Young-Onset Cerebral Small Vessel Disease Associated with COLGALT1 Mutation

Dear Editor, Cerebral small vessel disease (CSVD) affects the brain’s small arteries, arterioles, venules, and capillaries. Approximately 5% of CSVD cases are hereditary. Monogenic CSVD represents a rare subset of CSVD that is linked to specific genetic mutations. The most common of these are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, Apert syndrome, (mutations in the FGFR2 or FGFR1 gene), retinal vasculopathy with cerebral leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and COL4A1/COL4A2-related disorders.[1–5] COL4A1/COL4A2 variants account for ~20%–30% of hereditary CSVD, whereas collagen beta (1-O) galactosyltransferase 1 (COLGALT1) variants are a newly described rarer type. We present the first case of COLGALT1 CSVD from India. A 48-year-old man was admitted with difficulty in walking and left-sided weakness for 2 days. He had a history of left hemiplegia at the age of 15 years and one more episode of dysarthria at the age of 29 years. He was then diagnosed with probable cerebral vasculitis and started on azathioprine that was given for 1 year. For the last 5 years, he had been taking mycophenolate mofetil 1 g/day. There was no family history of stroke or premature cardiovascular events. He did not have a history of migraine, psychiatric disorders, diabetes mellitus, or hypertension and was a non-smoker. On examination, he had a left hemiparesis, grade 4/5 in the upper and lower limbs. The ocular fundus examination was normal. There were no features of a joint hyperextensibility syndrome. Neuropsychologic evaluation revealed mildly impaired executive functioning and abstract reasoning. Magnetic resonance imaging of the brain showed an acute lacunar infarct in the right corona radiata, with the surrounding area blooming. Multiple other blooming areas were noted in the deep gray and white matter and superior cerebellar hemispheres. Symmetrical bilateral confluent fluid attenuated inversion recovery (FLAIR) hyperintensities were seen in the deep cerebral and cerebellar white matter, including the external capsule, along with multiple FLAIR hypointense areas in the subcortical white matter, right caudate nucleus, and right centrum semiovale. These appeared to be either enlarged perivascular spaces or cavitations [Figure 1]. The magnetic resonance (MR) angiogram was normal. Routine blood tests, echocardiogram, and Holter monitoring were normal. With the clinical and imaging findings, the differential diagnosis included a cavitating leukoencephalopathy, CADASIL, or other genetic CSVD. He was started on dual antiplatelets and atorvastatin. Mycophenolate was discontinued. His hemiparesis improved within 3 days, and he could be discharged with a Modified Rankin score (mRS) of 0.Figure 1: MR images. (a) Diffusion-weighted axial image shows a right subcortical acute infarct (arrow). (b and c) FLAIR images showing extensive leukoaraiosis with enlarged periventricular spaces (arrowheads). (e-g) GRE axial images showing scattered subcortical hemorrhages (arrows). (d and h) MR angiogram of the neck and brain showing normal vessels. FLAIR: fluid attenuated inversion recovery, MR: magnetic resonance, GRE: gradient echo sequencesBlood was sent for clinical exome and mitochondrial genomic sequencing. It revealed a homozygous mutation in exon 8 of the COLGALT1 gene [c.1129G>C] (p.Gly377Arg), suggestive of a brain small vessel disease (BSVD) 3, inherited in an autosomal recessive fashion. The variant was previously reported in a patient in a compound heterozygous state who was affected with CSVD. Functional studies show that the p.Gly377Arg variant shows residual activity, has a milder effect on ColGalT activity, and is thought to be a hypomorphic variant. In biallelic variants, this becomes clinically relevant in the presence of a significant loss-of-function variant. There are no reports as yet for cases with homozygosity of this variant.[6] Hence, the raw variant call format (VCF) file (a standard text file format used in bioinformatics for storing gene sequence variations) was also uploaded onto the AI-MARRVEL – a knowledge-driven artificial intelligence system for diagnosing mendelian disorders (https://ai.marrvel.org).[7] This tool uses a random forest machine learning classifier tool to aid in the primary diagnosis of genetic disorders, reanalysis of unsolved cases, and discovery of novel disease mutations. Based on the current literature evidence, and AI-MARRVEL analysis evaluation, the homozygous p.Gly377Arg variant is currently classified as a variant of unknown significance. BSVDs 1 and 2 are hereditary, autosomal dominant syndromes linked to variants in the COL4A1 and COL4A2 genes. These variants present with cerebrovascular, renal, ocular, cardiac, and muscular abnormalities. BSVD is caused by defects in type IV collagen that result in instability of the basal membrane of arteries, thus increasing the risk of CSVD. They may be associated with porencephalic cysts, periventricular leukoencephalopathy, lacunar infarcts, cerebral microbleeds, and calcifications. However, BSVD3 is caused by biallelic variants in the COLGALT1 gene (autosomal recessive). This gene encodes the ColGalT1 protein, which is crucial for the glycosylation of COL4A1 (and possibly COL4A2), an essential step in the formation of the triple helix of collagen IV. It is necessary for proper assembly and stabilization of collagen in the extracellular matrix, especially in cerebral vessels. Biallelic mutations lead to reduced secretion of COL4A and impaired collagen modification. As COL4A1 is an integral part of basement membranes, it leads to vessel fragility and abnormalities similar to those seen in COL4A1/COL4A2-related disorders.[6] The differences between COLGALT1- and COL4A1/COL4A2-associated CSVD are given in Table 1. Although COLGALT1 and COL4A1/COL4A2 are both involved in collagen biology and are linked to CSVD, they differ in their specific functions, molecular mechanisms, and clinical manifestations. COL4A1/COL4A2 CSVD is more likely to be associated with systemic manifestations than COLGALT1 CSVD.[8,9]Table 1: Differences between COLGALT1- and COL4A1/COL4A2-associated CSVDDue to the phenotypic variability of COLGALT1-related disorders, the time of onset and severity of the disease may vary greatly in individuals. COLGALT1-related disorders may present in utero or early infancy with global developmental delay, spasticity, and seizures. They may also present in childhood with normal or mildly delayed development punctuated by an acute intracranial hemorrhage and rapid neurologic decline.[10] They may also present in later life as in our patient. The MR imaging features of COLGALT1-related disorders closely resemble those of COL4A1/COL4A2-related disease. They include porencephaly, parenchymal or intraventricular hemorrhage, hydrocephalus, cerebral calcification, microbleeds, leukoaraiosis, lacunar infarcts, dilated perivascular spaces, and intracranial aneurysms. The combination of extensive leukoaraiosis, cerebral microbleeds, and dilated perivascular spaces in a young patient with stroke should prompt the clinician to consider COLGALT1 or COL4A1/COL4A2-associated CSVD in the differential diagnosis. Informed consent Appropriate informed consent was obtained. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.