The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada
Introduction
Glycogen storage disease (GSD) types VI and IX are caused by phosphorylase system deficiencies. Their estimated prevalence is 1:100,000 and they account for 25–30% of all GSDs [1], [2]. GSD type VI (GSD-VI) (Hers-disease; MIM #: 232700) is caused by hepatic glycogen phosphorylase deficiency encoded by the PYGL gene and inherited by autosomal recessive inheritance [1]. GSD type IX is caused by phosphorylase kinase (PhK) deficiency, which has 4 subunits. The PhK enzyme subunit deficiencies causing liver GSD type IX include: 1) α subunit, encoded by the PHKA2 gene (type IXa liver specific, X-linked inheritance) (MIM #: 306000); 2) β subunit, encoded by the PHKB gene (type IXb, liver type, autosomal recessive inheritance) (MIM # 261750); and 3) γ subunit, encoded by the PHKG2 gene (type IXc, liver type, autosomal recessive inheritance) (MIM #: 613027). GSD type IXa (GSD-IXa) is the most common subtype of GSD-IX and is divided into two subtypes: 1) Phk is deficient in the liver and red blood cells (RBCs) in GSD-IXa1; and 2) Phk activity is variable in the liver and normal or elevated in RBCs in GSD-IXa2 [2].
The majority of the GSD-VI and -IX patients present with hepatomegaly and short stature within the first 2 years of life. The phenotype ranges from mild (hepatomegaly and elevated liver enzymes) to severe (hypoglycemia, short stature, mild gross motor delays, progressive liver disease and liver cirrhosis) [1], [2]. Biochemically, patients have elevated liver enzymes and an increased risk of fasting hypoglycemia. Clinical and biochemical features tend to improve with age. Non-specific clinical and biochemical features at initial presentation may delay referral to a metabolic genetics clinic. Confirmation of the diagnosis is based on the molecular genetic studies for specific genes, which are available on a clinical basis in many North American and European clinical molecular diagnostic laboratories. Enzyme activity measurement in RBCs is available for GSD-IXa1, GSD-IXb and GSD-IXc, but normal RBC PhK does not rule out the diagnosis of GSD-IX. If mutation analysis is not able to identify underlying genetic defect, invasive liver biopsy is an important diagnostic method for the confirmation of the diagnosis by enzyme activity measurement in liver biopsy specimens.
To evaluate the natural history and long-term treatment outcome of the patients with GSD-VI and -IX, we performed an observational retrospective case study of 21 patients with confirmed diagnosis of GSD-VI and -IX at The Hospital for Sick Children in Toronto.
Section snippets
Material and methods
All patients with GSD-VI and -IX, diagnosed at The Hospital for Sick Children between 1990 and 2012, were included. Electronic and paper charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, diagnostic imaging, long-term outcome and treatment by two independent research team members. All information was entered into an Excel database. The Alamut database, Exome database (http://evs.gs.washington.edu/EVS/), and dbSNP database (//www.ncbi.nlm.nih.gov/projects/SNP/
Results
Twenty-one patients (17 males and 4 females (2 females with GSD-IXc and two females with GSD-VI)) from 17 unrelated families were included (Table 1) into this retrospective observational case study. Patient 15 was previously reported [3]. The average age was 11.66 ± 5.27 years standard deviation (SD) (age range: 3–18 years). Eleven patients (53%) had GSD-IXa; 3 patients (14%) had GSD-IXb (14%); 3 patients (14%) had GSD-IXc; and 4 patients (19%) had GSD-VI. There were two affected children in four
Discussion
We report on the natural history and treatment outcome of 21 patients with GSD-VI and -IX (20 new patients and one previously reported patient [3]) and 16 novel pathogenic mutations in the PHKA2, PHKB, PHKG2 and PYGL genes. In our patient cohort, GSD-IXa was the most common subtype (52%) and other subgroups were less than 20%. GSD-VI and IX, except GSD-IXc, were considered as benign and self-limited disorders in the past. GSD-IXc reported to cause liver fibrosis or cirrhosis similar to other
Acknowledgments
We would like to thank Leslie Steele from the Molecular Genetics Laboratory at The Hospital for Sick Children for her assistance with the Alamut-database.
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