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Technical Briefs |
1
Serv. de Bioquím.,
2
Neurol., i
3
Pediatr., Hosp. Univ. Sant Joan de Déu, Passeig de Sant Joan de Déu 2, 08950-Esplugues, Barcelona, Spain;
a author
for correspondence: fax 34-3-2803626
Hyperhomocysteinemia is a common condition with genetic and environmental causes (1), and associated, especially in its severe form, with risk of premature atherosclerosis and thrombosis (2). Testing for hyperhomocysteinemia in children may be useful for investigation of patients with clinical features of homocystinuria (2), and for the assessment of nutritional status (3). Moreover, the investigation of causes of mild hyperhomocysteinemia, such as diabetes (1) or renal failure (4), may clarify the etiology of this abnormality. The possibility of easily correcting hyperhomocysteinemia by diet suggests potential utility of screening within some populations (5).
Screening for hyperhomocysteinemia in children has rarely been reported. In infants, total homocysteine (tHcy) measurement was reported only in a group on macrobiotic diets (6) and, in children, in a group with leukemia (7). Recently, a group of children with premature cardiovascular death in their male relatives was studied and the modest increase of plasma tHcy was partly attributed to genetic factors (8).
Our aim was to screen for hyperhomocysteinemia in children at risk, owing to genetic or environmental causes, (a) to discover individual patients with primary hyperhomocysteinemia and (b) to compare tHcy concentrations of certain groups of children at risk with those of age-matched reference values.
Screening was performed in the following groups: Group 1: genetic factors: (a) possible heterozygotes for cystathionine ß-synthase (CBS; EC 4.2.1.22) deficiency (n = 10) among young relatives of patients; (b) Marfan phenotype (n = 5); (c) stroke [(n = 53): ischemic infarct and (or) thrombosis (n = 38); hemorrhage (n = 13) and MELAS syndrome (n = 2)]; (d) megaloblastic anemia (n = 1); Group 2: secondary abnormalities: (a) well-controlled diabetes mellitus without renal failure (n = 135); (b) renal failure [(n = 13): nephrotic syndrome (n = 7), cystinuria–lysinuria (n = 2) and Fanconi syndrome: cystinosis (n = 1), Löwe syndrome (n = 2), and tyrosinemia type I (n = 1)], and (c) anorexia nervosa (n = 43).
Reference values were established in apparently healthy children who
underwent presurgical analysis for minor interventions (n = 195;
age range 2 months–18 years). tHcy was independent of sex, and
increased significantly with age (9) (Table 1
). Samples of patients and controls were obtained in accordance
with the Helsinki Declaration of 1975, as revised in 1983.
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tHcy was determined by HPLC with fluorescence detection (9).
We found (Table 1
) two patients with primary CBS deficiency: a
12-year-old girl with marfanoid phenotype and cataracts and a
6-month-old male with fatal hemorrhagic infarct. Moreover, we found a
patient with a probable defect of cobalamin metabolism (CblE or CblG),
with isolated homocystinuria associated with megaloblastic anemia. We
also found 7 of 10 probable heterozygotes for CBS deficiency with mild
hyperhomocysteinemia. Significant differences were found in children
with stroke (P <0.02–P <0.0001) and in
adolescents with anorexia nervosa (P <0.001–P
<0.0001). In the stroke group, tHcy did not show significant
differences in children with hemorrhage (median 7.5; range 2.6–25.2
µmol/L; n = 13) compared with those with ischemic infarct
(median 7.7; range 3.5–15 µmol/L; n = 38), so that all of them
were grouped only according to age (Table 1
). Three patients from this
group showed mild hyperhomocysteinemia (15, 16.5, and 25.2 µmol/L) of
undetermined etiology. Children with renal failure and diabetes
mellitus did not show significant differences compared with reference
values.
The use of very sensitive methods with low detection limits (HPLC with fluorescence detection) to screen for tHcy is necessary, because moderate hyperhomocysteinemia (15–40 µmol/L) may be difficult to detect by routine amino acid analysis in some genetic defects [such as vitamin B6-responsive CBS, 5,10-methylenetetrahydrofolate reductase (EC 1.7.99.5), or cobalamin metabolism defects] and undernutrition states (5). Even with sensitive methods, detection of heterozygotes for CBS deficiency is poor in basal conditions and after methionine loading (10). Reference values for the loading test are difficult to obtain in children for ethical reasons. However, the investigation of family members of homocystinuric patients either by tHcy measurement or by molecular analysis of known mutations seems necessary in view of the risk involved in mild lifelong hyperhomocysteinemia and the possibility of correcting it by vitamin supplementation (1).
An increasing number of young patients have recently been reported with stroke episodes caused by genetic defects in homocysteine metabolism, either isolated or associated with other risk factors of thrombosis (factor V Leiden, protein C or S or antithrombin III deficiency) or exogenous triggering factors (diarrhea, dehydration, surgery) (11)(12). We diagnosed a classic homocystinuria within this group and three other patients with mild hyperhomocysteinemia.
Testing tHcy seems also indispensable in patients with atypical anemias. Defects in cobalamin metabolism (CblC, D, E, G) (2)(13) may be difficult to diagnose unless tHcy is measured; diagnosis is important, as the response to hydroxycobalamin therapy is good.
Although hyperhomocysteinemia was reported in adults with chronic renal failure (4), tHcy values were within the reference range in our children except for a girl with cystinuria–lysinuria and a boy with tyrosinemia type I. However, tHcy was significantly increased in the urine of the group with Fanconi syndrome and cystinuria–lysinuria, but not in those with nephrotic syndrome. Impaired tubular cell function may depress the intracellular Hcy metabolism accounting for the high tHcy observed in chronic renal failure (4).
Plasma tHcy was also normal in well-controlled diabetic children with normal renal function. Type I diabetes mellitus is not per se associated with increased plasma tHcy, provided renal function is conserved (1).
tHcy values were above the P97.5 of the reference values in 34% of our anorexic group, and higher than the P90 in 53% of patients. Methylmalonate excretion in 13 anorexic patients at diagnosis was within the reference range (data not shown), suggesting that intracellular folate depletion is preponderant in this group (3)(5).
In summary, testing for hyperhomocysteinemia is useful for investigation of children with phenotypic features of homocystinuria, especially stroke and atypical anemia, as well as undernutrition states.
Acknowledgments
We thank H.J. Blom (University Hospital Nijmegen, The Netherlands) for the enzymatic studies of CBS-deficient patients, and for their comments on these results. We also thank J. Moreno for skillful technical assistance.
References
The following articles in journals at HighWire Press have cited this article:
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  M. Cotellessa, G. Minniti, R. Cerone, F. Prigione, M. G. Calevo, and R. Lorini Low Total Plasma Homocysteine Concentrations in Patients With Type 1 Diabetes Diabetes Care, May 1, 2001; 24(5): 969 - 970. [Full Text]
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 E. Cardo, E. Monros, C. Colome, R. Artuch, J. Campistol, M. Pineda, and M. A. Vilaseca Children With Stroke: Polymorphism of the MTHFR Gene, Mild Hyperhomocysteinemia, and Vitamin Status J Child Neurol, May 1, 2000; 15(5): 295 - 298. [Abstract] [PDF]
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 I. M. van Beynum, J. A. M. Smeitink, M. den Heijer, M. T. W. B. te Poele Pothoff, and H. J. Blom Hyperhomocysteinemia : A Risk Factor for Ischemic Stroke in Children Circulation, April 27, 1999; 99(16): 2070 - 2072. [Abstract] [Full Text] [PDF]
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