Hereditary spastic paraplegia 26

Summary

Hereditary spastic paraplegia 26 (MONDO:0012213) is a disease caused by B4GALNT1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: B4GALNT1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0000079	Abnormality of the urinary system	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0006938	Impaired vibration sensation at ankles	Occasional (5-29%)
HP:0007024	Pseudobulbar paralysis	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0001265	Hyporeflexia	Very rare (<1-4%)
HP:0008209	Premature ovarian insufficiency	Very rare (<1-4%)
HP:0040171	Decreased serum testosterone concentration	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 26
Mondo ID	MONDO:0012213
MeSH	C536862
OMIM	609195
Orphanet	101006
DOID	DOID:0110777
SNOMED CT	726607007
UMLS	C1836632
MedGen	373138
GARD	0009587
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 26 · GM2 synthase deficiency · hereditary spastic paraplegia type 26 · spastic paraplegia 26 · spastic paraplegia 26, autosomal recessive · SPG26

Data availability: 22 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 26

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, 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, 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

22 retrieved; paginated sample, class counts are floors:

6 pathogenic, 4 likely pathogenic, 4 uncertain significance, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2573474	NM_001478.5(B4GALNT1):c.584del (p.Gly195fs)	B4GALNT1	Pathogenic	criteria provided, single submitter
4081205	NM_001478.5(B4GALNT1):c.1458dup (p.Leu487fs)	B4GALNT1	Pathogenic	criteria provided, single submitter
60523	NM_001478.5(B4GALNT1):c.395del (p.Pro132fs)	B4GALNT1	Pathogenic	criteria provided, single submitter
60524	NM_001478.5(B4GALNT1):c.682C>T (p.Arg228Ter)	B4GALNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
60525	NM_001478.5(B4GALNT1):c.263dup (p.Leu89fs)	B4GALNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60526	NM_001478.5(B4GALNT1):c.358C>T (p.Gln120Ter)	B4GALNT1	Pathogenic	criteria provided, single submitter
60527	NM_001478.5(B4GALNT1):c.1298A>C (p.Asp433Ala)	B4GALNT1	Pathogenic/Likely pathogenic	no assertion criteria provided
839034	NM_001478.5(B4GALNT1):c.532-2A>G	B4GALNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989143	NM_001478.5(B4GALNT1):c.1415G>C (p.Arg472Pro)	B4GALNT1	Pathogenic	criteria provided, single submitter
989144	NM_001478.5(B4GALNT1):c.1513C>T (p.Arg505Cys)	B4GALNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582464	NM_001478.5(B4GALNT1):c.532-2_532-1delinsTC	B4GALNT1	Likely pathogenic	criteria provided, single submitter
3064127	NM_001478.5(B4GALNT1):c.1322C>A (p.Ala441Glu)	B4GALNT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4536626	NM_001478.5(B4GALNT1):c.1293_1308del (p.Asp433fs)	B4GALNT1	Likely pathogenic	criteria provided, single submitter
4759242	NM_001478.5(B4GALNT1):c.1151del (p.Gly384fs)	B4GALNT1	Likely pathogenic	criteria provided, single submitter
1000899	NM_001478.5(B4GALNT1):c.512C>T (p.Ser171Phe)	B4GALNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
458224	NM_001478.5(B4GALNT1):c.728A>G (p.Glu243Gly)	B4GALNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
947526	NM_001478.5(B4GALNT1):c.1002G>T (p.Lys334Asn)	B4GALNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451967	NM_001478.5(B4GALNT1):c.1400G>A (p.Gly467Glu)	B4GALNT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
458218	NM_001478.5(B4GALNT1):c.1048A>G (p.Lys350Glu)	B4GALNT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
835530	NM_001478.5(B4GALNT1):c.1545G>A (p.Met515Ile)	B4GALNT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
851170	NM_001478.5(B4GALNT1):c.1088C>G (p.Ala363Gly)	B4GALNT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
239026	NM_001478.5(B4GALNT1):c.793G>A (p.Gly265Arg)	B4GALNT1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
B4GALNT1	Strong	Autosomal recessive	hereditary spastic paraplegia 26	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
B4GALNT1	Orphanet:101006	Autosomal recessive spastic paraplegia type 26

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
B4GALNT1	HGNC:4117	ENSG00000135454	Q00973	Beta-1,4 N-acetylgalactosaminyltransferase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
B4GALNT1	Beta-1,4 N-acetylgalactosaminyltransferase 1	Involved in the biosynthesis of gangliosides GM2, GD2, GT2 and GA2 from GM3, GD3, GT3 and GA3, respectively.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
B4GALNT1	Enzyme (other)	yes	2.4.1.92	Glyco_trans_2-like, GM2_synthase, Nucleotide-diphossugar_trans

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
B4GALNT1	175	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
B4GALNT1	885

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
B4GALNT1	Q00973	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 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
Glycosphingolipid biosynthesis	1	601.0×	0.008	B4GALNT1
Glycosphingolipid metabolism	1	300.5×	0.008	B4GALNT1
Sphingolipid metabolism	1	167.9×	0.010	B4GALNT1
Metabolism of lipids	1	31.6×	0.040	B4GALNT1
Metabolism	1	11.6×	0.086	B4GALNT1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycosphingolipid metabolic process	1	2407.4×	0.003	B4GALNT1
vacuole organization	1	1532.0×	0.003	B4GALNT1
ganglioside biosynthetic process	1	1123.5×	0.003	B4GALNT1
nerve development	1	936.2×	0.003	B4GALNT1
motor behavior	1	561.7×	0.003	B4GALNT1
lipid storage	1	543.6×	0.003	B4GALNT1
determination of adult lifespan	1	432.1×	0.003	B4GALNT1
limb development	1	411.0×	0.003	B4GALNT1
carbohydrate metabolic process	1	135.9×	0.008	B4GALNT1
spermatogenesis	1	35.2×	0.028	B4GALNT1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
B4GALNT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B4GALNT1	2.4.1.92	(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	B4GALNT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
B4GALNT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.