Search

Background: As the lowest natural site on earth (-415 meters), the Dead Sea is unique for its high pressure and oxygen tension in addition to the unparalleled combination of natural resources. Furthermore, its balneotherapeutic resorts have been reported to be beneficial for patients with various chronic diseases., Objectives: To evaluate the safety, quality of life (QoL), exercise capacity, heart failure, and arrhythmia parameters in patients with systolic congestive heart failure (SCHF) and implantable cardioverter defibrillator (ICD) following descent and stay at the Dead Sea., Methods: The study group comprised patients with SCHF, New York Heart Association functional class II-III after ICD implantation. The following parameters were tested at sea level one week prior to the descent, during a 4 day stay at the Dead Sea, and one week after return: blood pressure, 02 saturation, ejection fraction (echocardiography), weight, B-type natriuretic peptide (BNP), arrhythmias, heart rate, heart rate variability (HRV), and QoL assessed by the Minnesota Living with Heart Failure questionnaire., Results: We evaluated 19 patients, age 65.3 +/- 9.6 years, of whom 16 (84%) were males and 18 (95%) had ICD-cardiac resynchronization therapy. The trip to and from and the stay at the Dead Sea were uneventful and well tolerated. The QoL score improved by 11 points, and the 6 minute walk increased by 63 meters (P < 0.001). BNP levels increased slightly with no statistical significance. The HRV decreased (P = 0.018). There were no significant changes in blood pressure, weight, 02 saturation or ejection fraction., Conclusions: Descent to, ascent from, and stay at a Dead Sea resort are safe and might be beneficial in some aspects for patients with SCHF and an ICD.

Background: Dead Sea climatotherapy (DSC) is a highly effective treatment for psoriasis; however, there are scanty data concerning the duration of post-therapy remission., Objective: Assessment of the duration of remission in patients suffering from plaque-type psoriasis after a 4-week DSC., Methods: Sixty-four patients from Germany (66% men; average age: 41.5 years) underwent a 4-week course of DSC between September 2001 and November 2002. After returning home, patients were asked to inform their dermatologist immediately when new lesions appeared. In parallel, they were called every 3 months by telephone. All patients who reported new skin lesions underwent a physical examination, including a Psoriasis Assessment Severity Index (PASI)., Outcomes: (1) Time of recurrence of a psoriatic lesion after complete or almost complete clearance, defined as duration of remission; (2) time that elapsed until a relapse of 50% of the PASI improvement occurred, defined as duration of therapeutic effect., Results: Mean PASI value before and after treatment was 31.7 and 1.42, showing a 95.5% improvement. All patients reached PASI 50, and 75.9% of them reached PASI 75 after 1 month of DSC. The median time of remission was 23.1 weeks. The median time of duration of therapeutic effect was 33.6 weeks. Statistical multivariable analysis indicated that a patient's younger age at the time of treatment was associated with a longer period of remission., Conclusion: Four-week DSC is an effective remittive treatment for plaque-type psoriasis. The period of remission induced compares favorably with other accepted modalities of treatment.

Carnitine-acylcarnitine translocase CACT deficiency is a very rare autosomal recessive disease. The neonatal phenotype of CACT deficiency is characterized by hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy and skeletal muscle weakness culminating in early death. The disease is caused by mutations in the CACT gene, which encodes a protein transporting long-chain fatty acid carnitine esters into the mitochondrial matrix. In this report, we describe the first case of CACT deficiency in the Bedouin population in Israel. The patient, the first son of consanguineous parents, was born at term after uneventful delivery. During the second day of life, he developed clinical signs of an acute metabolic crisis with severe hypoglycaemia and hyperammonaemia. Biochemical investigation suggested the diagnosis of CACT deficiency. Genetic molecular analysis confirmed this diagnosis by demonstrating that the affected child was homozygous for a novel missense mutation 793A>G, substituting glutamine by arginine (Q238R) in exon 7 of the CACT gene. Despite medical treatment and adequate nutrition, the patient died at 6 months of age.

