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An Omani infant boy who presented in the neonatal period with cardiac failure secondary to hypertrophic cardiomyopathy is reported. He subsequently progressed to show features of a metabolic disorder with multisystem involvement and was diagnosed to have Type II glycogenosis (Pompe's disease). The differential diagnosis and management of metabolic cardiomyopathy are outlined.
Furazolidone (FZ) at 700 ppm was added to feed mixtures fed turkey poults two weeks posthatching to induce acute experimental cardiomyopathy. Poults in the control pen received the same ration but without FZ. Four of the control poults developed spontaneous round heart disease. From EKG data and blood samples obtained at weekly intervals, poults were selected for sacrifice at 5 weeks of age. Tissue samples from the left myocardial wall, liver, and pectoralis major and tibialis anterior muscles were analyzed for glycogen by biochemical assay. Blood glucose was determined with the Technicon autoanalyzer. Deposition of glycogen increased significantly (p less than 0.05) in the myocardium of all affected poults and in the liver of all FZ-treated poults. Glycogen levels of the pectoralis major and tibialis anterior muscles were not affected by FZ, but a significant increase (p less than 0.05) was apparent in the pectoralis major muscle of spontaneous round heart poults. It was concluded that FZ influences glycogen metabolism, probably by enzyme inhibition, and that it tends to magnify effects seen in the spontaneous round heart syndrome. Glycogen infiltration of tissues such as the heart and white skeletal muscle suggests that the round heart syndrome may be a manifestation of the glycogen storage disease, idiopathic generalized glycogenosis. Lack of significant differences in the blood serum glucose levels of all poults indicates that these levels are not a reliable clinical parameter for monitoring development of the round heart syndrome.
Liver transplant currently represents the therapeutic method for irreversible acute and chronic liver diseases without any other available therapy. In some cases, before or after liver transplantation, it is necessary to replace the functions of the liver. We report the case of a 7 year-old female patient with type I glycogenosis who was transplanted in July 2001 using living-related donor transplantation and who developed chronic rejection two months later. In this case, we used MARS (Molecular Adsorbents Recirculating System) detoxification therapy to optimise the patient's clinical and biological status and to create a bridge that allowed the patient's survival until retransplantation was available. The therapy was well tolerated, with no major incidents. We noted favourable clinical effects and significant improvement in serum bilirubin level, urea nitrogen level and serum creatinine level. We consider that MARS treatment is a temporary solution for patients with acute and acute-on-chronic liver failure, indicated in those cases with real chances of recovery of the hepatic functions or in patients on the liver transplantation waiting list.
Mc Ardle's disease is a genetic glycogenosis characterized by the accumulation of glycogen in skeletal muscle secondary to the deficiency of muscle glycogen phosphorylase. The clinical consequences are an exercise intolerance with rapid muscle fatigue and muscle pain combined with a myoglobinuria. We report the medical story of a 45 years old man who suffers from Mc Ardle disease for ten years. He holds his family's doctor because of an oliguria and a weight gain of 5 kg after one week of skiing and one afternoon of gardening. Moreover he complains of quadriceps muscle pains. His urine is orange-red. The supplementary examinations show a rhabdomyolysis and an acute renal failure. The patient benefits of a hemodialysis treatment with a progressive and complete recovery of his renal function after two weeks of treatment.
By cytofluorometric method, a study was made of the total glycogen and its two fractions in liver parenchymal cells both in the donors (20 men) and in patients with cirrhosis of different etiology (39 men). The examination was performed on preparations--smears of isolated hepatocytes, obtained from the live functional liver biopsies. The quantitative analysis has shown an increase in the total glycogen content in hepatocytes of patients with cirrhosis by 3 times compared to the norm, and this increase is independent on the etiology of liver cirrhosis. To study the mechanism of the discovered glycogenosis, the activity of key enzymes of glycogenolyses was determined. It was shown that glucose-6-phosphatase and glycogen-phosphorylase activity in the liver with cirrhosis was lower than in the norm. The most considerable changes were shown in hepatocytes of patients with liver cirrhosis in fractional glycogen composition and, even more significant, in the content of a hard soluble fraction. The hard soluble fraction portion was higher in hepatocytes of the patients with liver cirrhosis of alcohol etiology. The quantitative analysis of glycogen fraction contents in liver cells may be the best marker in the differential diagnosis of symptomless elapsing liver cirrhosis.
