Proximal spinal muscular atrophy

Summary

Proximal spinal muscular atrophy (MONDO:0019079) is a disease (an umbrella term covering 6 Mondo subtypes) with 3 cohort genes and 18 clinical trials. Top therapeutic interventions include nusinersen, pyridostigmine, and riluzole.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 50
• Clinical trials: 18

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.6	Europe	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Prevalence at birth	1-5 / 10 000	20	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003701	Proximal muscle weakness	Very frequent (80-99%)
HP:0001283	Bulbar palsy	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001308	Tongue fasciculations	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002100	Recurrent aspiration pneumonia	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0003327	Axial muscle weakness	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003731	Quadriceps muscle weakness	Frequent (30-79%)
HP:0004878	Intercostal muscle weakness	Frequent (30-79%)
HP:0004891	Recurrent infections due to aspiration	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0031108	Triceps weakness	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002091	Restrictive ventilatory defect	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002578	Gastroparesis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002791	Hypoventilation	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002828	Multiple joint contractures	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0002942	Thoracic kyphosis	Occasional (5-29%)
HP:0003698	Difficulty standing	Occasional (5-29%)
HP:0006380	Knee flexion contracture	Occasional (5-29%)
HP:0006844	Absent patellar reflexes	Occasional (5-29%)
HP:0008959	Distal upper limb muscle weakness	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0001662	Bradycardia	Very rare (<1-4%)
HP:0001942	Metabolic acidosis	Very rare (<1-4%)
HP:0002987	Elbow flexion contracture	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	proximal spinal muscular atrophy
Mondo ID	MONDO:0019079
Orphanet	70
UMLS	C4024957
MedGen	870510
GARD	0004531
NORD	1729
Is cancer (heuristic)	no

Also known as: SMA

Data availability: 3 ClinVar variants · 101 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › proximal spinal muscular atrophy

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, adult-onset proximal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, segmental, spinal muscular atrophy, Ryukyuan type, scapuloperoneal spinal muscular atrophy, autosomal recessive, X-linked distal spinal muscular atrophy type 3, infantile-onset X-linked spinal muscular atrophy, autosomal recessive distal spinal muscular atrophy 1, autosomal recessive distal spinal muscular atrophy 2, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 4, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal dominant, bulbospinal muscular atrophy, spinal muscular atrophy with respiratory distress type 2, spinal muscular atrophy type 0

Subtypes (6): spinal muscular atrophy, type 1, spinal muscular atrophy, type III, spinal muscular atrophy, type II, spinal muscular atrophy, type IV, lower motor neuron syndrome with late-adult onset, autosomal dominant childhood-onset proximal spinal muscular atrophy

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

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6816	NM_003119.4(SPG7):c.233T>A (p.Leu78Ter)	SPG7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549697	NM_006329.4(FBLN5):c.605G>T (p.Gly202Val)	FBLN5	Uncertain significance	no assertion criteria provided
549704	NM_015046.7(SETX):c.7711C>T (p.Pro2571Ser)	SETX	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
FBLN5	Orphanet:280598	Hereditary sensorimotor neuropathy with hyperelastic skin
FBLN5	Orphanet:90348	Autosomal dominant cutis laxa
FBLN5	Orphanet:90349	Autosomal recessive cutis laxa type 1
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2

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
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
FBLN5	HGNC:3602	ENSG00000140092	Q9UBX5	Fibulin-5	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	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.
FBLN5	Fibulin-5	Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
FBLN5	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C

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 lobe of thyroid gland	1
primordial germ cell in gonad	1
sural nerve	1
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
calcaneal tendon	1
left testis	1
right testis	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
FBLN5	261	ubiquitous	marker	thoracic aorta, ascending aorta, descending thoracic aorta
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPG7	3,970
SETX	3,127
FBLN5	2,301

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPG7	Q9UQ90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBLN5	Q9UBX5	83.69
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Processing of SMDT1	1	317.2×	0.011	SPG7
Mitochondrial calcium ion transport	1	271.9×	0.011	SPG7
Elastic fibre formation	1	167.9×	0.011	FBLN5
Molecules associated with elastic fibres	1	154.3×	0.011	FBLN5
Mitochondrial protein degradation	1	57.1×	0.024	SPG7
Transport of small molecules	1	12.6×	0.091	SPG7
Metabolism of proteins	1	6.2×	0.155	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of termination of DNA-templated transcription	1	5617.3×	0.003	SETX
intramembranous bone growth	1	5617.3×	0.003	FBLN5
mitochondrial outer membrane permeabilization involved in programmed cell death	1	2808.7×	0.004	SPG7
regulation of calcium import into the mitochondrion	1	1872.4×	0.004	SPG7
positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1	1872.4×	0.004	SETX
mitochondrial protein processing	1	936.2×	0.005	SPG7
regulation of removal of superoxide radicals	1	936.2×	0.005	FBLN5
secretion	1	702.2×	0.005	FBLN5
nervous system development	2	30.6×	0.005	SPG7, SETX
positive regulation of DNA-templated transcription initiation	1	624.1×	0.005	SETX
DNA-templated transcription termination	1	510.7×	0.006	SETX
elastic fiber assembly	1	510.7×	0.006	FBLN5
regulation of mitochondrial membrane permeability	1	468.1×	0.006	SPG7
termination of RNA polymerase II transcription	1	432.1×	0.006	SETX
positive regulation of osteoblast proliferation	1	401.2×	0.006	FBLN5
positive regulation of RNA splicing	1	351.1×	0.006	SETX
mRNA splice site recognition	1	267.5×	0.007	SETX
anterograde axonal transport	1	193.7×	0.010	SPG7
protein localization to cell surface	1	165.2×	0.011	FBLN5
DNA recombination	1	112.3×	0.015	SETX
circadian rhythm	1	81.4×	0.019	SETX
cellular response to hydrogen peroxide	1	78.0×	0.019	SETX
positive regulation of transcription by RNA polymerase II	2	9.9×	0.019	FBLN5, SETX
RNA processing	1	73.0×	0.019	SETX
double-strand break repair	1	67.7×	0.020	SETX
negative regulation of angiogenesis	1	56.2×	0.023	FBLN5
cell-matrix adhesion	1	54.5×	0.023	FBLN5
cellular response to oxidative stress	1	51.5×	0.023	SETX
positive regulation of neuron projection development	1	45.7×	0.025	SETX
DNA damage response	1	17.8×	0.062	SETX

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
SPG7	0	0
FBLN5	0	0
SETX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPG7	3.4.24.B18

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

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	SPG7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FBLN5, SETX

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	—
FBLN5	0	—
SETX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE3	5
PHASE2	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04042025	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT00774423	PHASE2/PHASE3	COMPLETED	Study to Evaluate the Efficacy of Riluzole in Children and Young Adults With Spinal Muscular Atrophy (SMA)
NCT03461289	PHASE3	COMPLETED	Single-Dose Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT07047144	PHASE2	RECRUITING	A Study to Evaluate How Apitegromab Works in Subjects Who Are Less Than 2 Years Old and Have Spinal Muscular Atrophy
NCT02941328	PHASE2	COMPLETED	SPACE Trial: Pyridostigmine vs Placebo in SMA Types 2, 3 and 4
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT04292574	Not specified	RECRUITING	UK SMA Patient Registry
NCT05102916	Not specified	RECRUITING	Swiss Registry for Neuromuscular Disorders
NCT06147414	Not specified	RECRUITING	Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders
NCT06300996	Not specified	ACTIVE_NOT_RECRUITING	Spinal Cord Stimulation for the Treatment of Motor Deficits in People With Spinal Muscular Atrophy - Upper Limb
NCT06322654	Not specified	RECRUITING	A Head-to-head Study Comparing the Functional Value of Two Models of Robotically Assisted Rehabilitation in SMA (Spinal Muscular Atrophy) Patients
NCT07321990	Not specified	RECRUITING	Study of the Reproducibility of the French Version of the Modified SMAFRS Scale
NCT01984957	Not specified	COMPLETED	Differential Study of Muscle Transcriptome
NCT04825119	Not specified	UNKNOWN	Hyperkinetic Movements in Patients With Disease of Motor Neurons and Their Response to Treatment With Nusinersen
NCT06877689	Not specified	NO_LONGER_AVAILABLE	EAP of Apitegromab for Patients With Spinal Muscular Atrophy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NUSINERSEN	4	2
PYRIDOSTIGMINE	4	1
RILUZOLE	4	1
RISDIPLAM	4	1
APITEGROMAB	3	5
TALDEFGROBEP ALFA	3	1