Phosphorylase Kinase Deficiency
Summary
Clinical 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 restriction, 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). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that patients need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
Diagnosis/testing.
The enzyme PhK comprises four copies each of four subunits (α, β, γ, and δ).
Pathogenic variants in:
- PHKA1, encoding subunit α, cause the rare X-linked disorder muscle PhK deficiency;
- PHKA2, also encoding subunit α, cause the most common form, liver PhK deficiency (X-linked liver glycogenosis);
- PHKB, encoding subunit β, cause autosomal recessive PhK deficiency in both liver and muscle;
- PHKG2, encoding subunit γ, cause autosomal recessive liver PhK deficiency.
The diagnosis of PhK deficiency is established in a proband with the characteristic clinical findings, a family history of suspected storage disease, and/or a hemizygous pathogenic variant in PHKA1 or PHKA2 or biallelic pathogenic variants in PHKB or PHKG2 identified by 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.
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. Echocardiogram should be performed at least every two years.
- Muscle PhK deficiency. Regular evaluation by a metabolic physician, a metabolic nutritionist, and a 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) or drugs known to mask symptoms of hypoglycemia such as beta blockers; 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 pathogenic variant[s] are known) and/or evaluation by a metabolic physician (if the family-specific pathogenic variant[s] are not known) allows early diagnosis and treatment for sibs at increased risk for GSD IX.
Pregnancy management: Individualized dietary management is necessary 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 of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers); the development of symptoms in individuals depends on the pattern of X-chromosome inactivation. Affected males pass the pathogenic variant to all of their daughters and none of their sons.
- 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, prenatal testing for pregnancies at risk, and preimplantation genetic testing are possible if the pathogenic variant(s) 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 is composed of four copies each of four subunits (α, β, γ, and δ), results in considerable clinical variability [Chen 2001, Kishnani & Chen 2010].
For the purposes of this review, phosphorylase kinase (PhK) deficiency has been divided into liver PhK deficiency and muscle PhK deficiency (see Figure 1 and Figure 2). Liver PhK deficiency is further divided into three subtypes based on the gene in which pathogenic variants occur (PHKA2, PHKB, and PHKG2) and inheritance pattern. It should be noted that pathogenic variants in PHKB and, rarely, PHKG2 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 pathogenic variants in PHKA2.
Figure 1.
Phosphorylase kinase subunit expression Note: The CALM genes and PHKG1 are not involved in GSD IX.
Figure 2.
Phosphorylase kinase (PhK) enzyme subunits and genes that encode them
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.
Muscle PhK deficiency in this review refers to PHKA1-related GSD IX.
PHKG1 has not yet been associated with PhK deficiency.
The delta subunit of PhK, calmodulin, is encoded by three different genes: CALM1, CALM2, and CALM3. To date these have not been associated with PhK deficiency.
Suggestive Findings
Liver or muscle phosphorylase kinase (PhK) deficiency resulting in glycogen storage disease type IX (GSD IX) should be suspected in individuals with the phenotypic findings shown in Table 1.
Table 1.
PhK Deficiency: Suggestive Phenotypic Findings
| PhK Deficiency Type | Clinical Findings | Laboratory Test Results |
|---|---|---|
| Liver PhK deficiency |
|
|
| Muscle PhK deficiency |
|
|
- 1.
Lactic acid levels may be elevated postprandially [Davit-Spraul et al 2011].
- 2.
There is considerable variability in the clinical presentation. Some patients may be virtually asymptomatic.
- 3.
Note: Normal ranges tend to be laboratory specific.
Establishing the Diagnosis
The diagnosis of PhK deficiency is established in a proband with the characteristic clinical findings (see Suggestive Findings), a family history of suspected storage disease, and/or a hemizygous pathogenic variant or biallelic pathogenic variants in one of the genes listed in Table 2. If molecular genetic testing is not diagnostic, PhK activity can be measured in snap-frozen liver biopsy, erythrocytes, leukocytes, and frozen muscle biopsy tissue.
Note: While liver biopsy or muscle biopsy was done routinely in previous years to measure PhK activity, the availability of molecular genetic testing has reduced the need for such invasive procedures.
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PhK deficiency is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with hepatomegaly and/or muscle weakness or with atypical phenotypic features are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of PhK deficiency, molecular genetic testing approaches can include use of a multigene panel or single-gene testing.
A multigene panel that includes PHKA1, PHKA2, PHKB, PHKG2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Note: Single-gene testing may be appropriate given the following clinical presentations:
- For liver PhK deficiency, perform sequence analysis of PHKA2 first, followed by PHKG2, and then PHKB. If only one (in PHKG2 or PHKB) or no pathogenic variant (PHKA2, PHKG2, or PHKB) is found, perform gene-targeted deletion/duplication analysis.
- For muscle PhK deficiency, perform sequence analysis of PHKA1 first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis.