Glycogenosis type V (McArdle disease) is a serious metabolic disorder with an exercise intolerance, myalgia, early fatigue and stiffness of exercising muscles, relieved++ by rest. The authors present a case report of patient with McArdle's disease, and diagnostic procedures which can be used in different diagnostic of metabolic myopathies, especially between myoadenylate deaminase deficiency and different types of gly(geno)lytic myopathies. The importance of "ischemic forearm test" and muscle biopsy is emphasized.
A retrospective study of 40 patients with various neuromuscular disorders and more than 3 muscle fibers with rimmed vacuoles has been performed. Two subgroups of patients were distinguished according to the presence or absence of inflammatory exudates. In the first group (14 patients), inflammatory exudates were observed and numerous fibers showed partial invasion. Abnormal filamentous inclusions (16-18 nm in diameter) were found by electron microscopy in muscle fibers cytoplasm and/or nuclei. The diagnosis of inclusion body myositis (IBM) was made in these cases. They presented with insidious proximal muscle weakness and were not improved by immunosuppressive therapy. Immunohistological studies demonstrated T lymphocytes predominance, only few natural killer and B lymphocytes. The number of T8 lymphocytes was high in endomysial sites while T4 were more numerous in perivascular exudates. Abnormal membranous expression of class I MHC antigens was observed on muscle fibers lying near the inflammatory exudates. In the second group of cases (26 patients), no inflammatory exudate was observed. This group of neuromuscular diseases with rimmed vacuoles was heterogeneous. In 10 cases, abnormal filamentous inclusions (16-18 nm in diameter) were observed in rimmed vacuoles. However, this ultrastructural feature did not help in distinguishing subgroups. Various neuromuscular disorders were observed in this group: oculopharyngeal muscular dystrophy (12 cases with IBM like filaments in 4 cases), chronic spinal atrophy (5 cases with IBM like filaments in 3 cases), post poliomyelitis syndrome (2 cases with IBM-like filaments in one), muscle glycogenosis with IBM like filaments (2 cases), hereditary limb girdle myopathy or distal myopathy (3 cases) and 1 patient clinically presenting with polymyositis and another with cramps and myalgias. No abnormal sarcolemmal expression of class I MHC was found in this group. The pathogenesis of IBM is discussed. Besides T cell mediated cytotoxicity, denervation may be involved. The nature of the abnormal 16-18 nm filamentous inclusions remains unknown. These filaments are not IBM specific.
Exercise-induced enzymatic myopathies include carnitine palmityl transferase deficiency and, among muscular glycogenoses, Mac Ardle's and Tarui diseases. These diseases are usually recognized when exercise-induced myalgias, myoglobinuria and raised creatinine kinase (CK) levels are present. However, myoglobinuria may be absent in 10 to 50 percent of the cases, and CK levels are often normal at rest; thus, the diagnosis is often delayed for several years, with a risk of acute renal failure in 10 to 30 percent of the patients. We report 6 cases of exercise-induced enzymatic myopathies with normal CK levels and with electromyographic studies at rest. The main clinical features of these cases and those of similar conditions reported in the literature are male sex, onset of the disease before the age of 15 years, episodes of severe exercise-induced myalgias, cramps and muscle weakness and myogenic hyperuricaemia at rest in muscular glycogenosis.
Tarui's diseases affecting a brother and sister was studied. On the basis of these case, a general review is undertaken of this rare muscle glycogenosis, of which only six cases have been reported up to the present. This study underlines the characteristics of the responsible phosphofructokinase deficiency which has the special characteristic of manifesting itself at one and the same time in muscle by a picture of non-traumatic rhabdomyolysis and in the red cells by haemolysis, in most cases sub-clinical. This sign, clinically evident in the first case, was nevertheless a fundamental diagnostic element. In the context of the diagnostic criteria, emphasis is placed upon the value of the measurement of blood lactic acid after effort, the results of which, in conjunction with an increase in muscle enzymes, confirm the presence of a true muscle glygenosis. Enzyme studies indicate the nature of the latter.
