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Glycogen Storage Disease Type 1

Hepatorenal Glycogenosis

Glycogen storage disease type 1 (GSD 1), also known as von Gierke's disease or Glycogen storage disease due to G6P deficiency, is the most common of the glycogen storage diseases.


Presentation

The major sign of GSD type 1 is the enlargement of the kidney and livers. In the first few weeks of life, the liver remains in its normal size. It gradually enlarges thereafter leading to symphysis in many patients. Enlargement of the abdomen due to hepatomegaly is one of the first signs noted by the mother of the patient [7].

The face of the patient is often round, and this is due to the deposition of fat. Mental develop often proceeds normally but growth is retarded. Unless otherwise expected from the genetically determined potential of their families, children with GSD type 1 condition never gain height commensurate with their age. The height is often below the third percentile for their age. The onset of puberty is often delayed.

In patients who are older than 20 years of age, hypertension, tubular defects, renal stones and renal function disturbance are some of the late complications of this disease condition. In many cases, dialysis and transplantation will be required as the deterioration of renal function will gradually progress to terminal insufficiency [8].

Dyspnea
  • The main presenting symptoms are exercise intolerance, exertional dyspnea and congestive heart failure in progressed cases. The disorder may be limited to muscle tissue and serum creatine kinase may be normal.[wjgnet.com]
Short Stature
  • stature Decreased body height Small stature [ more ] 0004322 5%-29% of people have these symptoms Xanthomatosis 0000991 Percent of people who have these symptoms is not available through HPO Abnormal bleeding Bleeding tendency 0001892 Autosomal recessive[rarediseases.info.nih.gov]
  • In addition, patients have thin extremities, a short stature, and protuberant abdomens (due to the severe hepatomegaly). Long-term complications are usually only seen now in adults whose disease was poorly treated early on.[themedicalbiochemistrypage.org]
  • GSD Ia is characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and short stature.[mayoclinic.pure.elsevier.com]
  • Glycogen storage disease type 1A is characterized by short stature and accumulation of glycogen in the liver and kidneys with fatty deposition in the liver and kidneys.[xpertdox.com]
Anemia
  • Other important laboratory values that must be obtained include: CBC and differential (eg, anemia, leukopenia, neutropenia), Gamma glutamyltransferase level, Serum triglyceride and cholesterol levels, Serum uric acid level, Blood pH, Serum lactate level[symptoma.com]
  • One such investigation reported no correlation between bone mineral density and turnover markers, indicating an uncoupling of bone turnover in patients with glycogen-storage disease. [7, 8 ] The cause of severe anemia in the absence of renal function[emedicine.medscape.com]
  • For those with more severe hemolytic anemia, splenectomy has been utilized successfully, although the red blood cell defect persists, but the anemia is better compensated.[cancertherapyadvisor.com]
  • Type VIII Muscle weakness Anemia Increased levels of uric acid Glycogen Storage Disease Diagnosis Glycogen storage disease diagnosis usually occurs in infancy or childhood as a result of the above symptoms.[chp.edu]
  • […] polyserositis, recurrent, polyserositis, familial paroxysmal;benign paroxysmal peritonitis; benign recurrent polyserositis; fmf; familial paroxysmal polyserositis; periodic disease Related symptoms: Autosomal recessive inheritance Seizures Pica Milia Anemia[mendelian.co]
