COL4A1-related disorders: a case report

Case presentation: Young male, 17 years old, born in Rio de Janeiro, with a history of global developmental delay and neuroimaging with leukoencephalopathy. Basic screening for inborn errors of metabolism, ophthalmoscopy and electroneuromyography did not show any changes. Specific enzyme measurements performed during diagnostic investigation excluded leukodystrophies and Tay-Sachs as possible etiologies. The presence of bilateral basal ganglia hyperdensity, compatible with calcifications, associated with a static clinical condition have pointed to the possibility of leukoencephalopathy due to congenital cytomegalovirus infection. From the age of 11, transient and recurring events of paresis and paresthesia were noted, from March 2016 to April 2022, consistent with stroke, predominantly of hemorrhagic etiology. The main cardiovascular, hematological, inflammatory and rheumatological causes were investigated and ruled out. At this time, genetic etiologies, such as Leukoencephalopathy with Calcifications and Cysts and the Small Brain Vessel Disease group, became the main hypotheses. A gene panel by next generation sequencing was performed identifying a heterozygous, probably pathogenic de novo variant in the COL4A1 c.2432G>T;p.Gly811Val gene, not previously reported.

Discussion: Variants in the COL4A1 gene, of autosomal dominant (AD) inheritance, are associated with a heterogeneous group of rare genetic conditions with endothelial dysfunction and fragility of variable phenotypic spectrum. One of the phenotypes related to COL4A1 variants is autosomal dominant brain small-vessel disease with hemorrhage. Clinical manifestations include brain hemorrhages in young, non-hypertensive patients, some degree of cognitive impairment, the possibility of ocular changes and, rarely, muscle and renal involvement. The radiological presentation includes leukoencephalopathy, lacunar infarcts, microhemorrhages, dilatation of the perivascular space, deep intracerebral hemorrhages, and calcifications.

Final comments: Cerebral small vessel disease represents a cluster of pathologies with heterogeneous etiology and mechanisms affecting elements of the vascular system, classified according to pathological, radiological and clinical criteria. The small vessel disease with COL4A1 mutation is included in the group of genetic etiology, with cerebral autosomal dominant arteriopathy with subcortical ischemic stroke and leukoencephalopathy (CADASIL) and Fabry's disease being the most well-described causes.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023