Thierry de Barsy

A gene on chromosome 11q23 coding for a putative glucose- 6-phosphate translocase is mutated in glycogen-storage disease types Ib and Ic.

Glycogen-storage diseases type I (GSD type I) are due to a deficiency in glucose-6-phosphatase, an enzymatic system present in the endoplasmic reticulum that plays a crucial role in blood glucose homeostasis. Unlike GSD type Ia, types Ib and Ic are not due to mutations in the phosphohydrolase gene and are clinically characterized by the presence of associated neutropenia and neutrophil dysfunction. Biochemical evidence indicates the presence of a defect in glucose-6-phosphate (GSD type Ib) or inorganic phosphate (Pi) (GSD type Ic) transport in the microsomes. We have recently cloned a cDNA encoding a putative glucose-6-phosphate translocase. We have now localized the corresponding gene on chromosome 11q23, the region where GSD types Ib and Ic have been mapped. Using SSCP analysis and sequencing, we have screened this gene, for mutations in genomic DNA, from patients from 22 different families who have GSD types Ib and Ic. Of 20 mutations found, 11 result in truncated proteins that are probably nonfunctional. Most other mutations result in substitutions of conserved or semiconserved residues. The two most common mutations (Gly339Cys and 1211-1212 delCT) together constitute approximately 40% of the disease alleles. The fact that the same mutations are found in GSD types Ib and Ic could indicate either that Pi and glucose-6-phosphate are transported in microsomes by the same transporter or that the biochemical assays used to differentiate Pi and glucose-6-phosphate transport defects are not reliable.

Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis

Orthotopic liver transplantation (OLT) has been proposed to treat patients with type IV glycogenosis because of early progressive cirrhosis. Reports have shown absence of disease progression in other organs after OLT and even regression of cardiac amylopectin infiltration in one case. We describe a 15-month-old child in whom a liver transplant was performed for type IV glycogenosis. There were no clinical signs of extrahepatic disease before OLT. Nine months later, the patient developed progressive cardiac insufficiency and died from cardiac failure. Because of massive amylopectin deposits, decreased myofibrils in cardiac cells, and exclusion of other causes of cardiac failure, death was attributed to amylopectinosis. Our observation contrasts with the Pittsburgh experience and suggests that cardiac amylopectionosis may progress after OLT.

The effect of glucose on the conversion of muscle phosphorylase a into b or b

Abstract The stimulatory effect of glucose on the conversion of muscle phosphorylase a into b by phosphorylase phosphatase or b′ by trypsin is AMP dependent at 30°, but not at 13°. These findings explain previous disagreement concerning the effect of the hexose on the inactivation of muscle phosphorylase a by its phosphatase. This glucose effect appears to be due to the binding of the hexose to phosphorylase a .

Brain metabolism in mitochondrial encephalomyopathy: a PET study.

Regional brain glucose metabolism has been studied in a case of mitochondrial encephalomyopathy with ragged red fibers, using positron emission tomography with fluorodeoxyglucose as the tracer. A marked decrease in glucose utilization was found in all gray structures, with a preponderance of metabolic alterations in posterior cortical regions and thalamus and a relative sparing of anterior cortical areas and basal nuclei.

Clinical and biochemical findings before and after portacaval shunt in a girl with type Ib glycogen storage disease.

Summary: A girl presented with an important growth retardation, hepatomegaly, fasting hypoglycemia, lactic acidosis, increased serum cholesterol, triglycerides and uric acid, and increased liver glycogen (7.5%). There was no rise in blood glucose after IV galactose or fructose, but glucagon gave a delayed response. Type Ib glycogen storage disease was suggested by the low normal activity of glucose-6-phosphatase (G-6-Pase) which reached 1.8 units/g (normal, 2 to 10 units/g) and the normal activity of other glycogenolytic enzymes, measured in homogenates prepared in H2O from previously frozen liver tissue. After portacaval shunt (PCS), height increased by 29 cm in 3 years. Serum cholesterol decreased from 618 to 216 mg/dl, and triglycerides decreased from 890 to 116 mg/dl. During an oral glucose tolerance test, peak values for glucose (mg/dl) and insulin (μunits/ml) were, respectively, 210 and 50 before and 280 and 90 after PCS. Sixty min after the IV administration of a tracer dose of [2-3H; U-14C]glucose, the 3H/14C ratio in blood glucose decreased to 24% of its initial value indicating a functional G-6-Pase (mean ± S.E. in control subjects: 59% ± 7; in type la CSD: 92% ± 3). The activity of G-6-Pase measured as described above increased to 3.8 units/g of liver 1 year after PCS and 7.85 units/g of liver after 3 years. At that time, a simultaneous assay of the enzyme in a fresh, previously not frozen liver biopsy, homogenized in 0.25 M sucrose, revealed only about 29% of the activity of the same sample prepared in H2O (mean ± S.E. in three controls: 95.8% ± 8.9).Speculation: The higher than normal utilization of [2-3H; U-14C]glucose observed after portacaval shunt hi this patient suggests that besides the postulated defect of the microsomal glucose-6-phos-phate transport system (19), other hitherto unexplored pathogenetic mechanisms should be investigated, including the regulation of the synthesis of glucose-6-phosphatase, to explain the unpaired degradation of glycogen hi type Ib glycogen storage disease.