Liver cell transplantation is an emerging procedure, consisting of infusing mature adult hepatocytes in the portal system of the recipient. It aims to correct inborn errors of liver metabolism, bridge unstable patients to transplantation, or even allow bridge to recovery in fulminant liver failure. The technique addresses ideally patients with inborn errors of metabolism, unstable but not sick enough for orthotopic transplantation. Best results have so far been obtained in metabolic diseases, such as urea cycle disorders, glycogenosis type I, Crigler Najjar, Refsum disease and factor VII deficiency. Cryopreserved hepatocytes can be used, allowing delay between cell isolation and patient's transplantation. The percentage of engraftment obtained can reach up 10%, with de novo expression of deficient enzyme activity. Better results of engraftment have been obtained in animal studies by different chemical or physical techniques, but not yet applied in humans. Because supply of human cells can be limited, research also aims to obtain transplantable cells from other sources, such as embryonic or adult stem cells, or liver progenitor cells that could be expanded in vitro. Careful progression in this field, and collaboration between centers are mandatory to validate further the technique for wider clinical use.
In two new cases of centronuclear myopathy, histochemical findings included failure to differentiate fiber type with oxidative enzymes, the presence of core glycogenosis, and core acid phosphatase activity. Fluorescence microscopy demonstrated autofluorescent lipochrome in fiber centers and nonspecific fiber injury in some immunofluorescent preparations. Electron microscopical findings included the observation of unusually small myofibrils arrayed between central nuclei.
The association of de Toni-Debré-Fanconi syndrome with alteration of galactose metabolism and glycogen hepatic storage, before further clarification, is defined as Fanconi-Bickel syndrome. The Authors present a case in which the alterations in galactose metabolism typically do not affect the enzymes responsible for galactosemia. In such patients a recognised enzymatic defect glycogenosis is not involved and glycogen storage in the liver can be a secondary phenomenon, which can increase, differing according to each subject. Liver biopsy to detect storage can be avoided when all the other diagnostic criteria are observed.
Glycogenosis type II or Pompe disease is an inherited autosomal recessive disorder known in 3 different clinical forms (infantile, juvenile and adult). We report on a case diagnosed as a classic infantile form with the worst outcome of all 3 described, if we had followed and executed a correct and complete diagnostic pathway. A 7 months old female child was admitted for fever and dyspnoea. At chest auscultation weepings and weezings were found; on the cardiac apex a murmur due to mitralic failure was retrieved. The thorax X-ray showed a greatly increased heart shadow with a cardiothoracic index of 0.75. ECG showed high voltages and signs of bilateral ventricular hypertrophy. Cardiac ultrasonography confirmed the presence of a big heart with an enormous swollen left ventricle and a severe mitralic failure. The clinical diagnosis of infantile Pompe disease was confirmed by the almost total absence of cellular acid a-glucosidase activity but we couldn't perform the assay because of the rapid exitus of our patient, which occurred before glycogen storage disease II was suspected. So, we tried to compare our case with others reported in the literature in order to ratify our diagnostic hypothesis. The contribution of genetic counseling practiced on all the couples at risk remains useful every time that a certain diagnosis is made.
This method has been developed for the prenatal diagnosis of a grave hereditary disease, a deficiency of amylo-1,6-glucosidase (A-1,6-G) activity. The methods suggested earlier did not rule out the effects of other glucosidases, that could result in false-positive data if the fetus was involved. The new method for measuring A-1,6-G activity includes sedimentation of acid alpha-glucosidase with rabbit blood antiserum to human placental acid alpha-glucosidase. A-1,6-G activity is estimated from the difference in glucose accrement with limit dextrin and glycogen used as substrates. A-1,6-G activities were measured in 15 chorion samples obtained in the first trimester of pregnancy by the developed method, and normal values of this parameter established, making up 39.77 +/- 8.1 nmol/h per g of protein. The method may be useful in the prenatal diagnosis of type III glycogenosis.
Gout is a chronic metabolic disease caused by a disorder of the purine metabolism leading to hyperuricaemia. It is determined by the deposition of monosodium urate crystals in joints and other tissues which causes an acute inflammatory response and can induce a permanent tissue damage which defines the urate chronic joint disease which is characterised by the appearance of ulceration of the joint cartilage, marginal osteophytosis, geodic and erosive lesions and chronic inflammation of synovial membrane. Gout and hyperuricaemia usually occur after the age of 30 years and more frequently in men. Hyperuricaemia is the result of an increased production of uric acid or its hypoexcretion by the kidneys, or both. In the pathogenesis of gout and hyperuricaemia are involved genetic and environmental factors; further, different pathologic condition such as glycogenosis, renal insufficiency, use of some drugs, are associated with gout. Treatment of acute gout includes colchicine, nonsteroidal anti-inflammatory drugs and glucocorticoids, whereas in the intercritical periods colchicine is effective for preventive purposes. Urate-lowering therapy with xanthine-oxidase inhibitors or uricosuric agents is indicate only in patients with more than two gout crisis per year, tophaceous deposits, uric acid nephrolithiasis, and interstitial renal disease, as asymptomatic hyperuricaemia does not requires any treatment but can be controlled with preventive dietetic measures and changes in lifestyle.
The discovery of a fructose-1,6-diphosphatase deficiency in two sisters leads to the discussion of the various loading tests which are required for the diagnosis. The diagnosis may be discussed clinically with type I glycogenosis, and biologically with hereditary fructose intolerance. The specific characteristics of these disorders are analyzed as well as the problem of fructose induced hypoglucosemia. The failure of the treatment with folic acid in one of the cases leads to emphasize the suppression of prolonged fast in order to avoid acute accidents.
The purpose of the study was differential diagnosis of lactic acidosis in 44 children aged from 2 weeks to 4 years. In all of them the lactate level in repeated determinations exceeded 27 mg/100 ml. From the point of view of clinical manifestations the children were divided into three groups: 26 with hepatomegaly and hypoglycaemia (I), 6 with ataxia and retardation of somatic development (II), 12 with mental retardation and muscular hypotonia (III). Together with basic biochemical studies other tests were done, if necessary, including glucose and alanine loading, lactate determination in cerebrospinal fluid, analysis of urinary organic acids by the GC-MS method, morphological examinations of muscle biopsy material, enzymatic determinations in liver biopsy material. In group I glycogenosis was suspected and its type was finally established after biochemical and enzymatic tests (types I, Ib, III, VI, VIa, XI). In one case fructose-1,6-diphosphatase deficiency was suspected. In group II the clinical manifestations resembled Leigh's syndrome. The tests demonstrated an inhibition of glucose formation from alanine, and lactate level in the cerebrospinal fluid was evidently raised above that in the serum. Gasometric index showed the presence of respiratory alkalosis with metabolic compensation rather than primary lactate acidosis. In group III, with considerable clinical variety of signs, in only nine out of 12 children the cause of lactate acidosis could have been established (pathological changes of mitochondria in 4 cases, secondary increase of lactate without pathogenetic importance in 4, and 3-hydroxy-3-methylglutaric acidosis in 1 case. In conclusion it is thought that this combination of diagnostic methods is useful in differential diagnosis of congenital lactate acidosis in children.
The results of clinical and biochemical investigations on a girl with all obligatory signs of Mauriac syndrome already in infancy were compared with the different hypotheses suggested in order to explain the pathogenesis of this disease. One possible explanation for the origin of MS might be a decreased sensitivity of adenylate-cyclase to glucagon or adrenalin. Hypersensitivity to insulin, resulting in a decreased production of cyclic AMP and activation of glycogen synthetase could be excluded by measuring the urine excretion of cAMP with and without insulin. Furthermore no signs of dyspituarism were detectable on our case and the hypothesis of MS being a combination of primary glycogenosis and diabetes mellitus could also be refuted. Liver enzyme activities were normal.