Glycogen Storage Disease Ia

A number sign (#) is used with this entry because glycogen storage disease Ia (GSD1A) is caused by homozygous or compound heterozygous mutation in the G6PC gene (613742), which encodes glucose-6-phosphatase (G6Pase), on chromosome 17q21.

Description

Glycogen storage disease type I, also known as von Gierke disease, typically manifests during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen. Affected individuals exhibit growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia, and in adults a high incidence of hepatic adenomas (summary by Lei et al., 1993).

Clinical Features

Burchell et al. (1987) reported 2 women, aged 51 and 22 years, with partial GSD type Ia, and a 54-year-old man with complete GSD type Ia. The patient with complete type Ia had had unexplained hepatomegaly and a bleeding diathesis since the age of 7 years and gout since age 38. He had spider angiomas, xanthomas, gouty tophi, severe hypoglycemia, and compensated metabolic acidosis. The diagnosis was not made until he presented with hepatocellular carcinoma. The 2 patients with partial type Ia had low or absent blood-glucose response to glucagon. Their hypoglycemic symptoms occurred with exercise, suggesting that they were unable to respond by increasing their hepatic glucose production above a certain level. In both cases, symptoms resolved after the introduction of frequent meals high in cornstarch, a treatment proposed by Chen et al. (1984). Of 2 sisters with type Ia GSD, both of whom had multiple hepatic adenomas, malignancy developed in 1 at the age of 20 years. AFP levels were normal throughout the entire course of this patient, whereas the younger sister had elevated levels despite the absence of malignant lesions.

Chen et al. (1988) found that of the 38 patients with type I glycogen storage disease under their care, the 18 children under age 10 years had normal renal function. Fourteen of the 20 older patients (aged 13 to 47 years) had disturbed renal function manifested by persistent proteinuria; many also had hypertension, hematuria, or altered creatinine clearance. Progressive renal insufficiency developed in 6 of these 14 patients, leading to death from renal failure in 3. At the onset of proteinuria, creatinine clearance was increased in 7 patients. Renal biopsies performed after an average of 10 years of proteinuria demonstrated focal segmental glomerulosclerosis.

In studies of 11 patients, Restaino et al. (1993) found that 5 had renal calculi, nephrocalcinosis or both, and 5 had hypercalciuria. All 9 who were tested had evidence of impaired acid excretion. Restaino et al. (1993) interpreted the findings as indicating the presence of an incomplete form of distal renal tubular acidosis, which may be the cause of hypercalciuria and nephrocalcinosis.

Obara et al. (1993) described the renal histology in 2 adult patients with type I glycogen storage disease, a 37-year-old woman and a 28-year-old man.

Smit (1993) studied retrospectively 41 patients over 10 years of age from 5 different European centers. Height was below the third percentile in 19. Hypoglycemia was still reported in 6. Hepatomegaly was present in 39 of the 40 and was marked in at least 11 of these. Adenomas were detected in 11 of 39 patients. Blood cholesterol concentration was elevated in 31 of 38 patients; blood triglycerides were elevated in 29 of 34 patients. Blood uric acid concentration was elevated in 19 of 35 patients, of whom 12 were being treated with allopurinol.

Ullrich and Smit (1993) reviewed the clinical aspects of type I GSD as discussed in a symposium. Pancreatitis in association with hypertriglyceridemia or severe metabolic acidosis was reported in isolated cases. No progression of hepatic adenoma after pregnancy was observed. A huge adenoma was successfully removed surgically in a female patient. The mechanism of renal hyperfiltration manifested by elevated glomerular filtration rate remained unclear. It had been found in children below the age of 1 year.

Liver adenomas are often present in GSD I (Howell et al., 1978) and may undergo malignant transformation (Zangeneh et al., 1969). Stevenson et al. (1984) described hepatocellular carcinoma developing in a 29-year-old man with GSD I who had been recognized 2 years before to have multiple liver adenomas. He was relatively asymptomatic in childhood and adolescence. His growth lagged behind that of his peers and puberty was delayed to age 17. He was active in competitive sports in high school, however, and was inducted into military service at age 27. Ito et al. (1987) described sibs with GSD I and hepatoblastoma.

Bianchi (1993) found 50 published cases of hepatocellular adenoma in GSD I and 10 cases of hepatocellular carcinoma.

Reitsma-Bierens (1993) pointed out that adult patients may have chronic renal disease. Gout, nephropathy, and renal stones are not the only complications; after a period of 'silent' hyperfiltration, renal damage develops with proteinuria, hypertension and renal dysfunction. Biopsies of such patients show focal glomerulosclerosis.

