Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 264580; DO: 0111042;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.13 | Glycogen storage disease, type IXa1 | 306000 | X-linked recessive | 3 | PHKA2 | 300798 |
| Xp22.13 | Glycogen storage disease, type IXa2 | 306000 | X-linked recessive | 3 | PHKA2 | 300798 |
A number sign (#) is used with this entry because glycogen storage disease type IXa (GSD9A1) and type IXa2 (GSD9A2) are caused by mutation in the PHKA2 gene (300798), which encodes the alpha-2 subunit of hepatic phosphorylase kinase, on chromosome Xp22.
Glycogen storage disease type IX (GSD9) is a metabolic disorder resulting from a deficiency of hepatic phosphorylase kinase, a hexadecameric enzyme comprising 4 copies each of 4 unique subunits encoded by 4 different genes: alpha (PHKA2), beta (PHKB; 172490), gamma (PHKG2; 172471), and delta (CALM1; 114180). Mutations within the PHKA2, PHKB, and PHKG2 genes result in GSD9A, GSD9B (261750), and GSD9C (613027), respectively. GSD IXa is an X-linked recessive disorder, whereas the others are autosomal recessive.
GSD IXa has been further divided into types IXa1 (GSD9A1), with no PHK activity in liver or erythrocytes, and IXa2 (GSD9A2), with no PHK in liver, but normal activity in erythrocytes. The clinical presentation of both subtypes is the same, and both are caused by mutations in the PHKA2 gene. However, mutations that result in IXa2 are either missense or small in-frame deletions or insertions enabling residual enzyme expression in erythrocytes (Keating et al., 1985; Hendrickx et al., 1994; Beauchamp et al., 2007).
See also X-linked muscle PHK deficiency (GSD9D; 300559), caused by mutation in the gene encoding the muscle-specific alpha PHK subunit (PHKA1; 311870).
Glycogen storage disease IXa is one of the mildest of the glycogenoses of man. Clinical symptoms include hepatomegaly, growth retardation, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis These clinical and biochemical abnormalities gradually disappear with age, and most adult patients are asymptomatic (Schimke et al., 1973; Willems et al., 1990).
Hendrickx et al. (1998) presented clinical, biochemical, and molecular findings in a patient with GSD IXa2 who had been followed for 40 years. Although growth was retarded early in life, he achieved a height of 182 cm at the age of 33 years. Thyroid therapy appeared to be helpful in this patient. Five male relatives also had liver glycogenosis. Genetic analysis identified a mutation in the PHKA2 gene (R186H; 300798.0008)
Beauchamp et al. (2007) reported 10 patients from 8 families with GSD IXa confirmed by genetic analysis. Age at diagnosis ranged from 12 months to 7 years. Clinical features were variable, and included hepatomegaly, short stature, liver dysfunction, hypoglycemia, hyperuricemia, hyperlipidemia, fasting ketosis, and mild motor delay. Five of the 8 probands had a demonstrable reduction of PHK activity in erythrocytes, consistent with GSD IXa1. The majority of patients had private mutations. The authors emphasized that molecular analysis results in accurate diagnosis for GSD IX when enzymology is uninformative, and thus allows for proper genetic counseling.
Roscher et al. (2014) reported on 21 patients (17 males and 4 females) from 17 unrelated families with GSD IXa, IXb (261750), IXc (613027), or VI (232700), which are caused by phosphorylation deficiencies. The average age was 11.66 years, with a range of 3 to 18 years. Eleven patients (53%) had GSD IXa; 3 (14%) had GSD IXb; 3 (14%) had GSD IXc; and 4 (19%) had GSD VI. The average age of initial presentation was 20 months (range 4-160 months). The GSD IXb patients presented earliest at the age of 5 months (range 4-6 months). Hepatomegaly was present in 95% of patients on physical examination and 100% on liver ultrasound. Four patients presented with failure to thrive, and 2 with short stature. None of the patients had intellectual disability or global developmental delay at most recent evaluation, although some had early developmental delay. Alanine transaminase (ALT) was elevated in 18 patients (86%), and aspartate transaminase (AST) was elevated in 19 (90%). Hypercholesterolemia was present in 14 of the 21 patients, and hypertriglyceridemia was present in 16. While previous reports noted hypoglycemia in 17 to 44% of patients with subtypes of GSD VI or GSD IX, hypoglycemia occurred in less than 5% of the patients in the cohort of Roscher et al. (2014). Two patients had developed likely liver adenomas at long-term follow-up, which had not theretofore been reported.
