Clinical Guidance

Genotype-phenotype correlations remain unclear, but are emerging .

• Individuals with the perinatal and congenital subtypes tend to have two null variants, including nonsense, frameshift, and splice site variants leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity;

• Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense variant.

These generalizations notwithstanding, considerable overlap exists both between and within the subtypes of GSD IV .

Source: GeneReviews — "Glycogen Storage Disease Type IV"

Diagnostic Criteria

The diagnosis of glycogen storage disease type IV (GSD IV) is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue. The diagnosis is confirmed by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts , and/or the identification of biallelic pathogenic variants in GBE1.

Suggestive Findings

Glycogen storage disease type IV (GSD IV) should be suspected in individuals with the features below. While subtypes with variable ages of onset, severity, and clinical features have been recognized, the GSD IV phenotype represents a continuum that ranges from mild to severe . Clinical features by subtype:

Source: GeneReviews — "Glycogen Storage Disease Type IV"

Differential Diagnosis

Perinatal and Congenital Neuromuscular Subtypes of GSD IV The differential diagnosis of the perinatal and congenital neuromuscular subtypes of GSD IV includes the disorders summarized in . Table 2a. Other Genes of Interest in the Differential Diagnosis of Perinatal and Congenital Neuromuscular Subtypes of GSD IV

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type IV (GSD IV), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Glycogen Storage Disease Type IV

Source: GeneReviews — "Glycogen Storage Disease Type IV"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Glycogen Storage Disease Type IV"

Surveillance Guidelines

No clinical guidelines for surveillance are available.

Table 4.

Recommended Surveillance for Individuals with Glycogen Storage Disease Type IV

System/Concern | Evaluation | Frequency

Hepatic

| • Liver function tests incl liver transaminases, albumin, coagulation profile (PT PTT)

• Abdominal ultrasound examination

| Frequency according to severity

Cardiac

| Echocardiogram | If cardiomyopathy was not seen on echocardiogram at diagnosis, repeat echocardiogram every 3 mos in infancy, every 6 mos in early childhood, annually thereafter.

Neurologic

| Neurologic assessment | Frequency according to severity

Gastrointestinal

| Nutritional assessment

Source: GeneReviews — "Glycogen Storage Disease Type IV"