Muscle-specific deficiency of phosphorylase kinase (Phk) causes glycogen storage disease, clinically manifesting in exercise intolerance with early fatiguability, pain, cramps and occasionally myoglobinuria. In two patients and in a mouse mutant with muscle Phk deficiency, mutations were previously found in the muscle isoform of the Phk alpha subunit, encoded by the X-chromosomal PHKA1 gene (MIM # 311870). No mutations have been identified in the muscle isoform of the Phk gamma subunit (PHKG1). In the present study, we determined Q1the structure of the PHKG1 gene and characterized its relationship to several pseudogenes. In six patients with adult- or juvenile-onset muscle glycogenosis and low Phk activity, we then searched for mutations in eight candidate genes. The coding sequences of all six genes that contribute to Phk in muscle were analysed: PHKA1, PHKB, PHKG1, CALM1, CALM2 and CALM3. We also analysed the genes of the muscle isoform of glycogen phosphorylase (PYGM), of a muscle-specific regulatory subunit of the AMP-dependent protein kinase (PRKAG3), and the promoter regions of PHKA1, PHKB and PHKG1. Only in one male patient did we find a PHKA1 missense mutation (D299V) that explains the enzyme deficiency. Two patients were heterozygous for single amino-acid replacements in PHKB that are of unclear significance (Q657K and Y770C). No sequence abnormalities were found in the other three patients. If these results can be generalized, only a fraction of cases with muscle glycogenosis and a biochemical diagnosis of low Phk activity are caused by coding, splice-site or promoter mutations in PHKA1, PHKG1 or other Phk subunit genes. Most patients with this diagnosis probably are affected either by elusive mutations of Phk subunit genes or by defects in other, unidentified genes.

Unlabelled: Thirty-three years after Von Gierke described the first patient with glycogen storage disease type 1 (GSD1) in 1929, the Coris detected glucose-6-phosphatase (G6Pase) deficiency. The first mutation of this enzyme was identified 41 years later and subsequently the gene was mapped to chromosome 17q21, its enzyme topology defined, a nine transmembrane helical model suggested, an enzyme deficient knockout mouse created and by infusing an adenoviral vector associated murine G6Pase gene, correction of the clinical and laboratory abnormalities was observed. A similar successful gene transfer has been performed in enzyme deficient canine puppies. To explain the function of the G6Pase complex, a multicomponent translocase catalytic model has been proposed in which different transporters shuttle glucose-6-phosphate (G6P), inorganic phosphate (Pi) and glucose across the microsomal membrane. It was suggested that GSD1b patients suffered from a G6P transporter (G6PT) defect and the first mutation in the G6PT gene subsequently recognised. The gene mapped to chromosome 11q23 and its structural organisation was defined which showed a close functional linkage between G6PT and hydrolysis. Nordlie identified the first patient with Pi transport deficiency (GSD1c). However putative GSD1c and 1d patients based on kinetic studies were found to harbour mutations in the G6PT gene so that GSD1 patients are presently divided into 1a and non-1a. G6PT deficient patients suffer from numerical and functional leucocyte defects. A mRNA leucocyte G6PT deficiency has been suggested to account for the glucose phosphorylation and subsequent calcium sequestration defects observed in theses cells. Inflammatory bowel disease which occurs frequently in GSD non-1a patients has been related to their leucocyte abnormalities. Dietary management of GSD1 patients, designed to maintain a normal blood glucose level can be achieved during the night by nocturnal gastric infusions of glucose-containing solution or by the administration of uncooked cornstarch around the clock or by a combination of both. Both therapeutic modalities, if conducted in a meticulous manner, have a major impact on the quality of life, prevention of complications and subsequent prognosis. Open questions relate to the source of endogenous glucose production in GSD1 patients which increases as a function of age from 50% to 100% of normal, concomitant with an improvement in the patients fasting tolerance. Several complications, the nature of which is incompletely understood, tend to occur after the first decade: Liver adenomata with a small risk of transforming into hepatoma, progressive renal disease, which may be related to the hyperlipidaemia observed in this disease, often leading to end stage renal failure, osteopenia apparently based on high bone turnover, growth retardation and delayed puberty., Conclusion: this review highlights the present knowledge of glycogen storage disease type 1 and subtypes, discussing unsolved questions, which reflect the limitation of our knowledge in the understanding of this intriguing group of diseases.

Glycogen storage disease type IV (GSD-IV), also known as Andersen disease or amylopectinosis (MIM 23250), is a rare autosomal recessive disorder caused by a deficiency of glycogen branching enzyme (GBE) leading to the accumulation of amylopectin-like structures in affected tissues. The disease is extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestations. The human GBE cDNA is approximately 3-kb in length and encodes a 702-amino acid protein. The GBE amino acid sequence shows a high degree of conservation throughout species. The human GBE gene is located on chromosome 3p14 and consists of 16 exons spanning at least 118 kb of chromosomal DNA. Clinically the classic Andersen disease is a rapidly progressive disorder leading to terminal liver failure unless liver transplantation is performed. Several mutations have been reported in the GBE gene in patients with classic phenotype. Mutations in the GBE gene have also been identified in patients with the milder non-progressive hepatic form of the disease. Several other variants of GSD-IV have been reported: a variant with multi-system involvement including skeletal and cardiac muscle, nerve and liver; a juvenile polysaccharidosis with multi-system involvement but normal GBE activity; and the fatal neonatal neuromuscular form associated with a splice site mutation in the GBE gene. Other presentations include cardiomyopathy, arthrogryposis and even hydrops fetalis. Polyglucosan body disease, characterized by widespread upper and lower motor neuron lesions, can present with or without GBE deficiency indicating that different biochemical defects could result in an identical phenotype. It is evident that this disease exists in multiple forms with enzymatic and molecular heterogeneity unparalleled in the other types of glycogen storage diseases.

Thirteen patients with congenital insensitivity to pain and anhidrosis, carrying a mutation at the TRK-A gene, were studied. Neurologic examination revealed vestigial pain sensitivity, suggesting an incomplete involvement of the affected nerves. All 13 patients manifested normal electrophysiologic studies but striking absence of sympathetic skin responses. We suggest the use of the sympathetic skin response test in the clinical evaluation of patients suspected of having congenital insensitivity to pain and anhidrosis.

Glycogen storage disease type 1a (von Gierke disease, GSD1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity. The cloning of G6Pase cDNA and characterization of the human G6Pase gene enabled the identification of the mutations causing GSD1a. Here we report on the clinical and biochemical features of three GSD1a siblings of a Muslin Arab family with a G270V mutation. Two older patients presented with an unusually mild clinical and biochemical course.

Glycogen storage disease type 1b (GSD-1b) is proposed to be caused by a deficiency in microsomal glucose 6-phosphate (G6P) transport, causing a loss of glucose-6-phosphatase activity and glucose homeostasis. However, for decades, this disorder has defied molecular characterization. In this study, we characterize the structural organization of the G6P transporter gene and identify mutations in the gene that segregate with the GSD-1b disorder. We report the functional characterization of the recombinant G6P transporter and demonstrate that mutations uncovered in GSD-1b patients disrupt G6P transport. Our results, for the first time, define a molecular basis for functional deficiency in GSD-1b and raise the possibility that the defective G6P transporter contributes to neutropenia and neutrophil/monocyte dysfunctions characteristic of GSD-1b patients.

Deficiency of glycogen phosphorylase in the liver gives rise to glycogen-storage disease type VI (Hers disease; MIM 232700). We report the identification of the first mutations in PYGL, the gene encoding the liver isoform of glycogen phosphorylase, in three patients with Hers disease. These are two splice-site mutations and two missense mutations. A mutation of the 5' splice-site consensus of intron 14 causes the retention of intron 14 and the utilization of two illegitimate 5' splice sites, whereas a mutation of the 3' splice-site consensus of intron 4 causes the skipping of exon 5. Two missense mutations, N338S and N376K, both cause nonconservative replacements of amino acids that are absolutely conserved even in yeast and bacterial phosphorylases. We also report corrections of the PYGL coding sequence, sequence polymorphisms, and a partial PYGL gene structure with introns in the same positions as in PYGM, the gene of the muscle isoform of phosphorylase. Our findings demonstrate that PYGL mutations cause Hers disease, and they may improve laboratory diagnosis of deficiencies of the liver phosphorylase system.

Glycogen storage disease type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen debranching enzyme (AGL). We report the finding of two new mutations in a GSD IIIa Ashkenazi Jewish patient. Both mutations are insertion of an adenine into a stretch of 8 adenines towards the 3' end of the coding region, one at position 3904 (3904insA) in exon 30, the second at position 4214 (4214insA) in exon 32. The mutations cause frameshifts and premature terminations of the glycogen debranching enzyme, the first causing a frameshift at amino acid 1304, the second causing a frameshift at amino acid 1408 of the total of 1532. These mutations demonstrate the importance of the 125 amino acids at the carboxy-terminus of the debrancher enzyme for its activity and support the suggestion that the putative glycogen binding domain is located in the carboxy-terminus of the AGL. The mutations cause distinctive single-strand conformation polymorphism (SSCP) patterns enabling easy detection.

Glycogen-storage disease type 1 (GSD-1), also known as "von Gierke disease," is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase) activity. There are four distinct subgroups of this autosomal recessive disorder: 1a, 1b, 1c, and 1d. All share the same clinical manifestations, which are caused by abnormalities in the metabolism of glucose-6-phosphate (G6P). However, only GSD-1b patients suffer infectious complications, which are due to both the heritable neutropenia and the functional deficiencies of neutrophils and monocytes. Whereas G6Pase deficiency in GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, indicating a separate locus for the disorder in the 1b subgroup. We now report the linkage of the GSD-1b locus to genetic markers spanning a 3-cM region on chromosome 11q23. Eventual molecular characterization of this disease will provide new insights into the genetic bases of G6P metabolism and neutrophil-monocyte dysfunction.

We have identified mutations in the phosphorylase kinase (Phk) beta subunit gene in a male patient with liver glycogenosis caused by Phk deficiency. The patient's DNA has been analyzed for mutations in the genes encoding the alpha L, beta, and gamma TL subunits of Phk, all of which can be responsible for liver glycogenosis, by a strategy primarily based on reverse transcription/polymerase chain reaction of blood RNA and complemented by analysis of genomic DNA. His alpha L and gamma TL coding sequences are normal, whereas he is compound-heterozygous for two mutations in the beta subunit gene, PHKB. The first is a splice-site mutation (IVS4 [-2A-->G]) causing the reading-frame-disrupting deletion of exon 5 in the mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon 5. This is the first missense mutation identified in PHKB, as opposed to nine translation-terminating mutations described to date. It offers an explanation for the unique biochemical phenotype of this patient. In his leukocytes, low Phk activity is measured when tested with the endogenous liver isoform of phosphorylase as the protein substrate, but normal activity is observed when tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his erythrocytes is low with both substrates. The missense mutation may selectively impair the interaction of Phk with one isoform of its substrate protein and may destabilize the enzyme in a cell-type-specific way. This phenotype shares some aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising from missense mutations in the alpha L subunit gene (PHKA2), but differs from XLG2 in other respects. The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types. Moreover, it emphasizes that missense mutations in Phk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.

Glycogen storage disease type 1a (von Gierke disease, GSD 1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity which catalyzes the final common step of glycogenolysis and gluconeogenesis. The recent cloning of the G6Pase cDNA and characterization of the human G6Pase gene enabled the characterization of the mutations causing GSD 1a. This, in turn, allows the introduction of a noninvasive DNA-based diagnosis that provides reliable carrier testing and prenatal diagnosis. In this study, we report the biochemical and clinical characteristics as well as mutational analyses of 12 Israeli GSD 1a patients of different families, who represent most GSD 1a patients in Israel. The mutations, G6Pase activity, and glycogen content of 7 of these patients were reported previously. The biochemical data and clinical findings of all patients were similar and compatible with those described in other reports. All 9 Jewish patients, as well as one Muslim Arab patient, presented the R83C mutation. Two Muslim Arab patients had the V166G mutation which was not found in other patients' populations. The V166G mutation, which was introduced into the G6Pase cDNA by site-directed mutagenesis following transient expression in COS-1 cells, was shown to cause complete inactivation of the G6Pase. The characterization of all GSD 1a mutations in the Israeli population lends itself to carrier testing in these families as well as to prenatal diagnosis, which was carried out in 2 families. Since all Ashkenzai Jewish patients harbor the same mutation, our study suggests that DNA-based diagnosis may be used as an initial diagnostic step in Ashkenazi Jews suspected of having GSD 1a, thereby avoiding liver biopsy.

