Hereditary spastic paraplegia 75

Summary

Hereditary spastic paraplegia 75 (MONDO:0014729) is a disease caused by MAG (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAG (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 272
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001310	Dysmetria	Very frequent (80-99%)
HP:0002495	Impaired vibratory sensation	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0000483	Astigmatism	Frequent (30-79%)
HP:0000540	Hypermetropia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0012511	Temporal optic disc pallor	Frequent (30-79%)
HP:0030187	Titubation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 75
Mondo ID	MONDO:0014729
OMIM	616680
Orphanet	459056
DOID	DOID:0110820
UMLS	C4225250
MedGen	896387
GARD	0017813
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 75 · hereditary spastic paraplegia caused by mutation in MAG · hereditary spastic paraplegia type 75 · MAG hereditary spastic paraplegia · spastic paraplegia 75, autosomal recessive · SPG75

Data availability: 272 ClinVar variants · 2 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 75

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 45, 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, 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

272 retrieved; paginated sample, class counts are floors:

133 likely benign, 101 uncertain significance, 12 benign, 8 pathogenic, 6 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
120188	NM_002361.4(MAG):c.1288T>G (p.Cys430Gly)	MAG	Pathogenic	no assertion criteria provided
1478560	NM_002361.4(MAG):c.719dup (p.Val241fs)	MAG	Pathogenic	criteria provided, single submitter
218187	NM_002361.4(MAG):c.399C>G (p.Ser133Arg)	MAG	Pathogenic	no assertion criteria provided
3764543	NM_002361.4(MAG):c.337G>A (p.Gly113Arg)	MAG	Pathogenic	no assertion criteria provided
4703049	NM_002361.4(MAG):c.1273C>T (p.Arg425Ter)	MAG	Pathogenic	criteria provided, single submitter
488543	NM_002361.4(MAG):c.517_521dup (p.Trp174Ter)	MAG	Pathogenic	criteria provided, single submitter
657878	NM_002361.4(MAG):c.328G>T (p.Glu110Ter)	MAG	Pathogenic	criteria provided, single submitter
976659	NM_002361.4(MAG):c.1126C>T (p.Gln376Ter)	MAG	Pathogenic	criteria provided, single submitter
976660	NM_002361.4(MAG):c.1522C>T (p.Arg508Ter)	MAG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585566	NM_002361.4(MAG):c.470del (p.Val157fs)	MAG	Likely pathogenic	criteria provided, single submitter
2857234	NM_002361.4(MAG):c.1520-3_1520-2del	MAG	Likely pathogenic	criteria provided, single submitter
3256730	NM_002361.4(MAG):c.809T>C (p.Leu270Pro)	MAG	Likely pathogenic	no assertion criteria provided
3643289	NM_002361.4(MAG):c.1616+1G>A	MAG	Likely pathogenic	criteria provided, single submitter
3644099	NM_002361.4(MAG):c.1232-3_1240del	MAG	Likely pathogenic	criteria provided, single submitter
1309654	NM_002361.4(MAG):c.600A>T (p.Ser200=)	MAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424686	NM_002361.4(MAG):c.452C>T (p.Ala151Val)	MAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
568410	NM_002361.4(MAG):c.1719C>T (p.Ser573=)	MAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
654572	NM_002361.4(MAG):c.1058C>T (p.Pro353Leu)	MAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
705599	NM_002361.4(MAG):c.1609C>T (p.Arg537Cys)	MAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
708514	NM_002361.4(MAG):c.971-5C>T	MAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424426	NC_000019.9:g.(?33167170)(36643309_?)dup	ALKBH6	Uncertain significance	criteria provided, single submitter
1029591	NM_002361.4(MAG):c.541G>T (p.Gly181Trp)	MAG	Uncertain significance	criteria provided, single submitter
1029592	NM_002361.4(MAG):c.795C>A (p.Ser265Arg)	MAG	Uncertain significance	criteria provided, single submitter
1341703	NM_002361.4(MAG):c.562C>T (p.Arg188Trp)	MAG	Uncertain significance	criteria provided, single submitter
1345617	NM_002361.4(MAG):c.1782C>A (p.Asp594Glu)	MAG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1351102	NM_002361.4(MAG):c.569G>A (p.Arg190Gln)	MAG	Uncertain significance	criteria provided, single submitter
1357205	NM_002361.4(MAG):c.157G>A (p.Ala53Thr)	MAG	Uncertain significance	criteria provided, single submitter
1362969	NM_002361.4(MAG):c.116C>T (p.Ser39Phe)	MAG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1369805	NM_002361.4(MAG):c.1688G>A (p.Arg563His)	MAG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1371244	NM_002361.4(MAG):c.1393C>T (p.Arg465Cys)	MAG	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 5 · 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
ERCC2	Strong	Autosomal recessive	hereditary spastic paraplegia 75	19
MAG	Strong	Autosomal recessive	hereditary spastic paraplegia 75	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
MAG	Orphanet:459056	Autosomal recessive spastic paraplegia type 75

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	gencc,clinvar
MAG	HGNC:6783	ENSG00000105695	P20916	Myelin-associated glycoprotein	gencc,clinvar
ALKBH6	HGNC:28243	ENSG00000239382	Q3KRA9	Probable RNA/DNA demethylase ALKBH6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
MAG	Myelin-associated glycoprotein	Adhesion molecule that mediates interactions between myelinating cells and neurons by binding to neuronal sialic acid-containing gangliosides and to the glycoproteins RTN4R and RTN4RL2.
ALKBH6	Probable RNA/DNA demethylase ALKBH6	Probable Fe(2+)/2-oxoglutarate-dependent dioxygenase involved in oxidative demethylation of nucleic acids.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
MAG	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
ALKBH6	Other/Unknown	no		Oxoglu/Fe-dep_dioxygenase_dom, AlkB-like, ALKBH6