The Retina in Lafora Disease: Light and Electron Microscopy

Lafora bodies are described in the retina of a 16 year old female who died five years after the onset of a typical familial progressive myoclonus epilepsy which was diagnosed as Lafora disease by brain biopsy and by autopsy findings. The patient was the offspring of consanguinous parents who had three affected siblings out of nine. The fine structure and distribution of Lafora bodies, which represent a specific non-lysosomal cell storage disorder, is reported for the first time in the human retina. The nature of the abnormal material in the Lafora bodies, which are identical to those present in the brain, heart and liver tissues in the same patient and in her brother, is discussed according to their iodide spectrum. In this respect, Lafora disease might be related to the inborn errors of carbohydrate metabolism and its relationship with Type IV Glycogenosis (Anderson’s disease) must be verified by further investigations.

Phosphorylase-kinase Deficiency - Severe Glycogen-storage Disease With Evidence of Autosomal Recessive Mode of Inheritance

Departments of ~ Pediatrics and 3 Pathology, University of Bergen, 5016 Haukeland Hospital, Bergen, Norway 2 Laboratoire de Chimie Physiologique, Universit6 Catholique de Louvain, Brussels, Belgium (497/U/1) were markedly elevated. Serum cholesterol (8.7 retool/l) as well as triglycerides (3retool/I) were elevated. Her height was between the 2.5th and 10th percentile. In summary, our patient presented the following features: marked hepatomegaly, muscular hypotonia, fasting hypoglycemia, minimal blood glucose response to glucagon in the fasting state, consanguinity between the parents, and barely detectable phosphorylase kinase activity in the liver. In conclusion, liver phosphorylase

Normal Metabolism and Disorders of Carbohydrate-metabolism

Carbohydrate metabolism has a primary role in muscle because of the unique function of glycolysis in providing ATP in anaerobic respiration. Indeed, muscle is the only tissue that can be severely deprived of oxygen under physiological conditions. Disorders of carbohydrate metabolism can therefore be classified into two main groups according to whether or not they result from insufficient glycolysis. Because glycogen is the most easily available substrate for glycolysis, the first group of disorders includes several of the known types of glycogenoses as well as a few specific defects of glycolytic enzymes. The second group of disorders is characterized by muscle degeneration resulting either from the lysosomal storage of glycogen (type II glycogenosis) or from the deposition of an abnormal polysaccharide (type IV glycogenosis and some ill-defined similar diseases). The field of glycogen storage diseases has recently been extensively covered by Hers et al (1989) in a review article in which additional information and references to original work can be found.

Les glycogénoses musculaires

Muscular glycogenosis is a disease resulting from genetic abnormalities altering an enzyme which is involved in glycogen metabolism (fig 1). In addition to disorders of glycogenolysis and glycolysis, there are other pathological processes such as acid maltase (alpha-glucosidase) deficiency and diseases associated with abnormal glycogen structure (1,2). Glycolysis (fig 2) is the only metabolic pathway that can produce ATP in the absence of oxygen. It is then easy to understand that any disturbance in this energy pathway can result in dysfunction of the muscle machine and in a number of symptoms which are common to these abnormalities. An overall review of the various diseases know to exist on the glycogenolytic and glycolytic pathway will enable the reader to acquire a better knowledge of their particular features.

Clinical and Biochemical Findings Before and After Portacaval-shunt (pcs) in Type Ib Glycogen Disease (gsd)

Clinical and biochemical findings before and after portacaval shunt (PCS) in type Ib glycogen disease (GSD).An 11-year-old girl with statural age of 5 yrs. and hepatomegaly (15cm) had fasting hypoglycaemia, acidosis, increased serum cholesterol, triglycerides and uric acid, and increased liver glycogen (7.5%). There was no rise in blood glucose after i.v.galactose or fructose but glucagon gave a delayed response. Type Ib GSD was suggested by the normal activity of glucose-6-phosphatase (G-6-Pase) and of other glycogenolytic enzymes in frozen liver. After PCS, at 12 6/12 yrs., height increased by 29cm in 3 yrs. Serum cholesterol decreased from 620 to 230mg/dl and triglycerides from 2400 to 200mg/dl. At oral GTT peak values for glucose (mg/dl) and insulin (U/1) were respectively 210 and 50 before, 290 and 90 after PCS. Higher than normal utilisation of (2-3H,U-14C)-glucose was shown by a 3H/14C ratio of 24% after 60 min.(mean ± S.E.M.: 59% ± 7 in normals and 92% ± 3 in type Ia GSD) and can be explained by peripheral hyperinsulinism. Assay of G-6-Pase in a fresh liver homogenate prepared in 0.25 M-sucrose revealed only 29% (96% ± 11 in 3 controls) of the enzyme activity as compared with an homogenate in H2O. The latter finding may be in favour of the hypothesis of Narisawa et al. (Biochem. Biophys. Res.Comm. 83: 1360, 1978) postulating a defect of the microsomal G-6-transport system in type Ib GSD, but is difficult to reconcile with the isotopic data.