TMEM165 Deficiency: Postnatal Changes in Glycosylation.

Congenital disorders of glycosylation form a rapidly growing group of inherited metabolic diseases. As glycosylation affects proteins all over the organism, a mutation in a single gene leads to a multisystemic disorder. We describe a patient with TMEM165-CDG with facial dysmorphism, nephrotic syndrome, cardiac defects, enlarged cerebral ventricles, feeding problems, and neurological involvement. Having confirmed the diagnosis via prenatal diagnostics, we were able to observe the glycosylation right from birth, finding a pathological pattern already on the first day of life. Within the next few weeks, hypoglycosylation progressed to less sialylated and then also to hypogalactosylated isoforms. On the whole, there has not been much published evidence concerning postnatal glycosylation and its adaptational process. This is the first paper reporting changes in glycosylation patterns over the first postnatal weeks in TMEM165-CDG.

Membrane translocation of glutaric acid and its derivatives.

The neurodegenerative disorder glutaric aciduria type I (GA I) is characterized by increased levels of cytotoxic metabolites such as glutaric acid (GA) and 3-hydroxyglutaric (3OHGA). The present report summarizes recent investigations providing insights into mechanisms of intra- and intercellular translocation of these metabolites. Initiated by microarray analyses in a mouse model of GA I, the sodium-dependent dicarboxylate cotransporter 3 (NaC3) was the first molecule identified to mediate the translocation of GA and 3OHGA with high and low affinity, respectively. More recently, organic anion transporters (OAT) 1 and 4 have been reported to be high-affinity transporters for GA and 3OHGA as well as D-2- and L-2-hydroxyglutaric acid (D2OHGA, L2OHGA). The concerted action of NaC3 and OATs may be important for the directed uptake and excretion of GA, 3OHGA, D2OHGA and L2OHGA in kidney proximal tubule cells. In addition, experimental data on cultured neuronal and glial cells isolated from mouse brain demonstrated that GA rather than 3OHGA may competitively inhibit the anaplerotic supply of tricarboxylic acid cycle intermediates from astrocytes to neurons. The identification of GA and GA derivative transporters may represent targets for new approaches to treat patients with GA I and related disorders.

Decreased plasma concentration of von Willebrand factor antigen (VWF:Ag) in patients with glycogen storage disease type Ia.

Despite highly increased blood lipids, patients with glycogen storage disease type Ia (GSD Ia) do not develop premature vascular complications. Since this could be due to changes of coagulation factors, coagulation tests (including von Willebrand factor (VWF) antigen (VWF:Ag) ELISA, VWF:collagen binding activity (VWF:CB) and VWF multimer analysis) were performed in 10 GSD Ia patients, single cases of other GSD types, and in both healthy and hyperlipidaemic controls. In 60% of GSD Ia patients we found abnormal results, with a decrease of VWF:Ag and multimer analysis showing reduced intensity of individual oligomers in the presence of all multimers with a normal triplet structure. We interpret these findings as an acquired 'von Willebrand syndrome type I' in GSD Ia. The underlying metabolic mechanism and a potential role in the protection from vascular complication still needs to be evaluated.

Animal models for glutaryl-CoA dehydrogenase deficiency.

In vitro studies suggest that excitotoxic cell damage is an underlying mechanism for the acute striatal damage in glutaryl-CoA dehydrogenase (GCDH) deficiency. It is believed to result from an imbalance of glutamatergic and GABAergic neurotransmission induced by the accumulating organic acids 3-hydroxyglutaric acid (3-OH-GA) and to a lesser extent glutaric acid (GA). Stereotaxic administration of 3-OH-GA and GA into the rat striatum have confirmed these results, but may not truly represent the effect of chronic exposure to these compounds. In an attempt to better understand the pathophysiology of GCDH deficiency in vivo , two animal models have been utilized. A mouse that lacks GCDH activity in all tissues was generated by gene targeting in embryonic stem cells. These animals develop the characteristic biochemical phenotype of the human disease. Pathologically, these mice have a diffuse spongiform myelinopathy similar to that in human patients; however, there is no evidence for acute striatal damage or sensitivity to acute encephalopathy induced by catabolism or inflammatory cytokines. A naturally occurring animal model, the fruit-eating bat Rousettus aegypticus, lacks hepatic and renal GCDH activity, but retains cerebral enzyme activity. Like the mouse, these bats develop the characteristic biochemical phenotype of glutaryl-CoA dehydrogenase deficiency, but lack overt neurological symptoms such as dystonia. It is not known whether they also develop the spongiform myelinopathy seen in the Gcdh-deficient mice. Otherwise, these constellations would suggest that cerebral GCDH deficiency is responsible for the development of neuronal damage. The lack of striatal damage in these two rodent models may also be related to species differences. However, they also highlight our lack of a comprehensive understanding of additional factors that might modulate the susceptibiliy of neurons to accumulating 3-OH-GA and GA in GCDH deficiency. Unravelling these mechanisms may be the key to understanding the pathophysiology of this unique disease and to the development of neuroprotective strategies.

Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I.

The metabolic hallmark of glutaric aciduria type I (GA I) is the deficiency of glutaryl-CoA dehydrogenase (GCDH) with subsequent accumulation of glutaric acid, 3-hydroxglutaric acid (3-OH-GA) and glutaconic acid. Current concepts regarding pathomechanisms of GA I focus on investigations of excitotoxic effects of 3-OH-GA. To identify pathogenetically relevant genes, microarray analyses were performed using brain material from GCDH-deficient (GCDH (-/-)) and control mice. These microarray data confirmed recent pathogenic models, but also revealed alterations in genes that had previously not been correlated to the disease, e.g. genes concerning vascular biology. Subsequent in vitro and in vivo experiments confirmed direct effects of 3-OH-GA on vascular permeability and endothelial integrity. Clinical observations underscore the involvement of vascular dysfunction. In MRI scans of GA I patients, subdural effusions as well as dilated transarachnoid vascular plexuses were detected independently of encephalopathic crises. In fact, some of these findings are already detectable shortly after birth. MRI scans of a GA I patient performed during an acute encephalopathic crisis detected a dilated intrastriatal vasculature with perivascular hyperintensity, indicating local extravasation. In conclusion, we hypothesize that 3-OH-GA affects prenatal development of vessels, thus leading to an increased vulnerability of endothelial structures and subsequent vascular dysfunction. These observations display an additional pathomechanism in GA I and might explain frontotemporal hypoplasia and chronic subdural effusions in this disease. Elucidation of the pathomechanisms of vascular dysfunction may give further insights into the pathogenesis of GA I.

Maintenance treatment of glutaryl-CoA dehydrogenase deficiency.

This paper summarizes the published experience as well as results of the 3rd International Workshop on Glutaryl-CoA Dehydrogenase Deficiency held in October 2003 in Heidelberg, Germany, on the topic treatment of patients with glutaryl-CoA dehydrogenase (GCDH) deficiency. So far no international recommendation for treatment of GCDH deficiency exists. Such an approach is hampered by several facts, namely the lack of an in-depth understanding of the pathophysiology of the disease, the lack of prospective studies, including the evaluation of drug monotherapy, and lack of objective documentation of clinical changes (e.g. video documentation) during pharmacotherapy.

Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity: a novel mutation in a Turkish patient with glutaric aciduria type I.

We report the first patient with the homozygous GCDH mutation M263V, displaying a high residual activity in fibroblasts of 30%, but presenting with a severe clinical phenotype.

[Use of disinfectant solutions at a university clinic]. / Untersuchungen zur Anwendung von Desinfektionsmittellösungen an einer Universitätsklinik.

As part of complex checkups of the antimicrobial regimen the application of disinfecting solutions (Fesia-form, Kombinal asept, Wofasept, Fesia-pin, peracetic acid-spirit SR, and Wofasteril) was studied at 12 institutions of the clinical centre of the medical school of the Friedrich Schiller University Jena from May 1986 to February 1988. It was the aim of the studies to show how properly the disinfecting solutions were applied and whether their concentrations was correct. Despite several discussions and intensive instruction at the workplace the criticized institutions showed positive changes, clearly but not yet satisfactorily, only after the third follow-up inspection. Our results demonstrate a wide gap between theoretical knowledge and application in practice. Possible reasons for that and ways for improvement of the objective and subjective components leading to an incorrect application of disinfectants are discussed.