How many forms of glycogen storage disease type I?

 Glucose-6-phosphatase is a multicomponent enzymatic system of the endoplasmic reticulum, which catalyses the terminal steps of gluconeogenesis and glycogenolysis by converting glucose-6-phosphate to glucose and inorganic phosphate. Glycogen storage diseases type I (GSD I) are a group of metabolic disorders arising from a defect in a component of this enzymatic system, i.e. the glucose-6-phosphate hydrolase (GSD Ia), the glucose-6-phosphate translocase (GSD Ib) and possibly also the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id). The genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase have both been cloned and assigned to human chromosomes 17q21 and 11q23, respectively. Investigation of patients with GSD I shows that those with GSD Ia are mutated in the glucose-6-phosphate hydrolase gene, whereas those diagnosed as GSD Ib, GSD Ic or GSD Id are mutated in the glucose-6-phosphate translocase gene, and are therefore GSD Ib patients, in agreement with the fact that they all have neutropenia or neutrophil dysfunction. This suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable. Conclusion In practice therefore appears to be only two types of GSD I (Ia and Ib), which can be differentiated by (1) measurement of glucose-6-phosphatase activity in fresh and detergent-treated homogenates and (2) by mutation search in the genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase. Received: 20 July 1999 and in revised form: 1 October 1999 / Accepted: 1 October 1999     

Consensus guidelines for management of glycogen storage disease type 1b—European study on glycogen storage disease type 1

Life expectancy in glycogen storage disease type 1 (GSD-1) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and therefore experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Based on data from the European Study on Glycogen Storage Disease Type 1, discussions within this study group together with those at the International SHS Symposium ‘Glycogen Storage Disease Type I and II: Recent Developments, Management and Outcome’, Fulda, Germany (2000) and on data from the literature, a series of guidelines were drawn up.Conclusions: the following guidelines for the management of patients with glycogen storage disease type 1b are in addition to those general guidelines for glycogen storage disease type 1 and address specific problems related to neutropenia and neutrophil dysfunction. Published online: 13 September 2002     

Is glycogen storage disease 1a associated with atherosclerosis?

Deficiency of microsomal glucose-6-phosphatase in liver and kidney leads to glycogen storage disease type la (GSD 1a). Notwithstanding intensive dietary therapy, moderate to severe dyslipidaemia and microal-buminuria, both known atherosclerotic risk factors, remain present. Although more patients reach adult age, no information is still available about accelerated athero-sclerosis. the aim of our study was to investigate whether GSD 1a was associated with premature atherosclerosis. In nine adolescent patients (mean age 22.7±3.4 years) and nine matched healthy control subjects, lipid profile, blood pressure, ankle-brachial indices, aortic distensibility and intima-media thickness (IMT) of the carotid and femoral arteries were determined. As expected, lipid profiles were significantly unfavourable in the patient group compared with the control group. No differences were found in blood pressure, ankle-brachial indices and aortic distensibility between both groups. IMT segments were comparable in both groups, with even thinner segments in the patient group. In different multivariate models, GSD la remained an independent predictor for a thinner IMT (R²=0.90; \=−0.69;P=0.018).Conclusion: glycogen storage disease type 1a is not associated with premature atherosclerosis, despite the existence of longstanding dyslipidaemia and microalbuminuria. Published online: 2 July 2002     

Acute rheumatic fever in a patient with glycogen storage disease type Ib: causal or coincidental simultaneous occurrence?

We report a Caucasian female who was diagnosed with glycogen storage disease type Ib (GSD-Ib) at the age of 4 months and whose clinical course was complicated by neutropenia and very frequent episodes of infection, including tonsillopharyngitis. Recurrent group A streptococcal infections resulted in multiple episodes of extremely high serum levels of antibodies to streptolysin O (5,000 IU/ml) and DNAse B (6,000 IU/ ml). At the age of 14 years she presented with carditis, migratory arthritis, fever, elevated erythrocyte sedimentation rate as well as serological evidence for recent streptococcal infection providing a diagnosis of acute rheumatic fever. CONCLUSION: the occurrence of these two very rare disorders in our patient may indicate that this association is not coincidental because neutrophil dysfunction in glycogen storage disease type Ib may have predisposed this patient to acute rheumatic fever due to increased susceptibility to group A streptococcal infections. aberrant glycogenolysis and gluconeogenesis, neutropenia and neutrophil dysfunction are regular findings in GSD-Ib. Neutropenia and neutrophil dysfunction in patients with GSD-Ib are due to defects in myeloid maturation, impaired neutrophil motility, defective chemotaxis and phagocytosis and diminished bactericidal activity resulting in recurrent bacterial infections.     