- In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of PHKA1 and PHKA2 first depending on muscle/liver symptoms.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by hepatomegaly and/or muscle weakness, or if an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used in Phosphorylase Kinase Deficiency
| Gene 1, 2 (MOI) | Proportion of PhK Deficiency Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| PHKA1 (XL) | Rare – muscle phenotype | 7/7 6, 7 | Unknown 8 |
| PHKA2 (XL) | 75% of individuals w/liver PhK deficiency | ~94% 6, 9 | ~6% 10 |
| PHKB (AR) | ~10% of individuals w/liver PhK deficiency | ~96% 11 | ~4% 12 |
| PHKG2 (AR) | ~10% of individuals w/liver PhK deficiency | ~99% 13 | Unknown 8 |
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by deletion/duplication analysis.
- 7.
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], Preisler et al [2012]
- 8.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 9.
Hendrickx et al [1999], Beauchamp et al [2007], Davit-Spraul et al [2011], Wang et al [2013], Brown et al [2015], Choi et al [2016]
- 10.
Davit-Spraul et al [2011], Wang et al [2013], Brown et al [2015], Choi et al [2016]
- 11.
Burwinkel et al [1997a], Burwinkel et al [1997b], Burwinkel et al [2003a], Beauchamp et al [2007], Davit-Spraul et al [2011], Brown et al [2015]
- 12.
Burwinkel et al [1997a], Alfadhel et al [2016]
- 13.
Burwinkel et al [1998b], Burwinkel et al [2003b], Beauchamp et al [2007], Davit-Spraul et al [2011], Bali et al [2014], Brown et al [2015]
Liver Biopsy
Histology
- Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [Johnson et al 2012, Tsilianidis et al 2013]. Liver cirrhosis and adenomas have been reported.
- Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
Enzyme testing. Phosphorylase b kinase (PhK) 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 <10% of normal level in the tissue being tested.
Note: (1) PhK is a labile enzyme that is highly sensitive to handling conditions and temperature exposure; thus, it is recommended that test blood samples be accompanied by a control blood sample drawn at the same time from an unrelated individual. Samples need to be kept cold (4°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.
Muscle Biopsy
Histology
- Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
- Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
Enzyme testing
- PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
- Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
Clinical Characteristics
Clinical Description
Glycogen storage disease type IX (GSD IX) is caused by PhK deficiency affecting primarily liver or muscle.
Liver PhK Deficiency
While liver PhK deficiency has been considered a mild condition, more severe involvement has been documented [Johnson et al 2012, Tsilianidis et al 2013]. The three subtypes, caused by pathogenic variants in three different genes (PHKA2, PHKB, and PHKG2), cannot be distinguished by their clinical features, which can vary significantly in severity. See also Genotype-Phenotype Correlations.
Presentation. Typically, an affected child presents in the first years of life with hepatomegaly and growth restriction. Hyperketotic hypoglycemia, if present, is usually mild but can be severe and recurrent.
Hepatomegaly
- Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [Roscher et al 2014].
- Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in PHKG2; it has also been reported in some individuals with pathogenic variants in PHKA2 [Johnson et al 2012, Tsilianidis et al 2013]. It has not yet been reported in association with PHKB variants but could occur given the findings in other liver PhK deficiency disorders.
- Liver adenoma has been reported but appears to be very rare and mostly associated with the PHKG2-related subtype [Roscher et al 2014, Bali et al 2017].
- Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [Beauchamp et al 2007, Roscher et al 2014].
- However, as patients live longer and the natural history and long-term complications are better understood, it is becoming clear that patients can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
Growth restriction is most pronounced in childhood, after which catchup growth and normal sexual development occur; most adults reach normal height [Roscher et al 2014, Bali et al 2017].
Hyperketotic hypoglycemia. Hyperketosis, with or without hypoglycemia, can occur following periods of prolonged fasting or decreased nutritional intake, or vomiting and diarrhea during illness. Hyperketonemia is defined as blood 3-β-hydroxybutyrate (βOHB) >1.0 mmol/L (normal <0.3 mmol/L) [Clarke et al 2008].
- Ketotic hypoglycemia varies from occasional to recurrent in some cases [Brown et al 2015, Hodax et al 2017].
- Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
Muscle concerns. Hypotonia and muscle weakness have been observed in some individuals.
- Mild delays in gross motor development are often seen in early childhood.
- Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in a patient with PHKB-associated liver PhK deficiency [Roscher et al 2014].
Genitourinary findings
- Polycystic ovaries have been noted in females with liver PhK deficiency [Lee & Leonard 1995]. While the frequency of fertility issues has not been well studied, dysmenorrhea, menstrual irregularity, and oligomenorrhea have been reported [Cho et al 2013].
- Renal tubular acidosis has been reported in some individuals [Burwinkel et al 1998a, Beauchamp et al 2007].
Other. Cognitive and/or speech delays that normalized later in life have been reported in a few individuals [Beauchamp et al 2007, Roscher et al 2014].
Adulthood. Symptoms and biochemical abnormalities improve with age in most individuals with liver PhK deficiency [Zhang et al 2017].
