Glycogen storage disease due to liver phosphorylase kinase deficiency

disease

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Summary

Glycogen storage disease due to liver phosphorylase kinase deficiency (MONDO:0020693) is a disease with 2 cohort genes.

At a glance

Prevalence: Unknown (Worldwide) [Orphanet-validated]
Cohort genes: 2
Phenotypes (HPO): 51

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0030272	Abnormal erythrocyte enzyme activity	Very frequent (80-99%)
HP:0001395	Hepatic fibrosis	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0001946	Ketosis	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0003124	Hypercholesterolemia	Frequent (30-79%)
HP:0003162	Fasting hypoglycemia	Frequent (30-79%)
HP:0410175	Hyperketonemia	Frequent (30-79%)
HP:0000147	Polycystic ovaries	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000858	Irregular menstruation	Occasional (5-29%)
HP:0000876	Oligomenorrhea	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001396	Cholestasis	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002913	Myoglobinuria	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003323	Progressive muscle weakness	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003546	Exercise intolerance	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0030232	Increased sarcoplasmic glycogen	Occasional (5-29%)
HP:0100607	Dysmenorrhea	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Very rare (<1-4%)
HP:0000939	Osteoporosis	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0001638	Cardiomyopathy	Very rare (<1-4%)
HP:0001744	Splenomegaly	Very rare (<1-4%)
HP:0001903	Anemia	Very rare (<1-4%)
HP:0001947	Renal tubular acidosis	Very rare (<1-4%)
HP:0002013	Vomiting	Very rare (<1-4%)
HP:0002014	Diarrhea	Very rare (<1-4%)
HP:0002018	Nausea	Very rare (<1-4%)
HP:0002040	Esophageal varix	Very rare (<1-4%)
HP:0003128	Lactic acidosis	Very rare (<1-4%)
HP:0004324	Increased body weight	Very rare (<1-4%)
HP:0006580	Portal fibrosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease due to liver phosphorylase kinase deficiency
Mondo ID	MONDO:0020693
Orphanet	264580
GARD	0017261
Is cancer (heuristic)	no

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › glycogen storage disease due to liver phosphorylase kinase deficiency

Subtypes (2): glycogen storage disease IXa1, glycogen storage disease IXc

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PHKA2	Definitive	X-linked	glycogen storage disease IXa1	5
PHKG2	Strong	Autosomal recessive	glycogen storage disease IXc	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PHKA2	Orphanet:264580	Glycogen storage disease due to liver phosphorylase kinase deficiency
PHKG2	Orphanet:264580	Glycogen storage disease due to liver phosphorylase kinase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PHKA2	HGNC:8926	ENSG00000044446	P46019	Phosphorylase b kinase regulatory subunit alpha, liver isoform	gencc
PHKG2	HGNC:8931	ENSG00000156873	P15735	Phosphorylase b kinase gamma catalytic chain, liver/testis isoform	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PHKA2	Phosphorylase b kinase regulatory subunit alpha, liver isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
PHKG2	Phosphorylase b kinase gamma catalytic chain, liver/testis isoform	Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PHKA2	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like
PHKG2	Kinase	yes	2.7.11.19	Prot_kinase_dom, Phosph_kin_gamma, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right lobe of liver	1
right uterine tube	1
granulocyte	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PHKA2	266	ubiquitous	marker	right lobe of liver, right uterine tube, apex of heart
PHKG2	204	ubiquitous	marker	left testis, right testis, granulocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHKA2	1,070
PHKG2	190

Intra-cohort edges

A	B	Sources
PHKA2	PHKG2	biogrid_interaction, intact

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHKG2	P15735	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHKA2	P46019	81.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen breakdown (glycogenolysis)	2	761.3×	6e-06	PHKA2, PHKG2
Glycogen metabolism	1	951.7×	0.002	PHKA2
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.022	PHKA2
Metabolism	1	5.8×	0.165	PHKA2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycogen metabolic process	2	526.6×	3e-05	PHKA2, PHKG2
generation of precursor metabolites and energy	2	343.9×	3e-05	PHKA2, PHKG2
positive regulation of glycogen catabolic process	1	2106.5×	0.001	PHKG2
glycogen catabolic process	1	601.9×	0.003	PHKG2
protein modification process	1	122.1×	0.013	PHKA2
carbohydrate metabolic process	1	68.0×	0.020	PHKA2
protein phosphorylation	1	34.0×	0.033	PHKG2
signal transduction	1	8.0×	0.121	PHKG2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PHKG2	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PHKG2	36	4
PHKA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AFATINIB	4	PHKG2
FEDRATINIB	4	PHKG2
ALECTINIB	4	PHKG2
RUXOLITINIB	4	PHKG2
AFATINIB DIMALEATE	4	PHKG2
VANDETANIB	4	PHKG2
NILOTINIB	4	PHKG2
BOSUTINIB	4	PHKG2
GILTERITINIB	4	PHKG2
BRIGATINIB	4	PHKG2
NINTEDANIB	4	PHKG2
SUNITINIB	4	PHKG2
MIDOSTAURIN	4	PHKG2
GEFITINIB	4	PHKG2
CRENOLANIB	3	PHKG2
ALVOCIDIB	3	PHKG2
DOVITINIB	3	PHKG2
LESTAURTINIB	3	PHKG2
SILMITASERTIB	2	PHKG2
SU-014813	2	PHKG2
OSI-632	2	PHKG2
BMS-690514	2	PHKG2
MIVAVOTINIB	2	PHKG2
DANUSERTIB	2	PHKG2
R-406	2	PHKG2
BI-2536	2	PHKG2
MILCICLIB	2	PHKG2
TOZASERTIB	2	PHKG2
PELITINIB	2	PHKG2
PHA-793887	1	PHKG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PHKG2	278	Binding:277, Functional:1
PHKA2	48	Binding:48

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHKA2	2.7.11.19	phosphorylase kinase
PHKG2	2.7.11.19	phosphorylase kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PHKG2	278

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
AFATINIB	4	PHKG2
FEDRATINIB	4	PHKG2
ALECTINIB	4	PHKG2
RUXOLITINIB	4	PHKG2
AFATINIB DIMALEATE	4	PHKG2
VANDETANIB	4	PHKG2
NILOTINIB	4	PHKG2
BOSUTINIB	4	PHKG2
GILTERITINIB	4	PHKG2
BRIGATINIB	4	PHKG2
NINTEDANIB	4	PHKG2
SUNITINIB	4	PHKG2
MIDOSTAURIN	4	PHKG2
GEFITINIB	4	PHKG2
CRENOLANIB	3	PHKG2
ALVOCIDIB	3	PHKG2
DOVITINIB	3	PHKG2
LESTAURTINIB	3	PHKG2
SILMITASERTIB	2	PHKG2
SU-014813	2	PHKG2
OSI-632	2	PHKG2
BMS-690514	2	PHKG2
MIVAVOTINIB	2	PHKG2
DANUSERTIB	2	PHKG2
R-406	2	PHKG2
BI-2536	2	PHKG2
MILCICLIB	2	PHKG2
TOZASERTIB	2	PHKG2
PELITINIB	2	PHKG2
PHA-793887	1	PHKG2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PHKG2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PHKA2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PHKA2	48	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: PHKA2, PHKG2