Lateral sclerosis

Summary

Lateral sclerosis (MONDO:0018155) is a disease with 1 cohort gene and 30 clinical trials. Top therapeutic interventions include florbetaben f18 and levetiracetam.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 26
• Clinical trials: 30

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.5	Europe	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0002493	Upper motor neuron dysfunction	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007034	Generalized hyperreflexia	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0002127	Abnormal upper motor neuron morphology	Very frequent (80-99%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0002200	Pseudobulbar signs	Frequent (30-79%)
HP:0002311	Incoordination	Frequent (30-79%)
HP:0002371	Loss of speech	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0003444	EMG: chronic denervation signs	Frequent (30-79%)
HP:0007199	Progressive spastic paraparesis	Frequent (30-79%)
HP:0007772	Impaired smooth pursuit	Frequent (30-79%)
HP:0010549	Weakness due to upper motor neuron dysfunction	Frequent (30-79%)
HP:0031993	Hoffmann sign	Frequent (30-79%)
HP:0001611	Hypernasal speech	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)
HP:0007002	Motor axonal neuropathy	Occasional (5-29%)
HP:0010873	Cervical spinal cord atrophy	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Excluded (0%)
HP:0002366	Abnormal lower motor neuron morphology	Excluded (0%)
HP:0003474	Somatic sensory dysfunction	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lateral sclerosis
Mondo ID	MONDO:0018155
Orphanet	35689
DOID	DOID:230
ICD-10-CM	G12.23
ICD-11	1686688462
NCIT	C129933
SNOMED CT	81211007
UMLS	C0154682
MedGen	57591
GARD	0010684
MedDRA	10036704
Is cancer (heuristic)	no

Also known as: adult-onset PLS · adult-onset primary lateral sclerosis · PLS · primary lateral sclerosis

Data availability: 1 GenCC gene-disease record · 122 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › motor neuron disorder › hereditary motor neuron disease › lateral sclerosis

Related subtypes (8): prenatal-onset spinal muscular atrophy with congenital bone fractures, spinal muscular atrophy, familial amyotrophic lateral sclerosis, neurogenic scapuloperoneal syndrome, Kaeser type, riboflavin transporter deficiency, motor neuron disease with dementia and ophthalmoplegia, distal hereditary motor neuropathy, ALS2-related motor neuron disease

Subtypes (2): juvenile primary lateral sclerosis, primary lateral sclerosis, adult, 1

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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	Supportive	Autosomal dominant	lateral sclerosis	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

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
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	gencc

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.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	1
primordial germ cell in gonad	1
sural nerve	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPG7	3,970

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPG7	Q9UQ90	1

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
Processing of SMDT1	1	634.4×	0.005	SPG7
Mitochondrial calcium ion transport	1	543.8×	0.005	SPG7
Mitochondrial protein degradation	1	114.2×	0.015	SPG7
Transport of small molecules	1	25.1×	0.050	SPG7
Metabolism of proteins	1	12.4×	0.081	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 1 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	8426.0×	6e-04	SPG7
regulation of calcium import into the mitochondrion	1	5617.3×	6e-04	SPG7
mitochondrial protein processing	1	2808.7×	8e-04	SPG7
regulation of mitochondrial membrane permeability	1	1404.3×	0.001	SPG7
anterograde axonal transport	1	581.1×	0.002	SPG7
nervous system development	1	45.9×	0.025	SPG7
proteolysis	1	34.2×	0.029	SPG7

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
SPG7	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: 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	SPG7
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)
SPG7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 30.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	28
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00324454	PHASE2	COMPLETED	Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease
NCT03067857	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Therapy for Motor Neuron Disease
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02567136	Not specified	RECRUITING	Imaging Biomarkers in ALS
NCT03489278	Not specified	RECRUITING	Clinical Procedures to Support Research in ALS
NCT03912987	Not specified	ACTIVE_NOT_RECRUITING	TRIAL READY (Clinical Trial Readiness)
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT05204017	Not specified	RECRUITING	Comprehensive Analysis Platform To Understand, Remedy and Eliminate ALS
NCT05271435	Not specified	ACTIVE_NOT_RECRUITING	Digital Tools for Assessment of Motor Functions and Falls in ALS
NCT05966038	Not specified	RECRUITING	ALS/MND Natural History Study Data Repository
NCT06315673	Not specified	RECRUITING	Digital Assessment of Speech and Fine Motor Control in ALS
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06878235	Not specified	ACTIVE_NOT_RECRUITING	Validation of the French Version of the Primary Lateral Sclerosis Functioning Rating Scale (PLSFRS)
NCT07187388	Not specified	RECRUITING	Investigating the Impact of Electrical Stimulation on Facial Pain, Jaw Movement and Oral Health in People With Motor Neuron Disease.
NCT07233148	Not specified	RECRUITING	Healing ALS Registry Observational Study (HAROS)
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT00015444	Not specified	COMPLETED	Screening and Natural History: Primary Lateral Sclerosis and Related Disorders
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT00821132	Not specified	COMPLETED	Genetics of Familial and Sporadic ALS
NCT01143428	Not specified	COMPLETED	Oxidative Stress in Motor Neuron Disease: COSMOS Add-On Study
NCT01459302	Not specified	WITHDRAWN	Genetic Study of Familial and Sporadic ALS/Motor Neuron Disease, Miyoshi Myopathy and Other Neuromuscular Disorders
NCT02574390	Not specified	COMPLETED	Answer ALS: Individualized Initiative for ALS Discovery
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT03560661	Not specified	COMPLETED	Acoustic and Perceptual Markers of Dysarthria in Amyotrophic Lateral Sclerosis (ALS)
NCT04055532	Not specified	WITHDRAWN	Biomarkers in Neurodegenerative Diseases
NCT05830214	Not specified	WITHDRAWN	Digital Smartwatch Measurements as Potential Biomarkers for Remote Disease Tracking in ALS
NCT06012110	Not specified	COMPLETED	Transcutaneous Electrical Stimulation for Spasticity in Patients With Primary Lateral Sclerosis
NCT06206551	Not specified	COMPLETED	Implementing Spiritual Care in Inpatient Palliative Care
NCT06320444	Not specified	UNKNOWN	Non-invasive Spinal, Cortical, and Sensorimotor Biomarkers in Motor Neurone Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLORBETABEN F18	4	1
LEVETIRACETAM	4	1