Homocystinuria is associated with the following symptoms and side effects if not treated
Clinical abnormalities in CbS deficiency (Mudd et al. )
Symptoms Return to top
Central nervous system
It is worth emphasizing that the patient with CbS deficiency is normal at birth and if left untreated, progressively develops the full-blown clinical picture .
Disruption of the thickened zonulae fibres causes the lens to dislocate inferiorly or nasally, or both, and is usually bilateral [32-34]. This disruption of the thickened zonulae fibres leads to increased curvature of the lens and thereby to lenticular myopia and astigmatism. Iridodenesis is the quivering of the iris by moving the eye ball and is a sign of the loosening of the lens. Acute pupillary block glaucoma may result from anterior dislocation of the lens .
In a study of 34 patients with CbS deficiency, Cruysberg et al reported on the prevalence of ocular manifestation in these patients and found that the highest prevalence were found for myopia > 1D (85%), high myopia > 5D (76%), ectopia lentis (76%), iridodenesis (56%), spherophakia (50%) and very high myopia >10D (50%). Ectopia lentis, associated with late diagnosis of CbS deficiency, was identified as the major risk factor for other ocular complications, including strabismus (24%), dense cataract (21%), acute pupillary block glaucoma (19%), retinal detachment (15%), and unilateral blindness (18%) .
Cruysberg et al in 1996 also pointed out that there should be a high level of suspicion that high myopia > 5D may be caused by ectopia lentis . In such high myopia, one or the other abnormality of ocular refraction of the axial length, the corneal curvature or the lens, the most likely, must be present. Other clues for lenticular myopia are abnormally rapid progression of myopia, high myopia in children as myopia > 5D is extremely rare in children under 2 years , progressive myopia in adult life as high myopia probably affects under 2% of adults , and high non-corneal astigmatism with subnormal visual activity .
As pointed out by Mudd et al, the data on age of lens dislocation is
more representative of the age/date of detection rather than it’s actual
occurrence . In homocystinuria, the age of development of high myopia >5D
prior to lens dislocation is a better indicator of the start of lens
dislocation. On one hand, a normal ophthalmological examination at any age
should not be a reason for rejecting the diagnosis of classical homocystinuria
, and on the other, a high level of suspicion for the diagnosis must be
present in those presenting with unusual myopia particularly if combined with
skeletal, vascular or central nervous system manifestation .
Osteoporosis, especially of the spine, is the most consistent skeletal abnormality on radiograph. Although it is not present at birth, it has been described as early as at the age of one year [41,44]. The frequency of osteoporosis in CbS deficient cases has been reported to be as high as 90-100% [38,40-42,44], with one exception in which study it was only 35% . Time-to-event curve for radiological evidence of spinal osteoporosis in untreated patients predicts a that 50% have radiological evidence of osteoporosis by age 15 years . Spinal osteoporosis generally occurs earlier in pyridoxine non-responsive cases than in those responsive . Osteoporosis may lead to scoliosis, however, it has also been reported in the absence of osteoporosis . Vertebral collapse may also be from the effects of osteoporosis .
Radiologically, there is posteriorly placed biconcavity of the vertebrae
(“codfish”) unlike the biconcavity typical of osteoporosis as pointed out by
Brenton et al. . The hands and feet are also the site of several
radiological changes with prominent growth arrest lines are often present in the
distal tibia  and curiously, development of the lunate has been selectively
retarded in some cases [41,42,46]. The bone age is not usually altered,
although on occasions, it may be either advanced or delayed .
Thrombophlebitis is the most frequent complication often leading to fatal pulmonary emboli [14,40,44,47-49] or chronic cor pulmonale [50,51]. Thrombosis of the great veins: inferior vena cava, femoral veins, iliac veins, renal veins  and vena portae , have all been reported in the literature.
Serious complications of thromboembolism have included optic atrophy secondary to occlusion of optic artery, hemiparesis, severe hypertension due to renal infarcts, seizures or focal neurological signs due to cerebral thrombi. Sagittal sinus thrombosis was the presenting feature in an otherwise asymptomatic adolescent . Mudd et al in their international survey of 629 cases of CbS deficiency reported that only 4% of all thromboembolic events produced myocardial infarction .
