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HOMOCYSTINURIA

Introduction

Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine. Homocystinuria is an autosomal recessively inherited defect in the transsulfuration pathway (homocystinuria I) or methylation pathway (homocystinuria II and III).

Pathophysiology

The accumulation of homocysteine and its metabolites is caused by disruption of any of the 3 interrelated pathways of methionine metabolism—deficiency in the cystathionine B-synthase (CBS) enzyme, defective methylcobalamin synthesis, or abnormality in methylene tetrahydrofolate reductase (MTHFR). Clinical syndromes resulting from each of these metabolic abnormalities have been termed homocystinuria I, II, and III. Three different cofactors/vitamins—pyridoxal 5-phosphate, methylcobalamin, and folate—are necessary for the 3 different metabolic paths. The pathway, starting at methionine, progressing through homocysteine, and onward to cysteine, is termed the transsulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed the remethylation pathway. A minor amount of remethylation takes place via an alternative route using betaine as the methyl donor. [2]

Epidemiology

The incidence of homocystinuria in the United States is approximately 1 per 100,000. Internationally, the reported incidence of homocystinuria varies between 1 in 50,000 and 1 in 200,000. Early diagnosis and intervention have helped in preventing some of the complications of homocystinuria, including ectopia lentis, mental retardation, and thromboembolic events. A mortality rate of 18% by age 30 has been reported by Mudd et al from a worldwide series of 629 patients with CBS enzyme deficiency. [4] Death is predominantly due to cerebrovascular or cardiovascular causes. Children with CBS deficiency (homocystinuria I) may be normal at birth. Data from Mudd et al suggest that starting at around age 20 years, these patients have an increasing likelihood of suffering a thromboembolic event. Patients with either defective methylcobalamin synthesis or defective tetrahydrofolate metabolism may present in early infancy.

Clinical Presentation

Homocystinuria is associated with the following physical findings: Downward dislocation of lens (ectopia lentis) Marfanoid habitus Pes excavatum, pes carinatum, and genu valgum Mental retardation Signs and symptoms of strokes in any vascular distribution: hemiplegia, aphasia, ataxia, and pseudobulbar palsy are among the most common findings. Patients with classic homocystinuria may first be recognized because of downward dislocation of the lens (ectopia lentis) [5] , marfanoid habitus, mental retardation [5] , and/or seizures. Patients with defective methylcobalamin synthesis may have all of these features, along with symptoms of methylmalonic acidemia (see Metabolic Disease and Stroke - Methylmalonic Acidemia). Acute stroke symptoms may occur in these patients. Traditional risk factors—hypertension, smoking, and diabetes—may or may not be present. The oral health of 14 patients with homozygote cystathionine beta synthase-deficient homocystinuria was evaluated in a Swedish study and found to be compromised in a majority of cases. The authors suggested that methionine restriction (low-protein diet) in the treatment of homocystinuria may result in a diet high in sugars. They therefore noted the need for regular dental checkups and preventive oral care for individuals suffering from homocystinuria. In addition, the authors noted that all patients had short dental roots, particularly of the central maxillary incisors. [6] In a Spanish cross-sectional survey sent to 35 hospitals, 75 patients were identified with homocystinuria: 41 with transsulfuration defects (1 death), 27 with remethylation defects (6 deaths), and 7 without a syndromic diagnosis. In 18 cases, more than one sibling was affected. Patients with remethylation defects had the most severe clinical manifestations. There was a high percentage of cognitive impairment, followed by lens diseases. Neurologic disorders were present in almost half of the patients, and there was increased vascular involvement in CBS-deficient adults. [7]