Hereditary spastic paraplegia 7

Summary

Hereditary spastic paraplegia 7 (MONDO:0011803) is a disease caused by SPG7 (GenCC Definitive), with 4 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SPG7 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 907
• Phenotypes (HPO): 30
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000605	Supranuclear gaze palsy	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001611	Hypernasal speech	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0006895	Lower limb hypertonia	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0007164	Slowed slurred speech	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008322	Abnormal mitochondrial morphology	Frequent (30-79%)
HP:0011446	Abnormality of higher mental function	Frequent (30-79%)
HP:0000543	Optic disc pallor	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003484	Upper limb muscle weakness	Occasional (5-29%)
HP:0001328	Specific learning disability	Very rare (<1-4%)
HP:0002015	Dysphagia	Very rare (<1-4%)
HP:0002354	Memory impairment	Very rare (<1-4%)
HP:0012514	Lower limb pain	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 7
Mondo ID	MONDO:0011803
MeSH	C564599
OMIM	607259
Orphanet	99013
DOID	DOID:0110816
SNOMED CT	715776003
UMLS	C1846564
MedGen	339552
GARD	0004927
Is cancer (heuristic)	no

Also known as: hereditary spastic paraplegia 7 · hereditary spastic paraplegia caused by mutation in SPG7 · hereditary spastic paraplegia paraplegin type · hereditary spastic paraplegia type 7 · spastic paraplegia 7 · spastic paraplegia 7, autosomal recessive · spastic paraplegia type 7 · SPG7 · SPG7 hereditary spastic paraplegia

Data availability: 907 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › hereditary spastic paraplegia 7

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

600 retrieved; paginated sample, class counts are floors:

232 uncertain significance, 160 likely benign, 51 conflicting classifications of pathogenicity, 49 likely pathogenic, 46 pathogenic, 29 pathogenic/likely pathogenic, 21 benign, 12 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3220907	NM_003119.4:c.[1049_1077del];[1045G>A]		Pathogenic	criteria provided, single submitter
3243422	NC_000016.9:g.(?89556653)(89623501_?)del	ANKRD11	Pathogenic	criteria provided, single submitter
1027420	NM_003119.4(SPG7):c.73_80del (p.Pro25fs)	LOC130059818	Pathogenic	criteria provided, multiple submitters, no conflicts
193253	NM_003119.4(SPG7):c.1A>G (p.Met1Val)	LOC130059818	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627663	NM_003119.4(SPG7):c.2T>G (p.Met1Arg)	LOC130059818	Pathogenic	no assertion criteria provided
3236318	NM_003119.4(SPG7):c.1A>C (p.Met1Leu)	LOC130059818	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236283	NM_003119.4(SPG7):c.183+1_184-1del	LOC130059819	Pathogenic	criteria provided, single submitter
3236324	Single allele	LOC130059820	Pathogenic	criteria provided, single submitter
3236312	Single allele	LOC130059821	Pathogenic	criteria provided, single submitter
1027419	NM_003119.4(SPG7):c.1940C>A (p.Ala647Glu)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029673	NM_003119.4(SPG7):c.1186G>T (p.Glu396Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070427	NM_003119.4(SPG7):c.2T>A (p.Met1Lys)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076752	NC_000016.9:g.(?89595875)(89595997_?)del	SPG7	Pathogenic	criteria provided, single submitter
1076753	NC_000016.9:g.(?89614405)(89617023_?)del	SPG7	Pathogenic	criteria provided, single submitter
1323644	NM_003119.4(SPG7):c.711del (p.Lys238fs)	SPG7	Pathogenic	criteria provided, multiple submitters, no conflicts
1323645	NM_003119.4(SPG7):c.415C>T (p.Arg139Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323646	NM_003119.4(SPG7):c.1704_1705del (p.Lys569fs)	SPG7	Pathogenic	criteria provided, single submitter
1335983	NM_003119.4(SPG7):c.1075G>C (p.Ala359Pro)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338869	NM_003119.4(SPG7):c.2166_2167insCAACAACCTG (p.Asp723fs)	SPG7	Pathogenic	criteria provided, single submitter
1344137	NM_003119.4(SPG7):c.244C>T (p.Gln82Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363777	NM_003119.4(SPG7):c.1053del (p.Gly352fs)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1417486	NM_003119.4(SPG7):c.861del (p.Phe287fs)	SPG7	Pathogenic	criteria provided, single submitter
1452161	NM_003119.4(SPG7):c.749del (p.Phe250fs)	SPG7	Pathogenic	criteria provided, single submitter
1454976	NM_003119.4(SPG7):c.1702C>T (p.Gln568Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455395	NM_003119.4(SPG7):c.201del (p.Leu67_Leu68insTer)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455682	NC_000016.9:g.(?89576878)(89579465_?)del	SPG7	Pathogenic	criteria provided, single submitter
1456367	NM_003119.4(SPG7):c.1124del (p.Gly375fs)	SPG7	Pathogenic	criteria provided, single submitter
1459618	NC_000016.9:g.(?89574826)(89597236_?)del	SPG7	Pathogenic	criteria provided, single submitter
1459620	NC_000016.9:g.(?89619467)(89620817_?)del	SPG7	Pathogenic	criteria provided, single submitter
1459932	NC_000016.9:g.(?89574826)(89579465_?)del	SPG7	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 7 · 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
SPG7	Definitive	Autosomal recessive	hereditary spastic paraplegia 7	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
RPL13	Orphanet:370015	Spondyloepimetaphyseal dysplasia, Isidor-Toutain type
ANKRD11	Orphanet:2332	KBG syndrome
ANKRD11	Orphanet:261250	16q24.3 microdeletion syndrome
MUTYH	Orphanet:247798	MUTYH-related polyposis
MUTYH	Orphanet:440437	Familial colorectal cancer Type X

