Variants in NGLY1 lead to intellectual disability,myoclonus epilepsy,sensorimotor axonal polyneuropathy and mitochondrial dysfunction

NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.     

Rapid diagnosis of leishmaniasis by fluorogenic polymerase chain reaction.

A fluorescent DNA probe (LEIS.P1) specific for a conserved region of the small-subunit ribosomal RNA gene of Leishmania and a pair of flanking primers (LEIS.U1 and LEIS.L1) were designed for use in a fluorogenic polymerase chain reaction. Optimal assay conditions with zero background were established to detect low levels of Leishmania from clinical samples. By use of this assay, we amplified DNA from 27 strains of cultured Leishmania (both Old and New World strains) and selectively amplified Leishmania DNA from 12 paraffin-embedded human biopsy samples and 3 fresh human skin biopsy specimens. For the fresh human tissue biopsies, the turnaround time from biopsy to test result was < 24 hr. No amplification was detected in negative control samples (including the kinetoplastid protozoa Trypanosoma rangelli and Crithidia fasiculata). This assay provides a specific and rapid diagnostic modality to detect infection with Leishmania.     

Identifikation von Berufskrankheiten aus der Sicht des Allergologen

Zusammenfassung Die Abklärung einer/eines Patienten im Hinblick auf eine mögliche arbeitsplatzbezogene allergische Erkrankung erfordert eine grosse Erfahrung des Allergologen. Ein Problem bietet die Interpretation von Hauttests und RAST. Bei einem positiven Test bleibt abzuklären, ob die nachgewiesene Sensibilisierung relevant ist. Ein Test kann negativ ausfallen, weil im Testmaterial das relevante Allergen nicht oder nicht in genügender Konzentration vorhanden war oder weil eine nicht-immunologische Pathogenese vorliegt. Provokationstests lassen sich sicherer interpretieren.

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Round table on the identification of occupational diseases: The view of the specialist of allergic disease

The investigation of a patient in regard to an occupational allergic disease requires a sound experience of the physician specialized in that field. The interpretation of skin and radio-allergo-sorbent tests (RAST) may be difficult. A positive test does not prove whether the sensibilisation is relevant or not. The outcome of a test may be negative, because the test material does not contain the relevant allergen, because its concentration is to low, or because the disease has no immunological origin. The interpretation of inhalative provocation tests is safer.

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Table ronde sur l'identification de maladies professionnelles: Point de vue de l'allergologue

Résumé L'investigation dans un cas ou l'on soupçonne une maladie allergique professionnelle requiert une grande expérience du médecin spécialiste dans ce domaine. L'interprétation de tests cutanés et radio-allergo-sorbants (RAST) peu poser des problèmes. Un test positif ne peut pas démontrer, si une sensibilation est la cause d'une maladie actuelle ou non. Un résultat négatif inclut la possibilité que le matériel testé ne contient pas du tout ou dans une concentration trop faible l'allergène responsable, ou bien que la maladie n'est pas d'origine immunologique. L'interprétation de tests de provocation par inhalation est plus sûre.

     

Studies on the effect of drugs on somatosensory cortical evoked potentials (author's transl)

The effect of the following drugs in therapeutic doses on somatosensory cortical evoked potentials was studied: methamphetamine, chlorpromazine, imipramine, diazepam, phenobarbital, pethidine, and novaminesulfone. Physiological saline was used as control. Each of these compounds was studied in 5 healthy subjects. Three evoked potentials were recorded before, and another three after administration of the drug. Each potential was averaged from 1024 single stimuli. None of the drugs, led to marked changes of the evoked potential, i.e., all data (latencies, amplitudes) were within the double standard deviation of the data obtained in normal subjects in a previous study. Although no significant changes were seen, some trends could be observed: methamphetamine and imipramine produced a decrease in the latency of the first positive peak, chlorpromazine increased the latency of the third positive peak. The amplitude of the third peak was reduced under phenobarbital. It is concluded that the drugs investigated in the presents study do not produce significant changes in the somatosensory cortical evoked potential and therefore drug application may be continued when evoked potentials are used for diagnostic purposes.     

Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics

BACKGROUND: The syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hyponatremia. Its diagnosis requires decreased serum osmolality, inappropriately diluted urine (e.g. >100 mOsm/kg), clinical euvolemia, and a urinary sodium (Na) excretion (U-Na) more than 30 mmol/liter. However, in hyponatremic patients taking diuretics, this definition is unreliable due to the natriuretic effect of diuretics. Here, we examined the diagnostic potential of alternative laboratory measurements to diagnose SIAD, regardless of the use of diuretics. METHODS: A total of 86 consecutive hyponatremic patients (serum Na <130 mmol/liter) was classified based on their history, clinical evaluation, osmolality, and saline response to isotonic saline into a SIAD and a non-SIAD group. U-Na, serum urate concentration, and fractional excretion (FE) of Na, urea, and uric acid (UA) were measured in all subjects. The accuracy to diagnose SIAD was assessed using receiver operating characteristic analysis. RESULTS: A total of 31 patients (36%) had a diagnosis of SIAD, and 55 (64%) were classified as non-SIAD. There were 57 patients (68%) who were on diuretics (15 in the SIAD group, 42 in the non-SIAD group). In the absence of diuretic therapy, SIAD was accurately diagnosed using U-Na (area under the receiver operating characteristic curve 0.96; 0.92-1.02). However, in patients on diuretics, the diagnosis was unreliable (area under the curve 0.85; 0.73-0.97). There, FE-UA performed best compared with all other markers tested (area under the curve 0.96; 0.92-1.12), resulting in a positive predictive value of 100% if a cutoff value of 12% was used. CONCLUSION: FE-UA allows the diagnosis of SIAD with excellent specificity. Combining the information on U-Na and FE-UA leads to a very high diagnostic accuracy in hyponatremic patients with and without diuretic treatment.     

Joint replacement. The primary care physician's role.

Ideally, primary care physicians can successfully manage cases of arthritis in a manner that obviates the need for reconstructive surgery. However, that is not always possible. When surgical intervention is believed to be of potential benefit, the primary care physician needs to enlist the help of a surgeon and other health professionals to determine the best approach. Primary care physicians should take an active role in preoperative planning, perioperative management, and rehabilitation. The unique characteristics of the patient's specific type of arthritis and use of medications must be carefully considered. This approach should optimize the chances for a successful outcome.