Biochemical characteristics and increased tetraglucoside excretion in patients with phosphorylase kinase deficiency

Abstract

Patients with glycogen storage disease type IXa present with infantile hepatomegaly and a specific growth pattern, and variable biochemical alterations in blood. We studied the clinical and biochemical characteristics including the urinary oligosaccharide excretion of seven unrelated children. The urinary tetraglucoside excretion was increased in four children, three of whom had persistently high cholesterol and triglyceride concentrations. We propose screening for urine tetraglucoside excretion and the measurement of serum cholesterol in patients with growth delay and/or hepatomegaly to assess a possible glycogenosis.

Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

“…However, some female carriers also exhibit symptoms ranging from mild hepatomegaly to more severe manifestations based on X inactivation. [34][35][36] Affected male children typically present in the first year or two of life with hepatomegaly, of varying degrees, and growth delay/deceleration. Further investigation often reveals mild to markedly elevated serum transaminases and hyperlipidemia.…”

“…60 Pathogenic variants in the PHKA2 gene (OMIM 300798; Xp22.2-p22.1) are the most common cause of the liver form of GSD IX, accounting for about 75% of cases. 25,35 If individual gene sequencing rather than panel approach is being taken, for a male patient, sequencing of the PHKA2 gene is recommended first, unless there is a clear indication of autosomal recessive inheritance. 25 It should be noted that female carriers of a PHKA2 pathogenic variant can have symptoms.…”

“…Fourth, there is suggestion that specific biomarkers, including urine glucose tetrasaccharide (Glc 4 ), urine organic acids, and serum biotinidase activity could be helpful in the diagnosis and monitoring of patients with hepatic GSDs, such as GSDs VI and IX. For example, urine Glc 4 is a limit dextrin of glycogen that is normally excreted in urine and is elevated in several types of GSD including II, III, VI, and IX 31,35,90,91 as well as other conditions. An association between clinical condition and urine Glc 4 level in patients with PHKA2 pathogenic variants has been reported.…”

Assessing disease severity in Pompe disease: The roles of a urinary glucose tetrasaccharide biomarker and imaging techniques

“…[Walker and Whelan, 1960; Ugorski et al, 1983]. Studies of the excretion of this tetrasaccharide have demonstrated that it is elevated in conditions associated with increased glycogen storage, including several of the glycogen storage disorders: GSD II [Lennartson et al, 1976; Lennartson et al, 1978; Kuriyama et al, 1985; Oberholzer and Sewell, 1990], GSD III [Lennartson et al, 1976, 1978; Oberholzer and Sewell, 1990], GSD VI [Oberholzer and Sewell, 1990], and GSD IX [Morava et al, 2005]; certain leukemias and sarcomas [Kumlien et al, 1988]; and pregnancy [Hallgren et al, 1977]. It was also reported to be elevated in conditions of muscle breakdown including Duchenne muscular dystrophy [Lennartson et al, 1976; Lundblad et al, 1979] and patients who had suffered muscle trauma [Kumlien et al, 1988], and in patients with acute pancreatitis [Kumlien et al, 1988].…”

Clinical and Molecular Variability in Patients with PHKA2 Variants and Liver Phosphorylase b Kinase Deficiency

“…Although there is no clear gene/phenotype correlation seen in PhK deficiency, patients with mutations in PHKG2 have been reported to have more severe symptoms and increased risk of developing liver cirrhosis in childhood (Maichele et al 1996;Burwinkel et al 1998aBurwinkel et al , b, 2000Burwinkel et al , 2003Beauchamp et al 2007a, b;Davit-Spraul et al 2011;Fahiminiya et al 2013;Albash et al 2014;Bali et al 2014;Roscher et al 2014), while those with mutations in PHKB tend to have milder involvement (Burwinkel et al 1997a, b;Beauchamp et al 2007a, b;Davit-Spraul et al 2011;Roscher et al 2014). A wide variability in clinical presentation and severity has been recognized among patients with the most common subtype, X-linked PhK deficiency, ranging from mild involvement to severe, recurrent hypoglycemia and liver cirrhosis in some reported cases (Burwinkel et al 1998a, b;Morava et al 2005;Beauchamp et al 2007a, b;Davit-Spraul et al 2011;Tsilianidis et al 2013;Roscher et al 2014). In this manuscript we further report the variability in clinical severity and laboratory findings in 12 male patients from 10 different families with X-linked liver PhK deficiency caused by mutations in PHKA2.…”