[Hepatic glycogenosis: a case report]. / Glucogenosis hepá tica: a propósito de un caso.

The glycogen storage diseases contain a range of diseases that are characterized by the abnormal storage or utilization of glycogen, the organs most affected being muscle and / or liver. Hepatomegaly may be a clinical sign that could guide to the diagnosis. We describe a 15-year-old patient with hepatomegaly, hypertransaminasemia and growth retardation. He was diagnosed with a glycogen storage disease by liver biopsy.

Glucogenosis hepática: a propósito de un caso / Hepatic glycogenosis: a case report

RESUMEN Las glucogenosis abarcan un rango de enfermedades que se caracterizan por el almacenamiento o utilización anormal del glucógeno, siendo los órganos más afectados el músculo y/o el hígado. La hepatomegalia puede ser un signo clínico que guie al diagnóstico. Describimos a un paciente de 15 años de edad con hepatomegalia, hipertransaminasemia y retraso del crecimiento, a quien se le diagnosticó glucogenosis por biopsia hepática.

ABSTRACT The glycogen storage diseases contain a range of diseases that are characterized by the abnormal storage or utilization of glycogen, the organs most affected being muscle and / or liver. Hepatomegaly may be a clinical sign that could guide to the diagnosis. We describe a 15-year-old patient with hepatomegaly, hypertransaminasemia and growth retardation. He was diagnosed with a glycogen storage disease by liver biopsy.

Liver disease and heart failure.

INTRODUCTION: Several systemic conditions, inflammatory disease, infections and alcoholism, may affect both the heart and the liver. Common conditions, such as the non-alcoholic fatty liver disease (NAFLD), may increase the risk of cardiac dysfunction. Patients with acute decompensated HF (ADHF) may develop acute ischemic hepatitis and, chronic HF patients may develop congestive hepatopathy (CH). EVIDENCE ACQUISITION: Laboratory anomalies of hepatic function may predict the outcome of patients with advanced HF and the evaluation of both cardiac and hepatic function is very important in the management of these patients. In clinically apparent ischemic hepatitis more than 90% of patients have some right-sided HF. There are systemic disorders characterized by the accumulation of metals or by metabolism defects that may affect primarily the liver but also the heart leading to symptomatic hypertrophic cardiomyopathy (HCM). EVIDENCE SYNTHESIS: Abnormal LFTs indicate the mechanism of liver injury: liver congestion or liver ischemia. In AHF, it's important an adequate evaluation of heart and liver function in order to choose the treatment in order to ensure stable hemodynamic as well as optimal liver function. CONCLUSIONS: Measurements of LFTs should be recommended in the early phase of ADHF management. Physicians with interest in HF should be trained in the evaluation of LFTs. It's very important for cardiologists to know the systemic diseases affecting both heart and liver and the first imaging or laboratory findings useful for a diagnosis. it is very important for internists, nephrologists, cardiologists, primary physicians and any physicians with interest in treating HF to recognize such signs and symptoms belong to rare diseases and liver diseases that could be mistaken for HF.

Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency.

OBJECTIVE: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis. METHODS: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response. RESULTS: Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal. CONCLUSIONS: The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder.

Adult polyglucosan body disease presenting as a unilateral progressive plexopathy.

INTRODUCTION: Adult polyglucosan body disease (APBD) usually presents with progressive spastic paraparesis, neurogenic bladder, and distal lower limb sensory abnormalities. It is caused by mutations in the glycogen branching enzyme gene (GBE1). METHODS: We describe a woman with an unusual phenotype manifesting as progressive left brachial more than lumbosacral plexopathies, with central sensory and corticospinal tract involvement. RESULTS: Magnetic resonance imaging of the brain and cervical spine showed abnormal T2 signal within the ventral pons and medulla bilaterally, involving the pyramidal tracts and the medial leminisci. There was also medullary and cervical spine atrophy. On nerve biopsy, large polyglucosan bodies were noted in the endoneurium. The patient was found to be compound heterozygous for 2 novel mutations in GBE1. Peripheral blood leukocyte GBE activity was markedly reduced to 7% of normal, confirming the diagnosis of APBD. CONCLUSIONS: In this report we describe a new phenotype of APBD associated with 2 novel mutations. Muscle Nerve 53: 976-981, 2016.

Adult polyglucosan body disease: clinical and histological heterogeneity of a large Italian family.

Adult Polyglucosan Body Disease (APBD) is a rare inherited leukodystrophy associated with axonal polyneuropathy, mainly reported in persons of Ashkenazi-Jewish descent. We describe three Italian siblings at disease onset, presenting in their fifties with a combination of pyramidal and ataxic signs, mild demyelinating neuropathy on neurophysiological investigation (1/3 cases) and transient symptoms (1/3). A leucoencephalopathy with infratentorial lesions without enhancement and medullary/spine atrophy was demonstrated on brain/spine MRI (3/3). Muscle biopsy was normal in 2/3; both muscle and nerve biopsy showed polyglucosan bodies in the sibling with polyneuropathy. This indicated a need for GBE1 sequencing, which revealed a novel missense mutation (c.1064G>A; p.Arg355His) and one previously described (c.1604A>G; p.Tyr535Cys) in all siblings. We highlight that peripheral neuropathy, deemed as disease hallmark, may be missing and that transient symptoms are confirmed as early disease manifestations. The pattern of damage at neuro-imaging described recurs irrespective of clinical presentation, constituting a unifying diagnostic clue.

Myocardial glycogen dynamics: new perspectives on disease mechanisms.

Cardiac glycogen regulation involves a complex interplay between multiple signalling pathways, allosteric activation of enzymes, and sequestration for autophagic degradation. Signalling pathways appear to converge on glycogen regulatory enzymes via insulin (glycogen synthase kinase 3ß, protein phosphatase 1, allosteric action of glucose-6-phosphate), ß-adrenergic (phosphorylase kinase protein phosphatase 1 inhibitor), and 5' adenosine monophosphate-activated protein kinase (allosteric action of glucose-6-phosphate, direct glycogen binding, insulin receptor). While cytosolic glycogen synthesis and breakdown are relatively well understood, recent findings relating to phagic glycogen degradation highlight a new area of investigation in the heart. It has been recently demonstrated that a specific glycophagy pathway is operational in the myocardium. Proteins involved in recruiting glycogen to the forming phagosome have been identified. Starch-binding domain-containing protein 1 is involved in binding glycogen and mediating membrane anchorage via interaction with a homologue of the phagosomal protein light-chain 3. Specifically, it has been shown that starch-binding domain-containing protein 1 and light-chain 3 have discrete phagosomal immunolocalization patterns in cardiomyocytes, indicating that autophagic trafficking of glycogen and protein cargo in cardiomyocytes can occur via distinct pathways. There is strong evidence from glycogen storage diseases that phagic/lysosomal glycogen breakdown is important for maintaining normal cardiac glycogen levels and does not simply constitute a redundant 'alternative' breakdown route for glycogen. Advancing understanding of glycogen handling in the heart is an important priority with relevance not only to genetic glycogen storage diseases but also to cardiac metabolic stress disorders such as diabetes and ischaemia.

Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage.

RATIONALE: AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase as a drug target. OBJECTIVE: We sought to identify the pro-growth-signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage. METHODS AND RESULTS: In a mouse model of N488I mutation of the Prkag2 gene (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate-stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth. CONCLUSIONS: Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of γ2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.

An infant with pulmonary interstitial glycogenosis: clinical improvement is associated with improvement in the pulmonary diffusion capacity.

Pulmonary interstitial glycogenosis (PIG) is an idiopathic interstitial lung disease of infants. The underlying pulmonary pathophysiology of PIG has not been well characterized. Herein we report a term-gestation infant who presented with persistent tachypnea and hypoxia. A chest CT scan demonstrated a diffuse ground glass appearance and lung biopsy demonstrated increased alveolar septae cellularity with glycogen-containing cells, consistent with a diagnosis of PIG. At 3 months of age, pulmonary function testing included: pre- and post-bronchodilator forced expiratory flows using the raised-volume technique and the ratio of pulmonary diffusing capacity for carbon monoxide to alveolar volume (DLCO /VA ). He was prescribed 5 days of oral prednisolone (2mg/kg/day) and pulmonary function testing (PFT) was repeated at 5, 13, and 20 months of age. Initial PFTs demonstrated reduced forced vital capacity (FVC: Z-score = -2.36) and an increased ratio of forced expiratory volume in 0.5 sec to FVC (FEV0.5/FVC: Z-score = 1.15) with no significant change following an inhaled bronchodilator. There was also a marked reduction in DLCO /VA (Z-score = -4.74) compared to age-matched controls. Follow-up demonstrated progressive clinical improvement as well as an increase in Z-FVC and normalization of DLCO /VA . Our in vivo physiological findings are consistent with previous reports that symptom resolution correlated with histological thinning of the alveolar septae upon repeat lung biopsy. The restrictive lung disease we observed is consistent with expected reduced compliance of an alveolar interstitial lung process like PIG, whereas the absence of a reduction in FEV0.5/FVC confirms the absence of obstructive airway disease.

McArdle's disease (glycogen storage disease type V) and anesthesia--a case report and review of the literature.

McArdles disease (glycogen storage disease type v) is a rare condition in which energy-metabolism in the muscle is hampered. A case report is presented and the possible risk for perioperative complications including malignant hyperthermia is discussed. A checklist for the anesthesiological management of patients with McArdles disease is provided. A short overview of anesthesiological challenges and perioperative complications of other glycogen storage diseases is given.

Progress and problems in muscle glycogenoses.

In this selective review, we consider a number of unsolved questions regarding the glycogen storage diseases (GSD). Thus, the pathogenesis of Pompe disease (GSD II) is not simply explained by excessive intralysosomal glycogen storage and may relate to a more general dysfunction of autophagy. It is not clear why debrancher deficiency (GSD III) causes fixed myopathy rather than exercise intolerance, unless this is due to the frequent accompanying neuropathy. The infantile neuromuscular presentation of branching enzyme deficiency (GSD IV) is underdiagnosed and is finally getting the attention it deserves. On the other hand, the late-onset variant of GSD IV (adult polyglucosan body disease APBD) is one of several polyglucosan disorders (including Lafora disease) due to different etiologies. We still do not understand the clinical heterogeneity of McArdle disease (GSD V) or the molecular basis of the rare fatal infantile form. Similarly, the multisystemic infantile presentation of phosphofructokinase deficiency (GSD VII) is a conundrum. We observed an interesting association between phosphoglycerate kinase deficiency (GSD IX) and juvenile Parkinsonism, which is probably causal rather than casual. Also unexplained is the frequent and apparently specific association of phosphoglycerate mutase deficiency (GSD X) and tubular aggregates. By paying more attention to problems than to progress, we aimed to look to the future rather than to the past.

Evaluation of Lunar Prodigy dual-energy X-ray absorptiometry for assessing body composition in healthy persons and patients by comparison with the criterion 4-component model.

BACKGROUND: Dual-energy X-ray absorptiometry (DXA) is widely used to assess body composition in research and clinical practice. Several studies have evaluated its accuracy in healthy persons; however, little attention has been directed to the same issue in patients. OBJECTIVE: The objective was to compare the accuracy of the Lunar Prodigy DXA for body-composition analysis with that of the reference 4-component (4C) model in healthy subjects and in patients with 1 of 3 disease states. DESIGN: A total of 215 subjects aged 5.0-21.3 y (n = 122 healthy nonobese subjects, n = 55 obese patients, n = 26 cystic fibrosis patients, and n = 12 patients with glycogen storage disease). Fat mass (FM), fat-free mass (FFM), and weight were measured by DXA and the 4C model. RESULTS: The accuracy of DXA-measured body-composition outcomes differed significantly between groups. Factors independently predicting bias in weight, FM, FFM, and percentage body fat in multivariate models included age, sex, size, and disease state. Biases in FFM were not mirrored by equivalent opposite biases in FM because of confounding biases in weight. CONCLUSIONS: The bias of DXA varies according to the sex, size, fatness, and disease state of the subjects, which indicates that DXA is unreliable for patient case-control studies and for longitudinal studies of persons who undergo significant changes in nutritional status between measurements. A single correction factor cannot adjust for inconsistent biases.

The natural course of non-classic Pompe's disease; a review of 225 published cases.

Pompe's disease is a neuromuscular disorder caused by deficiency of lysosomal acid alpha-glucosidase. Recombinant human alpha- glucosidase is under evaluation as therapeutic drug. In light of this development we studied the natural course of cases not fitting the definition of classic infantile Pompe's disease. Our review of 109 reports including 225 cases shows a continuous spectrum of phenotypes. The onset of symptoms ranged from 0 to 71 years. Based on the available literature, no criteria to delineate clinical sub-types could be established.A common denominator of these cases is that first symptoms were related to or caused by muscle weakness. In general, patients with a later onset of symptoms seemed to have a better prognosis. Respiratory failure was the most frequent cause of death. CK, LDH, ASAT, ALAT and muscle glycogen levels were frequently but not always elevated. In most cases a muscle biopsy revealed lysosomal pathology, but normal muscle morphology does not exclude Pompe's disease. In 10% of the cases in which the enzyme assay on leukocytes was used, a normal alpha-glucosidase activity was reported. Data on skeletal muscle strength and function, pulmonary function, disability, handicap and quality of life were insufficiently reported in the literature. Studies of non-classic Pompe's disease should focus on these aspects, before enzyme replacement therapy becomes generally available.

Diagnostic utility of a modified forearm ischemic exercise test and technical issues relevant to exercise testing.

The sensitivity and specificity of a modified forearm ischemic test (FIT) are described in the diagnosis of glycogen storage disease, myoadenylate deaminase deficiency, and mitochondrial disease. FIT and muscle biopsy results were reviewed from 99 patients (glycogen storage disease [GSD], myoadenylate deaminase deficiency [AMPD], mitochondrial disease [MITO], miscellaneous neuromuscular disorders, and controls). The influence of catheter placement and an antecedent sugar bolus were also assessed in healthy young men. The FIT had a sensitivity of 1.00 and a specificity of 1.00 for a diagnosis of GSD, whereas the corresponding values were 1.00 and 0.37 for AMPD deficiency. A baseline lactate of >2.5 mmol/L provided the highest sensitivity (0.62) and specificity (1.00) for MITO disease. A baseline and +1 min sample provided optimal sensitivity and specificity for GSD and AMPD deficiency. Catheter placement in any vein other than the ipsilateral antecubital resulted in attenuated lactate responses (P < 0.0001). A pre-FIT sugar bolus did not alter the postexercise lactate or ammonia response. Thus, a modified FIT was helpful in the diagnosis of GSD and excluding AMPD deficiency, but not in the diagnosis of MITO disease. Catheter placement is critical to the interpretation of a FIT, whereas pretesting diet is less important.

Muscle ultrasonography and electromyography correlation for evaluation of floppy infants.

Floppiness in an infant may have a number of different etiologies from disorders of the brain to spinal cord lesions, neuropathies, neuromuscular junction disorders and myopathies. In this study we aimed to investigate the correlation of muscle ultrasonography (US) and electromyography (EMG) in the diagnosis of floppy infants. The study encompassed 41 floppy infants aged 2-24 months. The muscle US and EMG examinations were performed without awareness of the clinical diagnosis. The final diagnosis was established by molecular genetic tests or muscle/nerve biopsy. The neurogenic group consisted of 16 infants according to their US and EMG findings. Fifteen of them had spinal muscular atrophy proven by genetic analysis and one had polyneuropathy diagnosed by nerve biopsy. Six infants were in the myopathic group according to their muscle US and EMG results. All of them underwent muscle biopsy and microscopic examination revealed five congenital muscular dystrophy and one glycogen storage disease. In two infants the US and EMG data conflicted. Their biopsies were also insufficient for the diagnosis. Seventeen infants had normal US and EMG findings but pathologic cranial magnetic resonance imaging or metabolic/genetic tests. They were considered in the group of central hypotonia. Our results suggest a high concordance of US and EMG findings in the diagnostic work-up of neurogenic and myopathic disorders.

Contraception and pregnancy in women affected by glycogen storage diseases.

UNLABELLED: During the last decades, better understanding of specific enzymatic deficiencies has led to improved dietary management of children suffering from glycogen storage disease (GSD). Normal growth and development of infants can be achieved by a diet of regular meals supplemented by glucose and cornstarch during the night, and by monitoring glucose blood levels. This has resulted in an increase in the number of patients reaching adulthood and reproduction age. Therefore, developing a strategy for an optimal management of contraception and pregnancy is crucial for young women affected by GSD. Contraception has to be adapted to the specific metabolic requirements of women with GSD. Hormonal contraception is classically based on the combination of various synthetic progestogens and ethinyloestradiol. Ethinyloestradiol should be avoided because of a link with hepatic adenomas and is contraindicated in patients with hypertriglyceridaemia and hypercholesterolaemia. Blockade of ovulation can be achieved using high doses of progestogen alone, administered from the 5th to the 25th day of the cycle. Another scheme of hormonal contraception is based on daily administration of low doses of progestogen, which usually acts on local parameters of fertility, and can also achieve blockade of ovulation for the most recent compound proposed. Mechanical contraception using intra-uterine device is controversial for nulliparous patients. Benefits and side-effects of these different proposals are discussed. During pregnancy, the maternal nutritional state is important and a healthy maternal response to feeding and fasting is modified to ensure a constant supply of glucose for the developing fetus. Women with GSD are at risk of frequent hypoglycaemia. Only a few cases of successful pregnancies have been reported for patients with GSD. The outcomes using different approaches of dietary and obstetric management are discussed. CONCLUSION: in the future, multidisciplinary management is necessary to improve obstetric outcome of pregnancy in females affected with glycogen storage disease.

Concentric-needle versus macro EMG. II. Detection of neuromuscular disorders.

OBJECTIVE: Little is known about the relation and sensitivity of macro-EMG (MA-EMG) compared with concentric-needle EMG (CN-EMG) in the detection of neuromuscular disorders. METHODS: CN-EMGs and MA-EMGs were recorded from the right brachial biceps muscle of 40 healthy subjects, aged 17-83 years, 20 patients with neurogenic disorders, aged 25-75 years, and 20 patients with myopathy, aged 18-76 years. Motor unit action potentials (MUAPs) were examined. RESULTS: In patients with neurogenic disorders CN-MUAP duration, CN-MUAP amplitude, percent polyphasia, MA-MUAP amplitude, MA-MUAP area and fibre density were significantly increased. In patients with myopathy, only fibre density was significantly increased. In patients with neurogenic disorders, the sensitivity of CN-EMG was 80%, and that of MA-EMG 85%. In myopathies, the sensitivity was 50% for each technique. Pooling the results of both EMG techniques, the sensitivity increased to 90% in patients with neurogenic disorders, and to 65% in myogenic disease. CONCLUSIONS: MA-EMG has a similar sensitivity in the detection of neuromuscular disorders as CN-EMG. Particularly when myopathy is suspected, both techniques should be applied if one is unrevealing.