Familial Partial Lipodystrophy (FPLD): Recent Insights

Figures & data

Table 1 Classification of Partial Lipodystrophies, Prevalence and OMIM (Online Mendelian Inheritance in Man) Phenotype Number

Familial Partial Lipodystrophy	Prevalence	OMIM Phenotype #
FPLD 1 or Köbberling type	Unknown	608,600
FPLD 2 or Dunnigan type (LMNA-related)	>500 Patients reported	151,660
FPLD 3 or PPARG-related	20 Families	604,367
FPLD 4 or PLIN1-related	4 Families	613,877
FPLD 5 or CIDEC-related	1 Patient	615,238
FPLD 6 or LIPE-related	2 Families	615,980
CAV1-related FPLD	3 Patients	606,721
ADRA2A-related FPLD	1 Family	-
AKT2-related FPLD	1 Family	-
Progeroid syndromes		OMIM Phenotype #
MAD type A	Extremely rare	248,370
Werner syndrome	Extremely rare	277,700
MDPL syndrome	Extremely rare	615,381
Complex genetic syndromes with partial lipodystrophy		OMIM Phenotype #
Bloom syndrome	Extremely rare	210,900
SHORT syndrome	Extremely rare	269,880
Autoinflammatory syndromes		OMIM Phenotype #
CANDLE syndrome	Extremely rare	177,046

Abbreviations: FPLD, familial partial lipodystrophy; MAD, mandibuloacral dysplasia; MDPL, mandibular hypoplasia-deafness-progeroid features-lipodystrophy.

Table 2 Clinical Features of Familial Partial Lipodystrophies

Metabolic abnormalities

Insulin resistance, acanthosis nigricans

Hyperglycemia, diabetes mellitus

Hypertriglyceridemia, eruptive xanthomas, pancreatitis

Ectopic fat deposition

Liver

Hepatic steatosis, hepatomegaly

Non alcoholic steatohepatitis

Liver cirrhosis

Heart

Cardiomyopathy

Atherosclerotic coronary heart disease

Reproductive

Hyperandrogenemia, hirsutism

Oligomenorrhoea, subfertility

Polycystic ovarian syndrome

Other

Proteinuric renal disease

Myopathy

Table 3 Gene Mutations Involved in Familial Partial Lipodystrophy (FPLD) Pathogenesis, Mode of Inheritance and Corresponding Phenotypes

Gene	Inheritance	Clinical Phenotype	Ref
Adipogenesis – Adipocyte Differentiation
PPAR-γ (FPLD3)	Autosomal dominant	Distal lipoatrophy – gluteofemoral fat loss, visceral adiposity, cardiovascular disease	[^Citation19^–^Citation21, ^Citation107,Citation108]
LMNA (FPLD2)	Autosomal dominant	Distal and truncal lipoatrophy, “cushingoid” appearance due to neck and face sparing, muscular dystrophy, dilated cardiomyopathy	[^Citation27,Citation31^–^Citation37,Citation109]
LMNA (MAD type A)	Autosomal recessive	Distal and truncal lipoatrophy, mandibular and clavicular hypoplasia, acroosteolysis, delayed dentition, progeroid features	[^Citation28,Citation110^–^Citation112]
ZMPSTE24 (MAD type B)	Autosomal recessive	Distal and truncal lipoatrophy, mandibular and clavicular hypoplasia, acroosteolysis, delayed dentition, progeroid features, segmental glomerulosclerosis	[^Citation37,Citation38,Citation113]
AKT2	Autosomal dominant	Distal lipoatrophy, severe insulin resistance	[^Citation42]
PIK3R1 (SHORT syndrome)	Autosomal dominant	Short stature, joint hyperextensibility, ocular depression, Rieger anomaly, teething delay, facial - truncal - upper limbs lipoatrophy with sparing of lower limbs	[^Citation43^–^Citation45]
Lipid Droplet Assembly – Lipolysis
CIDEC (FPLD5)	Autosomal recessive	Lower limbs lipoatrophy, visceral adiposity, ketosis prone insulin resistance, multilocular lipid droplets	[^Citation48,Citation114]
PLIN1 (FPLD4)	Autosomal dominant	Lower limbs lipoatrophy, facial acromegaloid features, muscular hypertrophy	[^Citation50,Citation115,Citation116]
LIPE (FPLD6)	Autosomal recessive	Distal lipoatrophy, visceral adiposity, progressive myopathy, vitiligo	[^Citation52,Citation53,Citation117]
ADRA2A	Autosomal dominant	Distal lipoatrophy, visceral and upper trunk adiposity, muscularity	[^Citation54]
CAV1	Polygenic	Facial and upper trunk lipoatrophy, cataracts, hypertriglyceridemia,	[^Citation58]
Cell Membrane Integrity
PCYT1A	Autosomal recessive	Distal lipoatrophy, short stature, visual impairment, spondylometaphyseal dysplasia	[^Citation59,Citation60]
PSMB8 (CANDLE syndrome)	Autosomal recessive	Fever, dermatosis, facial oedema, distal lipoatrophy, joint contractures	[^Citation61,Citation62,Citation118,Citation119]
DNA Repair
WRN (Werner syndrome)	Autosomal recessive	Distal lipoatrophy, short stature, progeroid features, Achilles ulcerations	[^Citation64,Citation120]
POLD1 (MDPL syndrome)	Autosomal dominant	Mandibular hypoplasia, deafness, progeroid features, distal lipoatrophy with visceral adiposity, hypogonadism	[^Citation65]
BLM (Bloom syndrome)	Autosomal recessive	Growth restriction, photosensitivity, telangiectasia, recurrent infection, increased cancer risk	[^Citation66,Citation67]
FPLD type 1	Polygenic	Distal lipoatrophy, visceral adiposity, insulin resistance, NASH	[^Citation69]

