For the mother, a low dose of pyridoxine was able to maintain a satisfactory plasma tHcy without dietary methionine restriction. This indicates that she had pyridoxine responsive homocystinuria. Patients homozygous for the R125Q mutation have been previously described as pyridoxine non-responsive [
1] or partially pyridoxine responsive if associated with the severe phenotype [
2]. Thus, the case of the patient's mother suggests that R125Q mutation in one copy, in association with another missense mutation (R224L), does not result in pyridoxine non-responsiveness. Moreover, we think that her severe phenotype was more related to late diagnosis than her genotype. Her son did not inherit her pyridoxine responsiveness as a high dose of pyridoxine was unable to significantly reduce plasma tHcy [
3]. He carried a novel, severe and pathogenic mutation (c.689 insC) of the CBS gene, in association with the maternally inherited R125Q, which resulted in a pyridoxine non-responsive homocystinuria. It is also likely that, after a period of good metabolic control during childhood, he failed to maintain a methionine-restricted diet in the teenage years, a potential problem encountered in adolescence during the follow-up of many patients with inborn errors of metabolism [
4]. In most patients, pyridoxine responsiveness is based on the presence of residual activity of mutant CBS, which have been closely linked to CBS mutations [
5]. For example, the frequent G370S mutation, in one or two copies, appears to be incompatible with pyridoxine responsiveness, producing a severe phenotype [
1]. Conversely, the I278T mutation usually confers pyridoxine responsiveness, whether in homozygotes or compound heterozygotes [
6]. In the case presented here, the son has inherited a severe pyridoxine non-responsive mutation from his father who presumably was a heterozygous carrier of this mutant CBS allele. It has been shown that an identical CBS genotype does not always result in the same phenotype, even within a family, and although pyridoxine responsiveness is absolutely constant within sibships, the clinical phenotype is often not [
5]. This indicates that non-heritable factors may influence the clinical expression of homocystinuria in genetically predisposed individuals.
Beyond the genotype-phenotype correlation, the homocystinuria described in this family shows that a maximal benefit from therapy may be expected when the disorder is detected in early infancy. Although it is generally recognized that pyridoxine responsive patients are more mildly affected than non-responsive patients, the cases reported here show that a methionine restriction diet started early can prevent or delay a number of important complications of CBS deficiency, in particular neurodevelopment and lens dislocation. This is consistent with previous data showing that patients carrying the G307S mutation seem to have moderate to severe phenotypes, except for those treated from birth [
5]. Newborn screening and early treatment for phenylketonuria dramatically alters the clinical phenotype and our cases mirror this. We recommend that offspring of people with homocystinuria should be screened early in infancy and if positive, treated appropriately whether they have pyridoxine responsive or unresponsive disease.