Fernandes et al. (2020) performed a comprehensive literature review of the clinical features of 183 individuals from 164 families with GSD9A2. The mean age at diagnosis was 4 years (range, 0.24 to 37 years). Of the 157 patients for whom initial presentation was reported, 141 presented with hepatomegaly, 56 with abnormal liver function, 47 with growth or developmental delay, 8 with frequent infections, 6 with frequent hunger, 6 with frequent hypoglycemia, 4 with fatigue, and 2 with anemia. Clinical features in the patient cohort included hepatomegaly (164 of 176 patients), delayed development (31 of 88 patients), and growth retardation (98 of 168 patients). Low enzyme activity was present in 101 of 116 patients tested. Other laboratory abnormalities included elevated AST/ALT levels (125 of 138 patients), hypertriglyceridemia (64 of 98 patients), fasting hypoglycemia (53 of 121 patients), fasting ketosis (21 of 34 patients), and hypercholesterolemia (41 of 90 patients). Sixty-eight patients had a liver biopsy at a mean age of 3.09 years, for which 46 pathology reports were evaluated; 24 biopsies showed no fibrosis, 7 showed mild fibrosis, 4 showed moderate fibrosis, 7 showed severe fibrosis, and 4 showed cirrhosis. One patient had a hepatic adenoma and no patients received a liver transplant.
In 4 boys with X-linked PHK-deficient glycogenosis, aged 29 months to 43 months, Garibaldi et al. (1978) found that dextrothyroxine (D-T4) had dramatic effects: the liver, previously greatly enlarged, returned to normal size; serum GOT, GPT, and triglycerides fell to normal; and hypoglycemia was corrected.
Kishnani et al. (2019) developed guidelines for the management of the multisystem effects of GSD IX and GSD VI (232700). To manage hepatic involvement, they recommended monitoring ALT, AST, albumin, gamma-glutamyl transferase (GGT), prothrombin time/INR, and alkaline phosphatase every 3-12 months, abdominal ultrasound every 12-13 months in children younger than age 18 years and an abdominal CT or MRI every 1-2 years in older patients. Monitoring of blood glucose and ketones was recommended to be done at diagnosis, after major dietary changes, and at times of stress including illness, intense activity, and rapid growth. Nutritional recommendations were aimed at improving metabolic control and preventing the primary (hypoglycemia, ketosis, hepatomegaly) and secondary (short stature, delayed puberty, cirrhosis) complications of both disorders. These recommendations included a high protein diet to provide 2 to 3 g/kg body weight or 20 to 25% of total calories, carbohydrates to provide 45 to 50% of total calories, and fat to provide 30% of total calories. Protein intake was recommended to be distributed throughout the day and consumed at each meal. The authors also noted that cornstarch may be required at bedtime to prevent overnight hypoglycemia. They recommended avoidance of medications that might mask symptoms of hypoglycemia (beta-blockers) or cause hypoglycemia (sulfonylureas), and noted that glucagon should not be used to treat hypoglycemia. Careful management to avoid hypoglycemia and other complications during pregnancy was also recommended.
Williams and Field (1961) found low leukocyte phosphorylase activity in 2 affected brothers, and normal activity in an unaffected brother and in the father. An intermediately low level in the mother, together with affected males, suggested X-linked inheritance. Wallis et al. (1966) restudied the family and with new methods found support for X-linkage.
