Familial partial lipodystrophy

Summary

Familial partial lipodystrophy (MONDO:0020088) is a disease (an umbrella term covering 10 Mondo subtypes) with 2 cohort genes and 12 clinical trials. Top therapeutic interventions include metreleptin, caffeine, and obeticholic acid.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 3
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial partial lipodystrophy
Mondo ID	MONDO:0020088
MeSH	D052496
OMIM	151660
Orphanet	98306
DOID	DOID:0050440
ICD-11	1661968243
NCIT	C84708
SNOMED CT	49292002
UMLS	C0271694
MedGen	124408
GARD	0011962
NORD	1131
Is cancer (heuristic)	no

Also known as: congenital partial lipodystrophy · FPLD · genetic partial lipodystrophy · lipodystrophy, familial partial

Data availability: 3 ClinVar variants.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › familial partial lipodystrophy

Related subtypes (10): congenital generalized lipodystrophy, lipodystrophy due to peptidic growth factors deficiency, Wiedemann-Rautenstrauch syndrome, SHORT syndrome, lipodystrophy-intellectual disability-deafness syndrome, Keppen-Lubinsky syndrome, severe neurodegenerative syndrome with lipodystrophy, lipoatrophy with diabetes, leukomelanodermic papules, liver steatosis, and hypertrophic cardiomyopathy, mandibuloacral dysplasia, Berardinelli-Seip congenital lipodystrophy

Subtypes (10): familial partial lipodystrophy, Dunnigan type, PPARG-related familial partial lipodystrophy, familial partial lipodystrophy, Kobberling type, PLIN1-related familial partial lipodystrophy, CIDEC-related familial partial lipodystrophy, LIPE-related familial partial lipodystrophy, autosomal semi-dominant severe lipodystrophic laminopathy, AKT2-related familial partial lipodystrophy, lipodystrophy, familial partial, type 8, lipodystrophy, familial partial, type 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14489	NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070305	NM_138711.6(PPARG):c.362A>G (p.Tyr121Cys)	PPARG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14517	NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 26 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1
PPARG	Orphanet:146	Differentiated thyroid carcinoma
PPARG	Orphanet:251576	Gliosarcoma
PPARG	Orphanet:251579	Giant cell glioblastoma
PPARG	Orphanet:696242	PPARG-associated congenital generalized lipodystrophy
PPARG	Orphanet:79083	PPARG-related familial partial lipodystrophy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
PPARG	HGNC:9236	ENSG00000132170	P37231	Peroxisome proliferator-activated receptor gamma	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
PPARG	Peroxisome proliferator-activated receptor gamma	Ligand-activated transcription factor that forms obligate heterodimers with the retinoic acid receptor and acts as a key regulator of biological processes, such as adipocyte differentiation, lipid metabolism, glucose homeostasis and beta-o…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	192.9×	0.010
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
PPARG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of stomach	1
nipple	1
skin of abdomen	1
adipose tissue of abdominal region	1
omental fat pad	1
peritoneum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
PPARG	194	ubiquitous	marker	omental fat pad, peritoneum, adipose tissue of abdominal region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPARG	7,747
LMNA	7,173

