambineri, Kathrin Heldt, Martin Heni, Lotte Kleinendorst, Kerstin Krause, Giovanna Lattanzi, Konstanze Miehle, Lavinia Palladino, Flavia Prodam, Ferruccio Santini, Ermelinda Santos Silva, David B Savage, Paolo Sbraccia, Thomas Scherer, Ekaterina Sorkina, Iztok Štotl, Marie-Christine Vantyghem, Corinne Vigouroux, Elena Vorona, David Araújo-Vilar, Martin Wabitsch, Gabriele Nagel, Julia von Schnurbein, Carolina Cerchetti, Laura Rotolo, Roza Sabia, Gisa Ufer, Marianna Beghini, Hippolyte Dupuis, Elaine Withers, Anna Stears, Héléna Mosbah, Sophie Lamothe, Bruno Donadille, Sonja Janmaat, Martina Romanisio, Silvia Magno, Donatella Gilio, and Giuseppe Novelli. Epidemiological and clinical data from the european lipodystrophy registry. European Journal of Endocrinology, 193:585-603, Oct 2025. URL: https://doi.org/10.1093/ejendo/lvaf214, doi:10.1093/ejendo/lvaf214. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kruger2024navigatinglipodystrophyinsights pages 1-2): Peter Krüger, Ramona Hartinger, and Karima Djabali. Navigating lipodystrophy: insights from laminopathies and beyond. International Journal of Molecular Sciences, 25:8020, Jul 2024. URL: https://doi.org/10.3390/ijms25158020, doi:10.3390/ijms25158020. This article has 14 citations.
(maung2026alteredlipidmetabolism pages 1-6): Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral, and Ormond A. MacDougald. Altered lipid metabolism and inflammatory programs associate with adipocyte loss in familial partial lipodystrophy 2. Journal of Clinical Investigation, Nov 2026. URL: https://doi.org/10.1172/jci198387, doi:10.1172/jci198387. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kruger2024navigatinglipodystrophyinsights pages 4-5): Peter Krüger, Ramona Hartinger, and Karima Djabali. Navigating lipodystrophy: insights from laminopathies and beyond. International Journal of Molecular Sciences, 25:8020, Jul 2024. URL: https://doi.org/10.3390/ijms25158020, doi:10.3390/ijms25158020. This article has 14 citations.
(maung2026alteredlipidmetabolism pages 6-11): Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral, and Ormond A. MacDougald. Altered lipid metabolism and inflammatory programs associate with adipocyte loss in familial partial lipodystrophy 2. Journal of Clinical Investigation, Nov 2026. URL: https://doi.org/10.1172/jci198387, doi:10.1172/jci198387. This article has 2 citations and is from a highest quality peer-reviewed journal.
(maung2026alteredlipidmetabolism pages 15-19): Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral, and Ormond A. MacDougald. Altered lipid metabolism and inflammatory programs associate with adipocyte loss in familial partial lipodystrophy 2. Journal of Clinical Investigation, Nov 2026. URL: https://doi.org/10.1172/jci198387, doi:10.1172/jci198387. This article has 2 citations and is from a highest quality peer-reviewed journal.
(fernandezpombo2023naturalhistoryand pages 1-2): Antía Fernández-Pombo, Sofía Sánchez-Iglesias, Ana I. Castro-Pais, Maria José Ginzo-Villamayor, Silvia Cobelo-Gómez, Teresa Prado-Moraña, Everardo Josué Díaz-López, Felipe F. Casanueva, Lourdes Loidi, and David Araújo-Vilar. Natural history and comorbidities of generalised and partial lipodystrophy syndromes in spain. Frontiers in Endocrinology, Nov 2023. URL: https://doi.org/10.3389/fendo.2023.1250203, doi:10.3389/fendo.2023.1250203. This article has 24 citations.
(valerio2025brazilianexpertconsensus pages 1-2): Cynthia Melissa Valerio, Luiz F. Viola, Natália Rossin Guidorizzi, Josivan Gomes Lima, Amélio F. Godoy-Matos, Alexandre Hohl, Fabio R. Trujilho, Joana R. Dantas, Julliane Tamara Araújo de Melo Campos, Lenita Zajdenverg, Raquel Beatriz Gonçalves Muniz, Rodrigo Oliveira Moreira, Virgínia Oliveira Fernandes, Maria Cristina Foss-Freitas, and Renan Montenegro. Brazilian expert consensus on the diagnosis, classification, screening for complications and treatment of familial partial lipodystrophy. Diabetology & Metabolic Syndrome, Jun 2025. URL: https://doi.org/10.1186/s13098-025-01733-5, doi:10.1186/s13098-025-01733-5. This article has 4 citations and is from a peer-reviewed journal.
