B Gebhardt

Mitochondrial Phosphate–Carrier Deficiency: A Novel Disorder of Oxidative Phosphorylation

The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.

N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria

In patients with methylmalonic aciduria (MMA), the accumulating metabolite propiony-CoA results in an inhibition of the urea circle via the decreased synthesis of N-acetylglutamate, an essential activator of carbamylphosphat synthetase (CPS). This results in one of the major clinical problems which is hyperammonaemia. In a patient with decompensated MMA, the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA-induced hyperammonaemia. Oral carbamylgutamate administration resulted in an impressive increase in ammonia detoxification compared to peritoneal dialysis. Safe, fast and easy to administer, carbamylglutamate improves the acute therapy of decompensated MMA by increasing ammonia detoxification and avoiding hyperammonaemia.

Maternal plasma homocysteine, placenta status and docosahexaenoic acid concentration in erythrocyte phospholipids of the newborn

Abstract The enhanced transport of long-chain polyunsaturated fatty acids, in particular docosahexaenoic acid (22:6 ω-3) (DHA), to the fetus is a placental function important for adequate membrane phospholipid formation and herewith decisive for the quality of fetal CNS myelination. A compromised placental function is correlated with signs of vascular pathology. As elevated plasma total homocysteine (tHcy) concentrations are considered an independent risk for premature occlusive vascular disease, the influence of maternal plasma tHcy concentrations on placental function was indirectly studied, determining the DHA content in erythrocyte membrane phospholipids of the newborn. A total of 60 unselected pregnant women (age range: 21 to 39 years) were investigated at delivery. Gestational age ranged from 26 to 41 weeks. Prior to delivery a placental ultrasound scan was performed. Complete sets of data could be obtained from 43 mothers and their offspring. tHcy concentrations were determined in the plasma of cord and maternal blood. The fatty acid pattern of erythrocyte membrane phospholipids was determined in the mothers and their newborns. Z-scores of the birth weights ranged from −3.4 to 2.1 and of the placental weights from −3.8 to 4.7. The mean maternal plasma tHcy concentration was 6.29 ± 3.34 μmol/l ranging from below our limit of detection up to 15 μmol/l. These maternal concentrations were correlated with those of their infants (r = 0.71; P < 0.0001). The tHcy concentrations were significantly higher in mothers with pregnancies complicated by gestosis or placental calcifications. The Z-scores of birth weights as well as placental weights showed a significant negative correlation with maternal plasma tHcy concentrations. The mean DHA percentage of total fatty acids in erythrocyte phospholipids was 3.2 ± 2.2% in the mothers and 3.4 ± 2.3% in their newborns. Most importantly the maternal plasma tHcy levels and the erythrocyte phospholipid DHA concentrations of their offspring were significantly correlated (r = −0.51; P < 0.0003). Conclusion In this study, total homocysteine concentrations were elevated in the plasma of pregnant women with signs of placental vasculopathy. Maternal plasma total homocysteine concentrations were positively correlated with erythrocyte phospholipid docosahexaenoic acid of their offspring and may be an indicator for the integrity of placental vascular function. The nutritional status as well as predisposing genetic factors of pregnant mothers need to be investigated more thoroughly.

Fatal Neonatal-Onset Mitochondrial Respiratory Chain Disease with T Cell Immunodeficiency

We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporo-occipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes II+III and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8+ T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8+ T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease.