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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Phosphorylase Kinase Deficiency

Synonyms: Glycogen Storage Disease Type IX, GSDIX, Phosphorylase b Kinase Deficiency, PhK Deficiency. Includes: Liver Phosphorylase Kinase Deficiency (Including: PHKA2-Related Phosphorylase Kinase Deficiency, PHKB-Related Phosphorylase Kinase Deficiency, PHKG2-Related Phosphorylase Kinase Deficiency), Muscle Phosphorylase Kinase Deficiency (Including: PHKA1-Related Phosphorylase Kinase Deficiency, PHKB-Related Phosphorylase Kinase Deficiency)

, PhD, , MS, , MD, and , PhD.

Author Information
, PhD
Biochemical Genetics Laboratory
Duke University Medical Center
Durham, North Carolina
, MS
Clinical Genetics
Department of Pediatrics
Duke University Medical Center
Durham, North Carolina
, MD
Clinical Genetics
Department of Pediatrics
Duke University Medical Center
Durham, North Carolina
, PhD
Biochemical Genetics Laboratory
Duke University Medical Center
Durham, North Carolina

Initial Posting: .

Summary

Disease characteristics. Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth retardation, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). Symptoms and biochemical abnormalities of liver PhK deficiency are thought to improve with age.

Diagnosis/testing. The enzyme PhK comprises four copies each of four subunits (α, β, γ, and δ). Mutations in PHKA1, encoding subunit α, cause the rare X-linked disorder muscle PhK deficiency; mutations in PHKA2, also encoding subunit α, cause the most common form, liver PhK deficiency (X-linked liver glycogenosis); mutations in PHKB, encoding subunit β, cause autosomal recessive PhK deficiency in both liver and muscle; and mutations in PHKG2, encoding subunit γ, cause autosomal recessive liver PhK deficiency. Diagnosis is based on clinical findings, assay of PhK activity in erythrocytes, or liver or muscle tissues (depending upon presentation) and confirmatory findings on molecular genetic testing.

Management. Treatment of manifestations: Liver PhK Deficiency: Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein. When hypoglycemia or ketosis is present, Polycose® or fruit juice is given orally as tolerated or glucose by IV. Liver manifestations (e.g., cirrhosis, liver failure, portal hypertension) are managed symptomatically. Muscle PhK Deficiency: Physical therapy based on physical status and function; optimization of blood glucose concentrations by a metabolic nutritionist based on activity.

Prevention of primary manifestations: Liver PhK Deficiency: Diet high in complex carbohydrates and protein to prevent hypoglycemia and ketosis if present. Muscle PhK Deficiency: Little published information is available.

Prevention of secondary complications: Liver PhK Deficiency: IV glucose infusion preoperatively for elective procedures followed by intraoperative and post-operative IV glucose infusion to prevent hypoglycemia; malignant hyperthermia precautions when general anesthesia is required.

Surveillance: Liver PhK Deficiency: Regular evaluation by a metabolic physician and a metabolic nutritionist. Monitoring of blood glucose concentration and blood ketones routinely as well as during times of stress (e.g., illness, intense activity, rapid growth, puberty) and reduced food intake. In children younger than age 18 years, liver ultrasound examination should be performed every 12 to 24 months. With increasing age, CT or MRI using intravenous contrast should be considered to evaluate for complications of liver disease. Muscle PhK Deficiency: Regular evaluation by a metabolic physician, a metabolic nutritionist, and physical therapist.

Agents/circumstances to avoid: Liver PhK Deficiency: Large amounts of simple sugars as they will increase liver storage of glycogen; prolonged fasting; high-impact contact sports if significant hepatomegaly is present; drugs known to cause hypoglycemia such as insulin and insulin secretogogues (the sulfonylureas); Alcohol (which may predispose to hypoglycemia). Muscle PhK Deficiency: Vigorous exercise; medications like succinylcholine and statins that can cause rhabdomyolysis.

Evaluation of relatives at risk: Molecular genetic testing (if the family-specific mutations are known) and/or evaluation by a metabolic physician (if the family-specific mutations are not known) allow early diagnosis and treatment for sibs at increased risk for liver PhK deficiency.

Pregnancy management: Dietary management to maintain euglycemia throughout pregnancy.

Genetic counseling. PHKA2-related liver PhK deficiency and PHKA1-related muscle PhK deficiency are inherited in an X-linked manner. PHKB-related liver and muscle PhK deficiency and PHKG2-related liver PhK deficiency are inherited in an autosomal recessive manner.

X-linked inheritance: If the mother is a carrier, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Affected males pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at risk are possible if the disease-causing mutation in the family has been identified.

Autosomal recessive inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible if the disease-causing mutations in the family have been identified.

Diagnosis

Phosphorylase kinase deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase (PhK), an enzyme with a key regulatory role in the breakdown of glycogen. Deficiency of this enzyme, which comprises four copies each of four subunits (α, β, γ, and δ), results in considerable clinical variability [Chen et al 2009, Kishnani & Chen 2010].

For the purposes of this review, phosphorylase kinase (PhK) deficiency has been divided into: liver PhK deficiency and muscle PhK deficiency (Table 1; Figure 1). Liver PhK deficiency is further divided into three subtypes based on the gene in which mutations occur (PHKB, PHKA2, and PHKG2) and inheritance pattern. It should be noted that mutations in PHKB result in PhK deficiency both in liver and muscle. However, the symptoms from muscle involvement can be mild or absent; thus, this subtype may be clinically indistinguishable from the liver PhK deficiencies caused by mutations in PHKA2 and PHKG2.

Figure 1

Figure

Figure 1. Phosphorylase kinase subnunit expression

PHKA2-related PhK deficiency is also known as X-linked liver glycogenosis (XLG) and is divided into two biochemical subtypes, XLG1 and XLG2, depending on enzyme activity in various tissues.

Table 1. Phosphorylase Kinase (PhK) Enzyme Subunits and Genes that Encode Them

Gene SymbolProportion of all GSD IXTissue AffectedEnzyme SubunitMode of Inheritance Number of ExonsFunction
Associated with PhK Deficiency
PHKA1~17% 1 muscle PhK deficiencyMuscleαXL32Regulatory
PHKA2~75% liver PhK deficiencyLiverαXL 33Regulatory
PHKBUnknownMuscle and liver 2βAR33Regulatory
PHKG2UnknownLiverγAR10Catalytic
Not Known to be Associated with PhK Deficiency
PHKG1UnknownUnknownγAR10Catalytic
CALM1UnknownUnknownδAR6Regulatory; calcium binding
CALM2UnknownUnknownδAR6Regulatory; calcium binding
CALM3UnknownUnknownδAR6Regulatory; calcium binding

1. The genetic basis of muscle PhK deficiency appears to be heterogeneous. A mutation in PHKA1 was found in one of six persons screened [Burwinkel et al 2003a]. None of the remaining affected individuals had pathogenic mutations in PHKB, PHKG1, CALM1, CALM2, or CALM3 (encoding calmodulin), PYGM (encoding muscle glycogen phosphorylase), or PRKAG2 and PRKAG3 (encoding the liver and muscle regulatory gamma 3 subunit of AMP-dependent kinase which may, directly or indirectly, affect PhK activity).

2. Despite PhK deficiency in muscle in individuals with mutations in PHKB, symptoms of muscle disease may not be present in childhood and this condition may be clinically indistinguishable from other liver PhK deficiencies caused primarily by mutations in PHKA2 and PHKG2.

Liver PhK Deficiency

The three subtypes of liver PhK deficiency, caused by mutations in three different genes (PHKA2, PHKB, and PHKG2), cannot be distinguished by their clinical features, which can range from mild to severe.

Liver PhK deficiency should be suspected in a child with:

  • Hepatomegaly
  • Growth retardation
  • Fasting ketosis and hypoglycemia

Blood / serum

Liver histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Septal fibrosis and low-grade inflammatory changes may also be seen. Rarely, liver cirrhosis and adenomas have been reported; so far these findings have been found in persons with PHKG2 mutations only [Chen et al 2009, Kishnani & Chen 2010]. However, liver cirrhosis may also be associated with mutations in other genes that encode PhK subunits, such as PHKA2 [Author, personal observation].

Liver glycogen content. Biochemical testing of snap-frozen liver biopsy tissue shows remarkably elevated glycogen content with normal glycogen structure.

Phosphorylase b kinase (PhK) activity is reduced in liver, erythrocytes, and leukocytes of most (not all) individuals with liver PhK deficiency.

  • Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin and in liver it is 0.1 μmol/min/mg protein.
  • Abnormal range is lower than 10% of normal level in the tissue being tested.

Muscle PhK activity is normal in individuals with mutations in either PHKA2 or PHKG2 and can be deficient in those with mutations in PHKB.

Notes: (1) PhK is a labile enzyme that is highly sensitive to handling conditions and temperature exposure; thus, it is recommended that patient blood samples be accompanied by a control blood sample drawn at the same time from an unrelated individual. Samples need to be kept cold (40 C) at all times including during transport.

(2) In a subset of affected individuals, in vitro PhK activity is normal or even elevated in erythrocytes and leukocytes and variable in liver. Most of these persons have a PHKA2 mutation (XLG2 biochemical subtype; see Testing Strategy); however, elevated PhK activity in blood cells has also been associated with mutations in PHKB and could potentially result from mutations in other genes as well [Burwinkel et al 1997b].

(3) Assay of PhK activity on snap-frozen liver biopsy tissue can help with diagnosis of liver PhK deficiency irrespective of which gene is mutated; however, normal PhK activity in liver does not rule out the diagnosis of liver PhK deficiency [Keating et al 1985; Hendrickx et al 1994; Hendrickx et al 1996; Author, personal observation].

(4) Because the enzyme PhK activates the enzyme glycogen phosphorylase b to the active form, phosphorylase a, activity of total phosphorylase could be reduced in individuals with PhK deficiency. Because primary deficiency of muscle or liver glycogen total phosphorylase causes GSD V and VI, respectively, low total phosphorylase activity in individuals with PhK deficiency could lead to a misdiagnosis of GSD V (if muscle symptoms are present) or GSD VI (if liver symptoms are present). Therefore, simultaneous assessment of PhK activity and total phosphorylase activity in liver or muscle biopsy, along with glycogen content, is recommended to permit accurate interpretation of test results.

(5) PhK deficiency may be secondary to a different, primary metabolic defect. For example, deficient PhK activity in some individuals with Fanconi-Bickel syndrome or PRKAG2 mutations may be a secondary phenomenon [Burwinkel et al 1999, Burwinkel et al 2005, Akman et al 2007].

Muscle PhK Deficiency

Muscle PhK deficiency with a confirmed mutation in PHKA1 has been found in only six individuals. It should be suspected in any individual ranging in age from childhood to adulthood with any of the following findings:

  • Exercise intolerance
  • Myalgia
  • Muscle cramps
  • Myoglobinuria
  • Progressive muscle weakness

Serum concentration of creatine kinase may be above the upper limits of normal. Note: Normal ranges tend to be laboratory specific.

Forearm ischemic exercise test is usually normal (see Glycogen Storage Disease V for details about this test), indicating that glycogenolysis is normal under maximal exercise (anaerobic) conditions [Haller 2008, Ørngreen et al 2008]. In contrast, conditions of submaximal exercise (cycle test) resulted in blunted glycogen breakdown in one individual who was studied. This suggests that PhK plays a larger role in the activation of muscle glycogen phosphorylase b (myophosphorylase) during submaximal exercise than during maximal exercise. During maximal exercise, metabolites such as AMP, inosine monophosphate, and inorganic phosphate may be sufficient for activation of myophosphorylase b [Ørngreen et al 2008].

Electromyography is usually normal.

Muscle histology shows excessive amounts of subsarcolemmal glycogen accumulation.

Muscle glycogen content measured biochemically is always elevated with normal glycogen structure.

Phosphorylase b kinase (PhK) enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts. Because the enzyme PhK activates the enzyme glycogen phosphorylase in muscle, the activity of glycogen phosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.

Molecular Genetic Testing

Genes. The enzyme phosphorylase kinase (PhK) is made up of four subunits (α, β, γ, and δ) encoded by eight independent genes located either on the X chromosome or various autosomes. Of these eight genes, four are known to harbor mutations that cause PhK enzyme deficiency (Table 1).