Short rib polydactyly syndrome—type I

Short rib polydactyly syndrome (SRPS) consists of a group of lethal skeletal dysplasias presenting with short limbs and ribs, hypoplastic thorax and polydactyly with or without visceral abnormalities. The authors report a case of SRPS in a fresh stillborn baby who had these features along with dysplastic kidneys. Clinical and radiological findings in this baby were consistent with SRPS-Type I (Saldino-Noonan Type). The diagnosis of SRPS, as in this case, can be made by antenatal ultrasonography     

Are animal models useful for understanding the pathophysiology of lysosomal storage disease?

Spontaneously occurring genetic lysosomal storage diseases are as rare in other mammalian species as in man. However, the advent of gene targeting technology has revolutionized the state of animal models of genetic diseases. Nearly all lysosomal storage diseases known in man have been duplicated in the mouse. The technology now allows, not only complete inactivation of endogenous genes, but also the introduction of essentially any type of mutation. These animal models can overcome many of the limitations inherent in studies of human patients--rarity of the disease, extremely complex genetic background and logistical and ethical constraints in the design and execution of experiments with human subjects. For example, genetic manipulations of germ cells or cross-breeding experiments between two mutants are readily feasible with animal models. Two major areas of the utility of animal models are the clarification of the pathophysiology/pathogenetic mechanism of disease and the exploration of therapeutic approaches. Examples of experiments using animal models of lysosomal storage disease are presented, primarily from studies undertaken in our own laboratory. CONCLUSION: Animal models have proved invaluable in extending our knowledge of the lysosomal storage diseases and exploring potential therapies.     

Tyrosinemia type I—Diagnostic issues and prenatal diagnosis

A fifteen-month-old boy, born to consanguineously married couple, presented with asymptomatic hepatomegaly. Investigations revealed midly deranged liver functions, necroinflammatory changes and cirrhosis on liver biopsy, a markedly raised alpha feto protein and tyrosine levels in plasma and a generalized aminoaciduria. His diagnosis of hereditary tyrosinemia was established on findings of raised serum and urine succinylacetone, and a deficient activity of fumaryl acetoacetate hydroxylase enzyme. Prenatal diagnosis of hereditary tyrosinemia was performed in a subsequent pregnancy in this family from India.     

Diabetes mellitus type I, celiac disease and Imerslund-Gräsbeck syndrome: only an incidental combination of rare diseases?

We describe the clinical course of a girl with onset of type I diabetes mellitus at the age of 3 years. At the age of 10, coeliac disease and shortly thereafter a vitamin B12 deficiency anemia (Imerslund-Gr?sbeck-syndrome) was diagnosed. Her younger sister also suffered from Imerslund-Gr?sbeck-syndrome when she was 11 year old. This unusual, so far not described association of rare diseases suggests a common autoimmune etiology.     

Ghosal type hemato-diaphyseal dysplasia: A rare variety of Engelmann’s disease

Ghosal type hemato-diaphyseal dysplasia is a recently described clinical entity. The authors describe such a case with severe anemia requiring transfusions and with clinical and radiological evidence of diaphyseal dysplasia. Very few such cases are reported in world literature.     

Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?

Ehlers Danlos syndrome (EDS) athrocalasia type (type VII), is characterized by joint hypermobility, skin hyperextensibility and tissue fragility. No heart involvement has been reported. Two forms have been described: type VII A and VII B. The abnormally processed collagen α2(I) and the skipping of the exon 6 in COL1A2 gene are typically detected in EDS type VII B. We describe a seven-year old female, with a phenotype consistent with EDS type VII B and a diagnosis further confirmed by biochemical and molecular analyses. Cardiac ultrasound showed normal data in the first year of life. When she was 5 years old, the patient developed mitral valve regurgitation, and aortic and tricuspidal insufficiency at 7 years of age. To our knowledge, this is the first report of cardiac valvular involvement in EDS VII B. This feature probably has been underreported for the limited follow-up of the patients. Echocardiography might be warranted in the clinical assessment of EDS VII patients.     

