Think classical homocystinuria if the genetic test did not confirm Marfan syndrome: Late diagnosis and phenotypic variability in adult siblings with classical homocystinuria

Classical homocystinuria is an inherited metabolic disease of homocysteine metabolism due to biallelic pathogenic variants in <i>CBS</i>. The biochemical hallmark is elevated homocysteine and methionine levels. The treatment consists of betaine supplementation and protein restricted diet. We report two adult siblings with late diagnosis of classical homocystinuria, a variable phenotype and good response to the treatment. Patient 1 is a 29-year-old female with a history of myopia, Marfanoid habitus with significant kyphoscoliosis, anxiety and a psychotic episode. Clinical exome sequencing identified compound heterozygous pathogenic variants in <i>CBS</i> (c.209+1G>A; c.992C>T (p.Ala331Val)). She had markedly elevated homocysteine (298 μmol/L) and methionine (1040 μmol/L) levels. Her brain magnetic resonance spectroscopy revealed a low <i>n</i>-acetyl-aspartic acid peak. She was started on betaine supplementation, and a protein-restricted diet (0.8 g/kg/day) leading to significant decrease in her homocysteine (37 μmol/L) and methionine (49 μmol/L) levels. Patient 2 is a 27-year-old female (younger sibling) with a history of anxiety, one generalized tonic-clonic seizure and a dural sinus thrombosis in neuroimaging. She had both familial <i>CBS</i> variants and markedly elevated homocysteine (152 μmol/L) and methionine (560 μmol/L) levels, which were improved significantly on betaine supplementation and the protein-restricted diet. Both siblings had average range intellectual abilities. Higher homocysteine levels may result in severe skeletal, and central nervous system phenotypes.