The two X-linked genes are:

  • PHKA1, which causes the rare disorder X-linked muscle PhK deficiency;
  • PHKA2, which causes the most common form of liver PhK deficiency, also known as X-linked liver glycogenosis (XLG).

The two autosomal genes are:

  • PHKB, which causes PhK deficiency in both liver and muscle but manifests primarly with liver symptoms with or without muscle involvement;
  • PHKG2, which causes PhK deficiency in liver.

Evidence for locus heterogeneity

  • Other genes encoding subunits of the enzyme PhK, such as PHKG1 and the muscle exon of PHKB (exon 26), are considered to be candidates for muscle PhK deficiency; to date, however, no pathogenic mutations have been identified in these genes [Burwinkel et al 2003b].
  • The three genes encoding calmodulin (CALM1, CALM 2, and CALM3) are ubiquitously expressed and are candidates for PhK deficiency in liver or muscle; to date, no mutations have been reported in the literature (see Table 1).

Clinical testing

PHKA1 and PHKA2 (X-linked)

  • Sequence analysis of the coding region and associated intronic regions of genomic DNA. Data are not yet available on mutation detection frequency for sequence analysis of these two genes [Author, communication].
    • PHKA1. In one study a mutation was found in only one of six individuals with PhK deficiency in muscle, suggesting that other factors (e.g., mutation in another gene or genes or falsely low PhK activity due to sample handling conditions) may be involved [Burwinkel et al 2003b].
    • PHKA2. The detection frequency for mutations is unknown but expected to be close to 100% in males.
    • Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in an affected male; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis cannot detect deletion of an exon(s) or a whole gene (large deletion) on an X chromosome in a carrier female.
  • Deletion / duplication analysis
    • PHKA1. No deletions or duplications have been reported; thus, the mutation detection frequency is unknown.
    • PHKA2. Deletion of exon(s) has been reported in individuals with liver PhK deficiency. For example, Fukao et al [2007] reported a deletion extending from intron 19 to intron 26.

PHKB and PHKG2 (autosomal recessive)

Research testing. Sequence analysis of PHKG1, the gene encoding the muscle-expressed gamma subunit of PhK. As yet, no mutations have been reported in this gene.

Table 2. Summary of Molecular Genetic Testing Used in Phosphorylase Kinase Deficiency

Gene Symbol (Mode of Inheritance)Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
PHKA1 (XL)Sequence analysisSequence variants 2~100%
Deletion/duplication analysis 3None to date 5Unknown
PHKA2 (XL)Sequence analysisSequence variants 2Unknown
Deletion/duplication analysis 3Exonic or whole gene deletionsUnknown
PHKB (AR)Sequence analysisSequence variants 4Unknown
Deletion/duplication analysis 3Exonic or whole gene deletionsUnknown
PHKG2 (AR)Sequence analysisSequence variants 4~100%
Deletion/duplication analysis 3None to date 5Unknown

XL=X-linked; AR= autosomal recessive

1. The ability of the test method used to detect a mutation that is present in the indicated gene.

2. In this X-linked gene, sequence analysis can detect small intragenic deletions/insertions, missense, nonsense, and splice site mutations in males and females. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. No deletions or duplications involving either PHKA1 or PHKG2 as causative of phosphorylase kinase deficiency have been reported.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

Liver PhK deficiency should be considered for any child with hepatomegaly and growth retardation, with or without evidence of fasting ketosis and hypoglycemia. (see also Differential Diagnosis)

  • Assay of PhK activity in erythrocytes should be performed in individuals with a suspected diagnosis of liver PhK deficiency. While it is recommended that liver biopsy be reserved for those individuals for whom no clear diagnosis can be made from blood-based testing, some specialists may recommend liver biopsy to further evaluate the etiology of hepatomegaly. In this case, electron microscopy, measurement of glycogen content, assay of PhK activity, and assay for enzyme deficiencies causing other liver glycogenoses (such as GSD VI and GSD III) should be performed. Results of the assay of PhK activity should be interpreted with caution because false positive and false negative results have been reported.
  • Deficiency of erythrocyte and/or liver PhK activity finding should be confirmed by molecular genetic testing. The order in which genes are tested can be guided by the following:
    • Gender: Males are most likely to have X-linked liver PhK deficiency (PHKA2). Females are more likely to have an autosomal recessive subtype (PHKB or PHKG2) but could be manifesting heterozygotes of the X-linked subtype (PHKA2) as a result of skewed X-chromosome inactivation.
    • Family history: If the family history is consistent with X-linked inheritance (PHKA2) or autosomal recessive inheritance (PHKB or PHKG2).
    • Presence of consanguinity suggests an autosomal recessive subtype (PHKB or PHKG2).
    • Severity of manifestations (see Genotype/Phenotype Correlations). Based on current knowledge:
      • PHKG2 mutations seem to result in an increased risk for liver fibrosis and cirrhosis, although not in all individuals.
      • PHKB mutations appear to be associated with a particularly mild clinical and biochemical phenotype.
      • The clinical phenotype associated with PHKA2 mutations varies from mild to severe.
  • If erythrocyte or liver PhK enzyme activity is normal, consider molecular genetic testing of PHKA2 because a significant proportion of individuals with mutation of this gene do not have PhK deficiency in vitro (XLG2 subtype) [Hendrickx et al 1999, Carriere et al 2008].
  • Normal PhK enzyme activity in blood cells (leukocytes) in vitro has also been found in individuals with mutation of PHKB [Burwinkel et al 1997b].

Note: When the diagnosis of liver PhK deficiency is confirmed through detection of pathogenic mutations, liver biopsy is not needed. Liver biopsy should be reserved for instances in which no diagnosis can be made from erythrocyte enzyme analysis and molecular genetic testing.

Muscle PhK deficiency should be suspected in an individual with muscle cramps and myoglobinuria on exercise, or progressive muscle weakness and atrophy. These symptoms are suggestive of several different disorders (see Differential Diagnosis).

  • Molecular genetic testing of PHKA1 identifies a causative mutation in a minority of this group [Burwinkel et al 2003a]; however, if the family history is consistent with X-linked inheritance, molecular genetic testing of PHKA1 is recommended. In some instances of PhK deficiency in muscle and normal PHKA1 sequence analysis, the cause remains unexplained.
  • For simplex cases (i.e., those with no family history of muscle PhK deficiency), muscle biopsy can be performed for histology and assay of enzyme activity to investigate PhK deficiency or other differential diagnoses. If PhK deficiency is found, molecular genetic testing of PHKA1 should be performed.

Carrier testing for relatives at risk for the two forms of X-linked PhK deficiency, caused by mutations in PHKA1 or PHKA2, requires prior identification of the disease-causing mutation in the family.

Note: (1) Female carriers are heterozygotes for these X-linked disorders. Carriers of mutations in PHKA2 may develop mild hepatomegaly, short stature in childhood, and biochemical abnormalities [Willems et al 1990, Morava et al 2005], and theoretically more severe symptoms (including hypoglycemia) resulting from skewed X-chromosome inactivation. No symptoms have been reported in female carriers of mutations in PHKA1 [Bak et al 2001] but it is possible that they too could exhibit symptoms as a result of skewed X-chromosome inactivation. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, using deletion/duplication analysis if available. (3) Enzyme-based carrier testing is not recommended for determining carrier status.

Carrier testing for relatives at risk for the two subtypes of autosomal recessive PhK deficiency (caused by mutations in PHKB or PHKG2) requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorders. (2) Enzyme-based carrier testing is not recommended for determining carrier status.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

Liver phosphorylase kinase (PhK) deficiency. With increasing understanding of liver PhK deficiency it is clear that clinical severity varies significantly. Although it has been considered to be a mild condition, more severe involvement has been documented [Morava et al 2005; Beauchamp et al 2007; Author, personal experience]. See also Genotype-Phenotype Correlations.

Typically, an affected child presents in the first years of life with hepatomegaly and growth retardation. Hyperketotic hypoglycemia, if present, is usually mild but can be severe and recurrent. It is also possible that blood glucose concentrations are maintained within normal limits when moderate to large ketosis results from increased fatty acid oxidation and gluconeogenesis is upregulated.

Mild delays in gross motor development are often seen in early childhood. Hypotonia and muscle weakness have been observed in some individuals, regardless of which gene is mutated.

Cognitive and/or speech delays have been reported in a few individuals [Burwinkel et al 1998a; Beauchamp et al 2007; Author, personal observation]. At this time, it is not clear whether these delays are directly related to PhK deficiency or are coincidental.

Growth retardation is most pronounced in childhood, after which catch-up growth occurs; most adults reach normal height [Willems et al 1990, Schippers et al 2003].

Puberty may be delayed [Willems et al 1990].

Liver fibrosis can occur and in rare instances progress to cirrhosis (typically associated with PHKG2 mutations). Liver adenoma appears to be very rare.

Renal tubular acidosis has been reported in some individuals [Burwinkel et al 1998a, Beauchamp et al 2007].

Polycystic ovaries are common in females with liver PhK deficiency [Lee & Leonard 1995].

Cardiac manifestations have not been reported in individuals with liver PhK deficiency.

Symptoms and biochemical abnormalities improve with age in most individuals with liver PhK deficiency. Most adults are practically asymptomatic despite persistent PhK deficiency [Willems et al 1990, Hendrickx et al 1998]. However, long-term effects in older persons have not been studied extensively. It is possible that long-term issues could emerge as affected individuals are followed longitudinally.

Muscle PhK deficiency presents any time from childhood to adulthood with a broad range of symptoms including exercise intolerance, muscle cramps, myalgia, myoglobinuria, and progressive muscle weakness [Chen et al 2009, Kishnani & Chen 2010]. Serious impairment seems to be the exception and may take years to develop [Wehner et al 1994]. Heart and liver do not seem to be involved.

One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with mutation of PHKA1 [Echaniz-Laguna et al 2010]. However, it is possible that another cause exists for the cognitive impairment in this person.

Genotype-Phenotype Correlations

Mutations in PHKA1 result in muscle glycogenosis; mutations in PHKA2 and PHKG2 cause liver glycogenosis; mutations in PHKB cause liver and muscle glycogenosis (muscle signs are variably present).

PHKA1. No correlation is observed between the type of mutation, residual muscle PhK activity, and age of onset [Wuyts et al 2005].

PHKA2. Symptoms range from mild to severe but no correlation has been observed between genotype and clinical severity [Beauchamp et al 2007]. Even persons with the same mutation can have significantly different clinical symptoms [Hirono et al 1998, Hendrickx et al 1999, personal communication].

Regarding correlation between genotype and biochemical phenotype, Hendrickx et al [1999] suggested that:

  • PHKA2 mutations resulting in reduced amounts of alpha subunit protein (e.g., nonsense and frameshift mutations or missense mutations that destabilize the protein) cause detectable PhK deficiency in vitro (XLG1 biochemical subtype)
  • PHKA2 mutations that disrupt activation of PhK enzyme activity (e.g., missense mutations or small in-frame insertions or deletions affecting regulatory sites of the enzyme) can result in the normal PhK activity that is observed in vitro in some affected persons (XLG2 biochemical subtype).

These subtle changes may allow normal amounts of PhK to be made; however, they:

Carrière et al [2008] showed that PHKA2 missense mutations and small in-frame deletions/insertions are concentrated into two domains of the protein:

  • In the N-terminal glucoamylase domain, mutations (principally leading to XLG2) are clustered within the predicted glycoside-binding site, suggesting that they may have a direct effect on a possible hydrolytic activity of the PhK alpha subunit.
  • In the C-terminal calcineurin B-like domain (domain D), mutations (principally leading to XLG1) are clustered in a region predicted to interact with the regulatory region of the PhK catalytic subunit and in a region covering this interaction site.

Further studies are needed to determine the molecular basis of the XLG1 and XLG2 biochemical subtypes. Of note, the same PHKA2 mutation (p.Arg295His) has been associated with normal and deficient PhK activity in vitro, suggesting that other factors, such as handling of the specimen and laboratory methodologies, can also affect the biochemical phenotype [Hendrickx et al 1999].

