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Niemann Pick type C (NP-C) is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol) as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2) and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3β,5α,6β-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay.

Phosphoglucomutase 1 deficiency has recently been reported as a novel disease that belongs to two different classes of metabolic disorders, congenital disorders of glycosylation (CDG) and glycogen storage diseases.This paper focuses on previously reported siblings with short stature, hypothyroidism, increased transaminases, and, in one of them, dilated cardiomyopathy (DCM). An intronic point mutation in the PGM1-gene (c.1145-222 GT) leads to a complex alternative splicing pattern and to almost complete absence of PGM1 activity.Exercise-induced muscle fatigue, chest pain, and rhabdomyolysis persisted into adulthood. Fainting occurred during the first minutes of strong exercise due to glucose depletion and serum heart troponin was increased. A second wind phenomenon with an improvement in exercise capacity after some minutes of training was observed. Regular aerobic training improved fitness and helped to avoid acute damage. DCM improved during therapy.Glycosylation deficiency was most prominent in childhood. Glycosylation improved with age and further improved with oral galactose supplementation even in adulthood. Optimal improvement of glycosylation-dependent phenotypes should be achieved by early and permanent galactose treatment.However, in case of mutations in ZASP, DCM can develop as a consequence of impaired binding of PGM1 to the heart-specific isoform of ZASP, independently of overall glycosylation efficiency. Thus, even if mutations in PGM1 impair the function of the ZASP-PGM1 complex, supplementation of galactose cannot be expected to restore that function. Therefore, knowledge of PGM1 deficiency in a patient should prompt surveillance of early signs of DCM and specific treatment if necessary.

Background The analysis of serum transferrin either by high-performance liquid chromatography (HPLC) or isoelectric focusing (IEF) is the standard diagnostic procedure in patients with the suspicion of a congenital disorder of glycosylation (CDG). Carbohydrate-deficient transferrin (CDT) is also analysed in monitoring programmes in cases of alcohol abuse. We report a novel transferrin variant that impairs the analysis using conventional methods and propose alternative forms of analysis. Methods Transferrin samples were analysed using HPLC, immunoprecipitation followed by SDS-PAGE and IEF. Neuraminidase treatment followed by conventional IEF and electrospray ionization time of flight mass spectrometry (ESI-TOF MS) were applied before sequencing of the transferrin gene was performed. Results The novel transferrin variant E592A, found both in homozygous and heterozygous form, causes an altered charge of the transferrin molecule, which changes the results of IEF and HPLC and mimics an increase in trisialo-transferrin. The change in charge can be detected either by neuraminidase digestion followed by IEF or by ESI-TOF MS. Conclusion Conventional diagnostic methods for CDG are hindered by the novel transferrin E592A. Neuraminidase treatment followed by IEF and ESI-TOF MS can identify the mutation. The mutation appears to be functionally normal.