Glucose-6-Phosphatase Deficiency Clinical Presentation

Updated: Jan 03, 2012
  • Author: Lawrence C Wolfe, MD; Chief Editor: George T Griffing, MD  more...
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It is usually diagnosed in first year of life. However, long-term care requires repeated documentation of symptoms to assess glycemic control and screen for complications. [6]

  • Parental consanguinity is an important factor because the disease is autosomal recessive. It is more likely to appear in consanguineous families.

  • Family history that includes one member with known GSD type Ia increases the likelihood of other kindred being affected and warrants careful evaluation of all newborns in the family.

  • Hypoglycemia may be symptomatic or asymptomatic. The lack of symptoms may be related to efficient usage of acetyl coenzyme A through the Krebs metabolic pathway.

  • Failure to thrive is a common but nonspecific presentation.

  • Patients have delayed pubertal onset and development.

  • Seizures may occur because of hypoglycemia but not because of an underlying CNS disorder.

  • Patients may have abdominal pain from hepatomegaly, uric acid nephrolithiasis, or pancreatitis.

  • Hematuria (stone disease) may be observed.

  • Bony pain or fracture, especially vertebral compression fractures from osteopenia, may be reported.

  • Patients may have joint symptoms (gouty arthritis).

  • Patients may have evidence of recurrent bacterial infections. These can be observed in association with GSD type Ib, which may otherwise appear identical to GSD type Ia.



In a report from the collaborative European Study on Glycogen Storage Disease Type I, patients (GSD Ia and GSD Ib) presented at a median age of 6 months (range 1 d to 12 y) and 4 months (range 1 d to 4 y), respectively. [7] This study reported the following features, from most to least common:

  • Protruding abdomen — 83%

  • Metabolic derangement — 71%

  • Growth failure — 25%

  • Recurrent infections — 3% in GSD Ia, 41% in GSD Ib

  • Muscular hypotonia — 13%

  • Delayed psychomotor development — 7%

Hepatomegaly is often the first clue to diagnosis and in the first year of life; asymptomatic hepatomegaly may be the only finding. Typically, no associated jaundice, ascites, or splenomegaly is present. The liver enlargement may be massive, with the lower border extending down to the pelvis in older patients. Hepatic adenomas are frequent and should be specifically sought during palpation. When present, they may give the liver a lumpy texture. They may even be tender, especially if any recent hemorrhage has occurred within the mass. The absence of palpable adenomas does not exclude their presence; it simply underlines the importance of hepatic imaging tests. Documenting the size of the liver and adenomas over time is important. This information can prove to be a good indicator of therapeutic response and can indicate the need for further investigation and management.

Height and growth velocity are usually subnormal, and pubertal development is usually delayed. This is thought to be a consequence of chronic disease and a chronic catabolic state similar to malnutrition. Usually, bone age is delayed and insulinlike growth factor 1 levels are subnormal. Abnormal growth patterns may be ameliorated by good, long-term compliance and control with treatment regimens. Serial documentation of height and pubertal stage may be used as surrogate markers for overall disease control.

Patients may have a tendency toward central adiposity (rounded abdomen). Following blood pressure levels regularly is key to the early diagnosis of renal insufficiency.

Physical signs of hyperlipidemia may be present, especially as xanthomas, which may be seen over the elbows, knees, shins, and possibly as eruptions over the buttocks.

Joint examination may reveal signs of hyperuricemia, including acute gouty arthritis or tophaceous gouty deposits. Spinal examination may document the presence of a deformity or pain over any of the vertebral bodies as a clue to potential osteoporotic fracture.

Some patients have an increased tendency to bruising or bleeding. The presence of recurrent bacterial skin infections may be a clue to the diagnosis of GSD type Ib, which is otherwise clinically identical to GSD type Ia.

Cardiac examination may reveal signs of pulmonary hypertension, including high jugular venous pressure, loud P2, right ventricular heave, tricuspid regurgitation, or right-sided S3. [8]



See the list below:

  • The gene for G-6-phosphatase has been cloned, and, to date, more than 17 different mutations have been reported in unrelated, affected patients.

  • Certain mutations have been suggested to be characteristic in specific ethnic groups, and early work indicates that specific mutations may predict a patient's therapeutic response or predilection for developing hepatic adenomas. [9]

  • Kishnani et al found evidence that mutations on chromosomes 6p and 6q may be linked to hepatic adenomas in patients with GSD type I. [10] The investigators found, for example, that expression of the candidate tumor suppressor genes IGF2R and LATS1 at 6q was reduced in some (although not all) of the GSD type Ia – associated hepatic adenomas in their study. The authors also found that in patients with GSD type Ia who had chromosome 6 mutations, hepatic adenomas were larger than they were in patients who did not have chromosome 6 mutations.

  • Many more studies are needed to clarify the issue of predictive associations in genetic testing.