Hereditary spastic paraplegia 2

Summary

Hereditary spastic paraplegia 2 (MONDO:0010733) is a disease caused by PLP1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLP1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 252
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002607	Bowel incontinence	Frequent (30-79%)
HP:0005340	Spastic/hyperactive bladder	Frequent (30-79%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 2
Mondo ID	MONDO:0010733
OMIM	312920
Orphanet	99015
DOID	DOID:0110773
SNOMED CT	723622007
UMLS	C0751604
MedGen	199692
GARD	0004923
Is cancer (heuristic)	no

Also known as: hereditary spastic paraplegia caused by mutation in PLP1 · hereditary spastic paraplegia type 2 · PLP1 hereditary spastic paraplegia · spastic gait type 2 · spastic paraparesis type 2 · spastic paraplegia 2 · spastic paraplegia 2, X-linked · spastic paraplegia 2, X-linked, X-linked recessive · spastic paraplegia type 2 · SPG2 · X-linked spastic paraplegia type 2

Data availability: 252 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › hereditary spastic paraplegia 2

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

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

252 retrieved; paginated sample, class counts are floors:

81 likely benign, 63 uncertain significance, 43 pathogenic, 17 benign, 16 likely pathogenic, 14 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1077188	Single allele	BEX2	Pathogenic	criteria provided, single submitter
1068867	NC_000023.10:g.(?103031924)(103045526_?)dup	PLP1	Pathogenic	criteria provided, single submitter
11075	NM_000533.5(PLP1):c.44C>T (p.Pro15Leu)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344466	NM_000533.5(PLP1):c.442C>T (p.His148Tyr)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458915	NC_000023.10:g.(?103031003)(103031929_?)del	PLP1	Pathogenic	criteria provided, single submitter
1459546	NM_000533.5(PLP1):c.205C>T (p.Gln69Ter)	PLP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1932099	NM_000533.5(PLP1):c.142_152del (p.Glu48fs)	PLP1	Pathogenic	criteria provided, single submitter
2015521	NM_000533.5(PLP1):c.553C>T (p.Gln185Ter)	PLP1	Pathogenic	criteria provided, single submitter
2043641	NM_000533.5(PLP1):c.435G>A (p.Trp145Ter)	PLP1	Pathogenic	criteria provided, single submitter
209183	NM_000533.5(PLP1):c.1A>G (p.Met1Val)	PLP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2138679	NM_000533.5(PLP1):c.697-1G>A	PLP1	Pathogenic	criteria provided, single submitter
2423244	NC_000023.10:g.(?103031924)(103045526_?)del	PLP1	Pathogenic	criteria provided, single submitter
2423246	NC_000023.10:g.(?103042707)(103045526_?)del	PLP1	Pathogenic	criteria provided, single submitter
2423248	NC_000023.10:g.(?103040922)(103042832_?)del	PLP1	Pathogenic	criteria provided, single submitter
267338	NC_000023.10:g.(?103031918)(103045531_?)dup	PLP1	Pathogenic	criteria provided, single submitter
2704479	NM_000533.5(PLP1):c.176_177dup (p.Tyr60fs)	PLP1	Pathogenic	criteria provided, single submitter
2815078	NM_000533.5(PLP1):c.406G>T (p.Glu136Ter)	PLP1	Pathogenic	criteria provided, single submitter
2847162	NM_000533.5(PLP1):c.361C>T (p.Gln121Ter)	PLP1	Pathogenic	criteria provided, single submitter
290425	NM_000533.5(PLP1):c.453G>A (p.Lys151=)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3255448	NM_000533.5(PLP1):c.676T>C (p.Ser226Pro)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3375465	NM_000533.5(PLP1):c.622+1G>A	PLP1	Pathogenic	criteria provided, single submitter
3603496	NM_000533.5(PLP1):c.4+1G>T	PLP1	Pathogenic	criteria provided, single submitter
3721817	NM_000533.5(PLP1):c.374dup (p.Ser126fs)	PLP1	Pathogenic	criteria provided, single submitter
417363	NC_000023.10:g.(?103031754)(103047548_?)dup	PLP1	Pathogenic	criteria provided, single submitter
488580	NM_000533.5(PLP1):c.817C>T (p.Arg273Ter)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520586	NM_000533.5(PLP1):c.354_355del (p.Gly120fs)	PLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521932	NM_000533.5(PLP1):c.2T>G (p.Met1Arg)	PLP1	Pathogenic	criteria provided, multiple submitters, no conflicts
533383	NM_000533.5(PLP1):c.415_418delinsAGT (p.Cys139fs)	PLP1	Pathogenic	criteria provided, single submitter
533385	NC_000023.10:g.(?103031893)(103045546_?)dup	PLP1	Pathogenic	criteria provided, single submitter
642236	NM_000533.5(PLP1):c.489G>A (p.Trp163Ter)	PLP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 8 · 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
PLP1	Definitive	X-linked	hereditary spastic paraplegia 2	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLP1	Orphanet:280210	Pelizaeus-Merzbacher disease, connatal form
PLP1	Orphanet:280219	Pelizaeus-Merzbacher disease, classic form
PLP1	Orphanet:280224	Pelizaeus-Merzbacher disease, transitional form
PLP1	Orphanet:280229	Pelizaeus-Merzbacher disease in female carriers
PLP1	Orphanet:280234	Null syndrome
PLP1	Orphanet:599376	Hypomyelination of early myelinating structures
PLP1	Orphanet:99015	Spastic paraplegia type 2
SPAST	Orphanet:100985	Autosomal dominant spastic paraplegia type 4