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPARG	P37231	380
LMNA	P02545	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Breakdown of the nuclear lamina	1	1903.3×	0.010	LMNA
MECP2 regulates transcription factors	1	1142.0×	0.010	PPARG
Depolymerization of the Nuclear Lamina	1	380.7×	0.014	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.014	LMNA
IRE1alpha activates chaperones	1	259.6×	0.014	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.014	LMNA
Nuclear Envelope Breakdown	1	228.4×	0.014	LMNA
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	190.3×	0.014	PPARG
Unfolded Protein Response (UPR)	1	178.4×	0.014	LMNA
SUMOylation of intracellular receptors	1	167.9×	0.014	PPARG
Oncogenic MAPK signaling	1	124.1×	0.017	LMNA
XBP1(S) activates chaperone genes	1	107.7×	0.018	LMNA
Nuclear Receptor transcription pathway	1	100.2×	0.018	PPARG
Regulation of PTEN gene transcription	1	89.2×	0.018	PPARG
Signaling by BRAF and RAF1 fusions	1	85.2×	0.018	LMNA
Meiotic synapsis	1	70.5×	0.020	LMNA
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.021	PPARG
PPARA activates gene expression	1	47.2×	0.027	PPARG
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.029	PPARG
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.040	LMNA
Cellular responses to stress	1	18.4×	0.059	LMNA
Cellular responses to stimuli	1	15.7×	0.065	LMNA
Disease	1	6.5×	0.147	LMNA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cardiac muscle hypertrophy in response to stress	2	1872.4×	2e-05	LMNA, PPARG
cellular response to hypoxia	2	121.2×	0.003	LMNA, PPARG
negative regulation of connective tissue replacement involved in inflammatory response wound healing	1	4213.0×	0.003	PPARG
positive regulation of adiponectin secretion	1	2808.7×	0.003	PPARG
beige fat cell differentiation	1	2808.7×	0.003	PPARG
DNA double-strand break attachment to nuclear envelope	1	2808.7×	0.003	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	2106.5×	0.003	LMNA
negative regulation of extracellular matrix assembly	1	2106.5×	0.003	PPARG
negative regulation of cellular response to transforming growth factor beta stimulus	1	2106.5×	0.003	PPARG
positive regulation of lipid metabolic process	1	1685.2×	0.003	PPARG
positive regulation of fatty acid metabolic process	1	1685.2×	0.003	PPARG
nuclear pore localization	1	1685.2×	0.003	LMNA
negative regulation of mitochondrial fission	1	1685.2×	0.003	PPARG
positive regulation of lipoprotein transport	1	1685.2×	0.003	PPARG
negative regulation of receptor signaling pathway via STAT	1	1685.2×	0.003	PPARG
negative regulation of vascular endothelial cell proliferation	1	1685.2×	0.003	PPARG
positive regulation of gene expression	2	38.7×	0.004	LMNA, PPARG
negative regulation of mesenchymal cell proliferation	1	1404.3×	0.004	LMNA
positive regulation of cholesterol transport	1	1203.7×	0.004	PPARG
response to lipid	1	1203.7×	0.004	PPARG
negative regulation of type II interferon-mediated signaling pathway	1	1053.2×	0.004	PPARG
protein localization to nuclear envelope	1	1053.2×	0.004	LMNA
regulation of protein localization to nucleus	1	1053.2×	0.004	LMNA
positive regulation of vascular associated smooth muscle cell apoptotic process	1	1053.2×	0.004	PPARG
negative regulation of cholesterol storage	1	766.0×	0.004	PPARG
negative regulation of lipid storage	1	766.0×	0.004	PPARG
peroxisome proliferator activated receptor signaling pathway	1	766.0×	0.004	PPARG
ventricular cardiac muscle cell development	1	766.0×	0.004	LMNA
regulation of cellular response to insulin stimulus	1	766.0×	0.004	PPARG
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.005	PPARG

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Metreleptin	Approved (phase 4)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Obeticholic Acid, Volanesorsen.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LMNA	BEPRIDIL
PPARG	METHYLENE BLUE ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
PPARG	83	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PPARG	2,033	Binding:1593, Functional:380, ADMET:56, Toxicity:3, Unclassified:1
LMNA	12	Binding:9, Functional:3

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PPARG	2,033

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	LMNA, PPARG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	4
PHASE2/PHASE3	1
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06679270	PHASE3	RECRUITING	Open-label Extension Study to Evaluate Metreleptin in Patients With Partial Lipodystrophy
NCT02527343	PHASE2/PHASE3	TERMINATED	The BROADEN Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Partial Lipodystrophy
NCT02430077	PHASE2	COMPLETED	Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients
NCT02654977	PHASE2	COMPLETED	CLINICAL PROTOCOL to Investigate the Long-term Safety and Efficacy of Metreleptin in Various Forms of Partial Lipodystrophy
NCT03508687	PHASE1/PHASE2	COMPLETED	Study of Gemcabene in Adults With FPLD
NCT03514420	PHASE2	COMPLETED	Study of AKCEA-ANGPTL3-LRx (ISIS 703802) in Participants With Familial Partial Lipodystrophy (FPL)
NCT05088460	PHASE2	TERMINATED	A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD)
NCT02404896	Not specified	AVAILABLE	Expanded Access Metreleptin Study
NCT07412028	Not specified	NOT_YET_RECRUITING	Identification of Women With Severe Insulin Resistant Syndromes of Genetic Origin Among Patients With Classic Polycystic Ovary Syndrome (PCOS)
NCT02858830	Not specified	COMPLETED	Familial Partial Lipodystrophy Study
NCT04056000	Not specified	WITHDRAWN	Lipodystrophy and Fat Metabolism During Exercise
NCT07090629	Not specified	COMPLETED	The Benefits of the Measureof Epicardial Adipose Tissue During Coronary Calcium Assessment of the Refine Cardiovascular Risk Assessment at Reunion Island.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METRELEPTIN	4	3
CAFFEINE	4	1
OBETICHOLIC ACID	4	1
VOLANESORSEN	4	1
GEMCABENE	2	1
MIBAVADEMAB	2	1
VUPANORSEN	2	1
CHEMBL4303680	0	1
CHEMBL5197244	0	1
CHEMBL5412701	0	1