There are many lipodystrophy conditions, all of which share similarities as well as having many differences. Some lipodystrophy subtypes are inherited and to understand what that means we need to know a little bit about genetics.
Understanding the genetics
Our DNA is like a genetic blueprint that contains all the information needed to make you. This blueprint is packaged into 46 chromosomes – 22 pairs plus the X and Y (sex determining) chromosomes. Each chromosome pair carries information pertaining to particular phenotypes (outward characteristics, such as brown eyes). This information is coded in what we call genes. So there are two copies of every gene, each called an allele – one on each chromosome in a pair.
Our individuality is governed by which genes we inherit from our parents. Of our 22 pairs of chromosomes, one from a pair is inherited from our mother and the other from our father. In the same way our X and Y (sex) chromosomes are inherited, one from each parent – although X and Y are not strictly a pair as there are many differences between them.
Many different gene expression patterns (what genes are ‘turned on’) govern the outward characteristics that result from our unique combination of genes. For example:
- A dominant characteristic needs only one allele (one gene copy from the chromosome pair) to be positive for that trait in order for it to be expressed
- A recessive characteristic needs two alleles (two gene copies: one on each chromosome in a pair) to be positive for that trait in order for it to be expressed
- An autosomal (dominant/recessive) characteristic simply means the gene is one of those encoded on the 22 pairs of chromosomes (not the X/Y)
- A sex-linked (dominant/recessive) characteristic means the gene is one of those encoded by the sex chromosomes, X and/or Y
Familial Partial Lipodystrophy (FPLD)
Identified genes include:
- Autosomal dominant: LMNA, PPARgamma (γ), AKT2, PLIN1
- Autosomal recessive: CIDEC, LIPE, PCYT1A
Familial Partial Lipodystrophy, Type 1; (Kobberling Type); FPLD1
FPLD of the Kobberling type has suggested autosomal dominant inheritance. That means its inheritance is not connected to gender, and only one ‘mutant’ copy of the gene is required for the condition to present itself, i.e., passed on from one, but not both parents. A person, who does not have FPLD1 themselves, cannot pass it on to the next generation. However, the faulty gene has not yet been discovered/characterised.
Familial Partial Lipodystrophy, Type 2; (Dunnigan Type); FPLD2
FPLD of the Dunnigan type can be caused by a number of distinct but similar mutations in the gene that codes for a protein called lamin A/C (LMNA). FPLD2, or more accurately, the mutation that gives rise to the condition, is passed on through autosomal dominant inheritance. Again, that means its inheritance is not sex-linked, and only one ‘mutant’ copy of the gene from one parents is required for the condition to present itself. If you do not have FPLD2 yourself, you cannot pass it on to your children.
As well as causing partial lipodystrophy, different alterations in the Lamin A/C gene are known to be associated with a range of other conditions including muscle weakness, reduced heart function, nerve damage and some rarer conditions. In general, specific genetic changes cause either partial lipodystrophy or those other conditions, although we continue to learn about overlaps between them.
Familial Partial Lipodystrophy, Type 3; FPLD3
FPLD3 is caused by a mutation in the gene that encodes a protein called PPARg (Peroxisome Proliferator Activated Receptor Gamma), and shows autosomal dominant inheritance, i.e. not sex-linked and only one ‘mutant’ copy from one parent is needed. If you do not have FPLD3 yourself, you cannot pass it on to your children. In FPLD3 the loss of fat tissue is most striking over the arms, legs and buttocks, with fat deposits on the trunk unaffected.
Familial Partial Lipodystrophy, Type 4; FPLD4
FPLD4 shows autosomal dominant inheritance and is caused by a faulty version of a gene called PLIN1. Again, it is not sex-linked and only one copy of the faulty gene is needed for someone to have the condition.
Familial Partial Lipodystrophy, Type 5; FPLD5
FPLD5, caused by a mutant copy of the AKT2 gene, is also autosomal dominant.
Congenital Generalised Lipodystrophy (CGL)
Identified genes include:
- AGPAT2 (CGL1), BSCL2 (Berardinelli-Seip congenital lipodystrophy 2, CGL2), CAV1 (CGL3), PTRF (CGL4), PCYT1A, PPARgamma (γ)
Congenital Generalized Lipodystrophy, Type 1; CGL1
CGL1 is caused by a mutation in the gene encoding a protein called AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase-2), and shows autosomal recessive inheritance. That means, like FPLD inheritance it is not related to gender, but two mutant copies of the gene are required for the condition to present itself, i.e., one passed on from each parent (they themselves may only be carriers, having only one mutant copy of the gene). If you do not have CGL1 yourself, but you are a carrier of the gene mutation, it is possible you could pass it on to your children. Your children would be carriers of the condition if they only inherit one copy of the faulty gene from you, however, if your partner is also a carrier of the same faulty gene, it is possible for your child to inherit both faulty gene copies and therefore inherit CGL1. Needing two faulty copies of the gene for CGL1 to present itself is the reason why it is much less common than FPLD.
Congenital Generalized Lipodystrophy, Type 2; CGL2; Berardinelli-Sepi CGL2
CGL2 is caused by a mutation in the gene that codes for a protein called Seipin (also known as BSCL2), and shows autosomal recessive inheritance. Again, not sex-linked and two ‘mutant’ gene copies, one from each parent, are needed. As a carrier of the CGL2 gene mutation, you could potentially pass it on to your children. They too would be carriers by inheriting one faulty gene copy. To inherit the condition, a child would need two faulty copies, i.e., one from each parent (both of which would need to be carriers).
Progeroid Syndromes
Identified genes include:
- Autosomal dominant: LMNA, FBN1, CAV1, POLD1, KCNJ6
- Autosomal recessive: SPRTN, WRN, BANF1
- Mandibuloacral dysplasia (MAD) associated lipodystrophy: LMNA (type A) or ZMPSTE24 (type B)
- Mandibular hypoplasia, Deafness, Progeroid features (MDP) associated lipodystrophy syndrome: the faulty gene has not yet been discovered/characterised
- Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome), autosomal recessive: FBN1
Auto-Inflammatory Lipodystrophy Syndrome
Identified genes include:
- Autosomal recessive: PSMB8
Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Reiger anomaly and teething delay (SHORT) Syndrome
Identified genes include:
- PIK3R1
Acquired Partial Lipodystrophy
Acquired Partial Lipodystrophy is not inherited, may often be attributed to follow a viral infection and is frequently associated with the presence of an antibody in the circulation that accelerates the “complement pathway”. This is a pathway normally required for the protection of the body against infection, but when abnormally activated may instead cause damage to the body itself.