PHKB. The few PHKB mutations reported have been associated with a particularly mild clinical and biochemical phenotype [Beauchamp et al 2007]. No genotype/phenotype correlation has been reported for mutations in this gene.

PHKG2. Mutations in PHKG2 seem to result in more severe disease with an increased risk of liver fibrosis and cirrhosis, although persons with a milder course have been observed [Maichele et al 1996; Author, personal experience]. No correlation seems to exist between the type of PHKG2 mutation and disease severity.

Penetrance

Assay of enzyme activity has identified liver PhK deficiency in asymptomatic males following diagnosis of another family member [Willems et al 1990]. However, it is unclear whether these individuals were adults at the time of the study (and therefore findings had resolved) or whether findings (e.g., hepatomegaly or short stature in childhood) had ever been present. Presenting symptoms can be variable. For example, one child with a splice site mutation in PHKA2 had only short stature and no hepatomegaly or biochemical abnormalities at age 6.8 years [Hirono et al 1998]. Further family studies are required to fully determine variability and penetrance of presenting findings.

Nomenclature

Liver PhK deficiency. Historically, the numeric classification of liver PhK deficiency has ranged from GSD type VIa and VIb to GSD VIII to GSD IX.

Note: (1) Deficiency of the enzyme glycogen phosphorylase that causes GSD V (muscle specific) or GSD VI (liver specific) is distinct from deficiency of the enzyme PhK that causes GSD IX. However, confusion may have arisen in the past re-classification of these types of GSD: because the enzyme PhK activates the enzyme glycogen phosphorylase, PhK deficiency can also result in phosphorylase deficiency. (2) The classification GSD VIII no longer exists: in the past GSD VIII was used to describe some cases of PhK deficiency.

Liver PhK deficiency has been further subclassified into:

  • GSD IXa, now known as PHKA2-related glycogen storage disease type IX;
  • GSD IXb, now known as PHKB-related glycogen storage disease type IX;
  • GSD IXc, now known as PHKG2-related glycogen storage disease type IX.

Muscle PhK deficiency has been called GSD Vb and GSD IXd.

Prevalence

Liver PhK deficiency is thought to account for about 25% of all GSDs with an estimated prevalence of one in 100,000 [Maichele et al 1996]. However, the disorder may be underdiagnosed as a result of the variable presentation and challenges with diagnostic confirmation.

Muscle PhK deficiency appears to be rare, but could be underdiagnosed because of the milder muscle symptoms.

No populations are known to have an increased prevalence of PhK deficiency.

Differential Diagnosis

The following disorders have features in common with liver PhK deficiency:

Glycogen storage disease type VI (GSD VI) is caused by deficiency of liver glycogen phosphorylase, the enzyme activated by liver phosphorylase b kinase (PhK). It is not possible to distinguish GSD VI and liver PhK deficiency by clinical findings alone. Furthermore, liver glycogen phosphorylase activity can be low in in vitro assays in persons with liver PhK deficiency. The two disorders can be distinguished by enzymatic and molecular genetic testing.

Glycogen storage disease type I (GSD I) is characterized by growth retardation, hepatomegaly, and hypoglycemia, usually without ketosis. Although hypoglycemia tends to be more severe in GSD I than in liver PhK deficiency, on occasion severe hypoglycemia can occur in individuals with liver PhK deficiency. Elevated serum concentrations of lactate and uric acid, characteristic of GSD I, are usually not seen in liver PhK deficiency. Individuals with GSD Ib also have recurrent bacterial infections caused by neutropenia and impaired neutrophil function. Inheritance is autosomal recessive.

Glycogen storage disease type III (GSD III) presents with hepatomegaly, hypoglycemia, and growth retardation that improves with age. In GSD IIIa, muscle weakness and elevated serum creatine kinase (CK) are often present. Cardiomyopathy may also occur. Inheritance is autosomal recessive.

The following disorders have features in common with muscle PhK deficiency:

Glycogen storage disease type V (GSD V, McArdle disease) is caused by deficiency of muscle glycogen phosphorylase (myophosphorylase), the enzyme activated by muscle PhK. GSD V and muscle PhK deficiency have similar findings, including exercise-induced muscle cramps, episodes of myoglobinuria, and excess glycogen in muscle. Age of onset and clinical findings vary widely. However, the “second wind” phenomenon, noted in persons with GSD V, is not observed in those with muscle PhK deficiency [Ørngreen et al 2008]. X-linked inheritance of such findings suggests muscle PhK deficiency caused by a PHKA1 mutation. Inheritance of GSD V is autosomal recessive.

Glycogen storage disease type VII (GSD VII, Tarui disease, phosphofructokinase deficiency) causes severe exercise intolerance, usually appearing in childhood and associated with nausea, vomiting, and severe muscle pain; vigorous exercise can cause severe muscle cramps and myoglobinuria. Other features include compensated hemolysis, hyperuricemia, and absence of spontaneous second-wind phenomenon. Inheritance is autosomal recessive.

Other disorders with clinical features overlapping muscle PhK deficiency include: mitochondrial myopathy (see Mitochondrial Disorders Overview); myodenylate deaminase deficiency; carnitine palmitoyl transferase II deficiency; phosphoglycerate kinase deficiency; phosphoglycerate mutase deficiency (GSD X); lactate dehydrogenase deficiency (GSD XI); VLCAD deficiency; and LCHAD / mitochondrial trifunctional protein deficiency.

Severe infantile PhK deficiency in muscle with findings ranging from fatal arthrogryposis to severe muscular hypotonia, but without organomegaly, have also been reported [Ohtani et al 1982, Shin et al 1994, Sahin et al 1998, Buhrer et al 2000]. No molecular genetic testing has been performed on these infants and it is not clear whether PhK deficiency is the primary cause of their findings or if they are secondary.

Fanconi-Bickel syndrome. PhK deficiency may also occur as a secondary phenomenon in Fanconi-Bickel syndrome, caused by mutations in GLUT2 [Burwinkel et al 1999.

