High frequency of missense mutations in glycogen storage disease type VI.

Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly.

Trial of erythropoietin treatment in a boy with glutathione synthetase deficiency.

We report a 3-year-old boy with glutathione synthetase deficiency, who in the newborn period developed severe persistent haemolytic anaemia. Treatment with erythropoietin was introduced with good clinical and haematological response.

Compulsory hyperventilation and hypocapnia of patients with Leigh syndrome associated with SURF1 gene mutations as a cause of low serum bicarbonates.

Experimental data show that elevation of intracellular pH leads to severe lesions of brain cells. Acidification of intracellular fluid by accumulation of lactate may compensate the effect of respiratory alkalosis. Increased serum pH, and low PCO2, associated with hyperlactataemia (sometimes incorrectly called 'acidosis') have been reported in children with Leigh syndrome (LS). The aim of the study was to determine whether respiratory alkalosis is characteristic of patients with LS due to SURF1 mutations. All venous blood gas data (88 samples) of 18 spontaneously breathing LS patients with recently established SURF1 mutations, hospitalized during 1986-2000, were retrospectively reviewed. The data of an affected boy who survived on a respirator for more than 3 months (79 daily samples) were analysed separately. In spontaneously breathing patients, the data indicated that the patients had compensated or partially compensated respiratory alkalosis (pH 7.388+/-0.060, Pco2 29.2+/-5.7 mmHg, HCO3- 17.4+/-3.0 mmol/L, BE -6.7+/-3.2 mmol/L). Bicarbonate excretion was detected in urine of two examined LS cases in spite of decreased serum HCO3-. In the affected child maintained on a respirator, simple manipulation of the inspired CO2 tension to establish a normal pressure of 35-45 mmHg automatically caused an increase of serum HCO3- concentration to a normal value of 26.3+/-2.9 mmol/L (and BE to +2.2+/-3.1 mmol/L), in spite of cytochrome oxidase (COX) deficiency due to a confirmed SURF1 mutation. We suggest that respiratory alkalosis (hypocapnia) of Leigh syndrome patients with SURF1 mutations results from compulsory hyperventilation and speculate that hypocapnia may contribute to Leigh-like brain damage in the SURF1-deficient patients as well as in other patients presenting with Leigh-like syndrome. The supposition that accumulation of lactate may protect the brain of LS patients from alkalosis-related damage requires further study. Avoidance of any factors stimulating hyperventilation of LS patients and caution when attempting to correct low plasma bicarbonate are suggested.