Troyer syndrome

Summary

Troyer syndrome (MONDO:0010156) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 100
• Phenotypes (HPO): 52

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		36	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0001155	Abnormality of the hand	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001350	Slurred speech	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001760	Abnormal foot morphology	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005922	Abnormal hand morphology	Frequent (30-79%)
HP:0011094	Overbite	Frequent (30-79%)
HP:0012443	Abnormality of brain morphology	Frequent (30-79%)
HP:0100518	Dysuria	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000448	Prominent nose	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001172	Abnormal thumb morphology	Occasional (5-29%)
HP:0001609	Hoarse voice	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002064	Spastic gait	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0005288	Abnormality of the nares	Occasional (5-29%)
HP:0011098	Speech apraxia	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0025269	Panic attack	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Troyer syndrome
Mondo ID	MONDO:0010156
MeSH	C536858
OMIM	275900
Orphanet	101000
DOID	DOID:0050886
SNOMED CT	230264003
UMLS	C0393559
MedGen	97950
GARD	0005372
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 20 · childhood-onset spastic paraparesis-distal muscle wasting syndrome · Cross-McKusick syndrome · spastic paraplegia 20 · spastic paraplegia 20 (Troyer syndrome) · spastic paraplegia 20, autosomal recessive · SPG20 · Troyer syndrome

Data availability: 100 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › Troyer syndrome

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, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, 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

100 retrieved; paginated sample, class counts are floors:

61 uncertain significance, 13 conflicting classifications of pathogenicity, 9 likely benign, 7 pathogenic, 4 benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070060	NM_015087.5(SPART):c.1294del (p.Ser432fs)	SPART	Pathogenic	criteria provided, multiple submitters, no conflicts
1687408	NM_015087.5(SPART):c.894_898del (p.Met299fs)	SPART	Pathogenic	criteria provided, single submitter
183277	NM_015087.5(SPART):c.1450dup (p.Thr484fs)	SPART	Pathogenic	criteria provided, single submitter
1878642	NM_015087.5(SPART):c.696dup (p.Val233fs)	SPART	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3457	NM_015087.5(SPART):c.1110del (p.Lys370fs)	SPART	Pathogenic	criteria provided, multiple submitters, no conflicts
3458	NM_015087.5(SPART):c.364_365del (p.Met122fs)	SPART	Pathogenic	criteria provided, multiple submitters, no conflicts
379832	NM_015087.5(SPART):c.1369C>T (p.Arg457Ter)	SPART	Pathogenic	criteria provided, multiple submitters, no conflicts
989199	NM_015087.5(SPART):c.1474_1477del (p.Gln492fs)	SPART	Pathogenic	criteria provided, multiple submitters, no conflicts
1333334	NM_015087.5(SPART):c.592G>T (p.Gly198Ter)	SPART	Likely pathogenic	criteria provided, single submitter
2503433	NM_015087.5(SPART):c.1643-2A>G	SPART	Likely pathogenic	no assertion criteria provided
3383993	NM_015087.5(SPART):c.1324G>C (p.Ala442Pro)	SPART	Likely pathogenic	criteria provided, single submitter
3775802	NM_015087.5(SPART):c.1738G>T (p.Gly580Ter)	SPART	Likely pathogenic	criteria provided, single submitter
1339517	NM_015087.5(SPART):c.988A>G (p.Met330Val)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215884	NM_015087.5(SPART):c.75A>G (p.Leu25=)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216687	NM_015087.5(SPART):c.1172A>G (p.Asp391Gly)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216688	NM_015087.5(SPART):c.361G>T (p.Asp121Tyr)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240962	NM_015087.5(SPART):c.1155T>G (p.Arg385=)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311767	NM_015087.5(SPART):c.1414G>T (p.Ala472Ser)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311768	NM_015087.5(SPART):c.852G>A (p.Pro284=)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311770	NM_015087.5(SPART):c.627G>A (p.Pro209=)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311771	NM_015087.5(SPART):c.360A>G (p.Lys120=)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
380930	NM_015087.5(SPART):c.363C>T (p.Asp121=)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
461200	NM_015087.5(SPART):c.1130A>T (p.Lys377Met)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
512580	NM_015087.5(SPART):c.-8G>A	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
512598	NM_015087.5(SPART):c.1769C>T (p.Ala590Val)	SPART	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126425	NC_000004.11:g.92981313_93256907del	GRID2	Uncertain significance	no assertion criteria provided
311772	NM_015087.5(SPART):c.-33C>T	LOC130009569	Uncertain significance	criteria provided, single submitter
1032653	NM_015087.5(SPART):c.1399G>A (p.Val467Met)	SPART	Uncertain significance	criteria provided, single submitter
1301716	NM_015087.5(SPART):c.466C>T (p.Pro156Ser)	SPART	Uncertain significance	criteria provided, multiple submitters, no conflicts
1904669	NM_015087.5(SPART):c.1225C>G (p.Pro409Ala)	SPART	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
SPART	Supportive	Autosomal recessive	Troyer syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPART	Orphanet:101000	Autosomal recessive spastic paraplegia type 20
GRID2	Orphanet:363432	Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency

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
SPART	HGNC:18514	ENSG00000133104	Q8N0X7	Spartin	gencc,clinvar
GRID2	HGNC:4576	ENSG00000152208	O43424	Glutamate receptor ionotropic, delta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPART	Spartin	Lipophagy receptor that plays an important role in lipid droplet (LD) turnover in motor neurons.
GRID2	Glutamate receptor ionotropic, delta-2	Member of the ionotropic glutamate receptor family, which plays a crucial role in synaptic organization and signal transduction in the central nervous system.

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)
SPART	Other/Unknown	no		MIT_dom, Senescence/spartin_C, MIT_dom_sf
GRID2	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt

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
adrenal tissue	1
calcaneal tendon	1
left ovary	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPART	286	ubiquitous	marker	calcaneal tendon, adrenal tissue, left ovary
GRID2	114	broad	marker	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRID2	2,019
SPART	1,207

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRID2	O43424	6
SPART	Q8N0X7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
negative regulation of collateral sprouting in absence of injury	1	8426.0×	0.004	SPART
collateral sprouting in absence of injury	1	2808.7×	0.004	SPART
lipophagy	1	2808.7×	0.004	SPART
cerebellar granule cell differentiation	1	1053.2×	0.006	GRID2
positive regulation of long-term synaptic depression	1	936.2×	0.006	GRID2
synaptic signaling via neuropeptide	1	766.0×	0.006	GRID2
excitatory synapse assembly	1	648.1×	0.006	GRID2
prepulse inhibition	1	561.7×	0.006	GRID2
glutamate receptor signaling pathway	1	468.1×	0.006	GRID2
lipid droplet organization	1	468.1×	0.006	SPART
regulation of postsynaptic density assembly	1	443.5×	0.006	GRID2
midbody abscission	1	366.4×	0.007	SPART
regulation of neuron apoptotic process	1	351.1×	0.007	GRID2
regulation of mitochondrial membrane potential	1	271.8×	0.007	SPART
regulation of presynapse assembly	1	271.8×	0.007	GRID2
neuromuscular process	1	263.3×	0.007	SPART
regulation of postsynaptic membrane neurotransmitter receptor levels	1	247.8×	0.007	GRID2
excitatory postsynaptic potential	1	221.7×	0.007	GRID2
regulation of neuron projection development	1	216.1×	0.007	GRID2
adipose tissue development	1	200.6×	0.007	SPART
synaptic transmission, glutamatergic	1	179.3×	0.008	GRID2
heterophilic cell-cell adhesion	1	168.5×	0.008	GRID2
negative regulation of BMP signaling pathway	1	145.3×	0.009	SPART
lipid transport	1	131.7×	0.009	SPART
lipid catabolic process	1	122.1×	0.009	SPART
positive regulation of synapse assembly	1	122.1×	0.009	GRID2
BMP signaling pathway	1	100.3×	0.011	SPART
modulation of chemical synaptic transmission	1	91.6×	0.012	GRID2
intracellular protein localization	1	52.3×	0.020	GRID2
cell division	1	23.1×	0.043	SPART

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPART	0	0
GRID2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GRID2	1	Binding:1

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	SPART, GRID2

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)
SPART	0	—
GRID2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.