D-Glyceric Aciduria

A number sign (#) is used with this entry because of evidence that D-glyceric aciduria is caused by homozygous mutation in the GLYCTK gene (610516) on chromosome 3p21.

Description

D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).

Clinical Features

In the son of nonconsanguineous Serbian parents, Brandt et al. (1974, 1976) described nonketotic hyperglycinemia with the excretion of D-glyceric acid in the urine and the presence of this substance in the serum. Clinical features included neonatal hypotonia, delayed psychomotor development, mental retardation, and seizures. He died at age 3.5 years (Duran et al., 1987; Sass et al., 2010). Brandt et al. (1974) suggested that the large amounts of glycine found in bodily fluids were secondary to a hitherto undescribed enzymatic defect in the degradation of D-glyceric acid. Kolvraa et al. (1976) found that D-glyceric dehydrogenase activity in blood leukocytes was low. They suggested that accumulation of glycine was secondary to the organic acidemia. In the Serbian patient originally reported by Brandt et al. (1974), Sass et al. (2010) identified a homozygous frameshift mutation in the GLYCTK gene (610516.0001). The finding of increased glycine in this patient had been considered to be secondary to the GLYCTK defect. However, Swanson et al. (2017) identified a homozygous missense mutation in the AMT gene (S117L; 238310.0009) in cells derived from this patient, consistent with a diagnosis of glycine encephalopathy (GCE; 605899). The finding confirmed the unusual cooccurrence of 2 inborn errors of metabolism in this patient. In vitro functional expression studies showed that the S117S mutant AMT protein was unstable and had only 9% residual enzymatic activity compared to controls. Swanson et al. (2017) concluded that D-glyceric aciduria does not cause deficient glycine cleavage enzyme activity or nonketotic hyperglycinemia.

Bonham et al. (1990) reported a consanguineous Asian family in which 4 sibs showed variable manifestations of D-glutaric aciduria. Two sibs had microcephaly and mild speech delay, but the other 2 were completely healthy at ages 9 and 7 years, respectively. All attended normal schools. Biochemical studies of 2 patients showed increased D-glutaric acid excretion after both serine and fructose oral loading. The levels of serum D-glutaric acid were similar to those reported in other cases, and Bonham et al. (1990) was unable to explain the mild clinical presentation in their family.

Largilliere et al. (1991) reported a girl, born of consanguineous Turkish parents, who presented at age 8 months with poor growth and delayed psychomotor development. She had microcephaly, axial hypotonia, limb spasticity, and elevated levels of D-glyceric acid in urine, plasma, and CSF. She subsequently developed seizures and had episodes of hypertonia and opisthotonus. At age 3 years, she had severe spastic tetraplegia and encephalopathy. Biochemical studies showed an increase in D-glyceric acid levels after serine loading, and after fructose loading in the fed condition. Largilliere et al. (1991) considered that direct toxicity of D-glyceric acid was unlikely because of the clinical heterogeneity among reported patients.

Topcu et al. (2002) reported a 6-month-old boy, born of consanguineous Turkish parents, who presented with unresponsiveness and episodic jerky movements. He had poor eye contact, autistic behavior with head rocking movements, hypotonia, and hyperactive reflexes. EEG showed hypsarrhythmia, consistent with West syndrome. Laboratory studies at age 11 months showed D-glyceric aciduria. Brain MRI at age 16 months showed focal hyperintense areas in the periventricular and subcortical white matter, cerebral atrophy, and delayed myelination. There were also reversible abnormalities in the mesencephalon, thalami, and globus pallidum, which resolved after fructose restriction in the diet. Over the next few years, he continued to have seizures and showed severe motor and mental retardation. He also developed sensorineural hearing loss.

Sass et al. (2010) reported 2 unrelated infants with D-glyceric aciduria. A female infant was born prematurely of a Mexican mother and had multiple problems due to prematurity, including neonatal respiratory distress syndrome. She also had optic nerve hypoplasia, severe failure to thrive, microcephaly, and seizures. Brain MRI showed delayed myelination, and neurologic examination revealed hypotonia, spasticity, severe mental retardation, and refractory tonic-clonic seizures. A male infant, born of consanguineous Turkish parents, had recurrent episodic hypoglycemia beginning soon after birth, which was found to be due to combined pituitary hormone deficiency-5 (CPHD5; 182230) resulting from a homozygous mutation in the HESX1 gene (601802). Further laboratory studies showed increased urinary D-glyceric acid without oxalic aciduria.

Biochemical Features

Using a new, sensitive radiochemical assay, Van Schaftingen (1989) demonstrated that D-glycerate kinase (610516) was extremely unstable in extracts of liver prepared in water but was partially stabilized in a homogenization mixture containing inorganic phosphate, D-glycerate, and EGTA. In the liver of a patient with this disorder, glycerate kinase activity was less than 5% of normal. In contrast, D-glycerate dehydrogenase (glyoxylate reductase) and triokinase activities were not deficient in the liver of the same patient. Van Schaftingen (1991) suggested that D-glycerate kinase deficiency is a cause (and perhaps the only cause) of D-glyceric aciduria.

Molecular Genetics

In 3 unrelated patients with D-glyceric aciduria, Sass et al. (2010) identified 3 different homozygous loss of function mutations in the GLYCTK gene (610516.0001-610516.0003). One of the patients was the Serbian boy previously reported by Brandt et al. (1974).