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.

SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy.

PurposeSLC39A8 deficiency is a severe inborn error of metabolism that is caused by impaired function of manganese metabolism in humans. Mutations in SLC39A8 lead to impaired function of the manganese transporter ZIP8 and thus manganese deficiency. Due to the important role of Mn2+ as a cofactor for a variety of enzymes, the resulting phenotype is complex and severe. The manganese-dependence of ß-1,4-galactosyltransferases leads to secondary hypoglycosylation, making SLC39A8 deficiency both a disorder of trace element metabolism and a congenital disorder of glycosylation. Some hypoglycosylation disorders have previously been treated with galactose administration. The development of an effective treatment of the disorder by high-dose manganese substitution aims at correcting biochemical, and hopefully, clinical abnormalities.MethodsTwo SCL39A8 deficient patients were treated with 15 and 20 mg MnSO4/kg bodyweight per day. Glycosylation and blood manganese were monitored closely. In addition, magnetic resonance imaging was performed to detect potential toxic effects of manganese.ResultsAll measured enzyme dysfunctions resolved completely and considerable clinical improvement regarding motor abilities, hearing, and other neurological manifestations was observed.ConclusionHigh-dose manganese substitution was effective in two patients with SLC39A8 deficiency. Close therapy monitoring by glycosylation assays and blood manganese measurements is necessary to prevent manganese toxicity.

A novel mutation in PIGW causes glycosylphosphatidylinositol deficiency without hyperphosphatasia.

In recent years, many mutations have been identified that affect the biosynthesis of the glycosylphosphatidylinositol anchor, a biomolecule that attaches surface molecules to cell membranes. Here, we present two second-degree cousins with unexplained patterns of seizures. Next-generation sequencing identified the homozygous c.460A>G; p.(R154G) PIGW mutation in both patients. Transfection of the mutated allele into Pigw-defective CHO cells indicated impaired enzymatic activity of the mutated PIGW product. Alkaline phosphatase did not exceed the upper normal range and flow cytometry of CD16, CD24, and CD66c on granulocytes showed subtle changes of the cellular expression of the glycosylphosphatidylinositol-anchored proteins. The patients' phenotype is therefore remarkably different from the phenotype of the only other described individual with PIGW mutations. Patients might therefore be missed when relying on traditional flow cytometry of glycosylphosphatidylinositol-anchored proteins only and we suggest that glycosylphosphatidylinositol-deficiency should be considered even with patients not showing the typical clinical phenotypes. © 2016 Wiley Periodicals, Inc.

Covering skin defects with a xenogeneic collagen matrix in comparison with a skin graft - A multicenter randomized controlled trial.

The objective of this study was to analyze, in a randomized controlled multicenter trial, whether a xenogeneic collagen matrix (XCM) could be used to cover skin defects. Patients with the need for skin excisions were recruited and randomized to treatment with a skin graft after a period of granulation or to treatment with an XCM. The results were evaluated by two independent observers on the Patient and Observer Scar Assessment Scale. On this scale, scars are ranked from 1 to 10 in six different categories. Results range from 6 to 60, with lower scores representing scars closer to normal skin. The results 6 months after reconstruction were used as primary endpoint and compared in a non-inferiority approach. A total of 39 wounds in the head and neck region were analyzed. The mean results were 16.55 (standard deviation 6.8) for XCM and 16.83 (standard deviation 8.21) in the control group. The result of the XCM was not significantly inferior to the result of the skin graft (p = 0.91). Within the limitations of the study, it seems that the use of xenogeneic collagen matrices is a viable alternative to other approaches in small skin defects, and therefore should be taken into account whenever the reduction of patient morbidity to a minimum is the priority. TRIAL REGISTRATION: This trial was registered in the German Clinical Trials Register under registration identification number DRKS00010930 and can be found under the following URLs: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00010930. https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00010930.

SLC37A4-CDG: Mislocalization of the glucose-6-phosphate transporter to the Golgi causes a new congenital disorder of glycosylation.

Loss-of-function of the glucose-6-phosphate transporter is caused by biallelic mutations in SLC37A4 and leads to glycogen storage disease Ib. Here we describe a second disease caused by a single dominant mutation in the same gene. The mutation abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter leads to a congenital disorder of glycosylation instead of glycogen storage disease.