(valerio2025brazilianexpertconsensus pages 2-4): Cynthia Melissa Valerio, Luiz F. Viola, Natália Rossin Guidorizzi, Josivan Gomes Lima, Amélio F. Godoy-Matos, Alexandre Hohl, Fabio R. Trujilho, Joana R. Dantas, Julliane Tamara Araújo de Melo Campos, Lenita Zajdenverg, Raquel Beatriz Gonçalves Muniz, Rodrigo Oliveira Moreira, Virgínia Oliveira Fernandes, Maria Cristina Foss-Freitas, and Renan Montenegro. Brazilian expert consensus on the diagnosis, classification, screening for complications and treatment of familial partial lipodystrophy. Diabetology & Metabolic Syndrome, Jun 2025. URL: https://doi.org/10.1186/s13098-025-01733-5, doi:10.1186/s13098-025-01733-5. This article has 4 citations and is from a peer-reviewed journal.
(gilio2025clinicalguidancefor pages 3-4): Donatella Gilio, Maria Foss-Freitas, and Elif A. Oral. Clinical guidance for lipodystrophy syndromes: from diagnosis and work-up to treatment. Current Diabetes Reports, Sep 2025. URL: https://doi.org/10.1007/s11892-025-01603-4, doi:10.1007/s11892-025-01603-4. This article has 8 citations and is from a peer-reviewed journal.
(valerio2025brazilianexpertconsensus pages 4-5): Cynthia Melissa Valerio, Luiz F. Viola, Natália Rossin Guidorizzi, Josivan Gomes Lima, Amélio F. Godoy-Matos, Alexandre Hohl, Fabio R. Trujilho, Joana R. Dantas, Julliane Tamara Araújo de Melo Campos, Lenita Zajdenverg, Raquel Beatriz Gonçalves Muniz, Rodrigo Oliveira Moreira, Virgínia Oliveira Fernandes, Maria Cristina Foss-Freitas, and Renan Montenegro. Brazilian expert consensus on the diagnosis, classification, screening for complications and treatment of familial partial lipodystrophy. Diabetology & Metabolic Syndrome, Jun 2025. URL: https://doi.org/10.1186/s13098-025-01733-5, doi:10.1186/s13098-025-01733-5. This article has 4 citations and is from a peer-reviewed journal.
(gilio2025clinicalguidancefor pages 7-8): Donatella Gilio, Maria Foss-Freitas, and Elif A. Oral. Clinical guidance for lipodystrophy syndromes: from diagnosis and work-up to treatment. Current Diabetes Reports, Sep 2025. URL: https://doi.org/10.1007/s11892-025-01603-4, doi:10.1007/s11892-025-01603-4. This article has 8 citations and is from a peer-reviewed journal.
(semple2023systematicreviewof pages 1-5): Robert K. Semple, Kashyap A. Pate, Sungyoung Auh, and Rebecca J. Brown. Systematic review of genotype-stratified treatment for monogenic insulin resistance. medRxiv, Apr 2023. URL: https://doi.org/10.1101/2023.04.17.23288671, doi:10.1101/2023.04.17.23288671. This article has 1 citations.
(fossfreitas2024efficacyandsafety pages 1-3): Maria C. Foss-Freitas, Salman Imam, Adam Neidert, Anabela Dill Gomes, David T. Broome, and Elif A. Oral. Efficacy and safety of glucagon-like peptide 1 agonists in a retrospective study of patients with familial partial lipodystrophy. Diabetes Care, 47:653-659, Feb 2024. URL: https://doi.org/10.2337/dc23-1614, doi:10.2337/dc23-1614. This article has 34 citations and is from a highest quality peer-reviewed journal.
(fossfreitas2024efficacyandsafety pages 3-4): Maria C. Foss-Freitas, Salman Imam, Adam Neidert, Anabela Dill Gomes, David T. Broome, and Elif A. Oral. Efficacy and safety of glucagon-like peptide 1 agonists in a retrospective study of patients with familial partial lipodystrophy. Diabetes Care, 47:653-659, Feb 2024. URL: https://doi.org/10.2337/dc23-1614, doi:10.2337/dc23-1614. This article has 34 citations and is from a highest quality peer-reviewed journal.
(fernandezpombo2023clinicalspectrumof media da405135): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(fernandezpombo2023clinicalspectrumof media 983292a0): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(fernandezpombo2023clinicalspectrumof media 6e575424): Antia Fernandez-Pombo, Everardo Josue Diaz-Lopez, Ana I. Castro, Sofia Sanchez-Iglesias, Silvia Cobelo-Gomez, Teresa Prado-Moraña, and David Araujo-Vilar. Clinical spectrum of lmna-associated type 2 familial partial lipodystrophy: a systematic review. Cells, 12:725, Feb 2023. URL: https://doi.org/10.3390/cells12050725, doi:10.3390/cells12050725. This article has 44 citations.
(magno2026casereportfamilial pages 1-2): Silvia Magno, Caterina Pelosini, Melania Paoli, Donatella Gilio, Lavinia Palladino, Francesca Menconi, Andrea Barison, Giancarlo Todiere, Simona Ortori, Barbara Coco, Giordano Paolucci, Guido Salvetti, Maria Rita Sessa, Giovanni Ceccarini, and Ferruccio Santini. Case report: familial partial lipodystrophy, description of novel and ultrarare variants with distinct phenotypic spectrum. Frontiers in Endocrinology, Mar 2026. URL: https://doi.org/10.3389/fendo.2026.1725771, doi:10.3389/fendo.2026.1725771. This article has 0 citations.

