spastic paraplegia-Paget disease of bone syndrome

Summary

spastic paraplegia-Paget disease of bone syndrome (MONDO:0018005) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001258	Spastic paraplegia	Obligate (100%)
HP:0001288	Gait disturbance	Obligate (100%)
HP:0002064	Spastic gait	Obligate (100%)
HP:0002395	Lower limb hyperreflexia	Obligate (100%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Obligate (100%)
HP:0003324	Generalized muscle weakness	Obligate (100%)
HP:0003445	EMG: neuropathic changes	Obligate (100%)
HP:0003487	Babinski sign	Obligate (100%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0004563	Increased spinal bone density	Very frequent (80-99%)
HP:0011842	Abnormality of skeletal morphology	Very frequent (80-99%)
HP:0001308	Tongue fasciculations	Frequent (30-79%)
HP:0007289	Limb fasciculations	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia-Paget disease of bone syndrome
Mondo ID	MONDO:0018005
Orphanet	329475
UMLS	C4511969
MedGen	1388986
GARD	0021491
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant complex spastic paraplegia › spastic paraplegia-Paget disease of bone syndrome

Related subtypes (12): spastic paraplegia-epilepsy-intellectual disability syndrome, spastic paraplegia-nephritis-deafness syndrome, spastic paraplegia-neuropathy-poikiloderma syndrome, spastic paraplegia-precocious puberty syndrome, hereditary spastic paraplegia 17, hereditary spastic paraplegia 29, hereditary spastic paraplegia 38, hereditary spastic paraplegia 36, spastic paraplegia, intellectual disability, nystagmus, and obesity, autosomal dominant spastic paraplegia type 9, spastic paraplegia-facial-cutaneous lesions syndrome, spastic paraplegia 18a, autosomal dominant

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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
8108	NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 12 · 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
VCP	Definitive	Autosomal dominant	inclusion body myopathy with Paget disease of bone and frontotemporal dementia	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VCP	Orphanet:100070	Progressive non-fluent aphasia
VCP	Orphanet:275864	Behavioral variant of frontotemporal dementia
VCP	Orphanet:275872	Frontotemporal dementia with motor neuron disease
VCP	Orphanet:329475	Spastic paraplegia-Paget disease of bone syndrome
VCP	Orphanet:329478	Adult-onset distal myopathy due to VCP mutation
VCP	Orphanet:435387	Autosomal dominant Charcot-Marie-Tooth disease type 2Y
VCP	Orphanet:52430	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
VCP	Orphanet:803	Amyotrophic lateral sclerosis
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis

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
VCP	HGNC:12666	ENSG00000165280	P55072	Transitional endoplasmic reticulum ATPase	gencc
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VCP	Enzyme (other)	yes	3.6.4.6	CDC4_N-term_subdom, AAA+_ATPase, ATPase_AAA_core
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf

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
adrenal tissue	1
islet of Langerhans	1
stromal cell of endometrium	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VCP	294	ubiquitous	marker	stromal cell of endometrium, adrenal tissue, islet of Langerhans
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015
SQSTM1	7,269

