Rudolph's Pediatrics, 22nd Ed.

CHAPTER 139. Disorders of Glycine, Serine, and Proline Metabolism

Bernd Christian Schwahn

Four known defects in glycine metabolism lead to distinct biochemical or clinical pheno-types.

GLYCINE ENCEPHALOPATHY (NONKETOTIC HYPERGLYCINEMIA)

Glycine encephalopathy (GCE) is an inherited metabolic disorder in which large amounts of glycine are found in body fluids, without further metabolic abnormalities.

CLINICAL PRESENTATION

GCE typically presents with severe neonatal epileptic encephalopathy. Neonates appear normal at birth but develop myoclonic seizures, hiccough, apnea, muscular hypotonia, and unresponsiveness within the first 2 days of life. Their EEG shows a typical burst-suppression pattern. Many affected individuals die early, and survivors are severely retarded or developmentally arrested.1 Rarely, neonatal transient variants and late-onset forms have been described. These can present after an apparently asymptomatic period of months or even years with various symptoms such as mental retardation, episodes of chorea, vertical gaze palsy and delirium, or progressive spastic diplegia and optic atrophy.2,3

METABOLIC DERANGEMENT, INCLUDING PATHOPHYSIOLOGY

GCE is caused by defects in the mitochondrial glycine cleavage system (GCS) a multiprotein complex that catalyzes the degradation of glycine to CO2 and NH3, thereby transferring a one-carbon unit onto tetrahydrofolate to form 5,10-methylenetetrahydrofolate (MeTHF). A block in the GCS leads to accumulation of glycine and a lack of MeTHF, which promotes further production of glycine from serine.  The accumulation of glycine in GCE is most pronounced in the cerebral compartment, where its increased concentration is thought to be directly responsible for the observed neurological symptoms.

GENETICS

All forms of GCE (OMIM no. 605809) are inherited as autosomal recessive traits. The enzyme is multimeric with four distinct protein components.  Several mutations in the P and T genes and one in the H gene have been found, with the T protein being most commonly affected.4,5

DIAGNOSTIC TESTS, DIFFERENTIAL DIAGNOSES

Hyperglycinemia on plasma amino acid analysis in the absence of ketoacidosis makes GCE likely. Analysis of organic acids in urine helps to differentiate it from hyperglycinemia secondary to organic acidemia (see Chapter 137). In GCE, glycine is especially raised in CSF, and the ratio of its concentration in CSF to that in plasma is usually above 0.08, whereas it will be at least above 0.04 in most atypical cases.2,5 The diagnosis can be confirmed by enzyme assay in transformed lymphocytes9 or by liver biopsy.

TREATMENT, PROGNOSIS, AND LONG-TERM OUTCOME

There is no effective treatment for early onset GCE, and affected children have a very poor prognosis, with a shortened life span.1 In late-onset variants, there has been modest success with large doses of sodium benzoate, which is conjugated with glycine to form hippurate that can be excreted with urine.

Table 139-1. Other Rare Disorders of Glycine, Serine, and Proline Metabolism

SERINE SYNTHESIS DEFECTS

Three defects have been demonstrated in the synthesis of serine. They are extremely rare but potentially treatable and easy to diagnose.

DISORDERS OF PROLINE AND HYDROXYPROLINE METABOLISM

While a number of disorders in the metabolism of proline and hydroxyproline have been described, only three may be associated with clinical disease. In hyperprolinemia, a defect in the catabolism of proline leads to its accumulation alone (type 1) or together with the metabolite pyrroline-5-carboxylate (type 2). Delta-1-pyrroline 5-carboxylate synthetase deficiency is another example of an amino acid synthesis disorder.

HYPERPROLINEMIA TYPE 1

CLINICAL PRESENTATION

Hyperprolinemia type 1 is asymptomatic in most affected individuals but can be associated with cognitive impairment, epilepsy, and psychiatric features in a subset of patients.

DIAGNOSTIC TESTS, INCLUDING DIFFERENTIAL DIAGNOSES

Plasma or urinary amino acid analysis reveals grossly elevated proline concentrations in the range of 500 to 2000 μmol/L.

HYPERPROLINEMIA TYPE 2

CLINICAL PRESENTATION

Hyperprolinemia type 2 is usually associated with epilepsy and often with developmental retardation and cognitive impairment.

Plasma or urinary amino acid analysis reveals grossly elevated proline concentrations of over 2000 μmol/L. As in hyperprolinemia type 1, the urinary excretion of hydroxypro-line and glycine is increased.

DELTA-1-PYRROLINE-5-CARBOXYLATE SYNTHETASE (PCS) DEFICIENCY

CLINICAL PRESENTATION

Two children who presented with neurodegeneration, cataracts, joint hypermobility, and skin laxity were confirmed to suffer from PCS deficiency.38

METABOLIC DERANGEMENT, INCLUDING PATHOPHYSIOLOGY

PCS deficiency causes an insufficient synthesis of proline and ornithine. A relative deficiency of the urea cycle intermediates ornithine, citrulline, and arginine leads to hyperammonemia, which is aggravated by fasting.39,40

See Table 139-1 for other rare disorders of glycine, proline and serine metabolism.