Huijing and Fernandes (1969) studied 2 kindreds, 1 of which had 6 affected males and 2 possibly affected males. The other had 20 affected males, 2 affected females, and 7 probably affected males. X-linked inheritance was suggested. Huijing and Fernandes (1970) suggested that affected females studied by Hug et al. (1969) were heterozygotes.
By cloning cells of an obligate heterozygous female with GSD due to phosphorylase kinase deficiency, Migeon and Huijing (1974) demonstrated that some fibroblasts had enzymatic levels similar to those of affected hemizygotes. This was presented as proof of X-linkage and X-inactivation of the phosphorylase kinase locus.
Willems et al. (1991) performed linkage analysis with X-chromosomal polymorphic DNA markers in 2 families with X-linked liver glycogenosis. Multipoint linkage analysis indicated that the mutation responsible for X-linked liver glycogenosis was located on Xp22 between DXS143 and DXS41. Linkage to the muscle PHKA1 region on Xq12-q13 was excluded.
Hendrickx et al. (1992, 1993) found a combined multipoint lod score of 16.79 for linkage of X-linked liver glycogenosis to chromosome Xp22.
Hendrickx et al. (1994) performed linkage analysis in 4 families with GSD IXa2, who had residual PHK activity in erythrocytes, and showed that this form was also linked to Xp22. The authors concluded that this biochemical variant type was allelic to GSD IXa1, and that both diseases are likely caused by mutations in PHKA2. Hendrickx et al. (1994) proposed the classification of XLG into types I and II.
In affected members of 4 unrelated families with GSD IXa1, Hendrickx et al. (1995) identified 4 different mutations in the PHKA2 gene (300798.0001-300798.0004). Clinical features were somewhat variable, but included growth retardation, hepatomegaly, elevated liver enzymes, and normalization of symptoms with age. PHK activity was decreased to less than 20% of control values in erythrocytes and in liver, when measured.
Van den Berg et al. (1995) identified mutations in the PHKA2 gene (300798.0005 and 300798.0006) in affected members of 2 Dutch families with GSD IXa1. One of the families had been reported by Huijing and Fernandes (1969).
Burwinkel et al. (1996) identified mutations in the PHKA2 gene in patients with GSD IXa2 (see 306000.0008-306000.0010). The mutations appeared to cluster in limited sequence regions. Burwinkel et al. (1996) stressed that the clustering of type II mutations would further facilitate analysis by RT-PCR of blood cell mRNA and thus help avoid liver biopsy in the diagnosis.
In 4 unrelated patients with GSD IXa2, Hendrickx et al. (1996) identified 4 different mutations in the PHKA2 gene (306000.0011-306000.0014). The mutations resulted in minor abnormalities in the primary structure of the protein. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that may be involved in the regulation of PHK. Hendrickx et al. (1996) postulated that PHK activity may be regulated by phosphorylation of these sites and that type II GSD9a may be due to impaired activation of PHK activity. The findings may explain why the in vitro PHK enzymatic activity is not deficient in type II, whereas it is in type I.
Burwinkel et al. (1998) described 8 new mutations and phenotypic consequences in patients with X-linked liver glycogenosis. One of the patients reported by Burwinkel et al. (1998) had low PHK activity in the liver but elevated levels in erythrocytes, typical of XLG type II. This patient had a lys189-to-glu missense mutation (K189E; 306000.0015). The authors noted that this observation adds to the growing body of evidence that the XLG phenotype is associated with missense mutations clustering at a few sites in the PHKA2 gene.
Hendrickx et al. (1999) identified PHKA2 mutations in 10 patients with XLG types I and II. They proposed that mutations in XLG type I, in which PHK activity is decreased in both liver and erythrocytes, results from truncation or disruption of the PHKA2 protein. In contrast, all type II mutations, which result in residual activity in erythrocytes, were missense mutations or small in-frame deletions and insertions. These results suggested that the biochemical differences between the 2 types of XLG are due to the different nature of the disease-causing mutations in PHKA2. Type I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas type II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.