Idiopathic type 1 diabetes: a heterogenous disease or result of our ignorance?

Based on etiology a new classification for diabetes mellitus was proposed by the Experts of WHO in 1999. According to the classification, type 1 diabetes was subclassified as type 1A (autoimmune) and type 1B (idiopathic). Both forms result from the destruction of beta cells, however in type 1A the process is immune-mediated but in type 1B the origin of the beta cells impairment is still unknown. Moreover, subtype B is considered to be very heterogeneous and the diagnostic criteria are still not clear. The purpose of this article was to review studies on the pathogenesis of idiopathic type 1 diabetes.     

Mixed type I and II choledochal cyst: a new clinical subtype?

Traditionally, choledochal cyst (CC) is classified into five types according to Todani’s classification. Of 356 cases of CC treated at our institute since 1965, we experienced four cases of mixed type I and II choledochal cyst (MTCC). The incidence of MTCC was 1.1%. All four patients had a fusiform common bile duct (CBD) with a diverticulum originating from the mid-portion of the CBD. The cystic duct drained into the right side of the diverticulum. All had pancreaticobiliary malunion (PBMU). All presented with recurrent abdominal pain. MTCC was suggested on ultrasonography or computerized tomography and confirmed by endoscopic retrograde cholangiopancreatography (three cases) or magnetic resonance cholangiopancreatography (one case). Age at surgery ranged from 3 to 12 years. All had hepaticoenterostomy, and total excision of the CC/diverticulum/gallbladder. There were no complications and all cases are currently well. In all cases, histopathology showed that the wall of the diverticulum was identical to the CBD. Although the incidence of MTCC is very low, pediatric surgeons should be aware of it as a new subtype of CC. Based on our experiences and a review of the literature, we suggest that its etiology does not affect treatment because the surgical management of choice is the same as for type I CC.     

Serum macromolecular creatine kinase type 1 as a diagnostic clue in inflammatory bowel disease?

In adults, macromolecular creatine kinase (CK) type 1 has been linked to ulcerative colitis (UC), but not to Crohn’s disease (CD). We present two patients with pediatric inflammatory bowel disease (IBD) in which macrocreatine kinase (macro-CK) type 1 led to the final diagnosis of UC. A 13 year old with bloody diarrhea and weight loss was diagnosed with CD. CK elevation was interpreted as perimyocarditis attributed to CD. CK elevation persisted; however, cardiac evaluation remained unremarkable. CK gel electrophoresis revealed macro-CK type 1. During a disease flare-up and reevaluation (endoscopy and histology), the diagnosis was changed to UC. A 12-year-old girl with bloody diarrhea, weight loss, and anemia was diagnosed with CD (patchy distal colitis and aphtoid lesions). Repeated CK elevation was observed. Gel electrophoresis confirmed macro-CK type 1. After reevaluation during a flare-up (endoscopy and histology), the diagnosis was changed to UC. Conclusion CK elevation in pediatric IBD could suggest macro-CK type 1 formation, which is possibly linked to UC. In a subset of IBD patients, macro-CK type 1 could help differentiate UC from CD.     

Transient neonatal diabetes mellitus,type 4, type 1 diabetes mellitus,or MODY: which disease is it,anyway?

A 30year-old Hispanic male who presented with transient neonatal diabetes mellitus at 4 months has been intensively studied with 12 islet-cell secretagogues from 4 months to 24 years. He was both ICA- and GAD-65-negative, but at 28 years was diagnosed with hypothyroidism due to positive thyroperoxidase antibodies. The course of his disease(s) and the various presentations of hyperglycemia are documented and illustrated by the responses in islet cell hormone secretion, namely, insulin, glucagon, and C-peptide. Insulin secretion gradually fell over 24 years, glucagon secretion persisted from infancy to 24 years but was only minimal during i.v. glucose at 24 years, and C-peptide secretion remained normal, although modest, throughout the 24 years. These data suggest that, despite changing presentations of diabetes mellitus over time, the islets continued to process proinsulin, although the patient required insulin therapy.