Spastic paraplegia, optic atropy, and neuropathy

Summary

Spastic paraplegia, optic atropy, and neuropathy (MONDO:0012297) is a disease caused by KLC2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KLC2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		75	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0002828	Multiple joint contractures	Very frequent (80-99%)
HP:0003693	Distal amyotrophy	Very frequent (80-99%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0002267	Exaggerated startle response	Frequent (30-79%)
HP:0002600	Hyporeflexia of lower limbs	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003380	Decreased number of peripheral myelinated nerve fibers	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0007020	Progressive spastic paraplegia	Frequent (30-79%)
HP:0007054	Hyperreflexia proximally	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia, optic atropy, and neuropathy
Mondo ID	MONDO:0012297
MeSH	C563702
OMIM	609541
Orphanet	320406
DOID	DOID:0060491
UMLS	C1836010
MedGen	324411
GARD	0017479
Is cancer (heuristic)	no

Also known as: spastic paraplegia-optic atrophy-neuropathy syndrome · SPOAN · SPOAN syndrome

Data availability: 5 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › spastic paraplegia, optic atropy, and neuropathy

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, 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

5 retrieved; paginated sample, class counts are floors:

3 benign, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
222029	NM_001134775.1(KLC2):c.-451_-235del	KLC2	Pathogenic	no assertion criteria provided
1028782	NM_001318734.2(KLC2):c.1526G>A (p.Arg509Gln)	KLC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1300078	NM_001318734.2(KLC2):c.942+27T>C	KLC2	Benign	criteria provided, multiple submitters, no conflicts
1300079	NM_001318734.2(KLC2):c.1086C>T (p.Asp362=)	KLC2	Benign	criteria provided, multiple submitters, no conflicts
1300080	NM_001318734.2(KLC2):c.1444-24C>T	KLC2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
KLC2	Strong	Autosomal recessive	spastic paraplegia, optic atropy, and neuropathy	4
FLRT1	Supportive	Autosomal recessive	spastic paraplegia, optic atropy, and neuropathy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLC2	Orphanet:320406	Spastic paraplegia-optic atrophy-neuropathy syndrome
FLRT1	Orphanet:320406	Spastic paraplegia-optic atrophy-neuropathy syndrome

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
KLC2	HGNC:20716	ENSG00000174996	Q9H0B6	Kinesin light chain 2	gencc,clinvar
FLRT1	HGNC:3760	ENSG00000126500	Q9NZU1	Leucine-rich repeat transmembrane protein FLRT1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLC2	Kinesin light chain 2	Kinesin is a microtubule-associated force-producing protein that plays a role in organelle transport.
FLRT1	Leucine-rich repeat transmembrane protein FLRT1	Plays a role in fibroblast growth factor-mediated signaling cascades that lead to the activation of MAP kinases.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLC2	Other/Unknown	no		Kinesin_light, TPR-like_helical_dom_sf, Kinesin_light_repeat
FLRT1	Antibody/Immunoglobulin	yes		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
Brodmann (1909) area 10	1
frontal pole	1
olfactory bulb	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLC2	220	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FLRT1	188	broad	yes	Brodmann (1909) area 10, olfactory bulb, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KLC2	3,326
FLRT1	1,198

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KLC2	Q9H0B6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FLRT1	Q9NZU1	73.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 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
RHO GTPases activate KTN1	1	519.1×	0.031	KLC2
Downstream signaling of activated FGFR1	1	271.9×	0.031	FLRT1
Kinesins	1	89.2×	0.054	KLC2
Golgi-to-ER retrograde transport	1	66.4×	0.054	KLC2
COPI-dependent Golgi-to-ER retrograde traffic	1	55.4×	0.054	KLC2
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.054	KLC2
MHC class II antigen presentation	1	44.6×	0.054	KLC2
RHO GTPase Effectors	1	34.0×	0.056	KLC2
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.056	KLC2
Membrane Trafficking	1	18.5×	0.071	KLC2
Hemostasis	1	18.0×	0.071	KLC2
Vesicle-mediated transport	1	17.4×	0.071	KLC2
Signaling by Rho GTPases	1	17.1×	0.071	KLC2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.071	KLC2
Adaptive Immune System	1	14.9×	0.075	KLC2
Immune System	1	6.5×	0.158	KLC2
Signal Transduction	1	5.1×	0.187	KLC2

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
lysosome localization	1	263.3×	0.010	KLC2
neuron projection extension	1	263.3×	0.010	FLRT1
dendrite development	1	195.9×	0.010	FLRT1
microtubule-based movement	1	147.8×	0.010	KLC2
fibroblast growth factor receptor signaling pathway	1	142.8×	0.010	FLRT1
positive regulation of synapse assembly	1	122.1×	0.010	FLRT1
cell adhesion	1	18.7×	0.053	FLRT1

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
KLC2	0	0
FLRT1	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	1	FLRT1
E	Difficult family or no structure, no drug	1	KLC2

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)
KLC2	0	—
FLRT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.