COL4A1 brain small-vessel disease is an autosomal dominant monogenic COL4A1-related disorder that primarily causes cerebral small vessel disease.
The exact prevalence is unknown, but the condition is likely under-diagnosed.
The clinical presentation is varied but generally presents during adulthood (30-50 years of age) with CNS features, including 1-4:
- haemorrhagic stroke: generally subcortical in location, involving the centrum semiovale, deep grey matter, or brainstem
- ischaemic stroke: generally lacunar infarcts
- migraine with aura
- subarachnoid haemorrhage
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 haemorrhages, Axenfeld-Rieger anomaly, nephropathy, muscle cramps, mitral valve prolapse, arrhythmias, and Raynaud phenomenon 1-4.
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.
Histological analysis of affected blood vessels reveals interruption and thickening of basement membrane 1.
CT is non-specific, demonstrating white matter regions of low attenuation 1-4.
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 microhaemorrhages, predominantly involving the centrum semiovale, deep grey matter, or brainstem 1-4
- intracerebral haemorrhage in the same distribution as cerebral microhaemorrhages 1-4
- ischaemic stroke, most commonly lacunar infarcts 1-4
- porencephalic cysts, often unilateral 1-4
CTA / MRA
Treatment and prognosis
No specific disease-modifying treatment is currently available and symptomatic management and specialist screening is recommended 2.
General imaging differential considerations include:
- 1. Lanfranconi S, Markus HS. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel Disease. Stroke. 41 (8): e513. doi:10.1161/STROKEAHA.110.581918 - Pubmed
- 2. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel genetic multisystem disease. Current opinion in neurology. 24 (1): 63-8. doi:10.1097/WCO.0b013e32834232c6 - Pubmed
- 3. Renard D, Miné M, Pipiras E, Labauge P, Delahaye A, Benzacken B, Tournier-Lasserve E. Cerebral small-vessel disease associated with COL4A1 and COL4A2 gene duplications. Neurology. doi:10.1212/WNL.0000000000000769 - Pubmed
- 4. Lemmens R, Maugeri A, Niessen HW, Goris A, Tousseyn T, Demaerel P, Corveleyn A, Robberecht W, van der Knaap MS, Thijs VN, Zwijnenburg PJ. Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency. Human molecular genetics. 22 (2): 391-7. doi:10.1093/hmg/dds436 - Pubmed
- 5. Joutel A, Faraci FM. Cerebral small vessel disease: insights and opportunities from mouse models of collagen IV-related small vessel disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke. 45 (4): 1215-21. doi:10.1161/STROKEAHA.113.002878 - Pubmed
- 6. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E, John SW. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. The New England journal of medicine. 354 (14): 1489-96. doi:10.1056/NEJMoa053727 - Pubmed