COL4A1-related disorders

COL4A1-related disorders are a group of autosomal dominant disorders caused by a mutation in the COL4A1 gene.

Epidemiology

The exact prevalence is unknown, but the group of disorders is considered to be under-recognized, especially asymptomatic variants ¹.

Clinical presentation

The clinical presentation and onset of symptoms is very varied and largely depends on the phenotype that is expressed, which are summarized below. It should be noted that despite being traditionally divided into different phenotypes, there is a significant amount of overlap between them ^1,2, and there is no widely accepted consensus (as of September 2017) on their classification or naming.

COL4A1 brain small-vessel disease

This form of cerebral small vessel disease is characterized by intracerebral hemorrhage, although it can have other CNS manifestations, such as lacunar infarction, migraine with aura, seizures, and subarachnoid hemorrhage ³. Furthermore, many patients also have involvement of other body systems, especially the eyes ³.

See COL4A1 brain small-vessel disease for a detailed description.

Pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL)

This form of cerebral small vessel disease is characterized by lacunar infarcts and progressive white matter lesions typically involving the pons, subcortical white matter and basal ganglia ⁶. Clinically, it manifests with focal neurological sequelae of these infarcts and dementia ⁶. Unlike COL4A1 brain small vessel disease, hemorrhage is not a common feature.

See pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) for a detailed description.

Familial porencephaly

Also known as porencephaly type 1 or hereditary porencephaly, characterized by a wide spectrum of neurological features associated with antenatal or perinatal intracerebral hemorrhage that causes the porencephaly ⁴. There is often also significant leukoaraiosis noted, which differentiates it from other causes of porencephaly ⁴. Features of CNS dysfunction range from virtually none to profound (e.g. infantile hemiparesis, intellectual disability, etc.) ⁴. Rarely, ocular manifestations may also be seen ⁴.

See familial porencephaly for a detailed description.

Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome

As the name suggests, HANAC syndrome presents with cerebral small vessel disease, nephropathy with hematuria, intracranial aneurysms and muscle cramps ^2,5. In addition, these patients also commonly exhibit bilateral retinal artery tortuosity, as well as other multi-organ involvement ^2,5. Notably, unlike COL4A1 brain small-vessel disease, the cerebral small vessel disease in HANAC syndrome is generally asymptomatic ^2,5.

See HANAC syndrome for a detailed description.

Pathology

COL4A1-related disorders are a group of autosomal dominant conditions resulting from a number of different mutations to the COL4A1 gene ^1-5. This gene, located on the long arm of chromosome 13, normally encodes for the alpha-1 chain of type IV collagen ^1-5. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels ^1-5. While generally familial, up to 27% of cases are thought to have de novo mutations ¹.

Radiographic features

Radiographic features tend to overlap between the different COL4A1-related disorders ¹ and are discussed in depth in each of the individual articles.

Treatment and prognosis

No specific disease-modifying treatment is currently available and symptomatic management is recommended ¹.