Type Ib Glycogen Storage Disease

Updated: Sep 15, 2020
  • Author: Wayne E Anderson, DO, FAHS, FAAN; Chief Editor: George T Griffing, MD  more...
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Overview

Practice Essentials

Glycogen storage disease type Ib is an autosomal recessive condition that results from an enzyme defect. The enzyme deficiency leads to glycogen accumulation in tissues, and patients may initially present with hypoglycemic seizures. No specific treatment exists for glycogen storage diseases. [1]

Signs and symptoms of type Ib glycogen storage disease

Associated clinical features may include the following:

  • Hypoglycemic seizures
  • Reduced muscle force in patients with poor metabolic control
  • Frequent skin and pulmonary infections
  • Symptoms of inflammatory bowel disease, including cramps, fever, and abdominal pain
  • Hepatomegaly
  • Hypotonia in infants

See Presentation for more detail.

Diagnosis of type Ib glycogen storage disease

The following studies are typically included in the workup:

  • Muscle biopsy
  • Electromyelography
  • Ischemic forearm test
  • Creatine kinase measurement
  • Lipid profile
  • Fasting glucose measurement
  • Urine studies
  • Liver function studies

A biochemical assay for enzyme activity is the method of definitive diagnosis.

See Workup for more detail.

Management of type Ib glycogen storage disease

In general, no specific treatment exists for glycogen storage diseases. In some cases, dietary therapy is helpful. Ongoing research focuses on emerging gene therapies.

See Treatment for more detail.

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Background

A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but, in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

The image below illustrates the metabolic pathways for carbohydrates.

Metabolic pathways of carbohydrates. Metabolic pathways of carbohydrates.

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, Von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, there also is a GSD type 0, which is due to defective glycogen synthase.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. [2] In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on muscle biopsy, electromyelography, ischemic forearm test, creatine kinase levels, patient history, and physical examination. Biochemical assay for enzyme activity is the method of definitive diagnosis.

Acid maltase catalyzes the hydrogenation reaction of maltose to glucose. Acid maltase deficiency is a unique glycogenosis, because glycogen accumulation is lysosomal rather than in the cytoplasm. It also has a unique clinical presentation depending on age at onset, ranging from fatal hypotonia and cardiomegaly in the neonate to muscular dystrophy in adults.

Glucose-6-phosphatase (G-6-P) is the specific enzyme deficiency in Von Gierke disease. GSD type 1b is a similar condition with a defective G-6-P transporter protein. [3, 4] A newly described form, GSD type 1c, is not thought to be related to a transporter protein mutation.

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Pathophysiology

With an enzyme defect, carbohydrate metabolic pathways are blocked, and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues. The G-6-P transporter protein is found in the liver and kidney.

GSD type Ib is an autosomal recessive condition.

Glucose-6-phosphate is an intermediate in glycogen synthesis and glucose metabolism. GSD type Ib differs from GSD type Ia in that it is not explained by mutations of the phosphohydrolase gene. Veiga-da-Cunha et al provide evidence that all non-1a cases can be explained by mutations of the glucose-6-phosphate translocase gene. [5]

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Epidemiology

International data

Applegarth et al studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year. [6]

Age-related demographics

In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if the onset occurs in infancy.

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Prognosis

Morbidity/mortality

GSD type Ib, unlike GSD type Ia, involves bacterial infections, including brain abscesses. However, D'Eufemia et al reported one case of a 10-year-old boy with GSD type Ib with neutropenia and neutrophil dysfunction but without severe recurrent infections. [7]

Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications include nephropathy and hepatic adenoma.

GSD type Ib is not curable.

Complications

Complications of GSD type Ib include the following:

  • Hypoglycemic seizures

  • Nephropathy with renal failure

  • Hepatic adenoma with potential malignant transformation

  • Inflammatory bowel disease (recent evidence of an elevated platelet count in patients may be a warning sign of inflammatory bowel disease)

  • Recurrent pulmonary and skin infections, likely secondary to neutropenia

  • Secondary diabetes mellitus (may be a late complication)

  • Acute myelogenous leukemia (Pinsk et al suggest surveillance for acute myelogenous leukemia as a potential complication of GSD type Ib [8] )

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