SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.

SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably ß-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.

Activity and behavioral development in stunted and nonstunted children and response to nutritional supplementation.

It is frequently assumed that undernutrition in young children leads to poor development through reduced activity. 3 groups of 26 1-year-old stunted children were studied: nutritional supplementation, supplementation with psychosocial stimulation, and controls. 26 nonstunted comparison children were also studied. Activity levels were measured by extensive observation in the homes, and development using 4 subscales of the Griffith's Mental Development Scales. Initially, stunted children were less active than nonstunted ones (p < .01), but after 6 months they caught up regardless of treatment. The mental ages of the stunted children were lower than those of the nonstunted children initially, and improved with either treatment. Initially, activity levels made a significant contribution to the variance in the locomotor subscale only, but not 6 months later. Activity did not predict change in development over 6 or 12 months, nor did change in activity over 6 months predict change in development over 12 months.

Effects of nutrient intake on growth, insulin-like growth factors, and their binding proteins in a Laron-type dwarf.

In Laron-type dwarfism, a basal growth rate independent of GH and insulin-like growth factor-I (IGF-I) is maintained. This represents a unique model to further assess the relationship between growth and nutritional status. In a child aged 3 yr, 7 months with severe anorexia, growth was followed in relation to his caloric intake. While receiving 496 Cal/day with 11.6 g/day protein, he grew at a rate of 2 cm/yr (period I). The mean plasma IGF-I level was below 0.07 U/mL, insulin was 3.8 +/- 0.2 microU/mL, and blood glucose was 2.9 +/- 0.3 mM/L. During moderate hyperalimentation with 1280 Cal/day and 38.3 g/day protein (period II) for 7 months, growth rate increased to 9 cm/yr with no significant change in plasma IGF-I and persistence of relative hypoinsulinemia (low response to oral glucose tolerance test). IGF-binding proteins, analyzed by Western ligand blotting, showed that 41.5- and 38.5-kilodalton forms, which were initially low, increased to form a pattern similar to that observed in hypopituitarism. These results suggest that catch-up growth did not require normal circulating GH and/or IGF-I activity. Therefore, nutrition contributes to catch-up growth and achievement of potential statural growth by a distinct cellular effect.

[Two cases of gluten intolerance presenting as dwarfism (author's transl)]. / A propos de deux observations d'intolérance au gluten révélée par un nanisme.

Two patients with dwarfism were found to have intolerance to gluten. The authors describe the clinical, biological and radiological signs which enable the growth disorder to be related to its true cause, when obvious signs of a celiac syndrome are lacking. In fact, a small intestine biopsy is the essential diagnostic procedure. The hormonal changes found in such patients are discussed, and include normal HGH levels, reduced somatomedin activity which becomes normal after a gluten-free diet, and low blood insulin levels in the basal state as in insulin tolerance tests.

[Hereditary deficiency of isomaltase and saccharase responsible for a malabsorption syndrone (author's transl)]. / Hereditärer Isomaltase-Saccharase-Mangel der Dünndarmschleimhaut als Ursache für ein Malabsorptionssyndrom

Among 135 infants and children with a supposed malabsorption syndrome, a deficiency of isomaltase-saccharase of the duodenal mucosa was detected in 5 cases by measuring the disaccharidases directly in the mucosa homogenate. In one instance a deficiency of lactase was found in addition. In all patients the villi were of normal length, with an increased cell infiltration of the stroma detected in two cases. The loading tests with xylose-sucrose yielded a diminuished rise in the blood glucose level. Three of the patients were dwarfish, but only one showed an increased growth after the reduction of sucrose in the supplied diet. As a result of adaptation difficulties in the change of diet, one patient had to be treated with an additional saccharase substitution.