In a multicenter study in the United States and Canada, Talente et al. (1994) reviewed data from 37 patients with type Ia GSD, 5 patients with GSD type Ib (GSD1B; 232220), and 9 patients with GSD type III (GSD3; 232400), all of whom were 18 years of age or older. In the patients with GSD type Ia, problems included short stature (90%), hepatomegaly (100%), hepatic adenomas (75%), anemia (81%), proteinuria or microalbuminuria (67%), kidney calcifications (65%), osteopenia or fractures, or both (27%), increased alkaline phosphatase (61%) and gamma-glutamyltransferase (93%) activities, and increased serum cholesterol (76%) and triglyceride (100%) levels. Hyperuricemia was present in 89%. Talente et al. (1994) suggested that the hyperuricemia and pyelonephritis should be treated to prevent nephrocalcinosis and additional renal damage.

Pizzo (1980) and Furukawa et al. (1990) described vasoconstrictive pulmonary hypertension associated with GSD I. In both patients there was no evidence of portal hypertension; both patients developed pulmonary hypertension in their second decade. Furukawa et al. (1990) suggested that this rare complication, if not a coincidence, could be due to response of the pulmonary vascular bed to a circulating agent that could not be removed or inactivated by the damaged liver, or alternatively to nocturnal oxygen desaturation caused by abnormal breathing during sleep.

Michels and Beaudet (1980) and Kikuchi et al. (1991), among others, reported chronic pancreatitis as a complication of the hyperlipidemia of this disorder.

Ryan et al. (1994) described 3 successive pregnancies in a Chinese woman with GSD type Ia. The diagnosis had been made in childhood. At the age of 10 years, she was seen with hepatomegaly, renomegaly, anemia, fasting hypoglycemia, hyperuricemia, hypertriglyceridemia, frequent epistaxis, and prolonged bleeding time. An open liver biopsy revealed only trace amounts of glucose-6-phosphatase activities (1 to 2% of normal microsomal activity). She was started on a regimen of frequent day feedings, which maintained adequate nutritional support for growth and development. However, puberty was delayed, with menarche at age 14. When she was 23 years old, 2 liver masses consistent with hepatic adenomas were noted. Diet was augmented with nocturnal nasogastric feedings of Polycose (glucose polymers derived from controlled hydrolysis of cornstarch) at 90 gm/8 hours. This resulted in a reduction in total liver size but not in the size of the adenomas. The patient's first pregnancy, at age 29, ended in an unexpected fetal death at 33 weeks 5 days of gestation. At autopsy the fetus had no gross abnormalities that could explain the cause of death. An unrecognized hypoglycemic episode in the mother was suggested as a possibility. Two subsequent pregnancies were monitored in hospital after the thirty-third and thirty-fourth weeks, respectively. In the second pregnancy, cesarean section was performed at 35 weeks 4 days with delivery of a girl. A repeat cesarean section at 35 weeks 2 days was performed for the third pregnancy with delivery of a boy. Both infants were healthy and appeared to be unaffected by von Gierke disease. Hepatic adenomas did not enlarge during the pregnancies.

Wang et al. (2012) reported hematologic data and iron studies from 202 subjects (163 with GSDIa and 39 with GSDIb). Anemia was defined as hemoglobin concentration less than the 5th percentile for age and gender; severe anemia was defined as presence of a hemoglobin less than 10 g/dl. In GSDIa, 68 of 163 patients were anemic at their last follow-up. Preadolescent patients tended to have milder anemia secondary to iron deficiency, but anemia of chronic disease predominated in adults. Severe anemia was present in 8 of 163 patients, of whom 75% had hepatic adenomas. The anemia improved or resolved in all 10 subjects who underwent resection of liver lesions. Anemia was present in 72% of patients with GSDIb, and severe anemia occurred in 16 of 39 patients. Anemia in patients with GSDIb was associated with exacerbations of glycogen storage disease enterocolitis, and there was a significant correlation between C-reactive protein and hemoglobin levels (p = 0.036). Wang et al. (2012) concluded that although anemia is common to both GSDIa and GSDIb, their pathophysiology appears to be different. Severe anemia in GSDIa is likely due to hepatic adenomas, whereas anemia in GSDIb is likely due to enterocolitis.

Minarich et al. (2012) studied bone mineral density in patients with GSDIa and Ib. In GSDIa, 23 of 42 patients (55%) had low bone mineral density, which tended to be associated with other disease complications (p = 0.02) and lower mean serum 25-hydroxyvitamin D concentration (p = 0.03). In patients with GSDIb, 8 of 12 (66.7%) had low bone mineral density. Minarich et al. (2012) did not detect an association with duration of granulocyte colony-stimulating factor therapy, mean triglyceride level, erythrocyte sedimentation rate, or 25-hydroxyvitamin D concentration, and there was no evidence that corticosteroid therapy was associated with lower bone mineral density.

