A revisit to the natural history of homocystinuria due to cystathionine β-synthase deficiency

Abstract

We review the evidence that in Denmark and probably certain other European countries the number of individuals identified with homocystinuria due to homozygosity for the widespread c.833T>C (p.I278T) mutation in the gene that encodes cystathionine β-synthase (CBS) falls far short of the number of such individuals expected on the basis of the heterozygote frequency for this mutation found by molecular screening. We conclude that the predominant portion of such homozygotes may be clinically unaffected, or may be ascertained for thromboembolic events occurring no sooner than the third decade of life. If so, there was significant ascertainment bias in the time-to-event curves previously published describing the natural history of untreated CBS deficiency [Mudd et al, 1985] and these curves should be used with care.

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

“…As not a single case was found in any of the other samples from other countries, only upper limits for prevalence estimates can be derived from the data sets. Merging all non-Qatari subgroups included in our analysis results in a prevalence estimate for HCU lower than 1:345,939, which is in agreement with some previously published estimates (see introduction and Skovby et al 2010, which estimated the frequency of classical CBS to 1:344,000).…”

Simultaneous Tromboembolic Events in a Patient with Heterozygous MTHFR Mutation

“…Extended profile of investigations is necessary in patients with arterial or venous thrombosis which occur repeateadly, in unusual sites or at young ages, when family aggregation of thrombotic events is identified, as well as in women with recurrent idiopathic pregnancy loss. It must include a complete blood count and erythrocyte sedimentation rate, a blood film examination, prothrombin time (PT) and activated partial thromboplastin time (aPTT), factor V Leiden, antithrombin and fibrinogen levels, protein C and S, prothrombin gene mutations, homocysteinemia, methylenetetrahydrofolate reductase (MTHFR) gene mutations and antiphospholipid antibodies [3].Homocysteine has been recognised as a cardiovascular risk factor besides the traditional ones such as smoking, obesity, diabetes mellitus and arterial hypertension, in line with the observations made in patients with homocystinuria [4][5][6]. This is an inborn error of methionine metabolism caused by deficient activity of cysthationine β-synthase (CBS) and thereby impairment of the transsulphuration pathway leading to excessive accumulation of homocysteine [7,8].…”

A Rapid Screening Method for the Measurement of Neonatal Total Homocysteine in Dried Blood Spots by Liquid Chromatography-Tandem Mass Spectrometry

“…For example, the incidence ranges between 1:6400 to 1:20,500 in European populations and between 1:1800 to 1:3000 in the Qatari population [2][3][4][5][6][7]. The true worldwide prevalence is likely underestimated because of undiagnosed cases [8]. More than 190 mutations have been reported in the CBS gene [9], but within the Qatari population, homocystinuria (HCU) is caused predominately by a single mutation c.1006C > T (p.R336C) [6].…”

“…Children with HCU appear normal in early infancy, but the subsequent natural course of CBS deficiency is severe, with patients presenting with ectopia lentis and myopia, mental retardation, marfanoid habitus, osteoporosis, and thromboembolic events, as well as decreased IQ [1,11,12]. Milder forms may manifest later in adulthood [8]. However, if detected early and with compliance to treatment, HCU can be successfully treated, resulting in normal cognitive development and prevention of physical complications [13].…”