The classification, particularly the numbering, of the glycogenoses has long been a matter of dispute. For example, Huijing (1970) referred to this disorder as glycogen storage disease type VIA; Hug (1974) assigned number VIII to a presumably recessive form of phosphorylase deficiency with brain involvement and number IX to phosphorylase kinase deficiency (see Schimke et al., 1973). McAdams et al. (1974) presented information on classification and morphology of the glycogenoses.
Schneider et al. (1993) reviewed the animal mutants that result in PHK-linked glycogenoses. Two different X-linked disorders are known, as well as an autosomal recessive PHK deficiency affecting the liver and most other tissues but not muscle, in the rat.
Beauchamp, N. J., Dalton, A., Ramaswami, U., Niinikoski, H., Mention, K., Kenny, P., Kolho, K.-L., Raiman, J., Walter, J., Treacy, E., Tanner, S., Sharrard, M. Glycogen storage disease type IX: high variability in clinical phenotype. Molec. Genet. Metab. 92: 88-99, 2007. [PubMed: 17689125] [Full Text: https://doi.org/10.1016/j.ymgme.2007.06.007]
Burwinkel, B., Amat, L., Gray, R. G. F., Matsuo, N., Muroya, K., Narisawa, K., Sokol, R. J., Vilaseca, M. A., Kilimann, M. W. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Hum. Genet. 102: 423-429, 1998. [PubMed: 9600238] [Full Text: https://doi.org/10.1007/s004390050715]
Burwinkel, B., Shin, Y. S., Bakker, H. D., Deutsch, J., Lozano, M. J., Maire, I., Kilimann, M. W. Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2). Hum. Molec. Genet. 5: 653-658, 1996. [PubMed: 8733134] [Full Text: https://doi.org/10.1093/hmg/5.5.653]
Fernandes, S. A., Cooper, G. E., Gibson R. A., Kishnani, P. S. Benign or not benign? Deep phenotyping of liver glycogen storage disease IX. Molec. Genet. Metab. 131: 299-305, 2020. [PubMed: 33317799] [Full Text: https://doi.org/10.1016/j.ymgme.2020.10.004]
Garibaldi, L. R., Borrone, C., De Martini, I., Battistini, E. Dextrothyroxine treatment of phosphorylase-kinase deficiency glycogenosis in four boys. Helv. Paediat. Acta 33: 435-444, 1978. [PubMed: 280544]
Goji, K., Morishita, Y., Kodama, S., Takahashi, T., Matsuo, T. Lymphocyte phosphorylase kinase activities in the sex-linked form of liver phosphorylase kinase deficiency. Europ. J. Pediat. 143: 179-182, 1985. [PubMed: 3987709] [Full Text: https://doi.org/10.1007/BF00442132]
Hendrickx, J., Bosshard, N. U., Willems, P., Gitzelmann, R. Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years. Europ. J. Pediat. 157: 919-923, 1998. [PubMed: 9835437] [Full Text: https://doi.org/10.1007/s004310050967]
Hendrickx, J., Coucke, P., Bossuyt, P., Wauters, J., Raeymaekers, P., Marchau, F., Smit, G. P. A., Stolte, I., Sardharwalla, I. B., Berthelot, J., Van den Bergh, I., Berger, R., Van Broeckhoven, C., Baussan, C., Wapenaar, M., Fernandes, J., Willems, P. J. X-linked liver glycogenosis: localization and isolation of a candidate gene. Hum. Molec. Genet. 2: 583-589, 1993. [PubMed: 8518797] [Full Text: https://doi.org/10.1093/hmg/2.5.583]
Hendrickx, J., Coucke, P., Dams, E., Lee, P., Odievre, M., Corbeel, L., Fernandes, J. F., Willems, P. J. Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease. Hum. Molec. Genet. 4: 77-83, 1995. [PubMed: 7711737] [Full Text: https://doi.org/10.1093/hmg/4.1.77]
Hendrickx, J., Coucke, P., Hors-Cayla, M.-C., Smit, G. P. A., Shin, Y. S., Deutsch, J., Smeitink, J., Berger, R., Lee, P., Fernandes, J., Willems, P. J. Localization of a new type of X-linked liver glycogenosis to the chromosomal region Xp22 containing the liver alpha-subunit of phosphorylase kinase (PHKA2). Genomics 21: 620-625, 1994. [PubMed: 7959740] [Full Text: https://doi.org/10.1006/geno.1994.1322]
Hendrickx, J., Coucke, P., Raeymaekers, P., Willems, P. J. X-linked liver glycogenosis: localization and isolation of a strong candidate gene. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A190 only, 1992.