Decreased 2-deoxyglucose (2-DOG) uptake is well described in the neutrophils of patients with glycogen storage disease type 1b (GSD 1b). We report a patient with GSD 1b who presented with a normal antenatal and perinatal 2-deoxyglucose uptake that showed a slow regression during the first months of life. These indicate limitations of 2-deoxyglucose uptake in the diagnosis of GSD 1b. While it appears that low uptake rate below 0.25 nmol/min in 10(6) cells is of significance, normal uptake does not rule out the presence of the disease. It seems that antenatal diagnosis of GSD 1b cannot be made by measurement of 2-deoxyglucose uptake in the fetal neutrophils.

Patients with glycogen storage disease (GSD) 1b suffer from recurrent bacterial infections related to neutropenia and impairment of neutrophil functions. One of these functions is the oxidative burst activity which is initiated by NADPH oxidase and depends on the availability of glucose. This activity was markedly reduced in the patient's intact neutrophils when either N-formyl-methionyl-leucyl-phenylalanine (fMLP), or phorbol myristate acetate were used as stimulants. In disrupted GSD 1b polymorphonuclear leucocytes (PMNs), in the presence of exogenous NADPH, this activity was within the normal range. Degranulation, which is calcium dependent but glucose independent, was not significantly different in neutrophils from the patients as compared to controls. Resting cytosolic calcium concentration was indistinguishable from controls. Activation with 10(-7) M fMLP, in the presence or absence of glucose, triggered a prompt and rapid elevation of cytosolic calcium both in the control and the patients' cells. We have previously shown that hexose monophosphate (HMP) shunt activity and glycolytic rate were found to be lower by 70% in intact PMN cells of the patients compared with controls. These activities were normal in disrupted neutrophils. The uptake of the non-metabolized glucose analogues 2-deoxyglucose (2-DOG) and 3-O-Methylglucose (3-OMG) into PMN of GSD 1b patients was studied. 2-DOG is phosphorylated within the cells, thus its uptake rate reflects hexose transport at low concentrations, as long as phosphorylation is not rate limiting. Under those conditions (5 microM 2-DOG) transport was found to be similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical and biochemical data on nine patients belonging to six families with fructose-1,6-diphosphatase deficiency are reported. Two of the six families were Jewish, three were Moslem Arabs and one was of Druze origin. All patients had had neonatal hypoglycemia, lactic acidosis and an abnormal fructose or glycerol loading test. At a later age, instances of hypoglycemia occurred in patients both with and without preceding illness. Hypoglycemic attacks were associated with severe hyperuricemia and metabolic acidosis. Therapeutic measures included a restriction in fructose intake and avoidance of prolonged fasting, particularly during febrile episodes.

Neutrophil functions and glucose metabolism are known to be impaired in glycogen storage disease (GSD) Ib patients. The uptake of nonmetabolizing glucose analogues into polymorphonuclear leukocytes (PMN) of GSD Ib patients was studied. 2-Deoxyglucose (2-DOG) and 3-O-methylglucose are transported across the cell membrane by facilitated diffusion mediated by the glucose transporter. Because 2-DOG is phosphorylated within the cell, its uptake rate reflects hexose transport as long as phosphorylation is not rate-limiting. These conditions prevail only at low 2-DOG concentrations. Transport of 5 microM DOG into GSD Ib patient PMN was found to be similar to controls (4.3 +/- 0.5 and 4.65 +/- 1.77 pmol/min X 10(6), respectively). In contrast, 2-DOG uptake at high concentrations (2 mM) decreased by 70% in patient PMN compared with control cells (0.17 +/- 0.06 and 0.51 +/- 0.11 nmol/min X 10(6), for patients and controls, respectively). Transport of 3-O-methylglucose (a glucose analogue that does not undergo intracellular phosphorylation) was not different in patient PMN compared with controls (1.86 +/- 0.53 and 2.19 +/- 0.30 nmol/min X 10(6), respectively). Hexose monophosphate shunt activity in PMN of GSD Ib patients at a glucose concentration of 2 mM was 43% of control values, whereas at 10 microM it was similar to controls. Taken together, these results suggest that the defect in glucose uptake and metabolism found in GSD Ib patient PMN is due to an impairment in hexose phosphorylation rather than in a reduction in the transmembrane glucose transport activity.

In this retrospective study from five centres, 139 patients over 10 years of age with glycogen storage disease types I, III, VI and IX are described. Almost half of the patients with glycogen storage disease type Ia had retarded growth and most had hyperlipidaemia. One-third of the patients had adenomas, although none of these showed malignant transformations. With increasing age the growth, liver size and hyperlipidaemia of patients with glycogen storage disease type III improve. However, there was a high incidence of myopathy and cardiomyopathy. Patients with glycogen storage disease types VI and IX had a normal growth pattern after childhood. Hepatomegaly and hypercholesterolaemia, however, were still present in half of the patients.

This review describes clinical, biochemical and genetic features of the four inborn errors affecting muscle glycogen breakdown, namely deficiencies of phosphorylase, phosphorylase kinase, amylo-1,6-glucosidase and acid alpha-glucosidase. They are characterized by a wide spectrum of clinical manifestation, affecting age of onset, clinical features, progress of disease and tissue involvement. Biochemically, variability of all four enzyme deficiencies is evident in terms of differences in residual enzyme present in tissues, and in the presence or absence of enzyme protein. Genetic heterogeneity, which has been documented in each of the enzyme deficiencies, manifests itself in terms of the presence, absence, quantity or size of mRNA. In phosphorylase deficiency heterogeneity has also been documented at the DNA level. In acid maltase deficiency nine mutant phenotypes have been described affecting various stages of lysosomal enzyme processing.

Thirty-two infants, aged 1 to 12 months, hospitalized with acute wheezing, were studied. They were randomly divided into four treatment groups of eight patients each. The treatments were intramuscular dexamethasone or placebo (double-blind), and salbutamol (oral and inhaled), or none (open), in all four possible combinations. The study was carried out as a randomized block design with eight blocks of four infants each, matched by age and clinical score. Average daily improvements, as reflected by changes in the clinical score and length of hospital stay, was essentially the same for infants treated with placebo, salbutamol alone, and dexamethasone alone. However, combined salbutamol-dexamethasone treatment resulted in more than twice the rate of improvement of the other treatments. The difference was statistically highly significant (P less than .01). Furthermore, the response of this combined treatment was observed within 24 hours; none of the ten infants in whom there was no significant improvement within 48 hours and neither of the two patients who developed respiratory failure received the combined salbutamol-dexamethasone treatment. A potentiating effect of corticosteroids on the beta-adrenergic responsiveness is a possible explanation for the advantage of this combined treatment in the management of acute wheezing in infancy.

In some patients with familial dysautonimia, plasma renin activity shows a paradoxical response to postural stimuli, i.e., levels of plasma renin activity are high when the patient is in the supine position and fall significantly during subsequent ambulation. Furthermore, there is no coordinated release of plasma renin activity and aldosterone. The aim of the present study was to determine whether these findings are accompanied by a disturbance of salt conservation. Six patients were studied in a summer camp while on normal and low-salt diets. Plasma and urinary aldosterone levels rose sharply and appropriately when four of the patients were placed on a low-sodium diet. In these subjects, urinary sodium output fell sharply although three of them failed to attain sodium equilibrium by the third day of the low-sodium regimen. Elevation of early morning plasma renin activity appeared to correlate with an inversion in the normal day-night rhythm in urinary volume.

The effect of ingestion of uncooked cornstarch (2 g/kg body weight) in water, uncooked starch (1 g/kg) added to a meal, and glucose (2 g/kg) in water, was studied in eight patients with type IA glycogen storage disease (GSD) and one patient with type IB GSD. Blood glucose concentrations were determined at 30-min intervals during each tolerance test; blood lactate, blood insulin, and expiratory hydrogen were determined at 60-min intervals. The glucose levels remained in the normal range (greater than or equal to 1.8 mM) during approximately 6.5-9.0 h, 3.5-6.5 h, and 2.25-4.0 h during the three tolerance tests, respectively. The lactate levels differed markedly for the different tests per patient, and for the same type of test between the patients. Blood insulin concentrations after starch administration did not exceed values of 50 mU/liter above fasting levels and were markedly lower than those after glucose administration (maximum levels of 280 mU/liter). The expiratory hydrogen excretion did not increase or only slightly increased after cornstarch administration (less than 20 ppm).

