Diagnosis criteria/Definition

Classical Homocystinuria (HCU) due to cystathionine b-synthase (CbS) deficiency [1-3] is an autosomal recessively inherited disorder of methionine metabolism [4]. Cystathionine b-synthase is an enzyme that converts homocysteine to cystathionine in the trans-sulphuration pathway of the methionine cycle and requires pyridoxal 5-phosphate as a cofactor. The other two cofactors involved in remethylation pathway of methionine include vitamin B12 and folic acid. (Figure 1)
The presence of one or more of the typical clinical signs may lead to a suspicion of CbS deficiency, but definitive diagnosis is based on the presence of certain biochemical abnormalities being confirmed in the laboratory. The characteristic amino acid profile typical of homocystinuria due to CbS deficiency includes Homocystinuria and hyperhomocysteinaemia, hypermethioninaemia and low plasma cystine and cystathionine [5].

Homocysteine nomenclature
Du Vignead et al first coined the term “homocysteine” and “ homocystine” in 1932 to represent the sulphydryl (reduced) and the disulphide (oxidised) forms of the next-higher homologues of cysteine and cystine [6]. Since then, homocysteine nomenclature has been confusing rather than helpful. Mudd and Levy (1995) pointed out that it was crucial that all workers concerned with homocysteine be familiar with the long-established nomenclature so as to avoid obscuring or confusing it [7].

A consensus statement on homocysteine terminology was published by Mudd and colleagues in 2000 [8].  In healthy subjects, 80-90% of homocysteine exists protein bound. The remaining free or non protein bound fraction (10-20%) consists of homocysteine-cysteine mixed disulphide and homocystine (Hcy-Hcy), the disulphide.
The total free (non protein bound) homocysteine is taken as twice homocystine plus homocysteine-cysteine mixed disulphide. Only a rate <2% exists as the reduced form, homocysteine. Together all these moieties make up what is called total homocysteine (tHcy) [8].

According to the data collected from countries that have screened over 200,000 newborns, the current cumulative detection rate of CbS deficiency is 1 in 344,000 [9]. In several individual areas, the reported incidence is much higher: 1 in 65,000 in Republic of Ireland [10], 1 in 73,000 in Northern Ireland [9] and 1 in 85,000 in the region of Manchester [9].  Amongst mentally retarded patients in institutions, the reported frequency has been as high as 1 in 300 to 4,500 [11-13], whilst that amongst those with non-traumatic ectopia lentis is 1 in 20 [14].

The worldwide rate of occurrence of classical homocystinuria, currently standing at 1 in 344,000, based on data from newborn screening is certainly underestimating the true rate of occurrence as indicated by the following lines of evidence:

1. Hypermethioninaemia used as a screening criterion for the condition may not be present in the first few days of life when most blood spots are taken for screening. [9,15].  This possibility may be enhanced by the current trend of infant breast feeding, leading to lower protein intakes [16] and that blood spots for screening are currently being collected earlier than was formerly the case [17].
2. The degree of hypermethioninaemia required to trigger further testing varies between different newborn screening programs and may then lead to cases being missed [9,18].
3. In the data used to calculate the cumulative rate of occurrence of CbS deficiency, at least one area namely New South Wales, Australia, with a relatively high frequency of 1 in 58,000 [19] based upon the number of diagnosed CbS deficient cases in their population, was not included as newborn screening had not been carried out [9].
4. Lastly, and perhaps the most important, is that pyridoxine-responsive cases, the most readily treatable form is preferentially missed by newborn screening methods currently in use [9].  The evidence for this was provided by an international survey of 55 cases detected by newborn screening.  Of the 55 cases identified, 13% were pyridoxine responsive, 78% were non-responsive and 9% had intermediate response [20]. These frequencies are quite different to those for cases in the total population survey (i.e. late-detected).  In this category of 529 late-detected cases, 43.7% were pyridoxine-responsive, 43.7% were non-responsive and 12.7% had intermediate response [9,20].

As calculated by McKusick in 1972, the frequency of homozygous CbS deficiency should be as high as 1 in 45,000, based upon the mutation rate formula, assuming a reproductive fitness of 0.1 compared to 1.0 in the average population [21].  This calculation seems to be in agreement with the estimated incidence, based on the number of diagnosed cases in the respective populations, of 1 in 24,000 for Northern Ireland [22] and 1 in 58,000 for New South Wales, Australia [19].

More recently, the incidence has been shown to be as high as 1 in 20,000 in the Danish  population [23] and 1 in 17,800 in the German population [24] using CbS mutational analysis.

Clinical description
Classical Homocystinuria is accompanied by an abundance and variety of clinical and pathological abnormalities, which show major involvement in four organ systems: the eye, skeletal, central nervous system, and vascular system.  Other organs, including the liver, hair, and skin have also been reported to be involved [9].  The clinical picture is extremely heterogeneous ranging from patients presenting all of the complications to individuals with no overt clinical involvement [19,25,26-28 ]. This wide range of clinical manifestation might reflect the abound heterogeneity of the mutant enzyme.  The clinical manifestations are listed in Table 1 and the four major organ systems involved will be discussed in greater detail.