Fever
  • ; FMF Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and inflammation in the peritoneum, synovium, or pleura, accompanied by pain.[mendelian.co]
  • - 7:Sly Glycoprotein Mucolipidosis - I-cell disease - Pseudo-Hurler polydystrophy - Aspartylglucosaminuria - Fucosidosis - Alpha-mannosidosis - Sialidosis Other Alpha 1-antitrypsin deficiency - Cystic fibrosis - Amyloidosis ( Familial Mediterranean fever[wikidoc.org]
  • Fever, diarrhea, and perioral and anal ulcers are the accompanying findings and symptoms. The severity of the primary disorder is not correlated with the intestinal symptoms.[wjgnet.com]
Congestive Heart Failure
  • Congestive heart failure, respiratory failure, and/or aspiration pneumonia are the most frequent causes of death, which usually occurs within 1 year [1].[path.upmc.edu]
  • heart failure Decreased numbers of nephrons Developmental regression Keratoconjunctivitis sicca Retinopathy Aseptic necrosis Muscle weakness Pyloric stenosis Hypogonadism Cerebral cortical atrophy Acute kidney injury Fatigue Proportionate short stature[mendelian.co]
  • The main presenting symptoms are exercise intolerance, exertional dyspnea and congestive heart failure in progressed cases. The disorder may be limited to muscle tissue and serum creatine kinase may be normal.[wjgnet.com]
Italian
  • Ninety-five patients (median age at the time of the study: 14.5 years) were enrolled from nine Italian referral centres for metabolic diseases.[ncbi.nlm.nih.gov]
  • Sechi A, Deroma L, Paci S, et al ; Quality of Life in Adult Patients with Glycogen Storage Disease Type I: Results of a Multicenter Italian Study. JIMD Rep. 2013 Dec 21.[patient.info]
Abdominal Pain
  • pain Delayed puberty Short stature Lactic acidosis Decreased glomerular filtration rate Hepatocellular carcinoma Focal segmental glomerulosclerosis Hypoglycemia Acidosis Stage 5 chronic kidney disease Myopathy Osteoporosis Nephrolithiasis Myocardial[mendelian.co]
Hepatomegaly
  • A male child presented at 5 months of age with vomiting, diarrhoea, hypoglycaemia and hepatomegaly.[ncbi.nlm.nih.gov]
  • The molecular pathways involved in liver pathologies, including steatosis, hepatomegaly (glycogenic hepatopathy) and the development of liver tumours are also compared.[ncbi.nlm.nih.gov]
  • PATIENTS: Two related children referred for failure to thrive, rickets, and hepatomegaly. INTERVENTION: Dietary and therapeutic measures for rickets and renal tubular acidosis.[ncbi.nlm.nih.gov]
  • —Two related children referred for failure to thrive, rickets, and hepatomegaly. Intervention. —Dietary and therapeutic measures for rickets and renal tubular acidosis. Measurements and Results.[jamanetwork.com]
  • More commonly though, infants of 3–4 months of age will manifest with hepatomegaly and hypoglycemic seizures. The hallmark features of this disease are hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia.[themedicalbiochemistrypage.org]
Jaundice
  • […] short stature Renal cell carcinoma Glycosuria Abnormality of the dentition Hypoplasia of the uterus Hypospadias Unilateral renal agenesis Glucose intolerance Polydipsia Mandibular prognathia Elevated serum creatinine Abnormality of the genital system Jaundice[mendelian.co]
Headache
  • […] artery atherosclerosis Accelerated atherosclerosis Tendon xanthomatosis Renal steatosis Eruptive xanthomas Aortic atherosclerosis Type IV atherosclerotic lesion Neutropenia Precocious atherosclerosis Recurrent bacterial infections Diarrhea Constipation Headache[mendelian.co]