The pharmacokinetics of caffeine were studied in young (age: 1 day, 7 days, 14 days, 30-45 days) and adult dogs following a single intravenous dose of 50 mg/kg. Mean (+/-SE) plasma elimination half life (T1/2) was 47.5 (+/-5.35) h in 1-day-old puppies, as opposed to 6.66(+/-0.85) h in adult dogs. A rapid decrease in plasma T1/2 values occurred during the first 2 weeks of life. At about 14 days of age caffeine plasma T1/2 was similar to that of adults. The volume of distribution was greatest (0.94+/- 0.03 liters/kg) and the total body clearance was smaller (2.81 +/- 0.73 liters/kg/min X 10(-4)) in the 1-day-old animals. The much smaller body clearance of caffeine in the newborn as compared to the adult dog could be due to a lower rate of metabolism and/or renal excretion of this drug in the young.

Necrotizing enterocolitis (NEC) is usually considered to be a neonatal disease, and is rarely described beyond the newborn period. During the last 15 years, 19 infants from the Negev region, Israel, with NEC were beyond the neonatal age group (range = 34-616 days, median = 90 days). Of this group only 16% were born prematurely, and only 16% had perinatal or neonatal pathology. Diarrhea and dehydration preceding NEC were common as was malnutrition. Bacteremia was detected in 42%. The mortality rate was 90%. Malnutrition, supposedly contributed to the formation of NEC and to the high mortality rate among these infants.

A workshop was held on "Aspects of treatment of patients with glycogen storage disease" within the framework of the Concerted Action "Inborn errors of metabolism" of the European Communities. Consensus was reached on the main issues of treatment of patients with deficiency of glucose-6-phosphatase, glucose-6-phosphate translocase, debranching enzyme, liver phosphorylase and phosphorylase-b-kinase. The resulting recommendations are reported.

Twenty patients with enzymatically proven glycogen storage disease type III (GSD III) aged 3-30 years underwent cardiological evaluation. Seventeen showed subclinical evidence of cardiac involvement in form of ventricular hypertrophy on ECG. Of 16 patients in whom an ECG examination was performed, 13 had abnormal echocardiographic features. Only 2 patients had cardiomegaly on X-ray. The cardiac findings in 1 of the patients, a 25-year-old female with clinically evident cardiomyopathy are described in detail. In view of our findings, patients with established GSD III, should not only be investigated regarding their muscular involvement, but should also undergo a detailed evaluation of their cardiac status.

Studies in 18 Jewish families from Morocco, Tunis, Turkey and Iran revealed 26 patients with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. The clinical expression of androgen excess varied widely in affected females, and range from solely enlarged clitoris in the mildest forms to severely hypertrophied clitoris with penile urethra and fused labial-scrotal folds in the most extreme forms of masculinization. Intermediate degrees of severity were manifested by ambiguous genitalia. There was no correlation between the degree of virilization and the signs of mineralocorticoid excess. Severe volume-induced hypertension leading to vascular accidents and death were also observed in severe as well as in mildly virilized patients, while completely masculinized females were sometime normotensive. Overt hypokalemia was present in 6 patients but was not a constant feature of hypertensives. However, all affected individuals, except for 2 infants, had very low levels of plasma renin activity suggesting that a state of volume expansion was indeed present in the majority of cases, even though changes in blood pressure did not always occur. The clinical expression of this disorder is characterized by a wide range of variability in the signs of both androgen and mineralocorticoid excess, which do not necessarily correlate with the quantity of hormones secreted.

Sixteen patients with glycogen storage disease type III (GSD III) aged 3 to 22 years underwent a detailed neuromuscular evaluation. A minimal impairment of skeletal muscle function was presented in eight patients, slight impairment in four and severe impairment in one patient. Serum creatinine phosphokinase (CPK) was elevated in all patients studied. In the nine patients, in whom electromyography (EMG) was performed; six exhibited a myopathic pattern while a "mixed" (neurogenic-myopathic) pattern was present in three. Muscle biopsies performed in 12 patients, revealed in all cases amylo-1,6,-glucosidase deficiency and biochemical as well as morphological evidence of glycogen accumulation. Two brothers suffered from late onset myopathy, which in the older sibling was associated with clinical, EMG and EM findings of a peripheral neuropathy. Fifteen patients had either electrocardiographic and or echographic evidence of cardiomyopathy. Observations based on this patient material suggest a widespread myopathy in GSD III patients with heterogeneous expression, while peripheral nerve involvement is rarely encountered.