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
stromal cell of endometrium	1
C1 segment of cervical spinal cord	1
inferior vagus X ganglion	1
spinal cord	1
endothelial cell	1
lateral nuclear group of thalamus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
MAG	187	broad	marker	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion
ALKBH6	248	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, pons

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC2	2,746
MAG	2,513
ALKBH6	427

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC2	P18074	51
ALKBH6	Q3KRA9	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAG	P20916	80.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 3 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
p75NTR regulates axonogenesis	1	1142.0×	0.015	MAG
Axonal growth inhibition (RHOA activation)	1	634.4×	0.015	MAG
Cytosolic iron-sulfur cluster assembly	1	380.7×	0.015	ERCC2
Basigin interactions	1	219.6×	0.015	MAG
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	203.9×	0.015	ERCC2
RNA Pol II CTD phosphorylation and interaction with CE	1	203.9×	0.015	ERCC2
mRNA Capping	1	190.3×	0.015	ERCC2
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.015	MAG
Formation of the Early Elongation Complex	1	167.9×	0.015	ERCC2
Formation of the HIV-1 Early Elongation Complex	1	167.9×	0.015	ERCC2
RNA Polymerase I Transcription Termination	1	163.1×	0.015	ERCC2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	132.8×	0.015	ERCC2
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	129.8×	0.015	ERCC2
Tat-mediated elongation of the HIV-1 transcript	1	129.8×	0.015	ERCC2
Dual Incision in GG-NER	1	129.8×	0.015	ERCC2
Formation of Incision Complex in GG-NER	1	126.9×	0.015	ERCC2
Formation of HIV elongation complex in the absence of HIV Tat	1	124.1×	0.015	ERCC2
HIV Transcription Initiation	1	116.5×	0.015	ERCC2
RNA Polymerase II HIV Promoter Escape	1	116.5×	0.015	ERCC2
RNA Polymerase II Promoter Escape	1	116.5×	0.015	ERCC2
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	1	116.5×	0.015	ERCC2
RNA Polymerase II Transcription Initiation	1	116.5×	0.015	ERCC2
RNA Polymerase II Transcription Initiation And Promoter Clearance	1	116.5×	0.015	ERCC2
RNA Polymerase I Transcription Initiation	1	112.0×	0.015	ERCC2
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.015	ERCC2
Formation of RNA Pol II elongation complex	1	96.8×	0.015	ERCC2
RNA Polymerase II Transcription Elongation	1	96.8×	0.015	ERCC2
p75 NTR receptor-mediated signalling	1	93.6×	0.015	MAG
TP53 Regulates Transcription of DNA Repair Genes	1	90.6×	0.015	ERCC2
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.015	ERCC2

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
central nervous system myelin formation	2	2407.4×	6e-06	ERCC2, MAG
positive regulation of mitotic recombination	1	4213.0×	0.005	ERCC2
transcription elongation by RNA polymerase I	1	1053.2×	0.006	ERCC2
hair cell differentiation	1	1053.2×	0.006	ERCC2
hair follicle maturation	1	1053.2×	0.006	ERCC2
embryonic cleavage	1	842.6×	0.006	ERCC2
regulation of mitotic cell cycle phase transition	1	842.6×	0.006	ERCC2
positive regulation of astrocyte differentiation	1	702.2×	0.006	MAG
transcription-coupled nucleotide-excision repair	1	601.9×	0.006	ERCC2
UV protection	1	601.9×	0.006	ERCC2
axon regeneration	1	561.7×	0.006	MAG
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	561.7×	0.006	MAG
erythrocyte maturation	1	421.3×	0.007	ERCC2
positive regulation of myelination	1	383.0×	0.007	MAG
hematopoietic stem cell differentiation	1	383.0×	0.007	ERCC2
negative regulation of axon extension	1	366.4×	0.007	MAG
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	337.0×	0.007	ERCC2
transmission of nerve impulse	1	324.1×	0.007	MAG
hematopoietic stem cell proliferation	1	324.1×	0.007	ERCC2
intrinsic apoptotic signaling pathway by p53 class mediator	1	290.6×	0.007	ERCC2
spinal cord development	1	255.3×	0.008	ERCC2
insulin-like growth factor receptor signaling pathway	1	247.8×	0.008	ERCC2
embryonic organ development	1	240.7×	0.008	ERCC2
determination of adult lifespan	1	216.1×	0.008	ERCC2
nucleotide-excision repair	1	191.5×	0.009	ERCC2
transcription initiation at RNA polymerase II promoter	1	187.2×	0.009	ERCC2
substantia nigra development	1	183.2×	0.009	MAG
bone mineralization	1	135.9×	0.011	ERCC2
negative regulation of neuron differentiation	1	135.9×	0.011	MAG
negative regulation of neuron projection development	1	118.7×	0.012	MAG

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
ERCC2	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC2	16	4
MAG	0	0
ALKBH6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAG	12	Binding:12
ERCC2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERCC2	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

16 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)
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ERCC2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MAG
E	Difficult family or no structure, no drug	1	ALKBH6

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)
MAG	12	—
ALKBH6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.