Isolated cardiac PhK deficiency. Rare instances of heart-specific PhK deficiency present early in life with severe isolated cardiomyopathy. Diagnosis of PhK deficiency isolated to cardiac tissue requires biopsy of heart tissue. Mutations in the genes encloding the PhK subunits (PHKA1, PHKA2, PHKB, PHKG1, PHKG2, CALM1, CALM2, or CALM3-3) have not be associated with this phenotype, but mutations in PRKAG2 (which encodes the regulatory subunit of AMP-activated protein kinase) have been identified in some persons with this phenotype [Burwinkel et al 2005, Akman et al 2007].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with liver PhK deficiency, the following evaluations are recommended:

  • Measurement of blood glucose concentration (normal >70 mg/dL) for two to three days: upon waking in the morning; prior to meals and night time supplementation with oral cornstarch; and after activity
  • Measurement of blood ketone levels for two to three days: upon waking in the morning; prior to meals and night time supplementation with oral cornstarch; and after activity. Elevated blood ketones (beta-hydroxybutyrate >1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.
  • Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (such as liver cirrhosis).
  • Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)
  • Prothrombin time
  • Lipid panel (cholesterol and triglyceride concentrations)
  • Serum creatine kinase measurement (Some individuals with liver PhK deficiency can have muscle involvement)
  • Baseline echocardiogram (Although cardiac problems have not been reported to occur in PhK deficiency [due to paucity of systematic investigation and lack of knowledge], baseline echocardiogram may be done as a precaution.)

To establish the extent of disease and needs of an individual diagnosed with muscle PhK deficiency, the following evaluations are suggested:

  • Physical therapy evaluation
  • Serum creatine kinase measurement

Treatment of Manifestations

Liver PhK Deficiency

Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein.

  • The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms.
  • Protein should be given as 15% to 25% of total calories (tailored to the patient’s age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.

For signs of hypoglycemia or ketosis, Polycose® or fruit juice should be given orally (if oral intake is tolerated) followed by a snack high in complex carbohydrates and protein. Blood glucose and ketone concentrations should be monitored periodically to ensure that they return to normal. If oral intake is not tolerated, an IV should be started. An initial glucose bolus (D50, or D10 if D50 not available) may be needed to maintain blood glucose concentrations above 70 mg/dL. The bolus can then be followed by 10% dextrose by IV.

Symptomatic management of liver manifestations such as cirrhosis, liver failure, portal hypertension is appropriate.

Muscle PhK Deficiency

Signs and symptoms should be managed as with other muscle GSDs, such as GSD III [Kishnani et al 2010].

  • Physical therapy evaluation and intervention based on physical status and function
  • Coordination with a metabolic nutritionist regarding monitoring and optimizing blood glucose concentrations based on levels of exercise and activity

Prevention of Primary Manifestations

Liver PhK Deficiency

Hypoglycemia. Frequent feedings high in complex carbohydrates and protein are given to prevent hypoglycemia. In some individuals, no additional treatment is required to prevent hypoglycemia. However, some persons with liver PhK deficiency have severe and recurrent hypoglycemia which can be prevented by ingestion of uncooked cornstarch (range of cornstarch dose 0.6 to 2.5 g/kg) one to four times per day, depending on the severity of the condition. Some individuals may require cornstarch only before bedtime. Requirements for cornstarch tend to lessen with age.

Muscle PhK Deficiency

Little published information is available on prevention of primary manifestations in individuals with muscle PhK deficiency; however, regular moderate aerobic exercise may be beneficial. Intense exercise should be avoided as it may promote rhabdomyolysis and muscle cramping.

Prevention of Secondary Complications

Liver PhK deficiency. Perioperative care for elective procedures should include IV glucose infusion preoperatively which should start as soon as the patient is made NPO. Continue with intraoperative and postoperative IV glucose infusion to prevent hypoglycemia. IV glucose should be tapered off gradually as the patient tolerates the usual diet. Abrupt discontinuation of fluids could result in hypoglycemia.

If general anesthesia is required, malignant hyperthermia precautions should be taken as individuals with liver PhK deficiency may have increased CK levels and myopathy [Author, personal experience]. (See Malignant Hyperthermia Susceptibility).

During childhood, routine immunizations should be given on the recommended schedule. Any immunizations that may prevent illness, such as influenza leading to hypoglycemia, should be offered.

Muscle PhK deficiency. Lipid-lowering drugs (e.g., statins) that can worsen or unmask myopathy should be used cautiously.

If general anesthesia is required, malignant hyperthermia precautions should be taken as individuals with muscle PhK deficiency have increased CK levels and myopathy. (See Malignant Hyperthermia Susceptibility).

During childhood, routine immunizations should be given on the recommended schedule.

Surveillance

Liver PhK deficiency

  • Regular evaluation by a metabolic physician familiar with liver PhK deficiency to monitor medical issues and a metabolic nutritionist to give dietary recommendations and monitor cornstarch requirement
  • Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced or meal and/or cornstarch dose or scheduling is altered.

    Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.
  • Liver imaging. In children younger than age 18 years, liver ultrasound examination every 12 to 24 months. With increasing age, consideration of CT or MRI using intravenous contrast to evaluate for complications of liver disease
  • Follow up echocardiogram. No guidelines established. Follow-up approximately every two years or earlier if symptoms are present

Muscle PhK deficiency

  • Regular evaluation by a metabolic physician familiar with liver PhK deficiency to monitor medical issues and a metabolic nutritionist to give dietary recommendations and monitor cornstarch requirement.
  • Regular evaluation by a physical therapist to look for progression in symptoms and to guide exercise program

Agents/Circumstances to Avoid

Liver PhK deficiency. Affected Individuals with should avoid the following:

  • Large amounts of simple sugars as they will increase liver storage of glycogen.
  • Prolonged fasting
  • High impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.
  • Drugs known to cause hypoglycemia such as insulin and insulin secretagogues (the sulfonylureas); though there are no reports in the literature of drugs precipitating hypoglycemia in children with liver PhK deficiency
  • Alcohol, as this may predispose to hypoglycemia.

Hypoglycemic events in adults with liver PhK deficiency are relatively uncommon; however, caution should be used with drugs causing potential hypoglycemia, particularly in persons with impaired liver function.