Hendrickx, J., Dams, E., Coucke, P., Lee, P., Fernandes, J., Willems, P. J. X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase. Hum. Molec. Genet. 5: 649-652, 1996. [PubMed: 8733133] [Full Text: https://doi.org/10.1093/hmg/5.5.649]
Hendrickx, J., Lee, P., Keating, J. P., Carton, D., Sardharwalla, I. B., Tuchman, M., Baussan, C., Willems, P. J. Complete genomic structure and mutational spectrum of PHKA2 in patients with X-linked liver glycogenosis type I and II. Am. J. Hum. Genet. 64: 1541-1549, 1999. [PubMed: 10330341] [Full Text: https://doi.org/10.1086/302399]
Hers, H. G. Etudes enzymatiques sur fragments hepatiques: application a la classification des glycogenoses. Rev. Int. Hepat. 9: 35-55, 1959. [PubMed: 13646331]
Hug, G., Schubert, W. K., Chuck, G. Deficient activity of dephosphophosphorylase kinase and accumulation of glycogen in the liver. J. Clin. Invest. 48: 704-715, 1969. [PubMed: 5774108] [Full Text: https://doi.org/10.1172/JCI106028]
Hug, G. Personal Communication. Cincinnati, Ohio 1974.
Huijing, F., Fernandes, J. X-chromosomal inheritance of liver glycogenosis with phosphorylase kinase deficiency. Am. J. Hum. Genet. 21: 275-284, 1969. [PubMed: 5306139]
Huijing, F., Fernandes, J. Liver glycogenosis and phosphorylase kinase deficiency. (Letter) Am. J. Hum. Genet. 22: 484-485, 1970. [PubMed: 5270453]
Huijing, F. Phosphorylase kinase in leucocytes of normal subjects and of patients with glycogen-storage disease. Biochim. Biophys. Acta 148: 601-603, 1967.
Huijing, F. Glycogen-storage disease type VIa: low phosphorylase kinase activity caused by a low enzyme-substrate affinity. Biochim. Biophys. Acta 206: 199-201, 1970. [PubMed: 5266383] [Full Text: https://doi.org/10.1016/0005-2744(70)90102-6]
Huijing, F. Phosphorylase kinase deficiency. Biochem. Genet. 4: 187-194, 1970. [PubMed: 5444101] [Full Text: https://doi.org/10.1007/BF00484029]
Keating, J. P., Brown, B. I., White, N. H., DiMauro, S. X-linked glycogen storage disease: a cause of hypotonia, hyperuricemia, and growth retardation. Am. J. Dis. Child. 139: 609-613, 1985. [PubMed: 3859203] [Full Text: https://doi.org/10.1001/archpedi.1985.02140080079037]
Kishnani, P. S., Goldstein, J., Austin, S. L., Arn, P., Bachrach, B., Bali, D. S., Chung, W. K., El-Gharbawy, A., Brown, L. M., Kahler, S., Pendyal, S., Ross, K. M., Tsilianidis, L., Weinstein, D. A. Watson, M. S. 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). Genet. Med. 21: 772-789, 2019. [PubMed: 30659246] [Full Text: https://doi.org/10.1038/s41436-018-0364-2]
McAdams, A. J., Hug, G., Bove, K. E. Glycogen storage disease, type I to X: criteria for morphologic diagnosis. Hum. Path. 5: 463-487, 1974. [PubMed: 4525190] [Full Text: https://doi.org/10.1016/s0046-8177(74)80024-9]
Migeon, B. R., Huijing, F. Glycogen-storage disease associated with phosphorylase kinase deficiency: evidence for X inactivation. Am. J. Hum. Genet. 26: 360-368, 1974. [PubMed: 4524311]
Roscher, A., Patel, J., Hewson, S., Nagy, L., Feigenbaum, A., Kronick, J., Raiman, J., Schulze, A., Siriwardena, K., Mercimek-Mahmutoglu, S. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Molec. Genet. Metab. 113: 171-176, 2014. [PubMed: 25266922] [Full Text: https://doi.org/10.1016/j.ymgme.2014.09.005]
Schimke, R. N., Zakheim, R. M., Corder, R. C., Hug, G. Glycogen storage disease type IX: benign glycogenosis of liver and hepatic phosphorylase kinase deficiency. J. Pediat. 83: 1031-1034, 1973. [PubMed: 4518931] [Full Text: https://doi.org/10.1016/s0022-3476(73)80544-x]
Schneider, A., Davidson, J. J., Wullrich, A., Kilimann, M. W. Phosphorylase kinase deficiency in I-strain mice is associated with a frameshift mutation in the alpha-subunit muscle isoform. Nature Genet. 5: 381-385, 1993. [PubMed: 8298647] [Full Text: https://doi.org/10.1038/ng1293-381]
van den Berg, I. E. T., van Beurden, E. A. C. M., Malingre, H. E. M., Ploos van Amstel, H. K., Poll-The, B. T., Smeitink, J. A. M., Lamers, W. H., Berger, R. X-linked liver phosphorylase kinase deficiency is associated with mutations in the human liver phosphorylase kinase alpha subunit. Am. J. Hum. Genet. 56: 381-387, 1995. [PubMed: 7847371]
Varsanyi, M., Vrbica, A., Heilmeyer, L. M. G., Jr. X-linked dominant inheritance of partial phosphorylase kinase deficiency in mice. Biochem. Genet. 18: 247-261, 1980. [PubMed: 7447922] [Full Text: https://doi.org/10.1007/BF00484240]
Wallis, P. G., Sidbury, J. B., Jr., Harris, R. C. Hepatic phosphorylase defect. Studies on peripheral blood. Am. J. Dis. Child. 111: 278-282, 1966. [PubMed: 5904467] [Full Text: https://doi.org/10.1001/archpedi.1966.02090060088008]
Willems, P. J., Gerver, W. J. M., Berger, R., Fernandes, J. The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Europ. J. Pediat. 149: 268-271, 1990. [PubMed: 2303074] [Full Text: https://doi.org/10.1007/BF02106291]
Willems, P. J., Hendrickx, J., Van der Auwera, B. J., Vits, L., Raeymaekers, P., Coucke, P. J., Van den Bergh, I., Berger, R., Smit, G. P. A., Van Broeckhoven, C., Kilimann, M. W., Van Elsen, A. F., Fernandes, J. F. Mapping of the gene for X-linked liver glycogenosis due to phosphorylase kinase deficiency to human chromosome region Xp22. Genomics 9: 565-569, 1991. [PubMed: 1674721] [Full Text: https://doi.org/10.1016/0888-7543(91)90347-h]
Williams, H. E., Field, J. B. Low leukocyte phosphorylase in hepatic phosphorylase deficient glycogen storage disease. J. Clin. Invest. 40: 1841-1845, 1961. [PubMed: 14007166] [Full Text: https://doi.org/10.1172/JCI104408]