Biochemical Features

In patients with glycogen storage disease type Ia, serum triglyceride concentrations are markedly raised, whereas phospholipids and cholesterol levels are only moderately raised. In addition, both VLDL and LDL lipoprotein fractions are raised. Despite these abnormalities, endothelial vascular dysfunction and atherosclerosis seem to be rare in such patients. Trioche et al. (2000) studied both apoE (107741) polymorphism (40 patients) and serum concentration (20 patients) in patients with glycogen storage disease type Ia. The distribution of each allele at the apoE locus was similar to that reported in the general population, whereas serum apoE concentrations were raised in the GSD Ia patients. Mean apoE concentrations were 10.35 +/- 3.80 mg/dL versus 4.08 +/- 1.23 mg/dL in 65 age-matched normal controls. Trioche et al. (2000) postulated that the raised apoE levels in the serum could play an important role in counterbalancing the increased atherosclerosis risk associated with the lipid profile of patients with GSD Ia. Trioche et al. (2000) suggested that increased hepatic synthesis is the likely etiology of the increased levels of apoE.

Diagnosis

Seydewitz and Matern (2000) achieved 100% mutation detection rate in a study of 40 patients with GSD Ia. They identified 5 novel mutations in the G6PC gene. The authors suggested that molecular genetic analysis is a reliable and convenient alternative to enzyme assay in fresh liver biopsy specimens for the diagnosis of GSD Ia.

Marcolongo et al. (1998) studied the transport of glucose-6-phosphate (G6P), glucose, and orthophosphate into liver microsomes isolated from 6 patients with various subtypes of GSD I using a light-scattering method. They found that G6P, glucose, and phosphate could all cross the microsomal membrane in 4 cases of GSD type Ia. In contrast, liver microsomal transport of G6P and phosphate was deficient in the GSD Ib (232220) and Ic (232240) patients, respectively. Marcolongo et al. (1998) stated that these results supported the involvement of multiple proteins (and genes) in GSD I. Since the results obtained with the light-scattering method were in accordance with conventional kinetic analysis of the microsomal glucose-6-phosphatase system, Marcolongo et al. (1998) suggested that this technique could be used to diagnose directly GSD types Ib and Ic.

Prenatal Diagnosis

Qu et al. (1996) performed prenatal diagnosis by chorionic villus sampling in an Ashkenazi Jewish family in which a previous child was homoallelic and both parents were heterozygous for the R83C mutation (613742.0002) in the G6PC gene. Molecular analysis showed that the fetus was not affected.

Clinical Management

Emmett and Narins (1978) found no improvement with renal transplantation. However, Selby et al. (1993) reported therapeutically successful orthotopic liver transplantation in a 16.5-year-old girl with GSD I.

Chen et al. (1984) presented experience with raw cornstarch diet as a substitute for continuous nocturnal infusions as a measure to counteract hypoglycemia, which is the common denominator in the pathogenesis of the main manifestations of the disorder. In infants with low levels of pancreatic activity, the therapy was ineffective.

Chen et al. (1990) found that indicators of proximal renal tubular dysfunction improved in patients who were given dietary therapy such as total parenteral nutrition, nocturnal nasogastric infusion of glucose, or frequent oral administration of uncooked cornstarch. The indexes used were urinary excretion of amino acids, phosphate, and beta-2-microglobulin (109700).

In 14 children with GSD Ia and GSD Ib who ranged in age from 4 to 16 years, Lee et al. (1996) found that the use of uncooked cornstarch achieved satisfactory glycemia lasting only a median of 4.25 hours (range 2.5 to 6).

The use of diazoxide in patients with GSD type Ia was first described by Rennert and Mukhopadhyay (1968) for improvement of glucose homeostasis. The treatment was abandoned because of skin rashes and later forgotten. Unaware of this early observation, Nuoffer et al. (1997) treated 2 originally prepubertal girls with GSD type Ia and short stature with low-dose diazoxide (3 to 4.8 mg/kg per day) for 7 and 4 years, respectively. Both showed an impressive catch-up growth. This appeared to be due to prolongation of normoglycemia after meals and reduction of fasting lactic acidosis by the drug. Nuoffer et al. (1997) speculated that blood lactic acidosis is a major cause of growth retardation in this disorder. The mode of action of diazoxide seems to be linked to K(+)-ATP channel activation. The resulting hyperpolarization of membranes decreases insulin release. The drug was given at the beginning of meals and before going to bed.

