Serine concentrations were markedly decreased in the cerebrospinal fluid of two brothers with congenital microcephaly, profound psychomotor retardation, hypertonia, epilepsy, growth retardation, and hypogonadism. The youngest boy also had congenital bilateral cataract. Magnetic resonance imaging of the brain showed evidence of dysmyelination. Plasma serine as well as plasma and cerebrospinal fluid glycine concentrations were also decreased but to a lesser extent. Treatment with oral serine in the youngest patient significantly increased cerebrospinal fluid serine and abolished the convulsions. In fibroblasts of both patients, a decreased activity was demonstrated of 3-phosphoglycerate dehydrogenase, the first step of serine biosynthesis ( 22% and 13% of the mean control value). This is an unusual disorder as the great majority of aminoacidopathies are catabolic defects. It is a severe but potentially treatable inborn error of metabolism that has not been previously reported in man.(Arch Dis Child 1996;74:542-545 Case reports The patients, two brothers, were from a Turkish family. The parents were first cousins. They were healthy and had a normal height and head circumference.Their first child was healthy and showed normal plasma amino acid concentrations. The third child (case 1) was born after a normal term pregnancy with weight of 2130 g (3rd centile 2600 g), length 43 cm (3rd centile 47 cm), and head circumference 29 cm (3rd centile 33 cm). At the age of 3.5 months he was admitted for investigation of congenital bilateral cataracts and feeding difficulties. Weight was 3700 g (3rd centile 5100 g), length 50.5 cm (3rd centile 58 cm), and head circumference 34.2 cm (3rd centile 39 cm). He was severely retarded, hypertonic, and hyperexcitable. Tendon reflexes were normal. There was adduction of the thumbs and pes calcaneovalgus. He also had small testes. At the age of 1 year he developed epilepsy. Laboratory investigation could not demonstrate intrauterine infection. Chromosomal analysis was normal. Plasma amino acid analysis by ion exchange chromatography and fluorescence detection revealed low fasting concentrations of serine (29 and 55; normal range for age 70-187 rnol/l) and low to normal fasting concentrations of glycine (77 and 97; 80-341 jimol/l). In the cerebrospinal fluid, protein was normal, serine was severely decreased (6; 35-80 gmol/l), and glycine was also decreased but less so (2.8; 3.6-9.0

NOTE.-Phosphomannomutase and protein were measured as described elsewhere (Van Schaftingen and Jaeken 1995; Jaeken et al. 1997a). Phosphomannose isomerase was assayed at 30ЊC in a reaction mixture (1 ml) containing 50 mM Hepes, pH 7.1, 5 mM MgCl 2 , 25 mM KCl, 1 mM dithiothreitol, 0.6 mM NAD ϩ , 0.5 mM mannose 6phosphate, 2.5 U/ml glucose 6-phosphate dehydrogenase from Leuconostoc mesenteroides, and 10 mg/ml phosphoglucose isomerase with 10 ml of an extract containing 5-20 mg protein/ml. Control and PMM deficient measures are mean values ‫ע‬ SD. Where two data are given, the values were obtained on two different subcultures.

The fundamental importance of correct protein glycosylation is abundantly clear in a group of diseases known as congenital disorders of glycosylation (CDGs). In these diseases, many biological functions are compromised, giving rise to a wide range of severe clinical conditions. By performing detailed analyses of the total serum glycoproteins as well as isolated transferrin and IgG, we have directly correlated aberrant glycosylation with a faulty glycosylation processing step. In one patient the complete absence of complex type sugars was consistent with ablation of GlcNAcTase II activity. In another CDG type II patient, the identification of specific hybrid sugars suggested that the defective processing step was cell type-specific and involved the mannosidase III pathway. In each case, complementary serum proteome analyses revealed significant changes in some 31 glycoproteins, including components of the complement system. This biochemical approach to charting diseases that involve alterations in glycan processing provides a rapid indicator of the nature, severity, and cell type specificity of the suboptimal glycan processing steps; allows links to genetic mutations; indicates the expression levels of proteins; and gives insight into the pathways affected in the disease process.

No abstract

The carbohydrate-deficient glycoprotein syndromes are a recently delineated group of genetic, multisystemic diseases with major nervous system involvement. Three distinct variants have been recognized and there are probably many more. They are characterized by a deficiency of the carbohydrate moiety of secretory glycoproteins, lysosomal enzymes and probably also membranous glycoproteins. The biochemical changes are most readily observed in serum transferrin and the diagnosis is usually made by isoelectric focusing of this glycoprotein. The deficiency of sialic acid, in particular, results in a cathodal shift and hence the presence of abnormal isoforms of transferrin with higher isoelectric points than normal. The basic defects are probably in the processing and synthesis of the carbohydrate moiety of glycoproteins; there is indirect evidence for a deficiency of asparagine-N-linked oligosaccharide transfer in type I (endoplasmic reticulum defect) and for a deficiency of N-acetylglucosaminyltransferase II in type II (Golgi defect). From the large number of patients detected in only a few years, it is expected that these diseases will become as important as, for example, the lysosomal, peroxisomal or mitochondrial disorders. Their study will undoubtedly yield a wealth of new information on the function of glycoproteins and of their carbohydrate moiety.