glycogen storage disease IXd

Summary

glycogen storage disease IXd (MONDO:0010362) is a disease caused by PHKA1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PHKA1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 574
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0003323	Progressive muscle weakness	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0009051	Increased muscle glycogen content	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:6000198	Reduced muscle phosphorylase kinase activity	Frequent (30-79%)
HP:0100595	Camptocormia	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0002913	Myoglobinuria	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003551	Difficulty climbing stairs	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease IXd
Mondo ID	MONDO:0010362
MeSH	C564485
OMIM	300559
Orphanet	715
DOID	DOID:0111040
UMLS	C1845151
MedGen	335112
GARD	0003858
Is cancer (heuristic)	no

Also known as: glycogen storage disease caused by mutation in PHKA1 · glycogen storage disease due to muscle phosphorylase kinase deficiency · glycogen storage disease type 9D · glycogen storage disease type IXd · glycogen storage disease, type IXd · glycogenosis due to muscle phosphorylase kinase deficiency · glycogenosis type 9D · glycogenosis type IXd · GSD due to muscle phosphorylase kinase deficiency · GSD IXd · GSD type 9D · GSD type IXd · GSD Vb · GSD9D · muscle glycogenosis, X-linked recessive · muscle phosphorylase kinase deficiency · muscular phosphorylase kinase deficiency · PHKA1 glycogen storage disease · PHKA1-related glycogen storage disease type IX

Data availability: 574 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 IXd

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

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

ClinVar germline variants

574 retrieved; paginated sample, class counts are floors:

276 uncertain significance, 188 likely benign, 33 conflicting classifications of pathogenicity, 25 benign, 23 pathogenic, 17 likely pathogenic, 9 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033522	NM_002637.4(PHKA1):c.2603_2604del (p.Ser868fs)	PHKA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1356420	NM_002637.4(PHKA1):c.1759C>T (p.Arg587Ter)	PHKA1	Pathogenic	criteria provided, single submitter
1413850	NM_002637.4(PHKA1):c.812_813dup (p.Asp272fs)	PHKA1	Pathogenic	criteria provided, single submitter
1686058	NM_002637.4(PHKA1):c.635T>G (p.Leu212Ter)	PHKA1	Pathogenic	criteria provided, single submitter
1935503	NM_002637.4(PHKA1):c.2460dup (p.Arg821fs)	PHKA1	Pathogenic	criteria provided, single submitter
2865051	NM_002637.4(PHKA1):c.2683C>T (p.Gln895Ter)	PHKA1	Pathogenic	criteria provided, single submitter
2869668	NM_002637.4(PHKA1):c.2587C>T (p.Arg863Ter)	PHKA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2877713	NM_002637.4(PHKA1):c.1531dup (p.Tyr511fs)	PHKA1	Pathogenic	criteria provided, single submitter
2879436	NM_002637.4(PHKA1):c.2755C>T (p.Arg919Ter)	PHKA1	Pathogenic	criteria provided, single submitter
3010358	NM_002637.4(PHKA1):c.389G>A (p.Trp130Ter)	PHKA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3653269	NM_002637.4(PHKA1):c.713del (p.Cys238fs)	PHKA1	Pathogenic	criteria provided, single submitter
3683387	NM_002637.4(PHKA1):c.2716C>T (p.Arg906Ter)	PHKA1	Pathogenic	criteria provided, single submitter
3700118	NM_002637.4(PHKA1):c.1489C>T (p.Arg497Ter)	PHKA1	Pathogenic	criteria provided, single submitter
3721392	NM_002637.4(PHKA1):c.2847_2848del (p.Pro951fs)	PHKA1	Pathogenic	criteria provided, single submitter
3726560	NM_002637.4(PHKA1):c.1123_1124del (p.Val375fs)	PHKA1	Pathogenic	criteria provided, single submitter
452732	NM_002637.4(PHKA1):c.2606+1G>A	PHKA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4749234	NM_002637.4(PHKA1):c.2335C>T (p.Gln779Ter)	PHKA1	Pathogenic	criteria provided, single submitter
578746	NM_002637.4(PHKA1):c.892C>T (p.Arg298Ter)	PHKA1	Pathogenic	criteria provided, multiple submitters, no conflicts
620183	NM_002637.4(PHKA1):c.1174C>T (p.Arg392Ter)	PHKA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
625792	GRCh37/hg19 Xq13.2(chrX:71801020-71804146)	PHKA1	Pathogenic	criteria provided, single submitter
832096	NC_000023.11:g.(?72644342)(72676170_?)del	PHKA1	Pathogenic	criteria provided, single submitter
9923	NM_002637.4(PHKA1):c.3334G>T (p.Glu1112Ter)	PHKA1	Pathogenic	criteria provided, multiple submitters, no conflicts
9924	NM_002637.4(PHKA1):c.3498+1G>C	PHKA1	Pathogenic	no assertion criteria provided
9925	NM_002637.4(PHKA1):c.896A>T (p.Asp299Val)	PHKA1	Pathogenic	no assertion criteria provided
9926	NM_002637.4(PHKA1):c.695del (p.Ala232fs)	PHKA1	Pathogenic	no assertion criteria provided
9927	NM_002637.4(PHKA1):c.667G>A (p.Gly223Arg)	PHKA1	Pathogenic	no assertion criteria provided
1174621	NM_002637.4(PHKA1):c.2806C>T (p.Arg936Ter)	PHKA1	Likely pathogenic	criteria provided, single submitter
1211358	NM_002637.4(PHKA1):c.2215C>T (p.Arg739Ter)	PHKA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685400	NM_002637.4(PHKA1):c.919-2A>G	PHKA1	Likely pathogenic	criteria provided, single submitter
1691438	NM_002637.4(PHKA1):c.1345_1346del (p.Glu449fs)	PHKA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PHKA1	Strong	X-linked	glycogen storage disease IXd	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PHKA1	Orphanet:715	Glycogen storage disease due to muscle phosphorylase kinase deficiency
PHKA2	Orphanet:264580	Glycogen storage disease due to liver phosphorylase kinase deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PHKA1	HGNC:8925	ENSG00000067177	P46020	Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform	gencc,clinvar
PHKA1-AS1	HGNC:40446	ENSG00000231944		PHKA1 antisense RNA 1	clinvar
PHKA2	HGNC:8926	ENSG00000044446	P46019	Phosphorylase b kinase regulatory subunit alpha, liver isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PHKA1	Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
PHKA2	Phosphorylase b kinase regulatory subunit alpha, liver isoform	Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PHKA1	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like
PHKA1-AS1	Other/Unknown	no
PHKA2	Enzyme (other)	yes	2.7.11.19	PHK_A/B_su, 6-hairpin_glycosidase_sf, GH15-like

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
gastrocnemius	1
skeletal muscle tissue of rectus abdominis	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
apex of heart	1
right lobe of liver	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PHKA1	227	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, biceps brachii
PHKA1-AS1	101		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
PHKA2	266	ubiquitous	marker	right lobe of liver, right uterine tube, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHKA2	1,070
PHKA1	973
PHKA1-AS1	0

Intra-cohort edges

A	B	Sources
PHKA1	PHKA2	intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHKA1	P46020	10

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 3 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 metabolism	2	1903.3×	9e-07	PHKA1, PHKA2
Glycogen breakdown (glycogenolysis)	2	761.3×	3e-06	PHKA1, PHKA2
Metabolism of carbohydrates and carbohydrate derivatives	2	120.2×	9e-05	PHKA1, PHKA2
Metabolism	2	11.6×	0.007	PHKA1, PHKA2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycogen metabolic process	2	526.6×	2e-05	PHKA1, PHKA2
generation of precursor metabolites and energy	2	343.9×	2e-05	PHKA1, PHKA2
positive regulation of glycogen catabolic process	1	2106.5×	8e-04	PHKA1
protein modification process	1	122.1×	0.010	PHKA2
carbohydrate metabolic process	1	68.0×	0.015	PHKA2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PHKA1	0	0
PHKA1-AS1	0	0
PHKA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PHKA2	48	Binding:48
PHKA1	20	Binding:20

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PHKA1	2.7.11.19	phosphorylase kinase
PHKA2	2.7.11.19	phosphorylase kinase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PHKA1
D	Druggable family + AlphaFold only, no drug	1	PHKA2
E	Difficult family or no structure, no drug	1	PHKA1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PHKA1	20	—
PHKA1-AS1	0	—
PHKA2	48	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.