Faivre et al. (1999) reported 3 patients with GSD Ia in whom liver transplantation was performed at 15, 17, and 23 years of age because of multiple hepatic adenomas in all 3 patients with a fear of malignant transformation, and of poor metabolic balance and severe growth retardation in the youngest. Renal function was normal in all patients. During the 6 to 8 years following transplantation, the quality of life was initially greatly improved, with none of the previous dietary restraints and a spectacular increase in height. However, long-term complications included chronic hepatitis C in 1 patient, gouty attacks in another, and focal segmental glomerulosclerosis with progressive renal insufficiency in the third. The experience was taken to indicate that liver transplantation does not prevent focal segmental glomerulosclerosis associated with GSD Ia.

Weinstein et al. (2001) studied 15 patients with type Ia glycogen storage disease and found a strong inverse exponential relationship between age and citrate excretion. Urinary citrate excretion was unrelated to markers of metabolic control. Hypercalciuria occurred in 9 of 15 patients and was also inversely correlated with age. Weinstein et al. (2001) concluded that hypocitraturia that worsens with age occurs in metabolically compensated patients with GSD Ia. The combination of low citrate excretion and hypercalciuria appears to be important in the pathogenesis of nephrocalcinosis and nephrolithiasis. Weinstein et al. (2001) suggested that citrate supplementation may be beneficial in preventing or ameliorating nephrocalcinosis and the development of urinary calculi in GSD Ia.

Wierzbicki et al. (2001) investigated the apoB turnover in GSD Ia using an exogenous labeling method in 1 sib from a kinship with established GSD Ia. Their study demonstrated normal hepatic secretion of VLDL, but hypocatabolism of VLDL, probably due to lack of lipoprotein lipase activity. The production rate of intermediate density lipoprotein (IDL) was slightly increased, but the turnover rate of LDL was normal. Wierzbicki et al. (2001) suggested that in addition to cornstarch diet and fat restriction, treatment of severe mixed hyperlipidemia in GSD Ia should possibly involve fibrates that activate lipoprotein lipase and may enhance the clearance of IDL, rather than omega-3 fatty acids, which principally suppress hepatic secretion of VLDL.

Inheritance

Glycogen storage disease Ia is an autosomal recessive disorder (Lei et al., 1993).

Population Genetics

Lei et al. (1993) stated that glycogen storage disease Ia has an incidence of 1 in 100,000 to 300,000.

Ekstein et al. (2004) found that the prevalence of GSD Ia in the Ashkenazi Jewish population is 1 in 20,000, 5 times higher than that for the general Caucasian population.

Molecular Genetics

In 2 patients with glycogen storage disease Ia, Lei et al. (1993) identified homozygous and compound heterozygous mutations, respectively, in the G6PC gene (613742.0001-613742.0003).

Lei et al. (1995) used SSCP analysis and DNA sequencing to characterize the G6PC gene of 70 unrelated patients with enzymatically confirmed diagnosis of type Ia GSD and detected mutations in all except 17 alleles (88%). They uncovered 16 mutations that were shown by expression to abolish or greatly reduce G6Pase activity and that, therefore, were responsible for the clinical disorder. R83C (613742.0002) and Q347X (613742.0004) were the most prevalent mutations found in Caucasians; 130X (613742.0001) and R83C were most prevalent in Hispanics; R83H was most prevalent in Chinese. The Q347X mutation was identified only in Caucasians, and the 130X mutation was identified only in Hispanic patients.

A form of GDS Ia, designated GSD IaSP and described in 1 patient by Burchell and Waddell (1990), was proposed to be caused by a defect in a 21-kD stabilizing protein, SP, purified on the basis of its ability to stabilize the G6Pase catalytic unit in vitro. Lei et al. (1995) demonstrated a mutation in exon 2 of the G6PC gene that converted an arg at codon 83 to a cys (R83C) in both alleles of the type IaSP patient. The R83C mutation (613742.0002) was also demonstrated in homozygous form in 1 and heterozygous form in 5 GSD type Ia patients, indicating that so-called type IaSP is a misclassification of GSD type Ia.

Kajihara et al. (1995) identified a splice mutation in exon 5 (727G-T) of the G6PC cDNA from the liver of a Japanese patient with GSD type Ia (613742.0005). Another 8 unrelated Japanese families with a total of 9 affected individuals were found to have the same mutation, thus representing 91% of patients and carriers of GSD Ia in Japan.

Chevalier-Porst et al. (1996) sequenced both alleles of 24 French GSD type Ia patients; 14 different mutations were found, allowing the identification of complete genotypes for all the patients. These included 9 new mutations. Five mutations, Q347X, R83C, D38V (613742.0006), G188R (613742.0012), and 158Cdel, accounted for 75% of the mutated alleles.

