Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly.

An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.

Impact of nutritional rehabilitation on enzymatic antioxidant levels in protein energy malnutrition.

To assess the role of enzymatic antioxidants in the pathogenesis of protein energy malnutrition (PEM) and the effect of nutritional rehabilitation, we studied 30 infants with PEM (mean age 10.63 +/- 4.39 months: 10 marasmic; 8 with kwashiorkor; 12 with marasmic kwashiorkor) and 15 controls. All underwent clinical examination and laboratory investigations, including superoxide dismutase (SOD) and glutathione peroxidase (GPx) estimation before and after nutrition rehabilitation. SOD and GPx were significantly lower in all malnourished infants compared to controls, and significantly increased after nutritional rehabilitation. These significant correlations suggest that antioxidants could be introduced during PEM nutritional rehabilitation to decrease morbidity and mortality.

Isolated congenital enterokinase deficiency. Recent findings and review of the literature.

We report a 13-mo-old patient with isolated congenital enterokinase deficiency and review the clinical features, diagnostic approach, and management of all 8 reported patients. Our patient presented with failure to thrive, diarrhea, and hypoproteinemia since birth. A normal sweat chloride with small intestinal histology, and nondetectable trypsin activity in the duodenal fluid should alert the physician to the possibility of isolated enterokinase deficiency. All reported patients, including our own, responded favorably to pancreatic enzyme replacement. In vitro studies of the small intestinal mucosal biopsy specimen suggest that enterokinase deficiency at least in part is due to altered enzymes with low enterokinase activity.

[Tryptic and chymotryptic activity in the faeces of children of different age groups (author's transl)]. / Tryptische und chymotryptische Aktivität im Stuhl von Kindern verschiedener Altersgruppen

Measurement of tryptic and chymotryptic activity in the faeces was not disturbed by bacterial proteolytic activity of different bacteria such as proteus, pseudomonas, coli, enterococci, bacteroides. Both activities within a group follow a logarithmic normal distribution. Lower limit of the standard deviation is 51% upper limit 129% for tryptic activity, respectively 60 and 170% for chymotryptic activity. There were no differences in chymotryptic activity between the 10 age groups comprising 157 healthy children, whereas a significant difference could be found for tryptic activity between premature and older children. Daily fluctuations of the enzyme activities are quite high in the same individual, and only reduced in "bottlefed" infants with constant nutrition. In prematures and very young infants chymotryptic activity predominates, later tryptic activity. Influence of increased and decreased bowel movements on deviation of the data was tested. There was, however, no real alteration of enzyme activity due to the bowel dysfunction beyond the standard deviation of the control groups. But passage time and nutrition have to be considered beside other factors in the wide distribution of the enzyme activities and the latter limits the value of this method.