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13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Characteristics Report: Familial Partial Lipodystrophy (FPLD)

1. Disease information

1.1 Definition and overview

1.2 Key identifiers and coding (from retrieved sources)

1.3 Synonyms and alternative names

1.4 Evidence sources: patient-level vs aggregated

2. Etiology

2.1 Primary causes

2.2 Genetic risk factors (causal genes)

2.3 Pathogenic variant types/classes (examples from retrieved sources)

2.4 Environmental risk factors / protective factors

2.5 Gene–environment interactions

3. Phenotypes (with suggested HPO terms)

3.1 Core adipose distribution phenotype

3.2 Metabolic complications (frequency data)

Diabetes / insulin resistance

Dyslipidemia / hypertriglyceridemia / pancreatitis

Fatty liver disease

Cardiovascular disease and arrhythmia

3.3 Reproductive/endocrine features

3.4 Pregnancy outcomes (FPLD2)

3.5 Quality of life impact

4. Genetic / molecular information

4.1 Causal genes (non-exhaustive from retrieved sources)

4.2 Mechanistic genotype–phenotype anchors

4.3 Modifier/protective genes and epigenetics

5. Environmental information

6. Mechanism / pathophysiology (with causal chain, GO/CL suggestions)

6.1 Unifying pathophysiologic concept

6.2 LMNA-associated FPLD2 (Dunnigan): nuclear lamina → adipocyte loss → metabolic disease

6.3 PPARG-associated FPLD3: impaired adipogenesis and lipid storage

7. Anatomical structures affected (UBERON suggestions)

8. Temporal development

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology and underdiagnosis

10. Diagnostics

10.1 Clinical suspicion criteria (Brazilian expert consensus, 2025)

10.2 Anthropometry and imaging aids

10.3 Laboratory evaluation and exclusion of secondary causes

10.4 Genetic testing strategy

11. Outcome / prognosis

11.1 Complications and mortality (recent cohort)

11.2 Registry-level survival differences

12. Treatment

12.1 Standard metabolic management (real-world practice)