Almost all disorders of amino acid metabolism are caused by defects in catabolic pathways. However, a few genetic disorders of the biosynthesis of nonessential amino acids have been identified. Deficient endogenous production of serine, proline, ornithine, or glutamine each leads to a deficiency of the respective amino acid and to distinct diseases. The diagnosis requires recognizing a decrease of amino acid concentrations below the reference range. Children with disorders of synthetic pathways are not prone to decompensation under catabolic stress. However, they share signs of compromised intrauterine development and central nervous dysfunction and, if severely affected, suffer from dysmorphism and congenital malformations.
DISORDERS OF L-SERINE SYNTHESIS
De novo synthesis of L-serine from glucose (see Fig. 133-1) is necessary to provide the organism with sufficient quantities of serine required for protein synthesis, modification of complex lipids, and as a donor of transferable 1-carbon units for the synthesis of the nucleotide bases adenine, guanine, and thymine. Genetic defects in each of the 3 steps of serine synthesis are associated with neurologic disease comprised of a global developmental disorder, microcephaly, seizures, and progressive polyneuropathy. Severe deficiency of any of the 3 enzymes is one of the main causes for the genetically heterogenous Neu-Laxova syndrome (NLS), which is characterized by intrauterine growth failure, facial dysmorphism (shortened eyelids, proptosis, round gaping mouth), microcephaly, hyperkeratosis or even ichthyosis, flexion deformities, peripheral edema, and malformations of central nervous system (CNS) and limbs, with an often fatal outcome.
Each of the 3 defects is very rare, but diagnosis is important, as children affected with attenuated forms benefit from L-serine supplementation, and each has an autosomal recessive risk of recurrence.
3-PHOSPHOGLYCERATE DEHYDROGENASE (3-PGDH) DEFICIENCY
PATHOGENESIS, EPIDEMIOLOGY, AND GENETICS
A biallelic disruption of the PHDGH gene on chromosome 1p12 is responsible for 3-PGDH deficiency (Online Mendelian Inheritance in Man [MIM] no. 601815). 3-PGDH catalyzes the first step in L-serine biosynthesis, and deficient enzyme activity leads to serine deficiency. At least 100 cases of Neu-Laxova syndrome have been described, and significantly fewer children have attenuated forms.
Attenuated 3-PGDH deficiency is a neurometabolic disease characterized by intrauterine growth failure, congenital microcephaly, intractable seizures, and later, a global developmental disorder and spasticity. Cataracts and hypogonadism have also been observed. Brain magnetic resonance imaging (MRI) shows severe atrophy and hypomyelination. Mild forms may manifest with isolated late-onset seizures and signs of polyneuropathy.
DIAGNOSIS INCLUDING DIFFERENTIAL DIAGNOSIS
Amino acid analysis in cerebrospinal fluid (CSF) or preprandial plasma reveals decreased serine and moderately low glycine concentrations. 5-Methylfolate in CSF can be decreased. Postprandial amino acid levels may be normal. The diagnosis can be confirmed by enzyme assay in fibroblasts or by DNA-based testing.