Parvari et al. (1997) reported the biochemical and clinical characteristics as well as mutational analyses of 12 Israeli GSD Ia patients of different families, who represent most of the GSD Ia patients in Israel. All 9 Jewish patients, as well as a Muslim Arab patient, were found to have the R83C mutation (613742.0002). Two Muslim Arab patients had the val166-to-gly (V166G) mutation (613742.0014), which had not been found in other populations.

Akanuma et al. (2000) identified G6PC mutations in all alleles from 51 unrelated Japanese patients with GSD Ia. A total of 7 mutations were identified, including 3 novel mutations. The most prevalent mutation, 727G-T, accounting for 88 of 102 mutant alleles, creates an aberrant 3-prime splice site within exon 5. The authors demonstrated that ectopically transcribed G6Pase mRNA can be detected in lymphoblastoid cells and may be used for the characterization of mutations that affect mRNA splicing. They concluded that noninvasive molecular diagnosis may ultimately replace the conventional method of enzymatic diagnosis that requires liver biopsy in Japanese patients.

Stroppiano et al. (1999) analyzed the G6Pase gene in 53 unrelated Italian patients and identified 88 mutant alleles (82.6%) with 18 (17.4%) remaining unidentified. The most prevalent mutation was R83C (46.2%), followed by Q347X (20.7%); 3 other mutations (R295C, D38V, and G270V) accounted for 5.6% of disease alleles. The authors suggested that noninvasive screening could be used in Italian patients clinically suspected of having GSD Ia, particularly in those from Sicily, where the R83C mutation was present in 80% of mutant alleles.

In all of 13 unrelated Korean patients with GSD Ia, Ki et al. (2004) identified mutant alleles of the G6PC gene. Three known mutations and 2 novel mutations were identified. The most frequent mutant allele was 727G-T, present in 21 of 26 alleles (81%), which was slightly lower than that in Japanese, where it was present in 86 alleles (92%), but much higher than that in Taiwan Chinese (present in 44.4% of alleles).

Hepatocellular adenoma is a frequent long-term complication of glycogen storage disease type I, and malignant transformation to hepatocellular carcinoma (HCC; see 114550) occurs in some cases. Kishnani et al. (2009) performed genomewide SNP analysis and mutation detection of target genes in 10 GSD Ia-associated HCA and 7 general population HCA cases. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Coincident gain of chromosome 6p and loss of 6q were seen only in GSD Ia HCA (3 cases), with 1 additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (p = 0.012). Expression of IGF2R (FCGR2A; 146790) and LATS1 (603473) candidate tumor suppressor genes at 6q was reduced in more than 50% of 7 GSD Ia HCA examined. None of the GSD Ia HCA had biallelic mutations in the HNF1A (142410) gene. The authors suggested that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and possibly in the general population.

Reviews

Chou and Mansfield (1999) reviewed the molecular genetics of type I glycogen storage diseases.

Animal Model

Lei et al. (1996) created a G6Pase knockout mouse that mimics the pathophysiology of human GSD Ia patients. In the knockout mouse, both the GTPase enzymatic activity and the glucose-6-P transport activity were destroyed. By examining G6Pase in liver and kidney, the primary gluconeogenic tissues, they demonstrated that glucose-6-P transport and hydrolysis are performed by separate proteins that are tightly coupled. They proposed a modified translocase catalytic unit model for G6Pase catalysis.

Using neonatal G6Pase-deficient mice, Sun et al. (2002) demonstrated that a combined adenovirus and adeno-associated virus vector-mediated gene transfer led to sustained G6Pase expression in both the liver and the kidney, and corrected the murine GSD Ia disease for at least 12 months.

Lam et al. (2005) reported that a primary increase in hypothalamic glucose levels in rats lowers blood glucose by inhibition of liver glucose production, due to inhibition of glucose-6-phosphatase. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of ATP-sensitive potassium channels.

History

Demonstration of the deficiency of glucose-6-phosphatase in type I glycogen storage disease by Cori and Cori (1952) is often pointed to as the first specific enzymopathy identified in a hereditary disorder. Although it was perhaps the first disorder characterized that can be viewed as a true garrodian inborn error of metabolism, enzyme deficiency was identified earlier in methemoglobinemia (250800) by Gibson (1948).

Senior and Loridan (1968) found that the effects of glycerol administered by mouth on levels of glucose and of lactate, together with the response to epinephrine or glucagon, permitted differentiation of the several types of hepatic glycogenosis (I, II, III and IV).