engleski

TWO RARE CASES OF CEREBROTENDINOUS XANTHOMATOSIS IN THE SAME FAMILY CAUSED BY AN INTRONIC MUTATION IN CYP27A1

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease associated with abnormally high blood cholestanol levels. Sterol 27-hydroxylase enzyme deficiency leads to abnormal metabolization of cholesterol and diverts the metabolic pathway in the direction of reduced production of chenodeoxycholic acid and an increased formation of 25-hydroxylated bile alcohols and cholestanol. CTX patients commonly have infantileonset diarrhea, childhood-onset cataract, adult-onset progressive neurologic symptoms, and adolescent to young adult-onset tendon xanthomas. Cholestanol accumulates in the brain, tendons, eyes, and blood vessels, causing a range of clinical manifestations, including ataxia, epilepsy, dementia, and even parkinsonism. We present a case of two brothers aged 34 and 38 with a similar clinical picture that includes ataxia, cognitive deficit, congenital cataract, and diarrhea since birth. The older brother also experienced grand mal seizures. Parents are healthy and are not in consanguinity. Moreover, other family members are without neuromuscular diseases and known heredity in the family. Patients came to the St. Catherine Specialty Hospital to perform genetic testing and counseling due to a suspicion of a genetic disorder. Next- generation sequencing of 444 genes associated with various neurological and neuromuscular disorders with clinical examination, radiological and biochemical analysis established a diagnosis of autosomal recessive cerebrotendinous xanthomatosis caused by a homozygous form of variant c.1184+1G>A in both brothers. This mutation affects a donor splice site in intron 6 of the CYP27A1 gene. Studies have shown that disruption of this splice site results in the skipping of 89 nucleotides of exon six and introduces a premature termination codon which results in mRNA nonsense-mediated decay. However, replacement therapy with chenodeoxycholic acid may prevent clinical deterioration. Early treatment in symptomatic patients was shown to stop progression and, in some cases, reduction of pre-existing neurological deficits. Patients were referred to systematic clinical monitoring and treatment under the supervision of the clinical medical team at St. Catherine Specialty Hospital.

sterol 27-hydroxylase, cholestanol, metabolic disease, CYP27A1, chenodeoxycholic acid

nije evidentirano