hereditary spastic paraplegia 3A

Summary

hereditary spastic paraplegia 3A (MONDO:0008437) is a disease caused by ATL1 (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: ATL1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 541
• Phenotypes (HPO): 20
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Point prevalence	1-9 / 1 000 000	0.14	Portugal	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0011448	Ankle clonus	Frequent (30-79%)
HP:0000012	Urinary urgency	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0002495	Impaired vibratory sensation	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0001260	Dysarthria	Very rare (<1-4%)
HP:0001510	Growth delay	Very rare (<1-4%)
HP:0002063	Rigidity	Very rare (<1-4%)
HP:0002067	Bradykinesia	Very rare (<1-4%)
HP:0002359	Frequent falls	Very rare (<1-4%)
HP:0006895	Lower limb hypertonia	Very rare (<1-4%)
HP:0100963	Hyperesthesia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 3A
Mondo ID	MONDO:0008437
MeSH	C536864
OMIM	182600
Orphanet	100984
DOID	DOID:0110791
NCIT	C142893
UMLS	C2931355
MedGen	419393
GARD	0005041
Is cancer (heuristic)	no

Also known as: ATL1 hereditary spastic paraplegia · autosomal dominant spastic paraplegia type 3 · FSP1 · hereditary spastic paraplegia caused by mutation in ATL1 · hereditary spastic paraplegia type 3A · spastic paraplegia 3 · spastic paraplegia 3, autosomal dominant · spastic Paraplegia 3A · spastic paraplegia 3a, autosomal dominant · SPG3A · strumpell disease · Strümpell disease

Data availability: 541 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

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 › hereditary spastic paraplegia 3A

Related subtypes (44): hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

541 retrieved; paginated sample, class counts are floors:

226 uncertain significance, 149 likely benign, 49 conflicting classifications of pathogenicity, 36 pathogenic, 27 likely pathogenic, 24 benign, 14 benign/likely benign, 13 pathogenic/likely pathogenic, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072586	NM_015915.5(ATL1):c.565C>G (p.His189Asp)	ATL1	Pathogenic	criteria provided, single submitter
1456145	NM_015915.5(ATL1):c.773A>T (p.His258Leu)	ATL1	Pathogenic	criteria provided, single submitter
157549	NM_015915.5(ATL1):c.353G>A (p.Arg118Gln)	ATL1	Pathogenic	criteria provided, single submitter
1685247	NM_015915.5(ATL1):c.466A>C (p.Thr156Pro)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191046	NM_015915.5(ATL1):c.988A>T (p.Lys330Ter)	ATL1	Pathogenic	criteria provided, single submitter
1996944	NM_015915.5(ATL1):c.584A>C (p.Glu195Ala)	ATL1	Pathogenic	criteria provided, single submitter
2037429	NM_015915.5(ATL1):c.1101C>A (p.Tyr367Ter)	ATL1	Pathogenic	criteria provided, single submitter
208489	NM_015915.5(ATL1):c.596T>A (p.Leu199Gln)	ATL1	Pathogenic	no assertion criteria provided
21531	NM_015915.5(ATL1):c.467C>T (p.Thr156Ile)	ATL1	Pathogenic	criteria provided, multiple submitters, no conflicts
219827	NM_015915.5(ATL1):c.1483C>T (p.Arg495Trp)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220424	NM_015915.5(ATL1):c.757G>A (p.Val253Ile)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2571508	NM_015915.5(ATL1):c.1024C>T (p.Pro342Ser)	ATL1	Pathogenic	criteria provided, single submitter
2571511	NM_015915.5(ATL1):c.1193C>T (p.Ser398Phe)	ATL1	Pathogenic	criteria provided, single submitter
2571515	NM_015915.5(ATL1):c.1319A>C (p.Asn440Thr)	ATL1	Pathogenic	criteria provided, single submitter
2826561	NM_015915.5(ATL1):c.1030_1040del (p.Pro344fs)	ATL1	Pathogenic	criteria provided, single submitter
2860253	NM_015915.5(ATL1):c.336G>A (p.Trp112Ter)	ATL1	Pathogenic	criteria provided, single submitter
3244009	NC_000014.8:g.(?51087297)(51095200_?)del	ATL1	Pathogenic	criteria provided, single submitter
3606208	NM_015915.5(ATL1):c.56_57del (p.Thr18_Tyr19insTer)	ATL1	Pathogenic	criteria provided, single submitter
3639402	NM_015915.5(ATL1):c.521del (p.Gln174fs)	ATL1	Pathogenic	criteria provided, single submitter
3729603	NM_015915.5(ATL1):c.1008T>G (p.Tyr336Ter)	ATL1	Pathogenic	criteria provided, single submitter
421566	NM_015915.5(ATL1):c.1225G>T (p.Gly409Cys)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4346	NM_015915.5(ATL1):c.715C>T (p.Arg239Cys)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4347	NM_015915.5(ATL1):c.776C>A (p.Ser259Tyr)	ATL1	Pathogenic	criteria provided, single submitter
4348	NM_015915.5(ATL1):c.773A>G (p.His258Arg)	ATL1	Pathogenic	criteria provided, multiple submitters, no conflicts
4349	NM_015915.5(ATL1):c.650G>A (p.Arg217Gln)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4351	NM_015915.5(ATL1):c.1222A>G (p.Met408Val)	ATL1	Pathogenic	criteria provided, single submitter
4352	NM_015915.5(ATL1):c.1243C>T (p.Arg415Trp)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4353	NM_015915.5(ATL1):c.470T>G (p.Leu157Trp)	ATL1	Pathogenic	no assertion criteria provided
4354	NM_015915.5(ATL1):c.1306_1308del (p.Asn436del)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446865	NM_015915.5(ATL1):c.1228G>A (p.Gly410Arg)	ATL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
ATL1	Definitive	Semidominant	hereditary spastic paraplegia 3A	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATL1	Orphanet:100984	Autosomal dominant spastic paraplegia type 3
ATL1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy

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
ATL1	HGNC:11231	ENSG00000198513	Q8WXF7	Atlastin-1	gencc,clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATL1	Atlastin-1	Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATL1	Other/Unknown	no		Guanylate-bd_N, P-loop_NTPase, G_GB1_RHD3_dom
BICD2	Other/Unknown	no		BICD

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
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
gingiva	1
gingival epithelium	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATL1	241	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BICD2	2,275
ATL1	1,206

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATL1	Q8WXF7	14
BICD2	Q8TD16	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	BICD2
Golgi-to-ER retrograde transport	1	132.8×	0.016	BICD2
Intra-Golgi and retrograde Golgi-to-ER traffic	1	104.8×	0.016	BICD2
Membrane Trafficking	1	37.1×	0.029	BICD2
Vesicle-mediated transport	1	34.8×	0.029	BICD2

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
microtubule anchoring at microtubule organizing center	1	4213.0×	0.003	BICD2
minus-end-directed organelle transport along microtubule	1	2106.5×	0.003	BICD2
endoplasmic reticulum membrane fusion	1	1685.2×	0.003	ATL1
endoplasmic reticulum tubular network membrane organization	1	1053.2×	0.003	ATL1
centrosome localization	1	443.5×	0.006	BICD2
protein localization to Golgi apparatus	1	401.2×	0.006	BICD2
regulation of microtubule cytoskeleton organization	1	271.8×	0.007	BICD2
endoplasmic reticulum organization	1	210.7×	0.008	ATL1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	168.5×	0.009	BICD2
microtubule-based movement	1	147.8×	0.009	BICD2
mRNA transport	1	131.7×	0.010	BICD2
axonogenesis	1	80.2×	0.014	ATL1
protein homooligomerization	1	61.1×	0.018	ATL1
protein transport	1	21.9×	0.045	BICD2

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
ATL1	0	0
BICD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ATL1, BICD2

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)
ATL1	0	—
BICD2	0	—

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
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia