Clinical Guidance

No clear genotype-phenotype correlation exists. The founder pathogenic variant in the Mennonite population, , generates a transcript lacking all or part of exon 13 while maintaining the reading frame. Either protein isoform is expected to have some residual enzyme activity, which may explain the milder GSD VI phenotype in individuals homozygous for this pathogenic variant in the Mennonite population .

Source: GeneReviews — "Glycogen Storage Disease Type VI"

Diagnostic Criteria

Suggestive Findings

Glycogen storage disease type VI (GSD VI) should be suspected in probands with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

• Hepatomegaly

• Growth deficiency

Laboratory findings

• Ketotic hypoglycemia

• Elevated hepatic transaminases

• Hyperlipidemia

• Low prealbumin level

Imaging findings. Abdominal ultrasound showing hepatomegaly with diffuse echogenicity Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of GSD VI is established in a proband with and biallelic pathogenic (or likely pathogenic) variants in PYGL identified by molecular genetic testing . If molecular...

Source: GeneReviews — "Glycogen Storage Disease Type VI"

Differential Diagnosis

Table 3. Glycogen Storage Disease Type VI: Differential Diagnosis

Management Guidelines

Clinical practice guidelines for GSD VI were developed in association with the American College of Medical Genetics and Genomics .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GSD VI, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Glycogen Storage Disease Type VI: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Gastrointestinal/

Hepatic

| • Assessment of liver size

• Abdominal ultrasound

• Hepatic transaminases (AST/ALT)

| Involvement of specialists in GSD VI (gastroenterologist, endocrinologist, metabolic geneticist)

Growth

| Growth assessment |

Myopathy

| • Assessment for hypotonia, fatigue, muscle cramping

• Assessment of motor development

• Total protein prealbumin

| A nutrition consultation is recommended to ensure that appropriate diet is commenced.

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of GSD VI to facilitate medical personal decision making

GSD VI = glycogen storage disease type VI; MOI = mode of inheritance

1. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Targeted Therapies

Source: GeneReviews — "Glycogen Storage Disease Type VI"

Clinical Guidance

Avoid the following:

• Excessive amounts of simple sugars and a high-carbohydrate diet to prevent excessive hepatic glycogen deposition

• Glucagon administration as a rescue therapy for hypoglycemia because blood glucose concentrations will not increase

• Growth hormone for short stature because it usually exacerbates ketosis and may increase the risk of complications

• Contact sports when hepatomegaly is present (or use appropriate cautions)

Source: GeneReviews — "Glycogen Storage Disease Type VI"

Therapies Under Investigation

There is an ongoing trial looking for a biomarker for glycogen storage diseases (NCT02385162). 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.

Source: GeneReviews — "Glycogen Storage Disease Type VI"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 7.

Glycogen Storage Disease Type VI: Recommended Surveillance

System/Concern | Evaluation | Frequency

Ketosis

| Measure blood ketone concentration upon wakening using portable blood ketone meter. | At least several times per month;1 goal is to maintain blood beta-hydroxybutyrate concentrations 0.3 mmol/L.

Hypoglycemia

| Self-glucose monitoring or continuous glucose monitoring | At least several times per month as needed1

Gastrointestinal

| Liver ultrasound | Annually beginning at age 5 yrs

Growth

| Growth assessment | At each visit until growth is complete

Musculoskeletal

| DXA scan to assess bone density | When puberty is complete as clinically indicated

Assessment for hypotonia, fatigue, muscle cramping | At each visit

Assessment for motor development | Annually throughout childhood

Kidney function

| 24-hr urine to screen for microalbuminuria | Annually

DXA = dual-energy x-ray absorptiometry

1. Blood glucose and ketone concentration should also be measured during times of stress including illness, intense activity, periods of rapid growth, or any time at which intake of food is reduced and before and after changes are made to the amount of cornstarch or protein intake. Frequency of surveillance should be tailored to individual needs.

Source: GeneReviews — "Glycogen Storage Disease Type VI"