Sarcosinemia

ABSTRACT

• Sarcosinemia is a phenotype characterized by increased concentration of sarcosine (N-methylglycine) in plasma and increased excretion of sarcosine in urine. Sarcosinemia occurs because of a defect in the conversion of sarcosine to glycine that is catalyzed by sarcosine dehydrogenase. A deficiency of sarcosine dehydrogenase can occur because of a genetic alteration in the apoenzyme, a dysfunction of a necessary electron transfer flavoprotein, or a severe deficiency of folic acid.

• The formation and degradation of sarcosine occur in liver and kidney tissue. Sarcosine is formed enzymatically from dimethylglycine by dimethylglycine dehydrogenase (EC 1.5.99.2) and converted to glycine by sarcosine dehydrogenase (EC 1.5.99.1). A small fraction of sarcosine may be generated from glycine by the enzyme glycine methyltransferase (EC 2.1.1.20)

• It was originally reported that sarcosinemia was causally related to mental retardation or neurologic problems. It is most probable that sarcosinemia is a “benign” condition that is unrelated to neurologic symptoms or significant clinical problems.

• Sarcosinemia that occurs from a genetic deficiency of sarcosine dehydrogenase activity is inherited as an autosomal recessive condition. The incidence of sarcosinemia found in newborn screening programs that evaluate urine specimens has varied from 1/350,000 (New England) to 1/28,000 (Quebec). Detection of heterozygotes by sarcosine loading studies is unreliable. The gene for human sarcosine dehydrogenase has been cloned and is located on chromosome 9q34.

• A mouse with the phenotype of sarcosinemia and sarcosinuria has been identified. In the mouse, sarcosinemia has occurred from a deficiency of sarcosine dehydrogenase activity in liver mitochondria. The phenotype is genetically transmitted as an autosomal recessive trait, and the gene has been mapped to chromosome 2 within 15 to 18 cM of the centromere.

INTRODUCTION

Sarcosinemia (MIM 268900) is a rare and controversial disorder. Originally described in 1966 in a child with mental retardation, it was assumed that sarcosinemia, in a manner similar to that seen in phenylketonuria, was responsible for the child's neurologic symptoms.¹ In the following years, additional persons were identified with sarcosinemia; some had symptoms of mental disorder, others had congenital defects, and still others were clinically normal. It was subsequently proposed that the finding of sarcosinemia in individuals with neurologic symptoms most likely occurred because of ascertainment bias, i.e., only persons with clinical problems routinely underwent evaluation for alterations in plasma or urine amino acid concentrations. This concept of sarcosinemia being a benign condition is currently the most prevalent belief, but some doubt remains, based on family data and the fact that more than a single biochemical mechanism may account for elevated concentrations of sarcosine in biologic fluid.

The enzymatic error in the most common phenotype of sarcosinemia is in the activity of sarcosine dehydrogenase. Precise and convincing enzymatic data are lacking in these patients because of the rarity of the clinical condition and the ethical limitations imposed in obtaining liver or kidney tissue for biochemical evaluation. Genetic data are consistent with an autosomal recessive mode of ...