It is to be noted here that during their young adult years, the chance that
an untreated CbS deficient individual previously free
of thromboembolic events would have such a clinically detected event during the
subsequent year was 1:25 . However, with the advent of ultrasonography, many
patients have been shown to have signs of early vascular disease even in the
absence of ischaemic symptoms. [9,53]. Mudd et al also surveyed 586
major surgeries and eye operations in CbS deficient
cases to establish postoperative thromboembolic complications and found six
fatal cases out of 25 postoperative thromboembolic events that developed .
Hence, if absolutely indicated, the great majority of surgery may be conducted
without vascular complications in patients with classical homocystinuria,
performed under stringent anticoagulant therapy and provided all special
precautions to prevent hypotension, dehydration and stasis of blood are adhered
to strictly [18,54-55].
Central nervous system involvement
About 21% of CbS deficient patients not treated from early infancy have had seizures, grand mal type accounting for 70% of it . Electroencephalographic abnormalities have been reported in cases of CbS deficiency, both with and without a history of convulsion. Excessive slow waves activity [25,49], is the most frequent finding, along with spikes or sharp waves discharges [9,21,56].
Abbott et al looked into the psychiatric manifestations among CbS
deficient individuals and found that four categories of mental illness
predominates: episodic depression (10%), chronic disorders of behaviour (17%),
chronic obsessive-compulsive disorder (5%), and personality disorder (19%).
Contrary to earlier anecdotal reports suggesting that schizophrenia may be
common amongst this group [14,43,51], Abbott et al did not find
sufficient evidence to establish a diagnosis of schizophrenia in any of the 63
individuals studied . Clinically significant psychiatric illness was found
Management and treatment
There are currently three recognized modalities of treatment :
Each of these modalities of treatment will be discussed here briefly.
Pyridoxine trial to ascertain responsive status 
The status of vitamin responsiveness in a neonate may be difficult to determine on biochemistry alone. While on a trial of pyridoxine, a falling homocysteine and methionine levels due to coincidental growth spurt, may be mistakenly attributed to vitamin responsiveness.
Doses of pyridoxine required for a response varies markedly among pyridoxine responders. Barber and Spaeth achieved responses to doses of 250 to 500 mg/day  while Gaull utilized 800-1200 mg/day of pyridoxine for similar response . However, Perry et al, pointed out that “a patient should not be considered unresponsive to pyridoxine until a dose of 500-1000 mg/day has been given for a period of several weeks” . In general, for older children, a dose of at least 150 mg/day of pyridoxine has been used, although an occasional patient has responded to only 25 mg/day . More recently, Wilcken et al has reported on doses of not more than 200mg/day achieving excellent control together with the appropriate additional therapy . Yap and Naughten in Ireland have used pyridoxine 50 mg tds in the neonate and for the older children, a dose of 100-200 mg tds .
Patient safety in the usage of these mega doses of pyridoxine has always featured in the minds of clinicians managing these cases. To date there are no reported side effects from the usage of high dose pyridoxine (up to 500mg/day) in classical homocystinuria, however, 7 non-homocystinuria adult cases have been reported with ataxia and sensory neuropathy on the misuse of megadoses of pyridoxine of 2 to 6 grams daily for 2 to 40 months . Such symptoms improved on withdrawal of pyridoxine.
It is appropriate here to remember that a biochemical response to pyridoxine may not manifest in a potentially responsive patient if folate depletion is present  and that patients not given folate while on pyridoxine becomes folate-depleted unless supplemented, but the optimal dose has not been established [64,66]. Centers in Sydney, Nijmegen, Dublin, Manchester and London, however, have used folate 5 mg daily .
For those that are responsive to pyridoxine, it remains debatable as to whether pyridoxine alone or in combination with other measures such as methionine restricted, cystine supplemented diet or betaine, a methyl donor, provides the optimal biochemical control. As shown by Boers et al, even the patients with maximal responsiveness to pyridoxine have reduced tolerance to methionine during methionine loading tests and pyridoxine only corrects the biochemical abnormalities in the fasting state . Such patients, in theory, may experience abnormal episodic surge in methionine or homocysteine following protein ingestion . Hence, it follows that these patients may benefit from some methionine restriction or the use of small frequent feedings [9,68] and Wilcken et al showed that the addition of betaine blunted the plasma total homocyst(e)ine in response to these methionine loads . They further suggested that betaine should be added to the treatment regimen of pyridoxine and folic acid in pyridoxine-responsive patients so that the homocysteine accumulation will be normal throughout the day during normal dietary intake [9,69].