Note: Genes are grouped according to function.

Abbreviations: AKT2, protein kinase B; MAD, mandibuloacral dysplasia; MDPL, mandibular hypoplasia-deafness-progeroid features-lipodystrophy; PCYT1A, phosphate cytidyltransferase 1A; PIK3R1, phosphatidylinositol 3 kinase regulatory subunit 1; POLD1, DNA polymerase delta 1; PPAR γ, peroxisome proliferator-activated receptor γ; PSMB8, proteasome subunit beta type 8; ZMPSTE24, zinc metalloproteinase STE24.

Figure 1 Pathways involved in the molecular pathogenesis of familial partial lipodystrophies. Responsible genes may affect adipocyte differentiation, cell membrane integrity, DNA repair, lipid droplet formation and lipolysis. PPARγ, the “master regulator” of adipogenesis coordinates the transcription of proteins central to the adipocyte function. AKT2 and PIK3R1 are involved in insulin signaling pathways, mediating adipocyte differentiation. LMNA gene encodes lamins A/C which are essential components of the nuclear envelope. ZMPSTE24 is responsible for the proteolysis of prelamin A to mature/active lamin A. PSM8 and PCYT1A are responsible for the composition and integrity of cell membranes. Mutations lead to intracellular oxidative stress, inflammation and apoptosis. WRN, POLD1 and BLM participate in DNA repair and replication, ensuring genomic stability. Caveolin 1, the product of CAV1, participates in the formation of caveolae. Caveolin vesicles are created from endocytosis of caveolae which carry cholesterol and sphingolipids from the cell surface. Caveolin vesicles are merged with the lipid droplet, mediating the transcytosis of fatty acids. CIDEC is responsible for the formation of unilocular lipid droplets and PLIN1 for the structure of the lipid droplets. Finally, LIPE and ADRA2A regulate triglyceride lipolysis to free fatty acids and glycerol.

Figure 2 “Fat shadows”: reconstructed DXA scan images using color-coded representation to highlight adipose tissue. Patients with (A) congenital type 2 (i) and type 1 (ii) and (B) acquired generalized lipodystrophy have minimal residual fat depots. Patients with (C) FPLD of the Dunnigan (i and ii), and Köbberling variety (iii and iv), present with lipoatrophy of subcutaneous fat and hypertrophy of adipose tissue in the neck and upper trunk. Identification of the “Dunnigan sign” is diagnostic of FLPD2. Patients with acquired partial lipodistrophy (D) have loss of fat from the upper extremities and truncal region with lower half depots being either normal (i) or hypertrophied (ii). (E) Lean (i and iii) and obese (ii and iv) control subjects present gender-specific fat distribution. American Diabetes Association. “Fat Shadows” From DXA for the Qualitative Assessment of Lipodystrophy: When a Picture Is Worth a Thousand Numbers, Diabetes Care, 2018. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.⁷²

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