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].
Incidence
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.