Methionine restricted, cysteine supplemented diet
Perry et al devised a similar diet initially as treatment for a newborn infant, again a sibling to two known affected children . The diet entails reducing daily methionine intake to approximately 20-25 mg/kg body weight for infants, to 10-15 mg/kg body weight for growing children, and to 8-10 mg/kg for adults. L-cystine supplementation of 100-300 mg/kg body weight per day was instituted . They found that with this diet, the patient’s plasma methionine showed dramatic reduction with continued presence of homocystine and continuously subnormal plasma cystine despite supplementation. However, the plasma cystine did approach normal on the occasions when the plasma homocystine has been unusually low . This patient at 7.5 years old had normal growth and none of the recognized complications associated with the condition, a marked contrast to his two other affected siblings in whom had developed severe clinical disease by the age of 6 months . These children were not pyridoxine responsive.
Amelioration of biochemical findings was also noted in those late detected cases in whom some clinical disease may be already present when a methionine restricted cystine supplemented diet was commenced [1,72-6]. As to be expected there was no reversal of the major abnormalities already present before the commencement of dietary treatment, however, further progression of complications seems to be halted or ameliorated.
The parameters recommended to be monitored during dietary treatment are
normal growth rate, methioninaemia (< 40 mmol/L) and normal plasma
homocyst(e)ine. Plasma cystine should be maintained within the normal range of
67 ± 20 mmol/L and supplemented accordingly (up to 200 mg/kg/day) .
Currently, proprietary formulas based on a methionine-free synthetic mixture
supplemented with cystine are virtually in exclusive use [9,60].
Betaine-A methyl donor
Betaine is presumed to produce its biochemical effects by increasing the rate of homocysteine remethylation by betaine-homocysteine methyltransferase as more substrate for this reaction is made available. The resultant hypermethioninaemia does not appear to influence the pathophysiology of the disease and has so far not been reported to have any side effects in the literature. More recently, Wilcken et al reported that betaine used as an additional therapy is safe and effective for at least 16 years . Hence, betaine may be useful in pyridoxine nonresponsive patients who will not tolerate methionine restriction or as an adjunct to such a diet . Betaine is usually prescribed at 4 - 6 g/day divided into three daily doses [80,82].
Harker et al reported that pyridoxine in pyridoxine responsive cases and dipyridamole, a platelet aggregation inhibitor, in pyridoxine nonresponsive cases normalized decreased platelet survival and showed a marked decrease in vascular intimal lesions [84-8]. It is from these data that they recommended treatment with dipyridamole 400 mg daily or with the combination of dipyridamole 100mg daily and aspirin 1g daily. While on this regimen, they showed that two patients were free from thromboembolic events in the three years following the commencement of this regimen, whereas there were at least 5 such events in these patients in the year prior to the start of therapy. However, Schulman et al reported on 2 pyridoxine nonresponsive patients who suffered thromboembolic events while on this regimen [88,89].
As thromboembolic events are the major cause of morbidity and mortality in CbS
deficient patients, it is perhaps wise to avoid activities associated with an
increased risk of thromboembolism, e.g. the use of oral contraceptives
and perhaps, even pregnancy. Several workers have reported on the deleterious
vascular effects shortly after the start with oral contraceptives in females
with CbS deficiency [28,91-3]. More recently, in
normal women taking a monophasic sub-50 oral contraceptive there has been a
small but significant rise in fasting total homocyst(e)ine during the
low-hormone phase of the treatment cycle [9,93].
Diagnosis and diagnostic methods
Urinary amino acid analysis using column chromatography is less indicative
than in blood. Hypermethioninuria is not completely obligatory in CbS
deficiency and homocystinuria on its own does not confirm CbS
deficiency, however, if both are concomitantly present then it is conclusive.
