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Prevalence is unknown. Annual incidence at birth is around 1/100,000. Type Ia affects 80% of patients, and type Ib 20%.

The disease may manifest at birth by hepatomegaly or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia. Patients have enlarged liver, growth delay, osteopenia, sometimes osteoporosis, full-cheeked round face, nephromegaly and frequent epistaxis due to platelet dysfunction. In addition, in type b, infections and inflammatory bowel disease are due to neutropenia and neutrophil dysfunction. Late complications are hepatic (hepatocellular adenomas and more rarely hepatocellular carcinoma) and renal (proteinuria and sometimes renal insufficiency).

The disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Mutations in the G6PC gene (17q21) cause a deficit of the catalytic subunit G6P-alpha restricted to expression in the liver, kidney and intestine (type a), and mutations in the SLC37A4 gene (11q23) cause a deficit of the ubiquitously expressed G6P transporter (G6PT) or G6P translocase (type b).

Diagnosis is based on clinical presentation, and glycemia and lactacidemia levels, after a meal (hyperglycemia and hypolactacidemia), and after three to four hours fasting (hypoglycemia and hyperlactacidemia). Uric acid, triglycerides, and cholesterol serum levels are increased. There is no glycemic response to glucagon. Molecular genetic testing enables confirmation of diagnosis. Liver biopsy to measure G6P activity is no longer performed.

Differential diagnoses include the other glycogenoses, in particular glycogen storage disease due to glycogen debranching enzyme deficiency (GDE deficiency) or GSD type III but in this case, glycemia and lactacidemia are high after a meal and low in a fasting period. Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but easily ruled out through clinical and ultrasound data.

Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Management aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube or a gastrostomy (only in type Ia patients), and later oral addition of uncooked starch), acidosis (restricted fructose and galactose intake, oral supplementation in bicarbonate), hypertriglyceridemia (diet, cholestyramine, statines), hyperuricemia (allopurinol) and hepatic complications. Renal protection using converting enzyme inhibitors must be started should microalbuminuria be detected. Liver transplantation, performed on the basis of poor metabolic control or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type b. Kidney transplantation can be performed in case of severe renal failure. Combined liver-kidney grafts have been performed in a few cases.

With adapted management, prognosis is better: patients have almost normal life span.

Last update: October 2023 - Expert reviewer(s): Pr Philippe LABRUNE | MetabERN*

* European Reference Network