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VCP	P55072	144
SQSTM1	Q13501	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 72. 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
Selective autophagy	2	278.5×	9e-04	SQSTM1, VCP
Autophagy	2	148.3×	0.001	SQSTM1, VCP
Cellular response to chemical stress	2	142.8×	0.001	SQSTM1, VCP
KEAP1-NFE2L2 pathway	2	120.2×	0.001	SQSTM1, VCP
Macroautophagy	2	115.3×	0.001	SQSTM1, VCP
Diseases of signal transduction by growth factor receptors and second messengers	2	56.8×	0.004	SQSTM1, VCP
Neddylation	2	47.4×	0.005	SQSTM1, VCP
Attachment and Entry	1	1427.5×	0.006	VCP
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1	1142.0×	0.006	VCP
DNA Damage Bypass	1	1142.0×	0.006	VCP
Cellular responses to stress	2	36.8×	0.006	SQSTM1, VCP
p75NTR signals via NF-kB	1	951.7×	0.006	SQSTM1
Cellular responses to stimuli	2	31.5×	0.006	SQSTM1, VCP
Hh mutants abrogate ligand secretion	1	713.8×	0.007	VCP
Mitophagy	1	519.1×	0.008	SQSTM1
Early SARS-CoV-2 Infection Events	1	519.1×	0.008	VCP
Josephin domain DUBs	1	475.8×	0.008	VCP
Pexophagy	1	475.8×	0.008	SQSTM1
p75NTR recruits signalling complexes	1	439.2×	0.008	SQSTM1
NF-kB is activated and signals survival	1	439.2×	0.008	SQSTM1
Protein ubiquitination	1	407.9×	0.008	VCP
NRIF signals cell death from the nucleus	1	356.9×	0.009	SQSTM1
Post-translational protein modification	2	19.2×	0.009	SQSTM1, VCP
Protein methylation	1	335.9×	0.009	VCP
Translesion Synthesis by POLH	1	300.5×	0.009	VCP
Attachment and Entry	1	300.5×	0.009	VCP
ABC transporter disorders	1	219.6×	0.012	VCP
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	211.5×	0.012	VCP
Cellular response to heat stress	1	196.9×	0.013	VCP
HSF1 activation	1	190.3×	0.013	VCP

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
macroautophagy	2	240.7×	0.001	SQSTM1, VCP
flavin adenine dinucleotide catabolic process	1	8426.0×	0.002	VCP
endoplasmic reticulum stress-induced pre-emptive quality control	1	4213.0×	0.002	VCP
positive regulation of protein K63-linked deubiquitination	1	4213.0×	0.002	VCP
mitotic spindle disassembly	1	2808.7×	0.002	VCP
brown fat cell proliferation	1	2808.7×	0.002	SQSTM1
protein targeting to vacuole involved in autophagy	1	2808.7×	0.002	SQSTM1
cytoplasm protein quality control	1	2808.7×	0.002	VCP
cellular response to arsenite ion	1	2808.7×	0.002	VCP
positive regulation of oxidative phosphorylation	1	2808.7×	0.002	VCP
regulation of protein localization to chromatin	1	2808.7×	0.002	VCP
autophagy	2	110.1×	0.002	SQSTM1, VCP
ubiquitin-dependent protein catabolic process	2	74.2×	0.002	SQSTM1, VCP
endosome to lysosome transport via multivesicular body sorting pathway	1	1404.3×	0.004	VCP
aggresome assembly	1	1404.3×	0.004	VCP
response to mitochondrial depolarisation	1	1404.3×	0.004	SQSTM1
stress granule disassembly	1	1203.7×	0.004	VCP
positive regulation of mitochondrial membrane potential	1	1053.2×	0.004	VCP
regulation of aerobic respiration	1	1053.2×	0.004	VCP
NAD+ metabolic process	1	936.2×	0.004	VCP
regulation of Ras protein signal transduction	1	936.2×	0.004	SQSTM1
aggrephagy	1	842.6×	0.004	SQSTM1
protein-DNA covalent cross-linking repair	1	842.6×	0.004	VCP
negative regulation of protein localization to chromatin	1	766.0×	0.005	VCP
cellular response to misfolded protein	1	702.2×	0.005	VCP
protein localization to perinuclear region of cytoplasm	1	702.2×	0.005	SQSTM1
positive regulation of ATP biosynthetic process	1	601.9×	0.005	VCP
viral genome replication	1	561.7×	0.005	VCP
negative regulation of toll-like receptor 4 signaling pathway	1	561.7×	0.005	SQSTM1
membraneless organelle assembly	1	561.7×	0.005	SQSTM1

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
VCP	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VCP	4	4
SQSTM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
CB-5083	1	VCP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VCP	120	Binding:120
SQSTM1	20	Binding:20

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VCP	3.6.4.6	vesicle-fusing ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VCP	120

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

4 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)
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
CB-5083	1	VCP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VCP
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SQSTM1

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)
SQSTM1	20	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.