Muscle PhK deficiency. Affected individuals should avoid the following:

  • Vigorous exercise
  • Medications that can cause rhabdomyolysis (e.g., succinylcholine)

Evaluation of Relatives at Risk

Molecular genetic testing (if the family-specific mutations are known) and/or evaluation by a metabolic physician during the first year of life (if the family-specific mutations are not known) allows for early diagnosis and treatment for sibs at increased risk for liver PhK deficiency.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Ideally, women with PhK deficiency consult with their health care team and maintain optimal metabolic control before conception.

It is extremely important that euglycemia is maintained throughout pregnancy to avoid upregulation of counterregulatory hormones which would result in lipolysis and ketosis, with risk of fetal demise. The appropriate diet during pregnancy is unique to each individual. For some, this may only require following a regular healthy diet, but for many it may mean increasing snacks to include more complex carbohydrates and protein and/or adding or increasing the amount of corn starch. Blood glucose concentrations and ketones should also be measured during pregnancy on a regular basis to ensure euglycemia. Adequate amounts of protein are necessary to provide an alternate source of glucose via gluconeogenesis.

Therapies Under Investigation

The improved and modified version of cornstarch, called Superstarch®, is under investigation for prevention of hypoglycemia in GSDs in general.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PHKA2-related liver PhK deficiency and PHKA1-related muscle PhK deficiency are inherited in an X-linked manner.

PHKB-related liver and muscle PhK deficiency and PHKG2-related liver PhK deficiency are inherited in an autosomal recessive manner.

Risk To Family Members — X-linked Inheritance

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.

    Note: If a woman has more than one affected child and no other affected relatives and if the disease-causing mutation cannot be detected in her leukocyte DNA, she has germline mosaicism. No data are available on the possibility or frequency of germline mosaicism in X-linked muscle or liver PhK deficiency
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier, or the affected male may have a de novo mutation, in which case the mother is not a carrier. The frequency of de novo mutations in PHKA1 and PHKA2 is unknown. No de novo cases have been documented.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers. No symptoms have been reported in female carriers of a PHKA1 mutation, although development of symptoms may occur, in theory, if skewed X-chromosome inactivation is present. Female carriers of a PHKA2 mutation may be unaffected, have mild hepatomegaly, or rarely may have more severe symptoms depending on the pattern of X-chromosome inactivation [Author, personal observation].
  • If the affected male is a simplex case (i.e., a single occurrence in a family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of his mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members. An affected male’s maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo mutation arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Carrier testing for at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

Risk To Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive PhK deficiency are obligate heterozygotes (carriers) for a disease-causing mutation in PHKB or PHKG2.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers or of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation(s) of an affected family member must be identified before prenatal testing can be performed. In the case of X-linked inheritance, usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like PhK deficiency) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Glycogen Storage Disease (AGSD)
    PO Box 896
    Durant IA 52747
    Phone: 563-514-4022
    Email: maryc@agsdus.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Phosphorylase Kinase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Phosphorylase Kinase Deficiency (View All in OMIM)

172471PHOSPHORYLASE KINASE, TESTIS/LIVER, GAMMA-2; PHKG2
172490PHOSPHORYLASE KINASE, BETA SUBUNIT; PHKB
261750GLYCOGEN STORAGE DISEASE IXb; GSD9B
300798PHOSPHORYLASE KINASE, LIVER, ALPHA-2 SUBUNIT; PHKA2
306000GLYCOGEN STORAGE DISEASE IXa1; GSD9A1
311870PHOSPHORYLASE KINASE, MUSCLE, ALPHA-1 SUBUNIT; PHKA1

Molecular Genetic Pathogenesis

The enzyme phosphorylase kinase (PhK) activates liver glycogen phosphorylase and muscle glycogen phosphorylase in response to neuronal and hormonal stimuli and thus is a key regulatory enzyme in glycogen breakdown. In liver PhK deficiency, the inability to break down glycogen results in risk for hypoglycemia and glycogen accumulation in the liver, which in turn causes hepatomegaly and liver damage.

Muscle PhK deficiency caused by PHKA1 mutation appears to cause myopathy by causing a defect in glycogen availability during submaximal exercise (oxidative metabolism; e.g., cycle test) presumably because PhK is required to activate glycogen phosphorylase under these conditions. Interestingly, anaerobic glycogenolysis is normal, suggesting that other regulatory factors are involved in phosphorylase activation in this situation [Ørngreen et al 2008].

PhK is a multi-subunit enzyme composed of four copies each of four subunits (α, β, γ, and δ). The gamma (γ)) subunit contains the catalytic activity and is regulated by the alpha (α), beta (β), and delta (δ) subunits. The inhibitory effect of the alpha and beta subunits is modulated by phosphorylation (phosphorylation removes the inhibitory effect); calcium levels modulate the regulatory effect of the delta subunit (calmodulin).

Each PhK subunit is encoded by at least one gene: PHKA1 and PHKA2 encode the muscle and liver isoforms of the alpha subunit, respectively; PHKB encodes the liver and muscle beta subunits; PHKG1 and PHKG2 encode the muscle and liver isoforms of the gamma subunit, respectively; and the delta subunit, calmodulin, is encoded by three genes, CALM1, CALM2, and CALM3. Further complexity is introduced by tissue-specific alternative splicing. The complexity of the enzyme PhK explains to some degree the clinical and biochemical heterogeneity of PhK deficiency.

PHKA1

Normal allelic variants. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. The longest transcript (NM_002637.3) consists of 32 exons and is transcribed into a 6-kb cDNA. PHKA1 spans approximately 133 kb of genomic DNA. A pseudogene, PHKA1P1, has been found on chromosome 1p22.2.

Pathologic allelic variants. To date, six predicted pathologic variants have been reported in PHKA1, each of which was found in only one individual. Mutations include missense (2), small deletions inducing frameshifts (2), nonsense (1), and splice site (1) changes [Wehner et al 1994, Bruno et al 1998, Burwinkel et al 2003a, Wuyts et al 2005, Ørngreen et al 2008, Echaniz-Laguna et al 2010].

A frameshift mutation in mouse ortholog Phka1 causes PhK deficiency in the I-strain mouse [Schneider et al 1993].

Normal gene product. PHKA1 encodes the muscle isoform of the alpha subunit of PhK, a 1223-amino acid protein (NP_002628.2).

Two alternatively spliced transcript variants encoding different isoforms have been identified [Harmann et al 1991]; alpha-FM is the predominant form in fast-twitch skeletal muscle and is also expressed in brain while alpha-prime is the predominant form in slow-twitch skeletal muscle. Alpha-prime has an internal deletion of 59 amino acids (amino acids 654-712) when compared to alpha-FM.

The degree of phosphorylation of the alpha subunit regulates the activity of PhK; the greater the phosphorylation the less the inhibitory effect.

Abnormal gene product. No studies have been done to determine how PHKA1 mutations cause PhK deficiency. Complete lack of PHKA1 protein is predicted to affect formation or stability of PhK holoenzyme. Production of an altered PHKA1 protein, resulting from missense mutation, may affect its ability to interact with other subunits or to activate PhK activity.

PHKA2

Normal allelic variants. The gene contains 33 exons [Hendrickx et al 1999] and spans 91.3 kb of DNA. An amino acid polymorphism, p.Glu38Gln (rs17313469) has been identified [Beauchamp et al 2007]. Two intronic changes, c.718-3C>T and c.1715-50G>C, were each found in one affected individual but are not thought to be pathologic [Beauchamp et al 2007]. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.

Pathologic allelic variants. About 50 different pathologic mutations have been reported in PHKA2. Most of them are missense or nonsense mutations or small deletions causing frameshifts. The mutations are distributed throughout the gene.

Normal gene product. PHKA2 encodes the liver alpha subunit of PhK. A 5325-bp mRNA is translated into a 1235-amino acid protein with high expression in liver and brain, but not in muscle [Hendrickx et al 1993]. PHKA2 is highly homologous to PHKA1 and PHKB.

Abnormal gene product. Two biochemical subtypes of X-linked glycogenosis (XLG) are caused by mutations in PHKA2 [Hendrickx et al 1994, Burwinkel et al 1996, Hendrickx et al 1996, Burwinkel et al 1998a, Hendrickx et al 1999]:

  • XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver.
  • XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable

While not yet fully understood, there are various theories as to how different mutations in PHKA2 could result in these different biochemical subtypes (see Genotype/Phenotype Correlation).

PHKB

Normal allelic variants. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. The longer transcript variant, NM_000293.2, is composed of 33 exons spanning 239 kb genomic DNA. Exons 26 and 27 are two homologous, mutually exclusively spliced exons that encode muscle and non-muscle PHKB respectively, and exon 2 is a facultatively used cassette exon encoding an alternative N-terminus [Wüllrich-Schmoll & Kilimann 1996].

c.2309A>G (p.Tyr770Cys) is found in 2%-3% of the normal population and is predicted to be non-pathologic [van den Berg et al 1997]. However, it is unclear whether this change in any way contributed to muscle PhK deficiency in two persons in whom it was found [Burwinkel et al 2003a].

A restriction fragment length polymorphism (deletion of ATTA at the end of intron 20 that abolishes an AsnI restriction site) has an allele frequency of 35% [Burwinkel et al 1997a].

Two processsed pseudogenes have been identified: PHKBP1 on chromosome 20p12.3-20p12.2 and PHKBP2 on chromosome 14q13.3 [Wüllrich-Schmoll & Kilimann 1996].

Pathologic allelic variants. Fourteen variants suspected or known to be pathologic have been reported in PHKB. These include nonsense (5), missense (3), splice site (3), small insertion (1), small deletion (1), and gross deletion (1) changes [Burwinkel et al 1997b, van den Berg et al 1997, Burwinkel et al 2003a, Beauchamp et al 2007]. Two of the missense changes (NM_000293.2:c.555G>T (p.Met185Ile) and NM_000293.2:c.1969C>A (p.Gln657Lys) were identified in heterozygotes in whom no other mutation was identified and, thus, the significance is unknown [Burwinkel et al 1997a, Burwinkel et al 2003a, Beauchamp et al 2007].

Another missense change (p.Tyr975His) was found in association with two nonsense mutations, suggesting that it may be non-pathogenic [Burwinkel et al 1997a].

Normal gene product. PHKB encodes the beta subunit of liver of muscle PhK. The degree of phosphorylation of the beta subunit determines the activity of the enzyme PhK.

Abnormal gene product. It is not known exactly how PHKB mutations result in PhK deficiency. Lack of PHKB protein would affect formation of the normal PhK holoenzyme and an abnormal PHKB protein would presumably affect its interaction with other PhK subunits and its regulatory function. Biochemical evidence suggests that an alpha-gamma-delta complex may form in the absence of the beta subunit, explaining the residual enzyme activity seen in some patients and the mild clinical features [Burwinkel et al 1997a, Brushia & Walsh 1999].

PHKG2

Normal allelic variants. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. The PHKG2 longer transcript isoform NM_000294.2 comprised ten exons spanning 9kb of genomic DNA. A complex microsatellite repeat has been identified at the beginning of intron 2 [Burwinkel et al 1998b].

Pathologic allelic variants. Thirteen predicted pathologic variants have been reported in PHKG2 including missense (7), nonsense (2), splice site (1), small deletion (2), and small insertion (1) changes [Maichele et al 1996, van Beurden et al 1997, Burwinkel et al 1998b, Burwinkel et al 2000, Burwinkel et al 2003b, Beauchamp et al 2007].

Normal gene product. PHKG2 encodes the catalytic gamma subunit of liver PhK, a 406-amino acid protein, NP_000285.1. Alternative splicing creates a variant of 374 amino acids with a different C-terminus.

Abnormal gene product. Mutations in PHKG2 are expected to affect the catalytic ability of the gamma subunit either by resulting in production of no protein or affecting the stability or confirmation of the protein.

References

Literature Cited

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Chapter Notes

Acknowledgments

We would like to thank Dr. YT Chen, Denise Petersen, Keri Fredrickson, and Dr. Catherine Rehder for their useful discussions and professional contributions to increasing the understanding and knowledge of this complicated disorder.

Revision History

  • 31 May 2011 (me) Review posted live
  • 7 September 2010 (db) Original submission
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