What is COL4A1 / COL4A2 syndrome?

COL4A1 / COL4A2 syndrome is a very rare genetic disorder.

Type IV alpha 1 and alpha 2 collagen (COL4A1 and COL4A2) is the main component of almost all basement membranes. For this reason, a mutation of the COL4A1 or COL4A2 gene causes a disorder that can affect any organ but typically the alteration of the gene is associated with the disease of the small cerebral vessels, a disorder transmitted as an autosomal dominant trait with variable age of onset and incomplete penetrance.

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COL4A1-COL4A2 syndrome

It’s a very rare genetic disorder with variable age of onset, from the prenatal period to adulthood.

Type IV alpha 1 and alpha 2 collagen (COL4A1 and COL4A2) is the main component of almost all basement membranes. For this reason, a mutation in the COL4A1 or COL4A2 gene causes a disorder that can affect any organ.

Typically, the alteration in the gene is associated with the small cerebral vessels disease, a disorder transmitted as an autosomal dominant trait (it is sufficient that a single copy of the gene is altered for the disease to occur), with variable age of onset (from the period prenatal to adulthood).

From a clinical point of view, the severity of the manifestations is very variable: from severe picture  with early onset to mild or asymptomatic cases.

The highly variable manifestations are mainly affecting the Central Nervous System (hemi-tetra-paresis, epileptic seizures, intellectual disability of varying degrees, motor disorders, headache) and derive from vascular alterations.

At the neuroradiological level, various anomalies can be highlighted: leukoencephalopathy of varying severity, micro- and macro-bleeding in the subcortical area, lacunar infarcts, aneurysms of the intracranial cerebral arteries and porencephalic cysts.

There may also be associated manifestations at the ocular level (tortuous retinal artery, anterior chamber anomalies, congenital cataract, glaucoma, microphthalmia, optic atrophy), muscle (muscle cramps and increase in muscle enzymes), renal (cyst, hematuria and glomerulopathy), hepatic (cyst), cardiovascular (heart rhythm abnormalities, mitral aortic valve prolapse), haematological (haemolytic anemia) and Raynaud’s phenomenon.

The brain.

One of the most frequent consequences is the alteration of the collagen of the cerebral vessels which causes stroke / hemorrhages and alterations of the white matter (leukoencephalopathy).

Furthermore, many of the patients suffer from epilepsy. The most frequent clinical consequences are: motor difficulties, visual disorders, language disorders, cognitive problems.

Today there are pharmacological treatments for epilepsy, and different kind of rehabilitation therapies for motor, visual and language problems.

From current evidence, the transmission is autosomal dominant (that is, a normal copy of a gene is inherited from one parent and a mutated copy from the other parent, but the mutated gene dominates and cancels the effect of the normal copy). In several cases, however, it was found that the mutation is not present in the parents, but only in the affected subject: we therefore speak of a “de novo” mutation.

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