COL4A1 brain small-vessel disease is an autosomal dominant monogenic COL4A1-related disorder that primarily causes cerebral small vessel disease.

Epidemiology

The exact prevalence is unknown, but the condition is likely under-diagnosed.

Clinical presentation

The clinical presentation is varied but generally presents during adulthood (30-50 years of age) with CNS features, including ^1-4:

• hemorrhagic stroke: generally subcortical in location, involving the centrum semiovale, deep grey matter, or brainstem 

• ischemic stroke: generally lacunar infarcts

• migraine with aura

• seizures

• subarachnoid hemorrhage

Notably, dementia is not a feature of COL4A1 brain small-vessel disease ¹. Furthermore, multi-organ involvement (including features of other COL4A1-related disorders) has also been rarely reported in patients with COL4A1 brain small-vessel disease, including cataracts, retinal hemorrhages, Axenfeld-Rieger anomaly, nephropathy, muscle cramps, mitral valve prolapse, arrhythmias, and Raynaud phenomenon ^1-4.

Pathology

COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen ^1-6. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels ^1-6.

A similar syndrome is seen in patients with mutation to the COL4A2 gene ³. 

Microscopic appearance

Histological analysis of affected blood vessels reveals interruption and thickening of basement membrane ¹.

Radiographic features

CT

CT is non-specific, demonstrating white matter regions of low attenuation ^1-4.

MRI

MRI is the investigation of choice and demonstrates the following features:

• widespread confluent, bilateral, symmetric white matter hyperintensities on T2-weighted sequences, with relative sparing of subcortical U-fibers ^1-4

• dilated perivascular spaces ^1-4

• cerebral microhemorrhages, predominantly involving the centrum semiovale, deep grey matter, or brainstem ^1-4

• intracerebral hemorrhage in the same distribution as cerebral microhemorrhages ^1-4

• ischemic stroke, most commonly lacunar infarcts ^1-4

• porencephalic cysts, often unilateral ^1-4

CTA/MRA

Angiographic studies may demonstrate the presence of intracranial cerebral aneurysms, most commonly affecting the intracranial internal carotid artery or middle cerebral artery ^1-4.

Treatment and prognosis

No specific disease-modifying treatment is available and symptomatic management and specialist screening is recommended ².

Differential diagnosis

General imaging differential considerations include:

• CADASIL

• CARASIL

• heterozygous HTRA1-related cerebral small vessel disease

• ​hypertensive microangiopathy

• cerebral amyloid angiopathy

• MELAS

• CNS vasculitis

• cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)