There are numerous disorders of methionine and sulfur metabolism (see the table Methionine and Sulfur Metabolism Disorders 
) as well as many other amino acid and organic acid metabolism disorders Overview of Amino Acid and Organic Acid Metabolism Disorders The kidneys actively reabsorb significant amounts of amino acids. Defects of amino acid transport in the renal tubule include cystinuria and Hartnup disease, which are discussed elsewhere. Amino... read more . See also Approach to the Patient With a Suspected Inherited Disorder of Metabolism Approach to the Patient With a Suspected Inherited Disorder of Metabolism Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more and testing for suspected inherited disorders of metabolism Initial testing Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and... read more .
Homocysteine is an intermediate in methionine metabolism; it is either remethylated to regenerate methionine or combined with serine in a series of transsulfuration reactions to form cystathionine and then cysteine. Cysteine is then metabolized to sulfite, taurine, and glutathione. Various defects in remethylation or transsulfuration can cause homocysteine to accumulate, resulting in disease.
The first step in methionine metabolism is its conversion to adenosylmethionine; this conversion requires the enzyme methionine adenosyltransferase. Deficiency of this enzyme results in methionine elevation, which is not clinically significant except that it causes false-positive neonatal screening Screening Tests for Newborns Screening recommendations for newborns vary by clinical context and state requirements. Blood typing is indicated when the mother has type O or Rh-negative blood or when minor blood antigens... read more results for homocystinuria.
Classic homocystinuria
This disorder is caused by an autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more deficiency of cystathionine beta-synthase, which catalyzes cystathionine formation from homocysteine and serine. Homocysteine accumulates and dimerizes to form the disulfide homocystine, which is excreted in the urine. Because remethylation is intact, some of the additional homocysteine is converted to methionine, which accumulates in the blood. Excess homocysteine predisposes to thrombosis and has adverse effects on connective tissue (perhaps involving fibrillin), particularly the eyes and skeleton; adverse neurologic effects may be due to thrombosis or a direct effect.
Arterial and venous thromboembolic phenomena can occur at any age. Many patients develop ectopia lentis (lens subluxation), intellectual disability, and osteoporosis. Patients can have a marfanoid habitus Marfan Syndrome Marfan syndrome consists of connective tissue anomalies resulting in ocular, skeletal, and cardiovascular abnormalities (eg, dilation of ascending aorta, which can lead to aortic dissection)... read more 
even though they are not usually tall.
Diagnosis of classic homocystinuria is by neonatal screening Screening Tests for Newborns Screening recommendations for newborns vary by clinical context and state requirements. Blood typing is indicated when the mother has type O or Rh-negative blood or when minor blood antigens... read more for elevated serum methionine; elevated total plasma homocysteine levels and/or DNA testing are confirmatory. Enzymatic assay in skin fibroblasts can also be done.
Treatment of classic homocystinuria Classic homocystinuria A number of defects in methionine metabolism lead to accumulation of homocysteine (and its dimer, homocystine) with adverse effects including thrombotic tendency, lens dislocation, and central... read more is a low-methionine diet and L-cysteine supplementation combined with high-dose pyridoxine (a cystathionine synthetase cofactor) 100 to 500 mg orally once a day. Because about half of patients respond to high-dose pyridoxine alone, some clinicians do not restrict methionine intake in these patients. Betaine (trimethylglycine), which enhances remethylation, can also help lower homocysteine. Betaine dosage is usually started at 100 to 125 mg/kg orally 2 times a day and titrated based on homocysteine levels; requirements vary widely, sometimes ≥ 9 g/day is needed. Folate 1 to 5 mg orally once a day is also given. With early treatment, intellectual outcome is normal or near normal. Vitamin C, 100 mg orally once a day, may also be given to help prevent thromboembolism.
Other forms of homocystinuria
Various defects in the remethylation process can result in homocystinuria. Defects include deficiencies of methionine synthase (MS) and MS reductase (MSR), delivery of methylcobalamin and adenosylcobalamin, and deficiency of methylenetetrahydrofolate reductase (MTHFR, which is required to generate the 5-methyltetrahydrofolate needed for the MS reaction). Because there is no methionine elevation in these forms of homocystinuria, they are not detected by neonatal screening.
Clinical manifestations are similar to other forms of homocystinuria. In addition, MS and MSR deficiencies are accompanied by neurologic deficits and megaloblastic anemia Megaloblastic Macrocytic Anemias Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based... read more 
. Clinical manifestation of MTHFR deficiency is variable, including intellectual disability, psychosis, weakness, ataxia, and spasticity.
Diagnosis of MS and MSR deficiencies is suggested by homocystinuria and megaloblastic anemia and confirmed by DNA testing. Patients with cobalamin defects have megaloblastic anemia and methylmalonic acidemia. MTHFR deficiency is diagnosed by DNA testing.
Treatment is by replacement of hydroxycobalamin 1 mg IM once a day (for patients with MS, MSR, and cobalamin defects) and folate in supplementation similar to characteristic homocystinuria.
Cystathioninuria
This disorder is caused by deficiency of cystathionase, which converts cystathionine to cysteine. Cystathionine accumulation results in increased urinary excretion but no clinical symptoms.
Sulfite oxidase deficiency
Sulfite oxidase converts sulfite to sulfate in the last step of cysteine and methionine degradation; it requires a molybdenum cofactor. Deficiency of either the enzyme or the cofactor causes similar disease; inheritance for both is autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more .
In its most severe form, clinical manifestations appear in neonates and include seizures, hypotonia, and myoclonus, progressing to early death. Patients with milder forms may present similarly to cerebral palsy Cerebral Palsy (CP) Syndromes Cerebral palsy refers to nonprogressive syndromes characterized by impaired voluntary movement or posture and resulting from prenatal developmental malformations or perinatal or postnatal central... read more and may have choreiform movements Chorea, Athetosis, and Hemiballismus Chorea is a nonrhythmic, jerky, rapid, nonsuppressible involuntary movement, mostly of the distal muscles and face; movements may be incorporated into semipurposeful acts that mask the involuntary... read more .
Diagnosis of sulfite oxidase deficiency is suggested by elevated urinary sulfite and confirmed by measuring enzyme levels in fibroblasts and cofactor levels in liver biopsy specimens and/or genetic testing. Treatment of sulfite oxidase deficiency is supportive.
More Information
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Online Mendelian Inheritance in Man® (OMIM®) database: Complete gene, molecular, and chromosomal location information
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
betaine |
CYSTADANE |