Reports of liver cirrhosis and hepatocellular carcinoma show that long-term monitoring is needed in individuals with liver PhK deficiency [Tsilianidis et al 2013, Roscher et al 2014]. Other long-term issues could emerge as affected individuals are followed longitudinally.
Muscle PhK Deficiency
Muscle-specific phosphorylase kinase deficiency is caused by the PHKA1 variant. However, muscle PhK deficiency caused by pathogenic variants in PHKB and (rarely) PHKG2 is also seen.
Presentation. This phenotype can present anytime from childhood to adulthood with a broad range of symptoms including exercise intolerance, muscle cramps, myalgia, myoglobinuria, and progressive muscle weakness [Chen 2001, Kishnani & Chen 2010]. In children, it is primarily manifested as mild gross motor delay [Roscher et al 2014, Bali et al 2017].
- Minor muscle involvement has been reported in some affected individuals, particularly associated with PHKG2-related muscle PhK deficiency.
- Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in PHKB [Roscher et al 2014].
Muscle concerns can include the following:
- Exercise-induced cramps, muscle pain, and fatigue [Wuyts et al 2005, Preisler et al 2012]
- Proximal limb-girdle weakness, especially of the pelvic girdle [Wuyts et al 2005]
- Progressive muscle weakness leading to muscular atrophy [Burwinkel et al 2000]
- Rhabdomyolysis [Burwinkel et al 2000]
- Asymptomatic elevation of plasma CK in some individuals
Other findings
- Liver involvement
- Liver involvement has not been reported in GSD IX caused by pathogenic variants in PHKA1.
- Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in PHKB.
- Interventricular septal hypertrophy has been reported in an individual with a PHKB variant [Roscher et al 2014].
- One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in PHKA1 [Echaniz-Laguna et al 2010]. However, it is possible that another cause exists for the cognitive impairment in this person.
Genotype-Phenotype Correlations
Pathogenic variants in PHKA1 result in muscle glycogenosis; pathogenic variants in PHKA2 and PHKG2 cause liver glycogenosis; pathogenic variants in PHKB and, rarely, PHKG2 cause liver and muscle glycogenosis (muscle signs are variably present).
There is no consistent genotype-phenotype correlation for pathogenic variants in any of the four genes. Pathogenic variants in PHKG2 appear to result in more severe disease with an increased risk of liver fibrosis and cirrhosis, although persons with a milder course have been observed. Progressive liver disease has also been noted in individuals with pathogenic variants in PHKA2.
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 reclassification 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 1:100,000 [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 and more variable muscle symptoms.
No populations are known to have an increased prevalence of PhK deficiency.
Differential Diagnosis
Table 3.
Genetic Disorders to Consider in the Differential Diagnosis of Phosphorylase Kinase (PhK) Deficiency
| PhK Deficiency Type | Disorder | MOI | Overlapping Features | Distinguishing Features | Gene(s) | Enzyme |
|---|---|---|---|---|---|---|
| Liver PhK deficiency | Glycogen storage disease type VI | AR | Clinical features can be indistinguishable. | In liver PhK deficiency: low liver glycogen phosphorylase activity on in vitro assay | PYGL | Glycogen phosphorylase, liver form |
| Glycogen storage disease type I (GSD I) | AR |
| In GSD I:
| G6PC1, SLC37A4 |
| |
| Glycogen storage disease type III (GSD III) | AR |
| In GSD III: hypoglycemia more severe & muscle involvement w/↑ CK concentrations | AGL | Glycogen-debranching enzyme | |
| Glycogen storage disease type IV (GSD IV) | AR |
| In GSD IV:
| GBE1 | 1,4-alpha-glucan-branching enzyme | |
| Fructose-1,6-bisphosphatase deficiency (Note: Other disorders of gluconeogenesis can also be considered. 6) | AR |
| In disorders of gluconeogenesis: hypoglycemia after more prolonged (e.g., overnight) fasting or during intercurrent illness w/reduced carbohydrate intake | FBP1 | Fructose-1,6-bisphosphatase 1 | |
| Alpha-1 antitrypsin deficiency 7 | AR |
| In alpha-1-antitrypsin deficiency: lack of fasting hypoglycemia & hyperlacticacidemia | SERPINA1 | Alpha-1 antitrypsin | |
| Deoxyguanosine kinase deficiency (mitochondrial DNA depletion syndrome 3) | AR |
| In deoxyguanosine kinase deficiency:
| DGUOK | Mitochondrial respiratory chain complexes (I, III, IV, V) | |
| Mitochondrial complex V (ATP synthase) deficiency (OMIM 604273) | AR | Hepatomegaly | In mitochondrial complex V deficiency:
| ATPAF2 | ATP synthase | |
| Glycerol kinase deficiency (OMIM 307030) | XL | Hypoglycemia | In glycerol kinase deficiency:
| GK | Glycerol kinase | |
| Niemann-Pick disease type B 8 (see Acid Sphingomyelinase Deficiency) | AR |
| In Niemann-Pick disease type B:
|