COL4A1-related disorders are a group of autosomal dominant disorders caused by a mutation in the COL4A1 gene.
The exact prevalence is unknown, but the group of disorders is considered to be under-recognized, especially asymptomatic variants 1.
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
Characterized by intracerebral hemorrhage, although 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.
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.
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 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.
- 1. Meuwissen ME, Halley DJ, Smit LS, Lequin MH, Cobben JM, de Coo R, van Harssel J, Sallevelt S, Woldringh G, van der Knaap MS, de Vries LS, Mancini GM. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genetics in medicine : official journal of the American College of Medical Genetics. 17 (11): 843-53. doi:10.1038/gim.2014.210 - Pubmed
- 2. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology. 73 (22): 1873-82. doi:10.1212/WNL.0b013e3181c3fd12 - Pubmed
- 3. 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
- 4. Breedveld G, de Coo IF, Lequin MH, Arts WF, Heutink P, Gould DB, John SW, Oostra B, Mancini GM. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Journal of medical genetics. 43 (6): 490-5. doi:10.1136/jmg.2005.035584 - Pubmed
- 5. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The New England journal of medicine. 357 (26): 2687-95. doi:10.1056/NEJMoa071906 - Pubmed