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLP1	HGNC:9086	ENSG00000123560	P60201	Myelin proteolipid protein	gencc,clinvar
SPAST	HGNC:11233	ENSG00000021574	Q9UBP0	Spastin	clinvar
RAB9B	HGNC:14090	ENSG00000123570	Q9NP90	Ras-related protein Rab-9B	clinvar
TMEM31	HGNC:28601	ENSG00000179363	Q5JXX7	Transmembrane protein 31	clinvar
BEX2	HGNC:30933	ENSG00000133134	Q9BXY8	Protein BEX2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLP1	Myelin proteolipid protein	This is the major myelin protein from the central nervous system.
SPAST	Spastin	ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated.
RAB9B	Ras-related protein Rab-9B	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
BEX2	Protein BEX2	Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	2.4×	0.608
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLP1	Other/Unknown	no		Myelin_PLP, Myelin_PLP_CS
SPAST	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
RAB9B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
TMEM31	Other/Unknown	no
BEX2	Transcription factor	no		BEX, TF_A-like/BEX

Expression context

Cohort genes with no expression data: 0.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	2
endothelial cell	2
corpus callosum	1
inferior vagus X ganglion	1
middle frontal gyrus	1
cortical plate	1
oocyte	1
secondary oocyte	1
left ventricle myocardium	1
left testis	1
right testis	1
sperm	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLP1	250	broad	marker	corpus callosum, middle frontal gyrus, inferior vagus X ganglion
SPAST	284	ubiquitous	marker	cortical plate, oocyte, secondary oocyte
RAB9B	207	broad	yes	left ventricle myocardium, Brodmann (1909) area 23, endothelial cell
TMEM31	159	tissue_specific	yes	sperm, right testis, left testis
BEX2	249	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, pons

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPAST	3,393
RAB9B	1,320
BEX2	1,124
TMEM31	476
PLP1	157

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPAST	Q9UBP0	7
PLP1	P60201	1
RAB9B	Q9NP90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BEX2	Q9BXY8	68.93
TMEM31	Q5JXX7	67.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 5 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
RHOBTB3 ATPase cycle	1	571.0×	0.021	RAB9B
Sealing of the nuclear envelope (NE) by ESCRT-III	1	173.0×	0.027	SPAST
Nuclear Envelope (NE) Reassembly	1	146.4×	0.027	SPAST
Retrograde transport at the Trans-Golgi-Network	1	109.8×	0.027	RAB9B
RAB geranylgeranylation	1	86.5×	0.028	RAB9B
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.031	RAB9B
Mitotic Metaphase and Anaphase	1	48.4×	0.031	SPAST
Mitotic Anaphase	1	48.4×	0.031	SPAST
M Phase	1	33.0×	0.040	SPAST
Cell Cycle, Mitotic	1	24.1×	0.049	SPAST
Cell Cycle	1	18.0×	0.060	SPAST
Neutrophil degranulation	1	11.5×	0.085	RAB9B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytokinetic process	1	1404.3×	0.010	SPAST
mitotic spindle disassembly	1	1404.3×	0.010	SPAST
positive regulation of microtubule depolymerization	1	842.6×	0.010	SPAST
axon ensheathment	1	702.2×	0.010	PLP1
central nervous system neuron axonogenesis	1	468.1×	0.010	SPAST
mitotic nuclear membrane reassembly	1	421.3×	0.010	SPAST
axonal transport of mitochondrion	1	351.1×	0.010	SPAST
protein hexamerization	1	351.1×	0.010	SPAST
microtubule severing	1	324.1×	0.010	SPAST
astrocyte development	1	280.9×	0.010	PLP1
exit from mitosis	1	263.3×	0.010	SPAST
central nervous system myelination	1	247.8×	0.010	PLP1
nuclear membrane reassembly	1	247.8×	0.010	SPAST
Rab protein signal transduction	1	247.8×	0.010	RAB9B
cytoskeleton-dependent cytokinesis	1	200.6×	0.012	SPAST
anterograde axonal transport	1	145.3×	0.015	SPAST
microtubule bundle formation	1	127.7×	0.017	SPAST
axon development	1	113.9×	0.017	PLP1
long-chain fatty acid biosynthetic process	1	110.9×	0.017	PLP1
membrane fission	1	102.8×	0.017	SPAST
positive regulation of cytokinesis	1	100.3×	0.017	SPAST
substantia nigra development	1	91.6×	0.018	PLP1
negative regulation of protein ubiquitination	1	71.4×	0.022	BEX2
mitotic cytokinesis	1	64.8×	0.023	SPAST
receptor-mediated endocytosis	1	55.4×	0.026	RAB9B
retrograde transport, endosome to Golgi	1	51.4×	0.027	RAB9B
endoplasmic reticulum to Golgi vesicle-mediated transport	1	34.0×	0.039	SPAST
protein homooligomerization	1	30.5×	0.042	SPAST
regulation of apoptotic process	1	20.9×	0.058	BEX2
chemical synaptic transmission	1	19.3×	0.061	PLP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLP1	0	0
SPAST	0	0
RAB9B	0	0
TMEM31	0	0
BEX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SPAST	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPAST	5.6.1.1	microtubule-severing ATPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	SPAST
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	PLP1, RAB9B, TMEM31, BEX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLP1	0	—
SPAST	1	—
RAB9B	0	—
TMEM31	0	—
BEX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.