Quantitative urinary amino acid analysis in CbS
deficiency may also reveal the presence of abnormal amounts of other sulphur-containing compounds, including the mixed disulphide of
cysteine-homocysteine, homolanthionine , S-adenosylhomocysteine, and
Accurate technique is crucial. In particular, the blood sample need to be deproteinised promptly, within 10 minutes, if underestimation of serum free Hcy is to be avoided due to the binding of sulphydryl and disulphide amino acid by disulphide interchange to the sulphydryl groups of plasma proteins. It is also important that the customary norleucine not be added to the sample as an internal standard in plasma amino acid analysis of homocystinuria as the mixed disulphide of cysteine and homocysteine is eluted at the same point making accurate quantitation impossible. g-aminobutyric acid or homoarginine, as well as other unusual amino acids, can be used as an internal standard. Rapid amino acid analyser systems that fails to separate homocystine from the ammonia peaks should also not be used in establishing a definitive diagnosis of classical homocystinuria or in biochemical response to treatment . If total Hcy is the measurement used in diagnosis, it is again imperative to separate the blood cells from the blood sample rather quickly to avoid inaccurate results.
Direct enzyme assays
Molecular diagnosis- CbS Mutational analysis
The catalytic activity of CbS in chorionic villi is insufficient for direct assay of the enzyme, however, using extracts of cells grown in tissue culture from chorionic villi, one CbS deficient fetus and two unaffected fetuses have been correctly diagnosed before the 12th week of gestation [9 ]. Hence, classical homocystinuria is one of the inherited metabolic disorders that can be reliably diagnosed in-utero.
Clinical outcome-Effect of chronic treatment
The efficacy of dietary treatment in the early treated patients on preventing ectopia lentis, mental retardation and especially radiographical evidence of osteoporosis and thromboembolic events was reported by Yap and Naughten . The Irish center reported on a lifetime free homocystine median of <11 mmol/L in those early treated, newborn screened pyridoxine non-responsive patients (n=15) with no complications. They all had vision of 20/20 . The full scale IQ ranged from 84 –120 (mean 105.8) in 13 of the Irish early treated and compliant patients (mean age 14.4 yrs; range 4.4-24.9). These patients also had comparable IQs to their unaffected siblings (n=10, mean age 19.4; range 9.7-32.9) with mean full scale IQ of 102 (range 76-116) . Similar findings were also reported in 11 pyridoxine non-responsive early treated patients in Manchester, England with median IQ of 100 (range 84-117), significantly better than the median of 58 (range 20-86) amongst those late diagnosed . There were no documented thromboembolic events amongst the Irish patients with 403.9 patient-years of treatment . Homocysteine-lowering treatment was also shown to reduce the vascular risk significantly, despite imperfect biochemical control, in a multicenter study involving 158 patients with 2822 patient-years of treatment 67.
Classical homocystinuria is a potentially treatable condition, especially if detected and treated early. Total homocysteine should be included in the work-up of patients with ectopia lentis, mental retardation, premature vascular events and osteoporosis.
Homocystinuria is inherited as an autosomal recessive trait, which means that the child must inherit the defective gene from both parents to be seriously affected. Usual findings in homocystinuria are nearsightedness, dislocation of the lens of the eye, and a tendency to develop blood clots in the veins and arteries.
Newborn infants appear normal, and early symptoms, if present at all, are vague and may occur as mildly delayed development or failure to thrive. Increasing visual problems may lead to diagnosis of this condition when the child, on examination, is discovered to have dislocated lenses and nearsightedness.
Some degree of mental retardation is usually seen, but some affected people have normal IQs. When mental retardation is present, it is generally progressive if left untreated. The condition can also increase the risk for psychiatric disorders.
Homocystinuria has several features in common with Marfan syndrome, including dislocation of the lens; a tall, thin build with long limbs; spidery fingers (arachnodactyly); and a pectus deformity of the chest. In addition, affected people may have high arches of the feet (pes cavus), knock-knees (genu valgum), and a curved spine (scoliosis).
Affected people commonly develop blood clots. These clots can dislodge and travel (i.e., form an embolus) and damage any tissue in which the clot lodges. Clots that travel to the brain can cause stroke, for example.