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	gencc,clinvar
RPL13	HGNC:10303	ENSG00000167526	P26373	Large ribosomal subunit protein eL13	clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
RPL13	Large ribosomal subunit protein eL13	Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Protease	1	9.2×	0.315
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
RPL13	Other/Unknown	no		Ribosomal_eL13, Ribosomal_eL13_CS
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
left lobe of thyroid gland	1
primordial germ cell in gonad	1
left ovary	1
right ovary	1
right uterine tube	1
stromal cell of endometrium	1
tendon of biceps brachii	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
RPL13	311	ubiquitous	marker	right uterine tube, right ovary, left ovary
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPL13	4,612
SPG7	3,970
ANKRD11	2,384
MUTYH	1,815

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL13	P26373	191
MUTYH	Q9UIF7	3
SPG7	Q9UQ90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD11	Q6UB99	39.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MUTYH substrate binding	1	3806.7×	0.003	MUTYH
Defective MUTYH substrate processing	1	3806.7×	0.003	MUTYH
Displacement of DNA glycosylase by APEX1	1	346.1×	0.025	MUTYH
Processing of SMDT1	1	211.5×	0.029	SPG7
Mitochondrial calcium ion transport	1	181.3×	0.029	SPG7
Recognition and association of DNA glycosylase with site containing an affected purine	1	68.0×	0.036	MUTYH
Cleavage of the damaged purine	1	68.0×	0.036	MUTYH
Peptide chain elongation	1	42.3×	0.036	RPL13
Viral mRNA Translation	1	42.3×	0.036	RPL13
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	1	41.8×	0.036	RPL13
Selenocysteine synthesis	1	40.1×	0.036	RPL13
Eukaryotic Translation Termination	1	40.1×	0.036	RPL13
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	39.2×	0.036	RPL13
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	1	39.2×	0.036	RPL13
Mitochondrial protein degradation	1	38.1×	0.036	SPG7
Formation of a pool of free 40S subunits	1	37.3×	0.036	RPL13
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	37.0×	0.036	RPL13
Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide	1	35.6×	0.036	RPL13
L13a-mediated translational silencing of Ceruloplasmin expression	1	33.7×	0.036	RPL13
SRP-dependent cotranslational protein targeting to membrane	1	33.4×	0.036	RPL13
GTP hydrolysis and joining of the 60S ribosomal subunit	1	33.4×	0.036	RPL13
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	32.5×	0.036	RPL13
Regulation of expression of SLITs and ROBOs	1	23.1×	0.048	RPL13
Major pathway of rRNA processing in the nucleolus and cytosol	1	20.6×	0.052	RPL13
Transport of small molecules	1	8.4×	0.119	SPG7
Metabolism of proteins	1	4.1×	0.223	SPG7

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
mitochondrial outer membrane permeabilization involved in programmed cell death	1	2106.5×	0.006	SPG7
regulation of calcium import into the mitochondrion	1	1404.3×	0.006	SPG7
depurination	1	1053.2×	0.006	MUTYH
mitochondrial protein processing	1	702.2×	0.007	SPG7
regulation of mitochondrial membrane permeability	1	351.1×	0.011	SPG7
negative regulation of necroptotic process	1	247.8×	0.013	MUTYH
blastocyst development	1	168.5×	0.013	RPL13
mismatch repair	1	162.0×	0.013	MUTYH
anterograde axonal transport	1	145.3×	0.013	SPG7
skeletal system morphogenesis	1	123.9×	0.013	ANKRD11
face morphogenesis	1	123.9×	0.013	ANKRD11
base-excision repair	1	117.0×	0.013	MUTYH
odontogenesis of dentin-containing tooth	1	75.2×	0.019	ANKRD11
bone development	1	69.1×	0.020	RPL13
cytoplasmic translation	1	46.3×	0.027	RPL13
translation	1	25.7×	0.046	RPL13
DNA repair	1	16.0×	0.068	MUTYH
nervous system development	1	11.5×	0.089	SPG7
proteolysis	1	8.6×	0.112	SPG7

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
RPL13	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPL13	1	4
SPG7	0	0
ANKRD11	0	0
MUTYH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPL13

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RPL13	90	Binding:90
MUTYH	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPG7	3.4.24.B18

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
GENTAMICIN SULFATE	4	RPL13

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RPL13
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SPG7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ANKRD11, MUTYH

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)
SPG7	0	—
ANKRD11	0	—
MUTYH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06261424	Not specified	RECRUITING	Effects of a Supervised Rehabilitation Program on Disease Severity in Spastic Ataxias
NCT05127967	Not specified	COMPLETED	Consequences of Mutations in the SPG7 Gene at the Heterozygous State