Hereditary spastic paraplegia 73

Summary

Hereditary spastic paraplegia 73 (MONDO:0014568) is a disease caused by CPT1C (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CPT1C (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 333
• Phenotypes (HPO): 19

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)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0002314	Degeneration of the lateral corticospinal tracts	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007020	Progressive spastic paraplegia	Very frequent (80-99%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0007199	Progressive spastic paraparesis	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0012898	Abnormal lower-limb motor evoked potentials	Frequent (30-79%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0000726	Dementia	Excluded (0%)
HP:0001250	Seizure	Excluded (0%)
HP:0002921	Abnormality of the cerebrospinal fluid	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 73
Mondo ID	MONDO:0014568
OMIM	616282
Orphanet	444099
DOID	DOID:0110818
UMLS	C5568981
MedGen	1800404
GARD	0017763
Is cancer (heuristic)	no

Also known as: autosomal dominant pure spastic paraplegia caused by mutation in CPT1C · autosomal dominant spastic paraplegia type 73 · CPT1C autosomal dominant pure spastic paraplegia · hereditary spastic paraplegia type 73 · spastic paraplegia 73, autosomal dominant · SPG73

Data availability: 333 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › pure hereditary spastic paraplegia › hereditary spastic paraplegia 73

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 8, hereditary spastic paraplegia 12, hereditary spastic paraplegia 19, hereditary spastic paraplegia 28, hereditary spastic paraplegia 37, hereditary spastic paraplegia 42, hereditary spastic paraplegia 41, hereditary spastic paraplegia 72, hereditary spastic paraplegia 62, autosomal recessive spastic paraplegia type 71

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

333 retrieved; paginated sample, class counts are floors:

151 uncertain significance, 134 likely benign, 16 benign, 11 conflicting classifications of pathogenicity, 8 pathogenic, 7 likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1431343	NM_001199753.2(CPT1C):c.2057_2061del (p.Ile686fs)	CPT1C	Pathogenic	criteria provided, single submitter
1455162	NM_001199753.2(CPT1C):c.1018C>T (p.Arg340Ter)	CPT1C	Pathogenic	criteria provided, single submitter
189198	NM_001199753.2(CPT1C):c.109C>T (p.Arg37Cys)	CPT1C	Pathogenic	no assertion criteria provided
2085835	NM_001199753.2(CPT1C):c.1669C>T (p.Arg557Ter)	CPT1C	Pathogenic	criteria provided, single submitter
2190149	NM_001199753.2(CPT1C):c.652C>T (p.Gln218Ter)	CPT1C	Pathogenic	criteria provided, single submitter
2722957	NM_001199753.2(CPT1C):c.558C>A (p.Tyr186Ter)	CPT1C	Pathogenic	criteria provided, single submitter
2733165	NM_001199753.2(CPT1C):c.1735_1736del (p.Arg579fs)	CPT1C	Pathogenic	criteria provided, single submitter
3668080	NM_001199753.2(CPT1C):c.1233dup (p.Ala412fs)	CPT1C	Pathogenic	criteria provided, single submitter
2032169	NM_001199753.2(CPT1C):c.2019+1G>C	CPT1C	Likely pathogenic	criteria provided, single submitter
2831950	NM_001199753.2(CPT1C):c.694-2A>G	CPT1C	Likely pathogenic	criteria provided, single submitter
3027450	NM_001199753.2(CPT1C):c.1045C>T (p.Arg349Ter)	CPT1C	Likely pathogenic	criteria provided, single submitter
3340522	NM_001199753.2(CPT1C):c.1081C>T (p.Gln361Ter)	CPT1C	Likely pathogenic	criteria provided, single submitter
3700548	NM_001199753.2(CPT1C):c.1450-2A>C	CPT1C	Likely pathogenic	criteria provided, single submitter
4537455	NM_001199753.2(CPT1C):c.733C>T (p.Arg245Ter)	CPT1C	Likely pathogenic	criteria provided, single submitter
978230	NM_001199753.2(CPT1C):c.2T>G (p.Met1Arg)	CPT1C	Likely pathogenic	criteria provided, single submitter
1001747	NM_001199753.2(CPT1C):c.1894G>A (p.Val632Met)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3005029	NM_001199753.2(CPT1C):c.1523C>T (p.Thr508Ile)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3008997	NM_001199753.2(CPT1C):c.598G>A (p.Asp200Asn)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3021656	NM_001199753.2(CPT1C):c.1736G>A (p.Arg579Lys)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3026048	NM_001199753.2(CPT1C):c.2396C>T (p.Thr799Ile)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
444480	NM_001199753.2(CPT1C):c.855C>T (p.Arg285=)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476175	NM_001199753.2(CPT1C):c.2092A>G (p.Asn698Asp)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542768	NM_001199753.2(CPT1C):c.2059C>G (p.Pro687Ala)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808620	NM_001199753.2(CPT1C):c.1308C>T (p.Tyr436=)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
915373	NM_001199753.2(CPT1C):c.899G>A (p.Arg300His)	CPT1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1701973	NM_133443.4(GPT2):c.1441G>A (p.Gly481Ser)	GPT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011768	NM_001199753.2(CPT1C):c.1954C>T (p.Arg652Cys)	CPT1C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021430	NM_001199753.2(CPT1C):c.1027C>T (p.Arg343Cys)	CPT1C	Uncertain significance	criteria provided, single submitter
1035925	NM_001199753.2(CPT1C):c.200G>A (p.Ser67Asn)	CPT1C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061896	NM_001199753.2(CPT1C):c.455C>T (p.Ala152Val)	CPT1C	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CPT1C	Strong	Autosomal dominant	hereditary spastic paraplegia 73	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CPT1C	Orphanet:444099	Autosomal dominant spastic paraplegia type 73
GPT2	Orphanet:477673	Postnatal microcephaly-infantile hypotonia-spastic diplegia-dysarthria-intellectual disability 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
CPT1C	HGNC:18540	ENSG00000169169	Q8TCG5	Palmitoyl thioesterase CPT1C	gencc,clinvar
GPT2	HGNC:18062	ENSG00000166123	Q8TD30	Alanine aminotransferase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CPT1C	Palmitoyl thioesterase CPT1C	Palmitoyl thioesterase specifically expressed in the endoplasmic reticulum of neurons.
GPT2	Alanine aminotransferase 2	Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate.

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)
CPT1C	Enzyme (other)	yes	2.3.1.21	Carn_acyl_trans, CAT-like_dom_sf, CPT_N
GPT2	Other/Unknown	no		Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
body of pancreas	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CPT1C	190	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GPT2	237	ubiquitous	marker	lower esophagus mucosa, body of pancreas, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPT2	2,823
CPT1C	1,448

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CPT1C	Q8TCG5	1
GPT2	Q8TD30	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Alanine metabolism	1	5710.0×	2e-04	GPT2

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 L-alanine metabolic process	1	8426.0×	7e-04	GPT2
L-alanine catabolic process	1	2106.5×	0.001	GPT2
carnitine metabolic process	1	1203.7×	0.002	CPT1C
2-oxoglutarate metabolic process	1	468.1×	0.003	GPT2
regulation of postsynaptic membrane neurotransmitter receptor levels	1	247.8×	0.005	CPT1C
fatty acid metabolic process	1	96.8×	0.010	CPT1C

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CPT1C	0	0
GPT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CPT1C	2.3.1.21	carnitine O-palmitoyltransferase

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	CPT1C
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GPT2

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)
CPT1C	0	—
GPT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.