Workup

In individuals suffering from GSD type 1, serum glucose and blood pH levels are often decreased but the cholesterol levels, triglyceride, serum lactate and uric acid are elevated [9]. The creatinine levels and urea may be elevated when renal function is impaired.

Other important laboratory values that must be obtained include: CBC and differential (eg, anemia, leukopenia, neutropenia), Gamma glutamyltransferase level, Serum triglyceride and cholesterol levels, Serum uric acid level, Blood pH, Serum lactate level, serum glucose, electrolyte levels, Serum alkaline phosphatase, calcium, phosphorus, urea, and creatinine levels,Urinary excretion levels of uric acid and calcium, Urinalysis for aminoaciduria, proteinuria, and microalbuminuria in older patients and Coagulation.

One important imaging test that must be carried out is liver and kidney ultrasonography. This needs to be performed for follow up of organomegaly and detection of hepatic adenomas and nephrocalcinosis.

Ketonuria
  • Laboratory findings are fasting hypoglycemia and ketonuria, hyperglycemia and hypergalactosemia in the postabsorptive state, hypercholesterolemia and hyper-lipidemia, moderately elevated ALP, hypophosphatemia, hyperaminoaciduria, glucosuria, galactosuria[wjgnet.com]
Fasting Hypoglycemia
  • MEASUREMENTS AND RESULTS: The main laboratory findings were fasting hypoglycemia and massive glucosuria, with evidence of multiple renal tubular dysfunction characteristic of the Fanconi syndrome.[ncbi.nlm.nih.gov]
  • —The main laboratory findings were fasting hypoglycemia and massive glucosuria, with evidence of multiple renal tubular dysfunction characteristic of the Fanconi syndrome.[jamanetwork.com]
  • It is a result of this, that patients who have GSD type 1 present fasting hypoglycemia. Endogenous glucose formation is not fully inhibited though irrespective of the metabolic block.[symptoma.com]
  • Interrelationships of metabolic pathway disruption in von Gierke disease : In the absence of glucose-6-phosphatase activity free glucose cannot be release from the liver contibuting to severe fasting hypoglycemia.[themedicalbiochemistrypage.org]
  • When impaired hepatic glycogen metabolism is present, patients have fasting hypoglycemia, ketosis and potentially progressive liver damage.[cancertherapyadvisor.com]
Hypertriglyceridemia
  • The lipid abnormalities, which include hypercholesterolemia (decreased high-density lipoprotein [HDL] cholesterol and increased low-density lipoprotein [LDL] cholesterol), together with the characteristic hypertriglyceridemia do not cause premature atherosclerotic[emedicine.medscape.com]
  • Hyperlipidemia and blood vessel effects [ edit ] A secondary effect of low insulin levels is hypertriglyceridemia.[en.wikipedia.org]
  • The cardinal features of this disorder are post absorptive hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia.[cags.org.ae]
  • In GSD, many laboratory abnormalities are present including anemia, neutropenia, hyperuricemia, hypercholesterolemia, and hypertriglyceridemia. Although platelet counts are normal in these patients, platelet dysfunction can lead to epistaxis.[cancertherapyadvisor.com]
  • Severe hypertriglyceridemia unresponsive to optimized dietary management may cause acute pancreatitis; lowering triglyceride concentrations with fenofibrate reduces the risk of pancreatitis.[clinicaladvisor.com]
Phosphate Decreased
  • In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 /- 0.08 vs. 0.86 /- 0.19 arbitrary units; P 0.001), whereas inorganic phosphate decreased (0.36 /- 0.08 vs. -0.43 /- 0.17 arbitrary units; P 0.01).[ncbi.nlm.nih.gov]
Glomerular Filtration Rate Decreased
  • filtration rate, decreased muscle mass, underdeveloped muscles, delayed pubertal development, doll-like facies, elevated hepatic transaminase, high liver enzymes, enlarged kidney, focal segmental glomerulosclerosis, gout, hepatocellular carcinoma, hepatomegaly[xpertdox.com]

Treatment

There is only symptomatic treatment available, which is very important. The main goal is to avoid hypoglycemia and maintain a normoglycemic state.

Prognosis

As long as the available dietary and medical measures are implemented, the prognosis is much better than what it used to be in the past [10].

Etiology

GSD type 1a: This subtype of GSD type 1 is caused by deficiency of hydrolase or G6pase. G6pase is an integral membrane protein and so, mutations in the protein’s transmembrane helices lead to the most severe enzyme activity deficiency.

GSD type 1b: This subtype of GSD is caused by deficiency of G6PT1. The G6PT1 gene is expressed in the hematopoietic progenitor cells, liver and kidney, it contains 8 exons and covers approximately 5kb.The gene had been mapped to band 11q23 [4].

The mutated allele is an inheritable autosomal recessive trait. The type of mutation in the G6PT gene and the severity of the disease don’t have any correlation. Therefore, other factors are believed to be responsible for the expression of different symptoms recorded. Neutropenia in patients for instance greatly influences the severity and the general course of the disease.

Epidemiology

Patients with GSD type 1 account for 24.6% of all patients suffering from glycogen storage disease. In GSD type 1, acute hypoglycemia may be fatal. Early death is no longer common due to the improvements in care and treatment.

Mortality is caused on adolescent and adults patients by hypertension, malignant alteration of hepatic adenomas, hypertension and renal failure. No racial or ethnic differences exist for GSD type 1 [3]. As it is with most genetic conditions, GSD type 1 develops at conception but the first signs of the disease appear at birth or much later.

Sex distribution
Age distribution

Pathophysiology

When there is insufficient G6Pase activity, G6p cannot be converted into free glucose. However, G6P is metabolized into lactic acid which ends up being incorporated into glycogen. In this manner, large amounts of glycogen are formed and stored away as molecules that have normal structure in the hepatocytes cytoplasm and the cells of the renal and intestinal mucosa [5]. This leads to the enlargement of the kidneys and liver which is the major clinical presentation of this disease. The major biochemical alteration recorded is hypoglycemia and hyperucemia, hyperlipidemia, metabolic acidosis and hyperlactatemia are common secondary abnormalities.

With hypoglycemia, the G6pase deficiency stops the glycogen degradation process and gluconeogenesis within the liver. This prevents the production of free glucose molecules. It is a result of this, that patients who have GSD type 1 present fasting hypoglycemia. Endogenous glucose formation is not fully inhibited though irrespective of the metabolic block. In young patients however, the free glucose produced only reaches 50% of the production recorded by healthy individuals. Adults on the other hand produce as much as two thirds of the healthy amount of free glucose. Hypoglycemia inhibits secretion of insulin and this stimulates the release of cortisol and glucagon [6].

Prevention

There are no guidelines for prevention of Glycogen storage disease type I.

Summary

Glycogen storage disease type I commonly known as GSD I or von Gierke’s disease is the most common amongst the different glycogen storage conditions. The condition is genetic and it arises in the presence of a glucose-6-phosphate deficiency [1].

The deficiency of this enzyme leads to impairment in the liver’s ability to produce free glucose from glycogen and through gluconeogenesis. Severe hypoglycemia is caused because the aforementioned processes are the only way through which a body in fasting receives glucose from the body. With severe hypoglycemia, the liver and kidneys see increased glycogen storage. This may lead to the enlargement of both organs. In childhood, the organs may function normally but towards adult hood, the organs are susceptible to a variety of problems [2].

Hyperlipidemia and lactic acidosis are some other metabolic derangements that arise due to this condition. The condition was named after Edgar von Gierke. He was the German doctor that discovered the condition. The condition is made of two subtypes GSD type 1a and GSD type 1b.

Patient Information

Parents and adult patients need to understand the measures required to control hypoglycemia and all other indeed all such related ailments. These measures will generally include proper care and nutrition.

Parents also need to understand the importance of continuous overnight feeding through a nasogastric tube. They need to learn how to correctly place the tube on their own to control the entire feeding process.

The treatment the individuals will be subjected to will vary due to various factors but the focus for most of the treatments is to help the patient stabilize the energy levels and blood sugar throughout the body. To achieve this, cornstarch or nutritional supplements like glucose is used. In some cases, the health professionals will recommend a high protein diet as these often prove helpful in the treatment of this condition.

For those who do not respond to treatments after taking the nutritional supplements for a while, there may be need for liver transplant. Also as protection against infection, antibiotics will be recommended by your health expert. Sticking judiciously to the prescription is very important.

Finally depending on the severity of the symptoms, the patient may have to undergo clinical treatment that is focused on the replacement of enzymes that are not working as should. In many cases, this treatment will reverse heart problems, muscle weaknesses etc.

References

Article

  1. Von Gierke E. Hepato-nephromegalia glykogenica (Glykogenspeicherkrankheit der Leber und Nieren). Beitr Path Anat. 1929;82:497-513.
  2. Cori GT, Cori CF. Glucose-6-phosphatase of the liver in glycogen storage disease. J Biol Chem. Dec 1952;199(2):661-7.
  3. Narisawa K, Igarashi Y, Otomo H, Tada K. A new variant of glycogen storage disease type I probably due to a defect in the glucose-6-phosphate transport system. Biochem Biophys Res Commun. Aug 29 1978;83(4):1360-4.
  4. McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Sci. 1951;10:13-33.
  5. Hers HG. alpha-Glucosidase deficiency in generalized glycogenstorage disease (Pompe's disease). Biochem J. Jan 1963;86:11-6.
  6. Melis D, Fulceri R, Parenti G, et al. Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature. Eur J Pediatr 2005; 164:501.
  7. Gerin I, Veiga-da-Cunha M, Achouri Y, et al. Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett 1997; 419:235.
  8. Chen SY, Pan CJ, Nandigama K, et al. The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic. FASEB J 2008; 22:2206.
  9. Chopra AR, Louet JF, Saha P, et al. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science 2008; 322:1395.
  10. Chou JY, Mansfield BC. Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. Hum Mutat 2008; 29:921.

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Last updated: 2018-06-21 18:39