Editorials

Homocystinuria

Although homocystinuria was described in 1962¹ and the ocular features were well characterised in 1973,² reports from different parts of the world suggest that the diagnosis is sometimes missed or delayed.^{3 4} In this week's BMJ, Cruysberg et al (p 1037) present data on 34 patients with homocystinuria in whom the mean delay in diagnosis was 11 years.⁵ Myopia was an early clinical sign in many patients, while some patients were diagnosed later because of subluxation of the lens (ectopia lentis), which may present as decreased vision, monocular diplopia or pain secondary to pupillary glaucoma, and vascular signs.

Ectopia lentis is present in 85 % of patients with homocystinuria,⁶ while as many as 5% of people with non-traumatic dislocation of the optic lens may be found to have homocystinuria.⁷ Why then is the diagnosis of homocystinuria problematic? Firstly, homocystinuria is rare, and other commoner diagnoses have to be considered. Secondly, there are technical problems in measuring the increased concentration of sulphur amino acids in body fluids.

Homocystinuria is due to deficiency of the enzyme cystathionine-ß-synthase, which converts methionine to cystathionine. The deficiency leads to the build up in the plasma of the intermediate chemicals homocysteine and homocystine (jointly refered to as homocyst(e)ine) and the excretion in the urine of homocystine. Homocystinuria is an autosomal recessive disorder with a worldwide distribution and an incidence of up to (in Ireland) 1 per 52 000 live births.⁸ Untreated, it carries risks of coronary artery disease, cerebrovascular disease, and thromboembolism. A meta-analysis of hyperhomocyst(e)inaemic patients has concluded that increases in total homocyst(e)ine concentrations of 5 µmol/l give an odds ratio for coronary artery disease of 1.6 and for cerebrovascular disease of 1.5.⁹ Homocystinuria is normally detected by measuring homocyst(e)ine in plasma or urine. Plasma samples should be deproteinised within a few minutes of collection since, on standing, homocyst(e)ine forms disulphide bonds with protein and will then be removed on deproteinisation.

The aim of treatment is to reduce the concentration of homocyst(e)ine in the body and therefore the potential for further systemic damage. Three main modes of treatment are available. The first intervention is usually to give supplemental vitamins. About half of patients respond to pyridoxine (vitamin B6) in doses up to 500mg/day.¹⁰ This increases the conversion of homocyst(e)ine to cystine. Fears about the risks of sensory neuropathy during long term treatment with pyridoxine have been allayed, but use is recommended of the smallest dose compatible with the absence of homocyst(e)ine from the plasma.¹¹ It may be necessary to add supplemental folate and vitamin B12 to achieve an adequate response to pyridoxine.¹² If a patient does not respond, dietary methionine restriction must be considered--to between 10 and 40 mg/day.¹⁰ The third therapeutic approach is to reduce the concentration of homocyst(e)ine by promoting its conversion back to methionine using the methyl donor, betaine,¹³ or its precursor, choline.¹⁰ Dietary treatment may need to be supported by treatment for specific systemic problems.

Cruysberg et al prompt questions as to whether the delay in diagnosis is preventable, at what cost, and at what benefit to the patient. The answers lie in what early interventions could be offered. An interesting study of five patients, three of whom presented with ectopia lentis and who commenced treatment after one and a half years, indicated that ectopia lentis progressed or developed in all the patients despite good biochemical control. In comparison, 11 of 14 patients who commenced treatment before 42 days and had good control did not develop ectopia lentis in the follow up period of 3.5-15.1 years.⁸ It is possible, therefore, that once damage to the zonular fibres that connect the lens to the ciliary body is initiated, subluxation occurs despite good biochemical control. It has been argued that surgical removal of the lens should be avoided if at all possible as some patients have died from thromboembolic disease after surgery or have suffered ocular complications. However, lensectomy has been offered to patients with subluxed lenses, and in two homocystinuric patients a visual acuity of 20/40 or better was achieved in the follow up period of 12 years.¹⁴

In terms of the other clinical effects associated with homocystinuria, family studies comparing untreated patients with siblings treated from birth with methionine restriction and cystine supplementation, demonstrated considerable clinical and biochemical improvement.¹⁰ However, dietary treatment offered later in life is less effective.¹³ Establishing the diagnosis is also important in the management of pregnancy¹⁵ and surgery.¹⁶ In addition, patients with thrombotic tendencies have been supported, on an experimental basis, with dipyridamole or aspirin.¹⁷ The answer to the implicit question posed by Cruysberg et al is that delay in diagnosis should be prevented as far as possible. Cruysberg and colleagues offer a helpful definition of "myopia plus" (as myopia associated with skeletal, central nervous, or vascular disease) to alert doctors to request appropriate diagnostic investigations.

Features of homocystinuria

Normal at birth

If untreated, patients develop:

   Progressive impairment of intellect

   Myopia and dislocation of optic lenses in childhood

   Thromboembolic events from the first year of life

   Marfanoid appearance

   Spinal osteoporosis in adolescence

About half of patients respond to vitamin B6

Non-responders need a methionine restricted diet

What are the implications of Cruysberg et al's observations for clinical practice and research? Firstly, their work emphasises the importance of undertaking appropriate tests in any patients with onset of severe myopia in childhood. This view is supported by a study of tests on 7500 urine and 4500 blood samples from 9000 selected patients, which resulted in the detection of four patients with homocystinuria.¹⁸ The natural course of homocystinuria is that lens dislocation will have occurred in half of patients by about 8 years of age whereas half of patients will have reached 29 years before a thromboembolic event occurs.⁶ There is therefore a window of opportunity of about 21 years to intervene to prevent thrombosis if a diagnosis is made at the time of lens dislocation. Secondly, Cruysberg et al's findings suggest the need for research into identifying suitable tests to undertake mass neonatal screening. Unfortunately, the use of hypermethioninaemia for this purpose is unreliable,^{6 19} and perhaps research would be better directed towards tests based on molecular genetic techniques.

DAVID M ISHERWOOD Consultant clinical biochemist

Department of Clinical Biochemistry, Royal Liverpool Children NHS Trust, Alder Hey Children's Hospital, Liverpool L12 2AP

David M Isherwood 

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