Homocystinuria Underrecognized in Clinical Practice
ABSTRACTS & COMMENTARY
Sources: Cruysberg JR, et al. Delay in diagnosis of homocystinuria: Retrospective study of consecutive patients. BMJ 1996;313:1037-1040; Petri M, et al. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-1124.
Cruysberg and colleagues performed a retrospective analysis of 34 consecutive patients who received a diagnosis of familial homocystinuria at a university hospital in the Netherlands. All patients reviewed had very high homocysteine levels, up to 20 times the normal upper limit of 19 umol/L. The mean age at diagnosis was 24 (range, 1-61), despite frequent prior documentation of ocular manifestations and serious complications in the vascular, skeletal, and central nervous system by clinicians of various disciplines. There was a mean delay of 11 years (range, 0-43) between the first major signs of disease and the ultimate diagnosis of homocystinuria. In 23 patients (68%), the diagnosis was not made until adulthood (range 20-61 years).
In a prospective analysis of 337 patients at Johns Hopkins Hospital with systemic lupus erythematosus (SLE), Petri et al examined plasma homocysteine levels to assess whether it was an independent risk factor for stroke and other thrombotic events. The investigators considered even slight elevations in homocysteine (> 14.1 umol/L) abnormal for the purposes of their study; these elevations were seen in 51 (15%) of SLE patients. Patients were followed for a mean of 4.8 years, during which time there were 29 cases of stroke and 31 arterial thrombotic events. In univariate analyses, raised homocysteine levels were significantly associated with stroke (odds ratio, 2.24; P = 0.01) and arterial thrombosis (odds ratio, 3.74; P = 0.0001). In comparison, other risk factors such as hypertension (odds ratio, 2.16; P = 0.05) or anticardiolipin antibodies (odds ratio, 1.39; P = 0.43) were less significant. There was a calculated 17.3% increased risk for stroke and 27.3% risk for arterial thrombosis with an elevation in homocysteine. The increased levels of plasma homocysteine were also associated with low folate and pyridoxal phosphate levels in the blood.
COMMENTARY
Although familial homocystinuria (the inability to convert methionine to cysteine due to an autosomal recessive deficiency of cystathionine synthetase) has been recognized for more than three decades (see Neuro Alert 1996;14:39), it appears from the study by Cruysberg et al that the diagnosis can often be missed or delayed. The relatively low incidence (up to 1 per 50,000 births) may contribute to it not being more frequently considered, but recognition of associated clinical features may help in making the proper diagnosis. Early, severe myopia or subluxation of the lens is present in 85% of patients up to 11 years before other systemic complications. Early diagnosis and treatment, with about half of patients responding to simple vitamin supplementation (pyridoxine or vitamin B6, folate, and vitamin B12) or dietary methionine restriction, may prevent serious complications of stroke.
While stroke in SLE has been recognized to occur by a variety of mechanisms (see Neuro Alert 1995;13:74-75), the prospective analysis by Petri et al may have identified another potentially modifiable risk factor in this young patient population. The significance of mildly elevated homocysteine levels for the general population was documented in the Framingham Heart Study with increased relative risk for stroke and carotid artery disease, and also appears to be an additional risk factor for this predisposed group of patients with collagen-vascular disease. Such slight increases in homocysteine in these patients are unlikely to have accompanying ocular or systemic manifestations seen in familial homocystinuria. Nonetheless, it would appear warranted to examine homocysteine levels in SLE patients with stroke, or other young patients with stroke of undetermined cause, and to begin empiric vitamin therapy for prevention of recurrent thrombotic events. Additional studies must be performed to determine how the disease course can be modified with simple nutritional supplementation. ba
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