Longevity Questions

2. Cutis Laxa (Lax Skin)

General Characteristics:

This is a group of genetically diverse disorders that share the same characteristic of loose, wrinkled, inelastic skin that hangs in folds and is very slow to straighten out after stretching.

Genetic Defects (Main forms related to elastin/assembly):

* Autosomal Dominant CL (ADCL): Often caused by mutations in the ELN (elastin) gene. These are usually mutations that result in a shortened protein that not only does not work itself, but also interferes with the normal protein from the second copy of the gene (dominant negative effect). Less commonly, ADCL is associated with mutations in the FBLN5 gene (fibulin-5, important for the attachment of elastin to cells and microfibrils).

* Autosomal Recessive CL type 1 (ARCL1): Usually more severe forms. Includes subtypes with mutations in genes critical for elastic fiber assembly:

* ARCL1A: Mutations in FBLN5 (both copies of the gene).

* ARCL1B: Mutations in FBLN4 (fibulin-4, also known as EFEMP2), important for localization of LOX activity and elastin deposition.

* ARCL1C: Mutations in LTBP4 (latent TGF-β-binding protein 4), involved in microfibril assembly and TGF-β regulation.

Transhumanism in a Distant City, [03.05.2025 08:13]
* Autosomal recessive CL type 2 (ARCL2): Associated with mutations in genes not directly related to elastic fiber components, but affecting general cellular processes affecting the ECM (e.g. ATP6V0A2 - affects protein glycosylation in the Golgi apparatus, PYCR1 - affects proline metabolism). Often accompanied by developmental delay and skeletal abnormalities.

* X-linked CL (Occipital horn syndrome): Caused by mutations in the ATP7A gene, encoding a copper transporter. Copper is required as a cofactor for LOX enzymes. Copper deficiency leads to impaired cross-linking of both collagen and elastin.

Clinical Manifestations:

* Skin: The main symptom is excess, loose, inelastic skin that forms folds, especially on the face ("bloodhound face", a look of premature aging), neck, armpits and groin. Slow straightening of the skin fold.

Systemic manifestations (more common and severe in recessive forms):

* Lungs: Pulmonary emphysema (even at a young age).

* Vessels: Tortuosity of arteries, stenosis (narrowing), aneurysms (dilation), problems with heart valves.

* Other organs: Hernias (inguinal, umbilical, diaphragmatic), diverticula of the intestine and bladder.

* Musculoskeletal system: Hypermobility of joints (usually less pronounced than in Ehlers-Danlos syndrome), skeletal abnormalities are possible.

* Nervous system: In some forms (especially ARCL2) - psychomotor retardation.
These diseases clearly demonstrate the critical importance of the correct structure and function of fibrillin-1 and elastin for the integrity and normal functioning of many human tissues and organs. Studying these diseases helps to understand the fundamental mechanisms of assembly and maintenance of the extracellular matrix.