Hereditary spastic paraplegia 45

Summary

Hereditary spastic paraplegia 45 (MONDO:0013165) is a disease caused by NT5C2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NT5C2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 194
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0005830	Flexion contracture of toe	Very frequent (80-99%)
HP:0006380	Knee flexion contracture	Very frequent (80-99%)
HP:0006466	Ankle flexion contracture	Very frequent (80-99%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0012043	Pendular nystagmus	Frequent (30-79%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 45
Mondo ID	MONDO:0013165
OMIM	613162
Orphanet	320396
DOID	DOID:0110797
SNOMED CT	765753004
UMLS	C3888209
MedGen	854816
GARD	0017477
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in NT5C2 · autosomal recessive spastic paraplegia type 45 · autosomal recessive spastic paraplegia type 65 · hereditary spastic paraplegia type 45 · NT5C2 autosomal recessive complex spastic paraplegia · spastic paraplegia 45, autosomal recessive · SPG45 · SPG65

Data availability: 194 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 45

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

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

194 retrieved; paginated sample, class counts are floors:

94 likely benign, 57 uncertain significance, 21 pathogenic, 7 benign, 6 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685993	NM_001351169.2(NT5C2):c.1624del (p.Gln542fs)	CNNM2	Pathogenic	criteria provided, single submitter
642627	NC_000010.11:g.(?103089662)(103174968_?)del	CNNM2	Pathogenic	criteria provided, single submitter
100904	NM_001351169.2(NT5C2):c.85C>T (p.Arg29Ter)	NT5C2	Pathogenic	criteria provided, single submitter
100905	NM_001351169.2(NT5C2):c.1225del (p.Ser409fs)	NT5C2	Pathogenic	no assertion criteria provided
100906	NM_001351169.2(NT5C2):c.989-1G>T	NT5C2	Pathogenic	no assertion criteria provided
100907	NM_001351169.2(NT5C2):c.445A>T (p.Arg149Ter)	NT5C2	Pathogenic	no assertion criteria provided
100908	NM_001351169.2(NT5C2):c.175+1G>A	NT5C2	Pathogenic	criteria provided, single submitter
1048080	NM_001351169.2(NT5C2):c.1449+2T>C	NT5C2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685994	NM_001351169.2(NT5C2):c.1403T>C (p.Leu468Pro)	NT5C2	Pathogenic	criteria provided, single submitter
1705923	NM_001351169.2(NT5C2):c.629del (p.Tyr210fs)	NT5C2	Pathogenic	criteria provided, single submitter
1981323	NM_001351169.2(NT5C2):c.1109del (p.Leu370fs)	NT5C2	Pathogenic	criteria provided, single submitter
2009302	NM_001351169.2(NT5C2):c.675T>G (p.Tyr225Ter)	NT5C2	Pathogenic	criteria provided, single submitter
2147372	NM_001351169.2(NT5C2):c.595C>T (p.Gln199Ter)	NT5C2	Pathogenic	criteria provided, single submitter
2413847	NM_001351169.2(NT5C2):c.1153_1154del (p.Lys385fs)	NT5C2	Pathogenic	criteria provided, single submitter
2729444	NM_001351169.2(NT5C2):c.226del (p.Arg76fs)	NT5C2	Pathogenic	criteria provided, single submitter
3024463	NM_001351169.2(NT5C2):c.1159+2T>G	NT5C2	Pathogenic	no assertion criteria provided
3706302	NM_001351169.2(NT5C2):c.115C>T (p.Arg39Ter)	NT5C2	Pathogenic	criteria provided, multiple submitters, no conflicts
375572	NM_001351169.2(NT5C2):c.771+573_814-298del	NT5C2	Pathogenic	no assertion criteria provided
4699797	NM_001351169.2(NT5C2):c.516dup (p.Thr173fs)	NT5C2	Pathogenic	criteria provided, single submitter
4717088	NC_000010.11:g.103091621_103091622insCCATCCTGGCTAACAAGGTGAAACCCCGTCTCTACTAAAAATACAAAAAATTAGCCGGGCGCGGTGGCGGGCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAAAAGTGCTAGTT	NT5C2	Pathogenic	criteria provided, single submitter
541762	NM_001351169.2(NT5C2):c.312_313del (p.Leu105fs)	NT5C2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810633	NM_001351169.2(NT5C2):c.430C>T (p.Arg144Ter)	NT5C2	Pathogenic	criteria provided, single submitter
834345	NM_001351169.2(NT5C2):c.1099C>T (p.Arg367Ter)	NT5C2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
952332	NM_001351169.2(NT5C2):c.1371T>A (p.Tyr457Ter)	NT5C2	Pathogenic	criteria provided, single submitter
4531311	NM_001351169.2(NT5C2):c.1456C>A (p.His486Asn)	CNNM2	Likely pathogenic	criteria provided, single submitter
1029182	NM_001351169.2(NT5C2):c.539+1G>T	NT5C2	Likely pathogenic	criteria provided, single submitter
1709433	NM_001351169.2(NT5C2):c.771+1G>A	NT5C2	Likely pathogenic	criteria provided, single submitter
3024462	NM_001351169.2(NT5C2):c.1106T>C (p.Phe369Ser)	NT5C2	Likely pathogenic	no assertion criteria provided
3064786	NM_001351169.2(NT5C2):c.176-2A>G	NT5C2	Likely pathogenic	criteria provided, single submitter
579655	NM_001351169.2(NT5C2):c.1272+1G>C	NT5C2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NT5C2	Definitive	Autosomal recessive	complex hereditary spastic paraplegia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NT5C2	Orphanet:320396	Autosomal recessive spastic paraplegia type 45
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome

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
NT5C2	HGNC:8022	ENSG00000076685	P49902	Cytosolic purine 5’-nucleotidase	gencc,clinvar
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NT5C2	Cytosolic purine 5’-nucleotidase	Broad specificity cytosolic 5’-nucleotidase that catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5’-monophosphates.
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NT5C2	Enzyme (other)	yes	3.1.3.5	HAD-SF_hydro_IG_5-nucl, Pur_nucleotidase, HAD_sf
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll

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
buccal mucosa cell	1
oral cavity	1
parotid gland	1
oocyte	1
right adrenal gland	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NT5C2	294	ubiquitous	marker	parotid gland, buccal mucosa cell, oral cavity
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NT5C2	1,513
CNNM2	1,230

Intra-cohort edges

A	B	Sources
CNNM2	NT5C2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NT5C2	P49902	43
CNNM2	Q9H8M5	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Abacavir metabolism	1	2855.0×	0.002	NT5C2
Abacavir ADME	1	1427.5×	0.002	NT5C2
Nucleotide catabolism	1	1268.9×	0.002	NT5C2
Purine catabolism	1	1038.2×	0.002	NT5C2
Ribavirin ADME	1	1038.2×	0.002	NT5C2
Metabolism of nucleotides	1	300.5×	0.004	NT5C2
Drug ADME	1	228.4×	0.005	NT5C2
Metabolism	1	11.6×	0.086	NT5C2

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
obsolete GMP catabolic process to guanine	1	8426.0×	0.001	NT5C2
GMP metabolic process	1	2808.7×	0.001	NT5C2
dGMP metabolic process	1	2808.7×	0.001	NT5C2
IMP metabolic process	1	2106.5×	0.001	NT5C2
negative regulation of defense response to virus by host	1	2106.5×	0.001	NT5C2
IMP catabolic process	1	1685.2×	0.001	NT5C2
dGMP catabolic process	1	1404.3×	0.001	NT5C2
adenosine metabolic process	1	1203.7×	0.001	NT5C2
obsolete amide catabolic process	1	1053.2×	0.001	NT5C2
allantoin metabolic process	1	936.2×	0.001	NT5C2
magnesium ion homeostasis	1	936.2×	0.001	CNNM2
protein K48-linked ubiquitination	1	84.3×	0.012	NT5C2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NT5C2	0	0
CNNM2	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
NT5C2	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NT5C2	3.1.3.5	5’-nucleotidase

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	NT5C2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CNNM2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NT5C2	7	—
CNNM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.