Inherited neurodegenerative disorder

Summary

Inherited neurodegenerative disorder (MONDO:0024237) is a disease (an umbrella term covering 82 Mondo subtypes) caused by KIF5A (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Causal gene: KIF5A (GenCC Definitive)
• Umbrella term: 82 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 1
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited neurodegenerative disorder
Mondo ID	MONDO:0024237
MeSH	D020271
Orphanet	183500
NCIT	C97073
UMLS	C5680568
MedGen	1825988
GARD	0020280
Is cancer (heuristic)	no

Also known as: genetic neurodegenerative disease · hereditary neurodegenerative disease · hereditary neurodegenerative disorder

Data availability: 1 ClinVar variant · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 82 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder

Related subtypes (21): synucleinopathy, eyelid degenerative disorder, senile degeneration of brain, olivopontocerebellar atrophy, neuroaxonal dystrophy, demyelinating disease, choroidal sclerosis, tauopathy, secondary Parkinson disease, infantile bilateral striatal necrosis, Marchiafava-Bignami disease, superficial siderosis, primary progressive apraxia of speech, human prion disease, primary progressive freezing gait, primary progressive aphasia, motor neuron disorder, brachial amyotrophic diplegia, cerebellar degeneration, cerebral degeneration, hypertrophic olivary degeneration

Subtypes (82): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2672172	NM_004984.4(KIF5A):c.646_648del (p.Glu216del)	KIF5A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · 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
KIF5A	Definitive	Autosomal dominant	inherited neurodegenerative disorder	15
SLC5A6	Moderate	Autosomal recessive	inherited neurodegenerative disorder	6
BORCS8	Limited	Autosomal recessive	inherited neurodegenerative disorder	3
NME3	Limited	Autosomal recessive	inherited neurodegenerative disorder

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF5A	Orphanet:100991	Autosomal dominant spastic paraplegia type 10
KIF5A	Orphanet:324611	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	gencc,clinvar
SLC5A6	HGNC:11041	ENSG00000138074	Q9Y289	Sodium-dependent multivitamin transporter	gencc
BORCS8	HGNC:37247	ENSG00000254901	Q96FH0	BLOC-1-related complex subunit 8	gencc
NME3	HGNC:7851	ENSG00000103024	Q13232	Nucleoside diphosphate kinase C	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).
SLC5A6	Sodium-dependent multivitamin transporter	Sodium-dependent multivitamin transporter that mediates the electrogenic transport of pantothenate, biotin, lipoate and iodide.
BORCS8	BLOC-1-related complex subunit 8	As part of the BLOC-one-related complex (BORC), it plays a role in the movement and localization of lysosomes at the cell periphery.
NME3	Nucleoside diphosphate kinase C	Catalyzes the transfer of a gamma-phosphoryl group from a nucleoside triphosphate, mainly ATP, to a nucleoside diphosphate via a ping-pong mechanism involving a phosphohistidine intermediate, therefore contributing to the nucleoside tripho…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Kinase	1	6.9×	0.273
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
SLC5A6	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, Na/Glc_symporter_sf
BORCS8	Other/Unknown	no		BORCS8
NME3	Kinase	yes	2.7.4.6	Nucleoside_diP_kinase, Nucleoside_diP_kinase_AS, NDK-like_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
cerebellar hemisphere	1
right frontal lobe	1
left testis	1
right lobe of liver	1
right testis	1
anterior cingulate cortex	1
cingulate cortex	1
prefrontal cortex	1
adenohypophysis	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere
SLC5A6	222	ubiquitous	marker	right lobe of liver, right testis, left testis
BORCS8	253	ubiquitous	marker	prefrontal cortex, anterior cingulate cortex, cingulate cortex
NME3	265	ubiquitous	marker	adenohypophysis, right hemisphere of cerebellum, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NME3	5,860
KIF5A	3,241
SLC5A6	1,281
BORCS8	489

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NME3	Q13232	7
KIF5A	Q12840	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BORCS8	Q96FH0	92.74
SLC5A6	Q9Y289	79.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Biotin transport and metabolism	1	346.1×	0.038	SLC5A6
RHO GTPases activate KTN1	1	346.1×	0.038	KIF5A
Vitamin B5 (pantothenate) metabolism	1	253.8×	0.038	SLC5A6
Insulin processing	1	152.3×	0.040	KIF5A
Interconversion of nucleotide di- and triphosphates	1	119.0×	0.040	NME3
Metabolism of nucleotides	1	100.2×	0.040	NME3
Peptide hormone metabolism	1	90.6×	0.040	KIF5A
Transport of vitamins, nucleosides, and related molecules	1	90.6×	0.040	SLC5A6
Metabolism of water-soluble vitamins and cofactors	1	60.4×	0.048	SLC5A6
Kinesins	1	59.5×	0.048	KIF5A
Golgi-to-ER retrograde transport	1	44.3×	0.054	KIF5A
Metabolism	2	7.7×	0.054	SLC5A6, NME3
Metabolism of vitamins and cofactors	1	38.8×	0.055	SLC5A6
COPI-dependent Golgi-to-ER retrograde traffic	1	37.0×	0.055	KIF5A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	34.9×	0.055	KIF5A
MHC class II antigen presentation	1	29.7×	0.060	KIF5A
RHO GTPase Effectors	1	22.7×	0.072	KIF5A
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.072	KIF5A
SLC-mediated transmembrane transport	1	19.7×	0.076	SLC5A6
Membrane Trafficking	1	12.4×	0.105	KIF5A
Hemostasis	1	12.0×	0.105	KIF5A
Vesicle-mediated transport	1	11.6×	0.105	KIF5A
Signaling by Rho GTPases	1	11.4×	0.105	KIF5A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.105	KIF5A
Adaptive Immune System	1	9.9×	0.113	KIF5A
Transport of small molecules	1	8.4×	0.128	SLC5A6
Immune System	1	4.3×	0.230	KIF5A
Metabolism of proteins	1	4.1×	0.231	KIF5A
Signal Transduction	1	3.4×	0.267	KIF5A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pantothenate transmembrane transport	1	4213.0×	0.004	SLC5A6
mitochondrial outer membrane fusion	1	4213.0×	0.004	NME3
iodide transmembrane transport	1	2106.5×	0.004	SLC5A6
biotin import across plasma membrane	1	2106.5×	0.004	SLC5A6
biotin transport	1	1404.3×	0.004	SLC5A6
biotin metabolic process	1	1053.2×	0.004	SLC5A6
dTTP biosynthetic process	1	842.6×	0.004	NME3
retrograde neuronal dense core vesicle transport	1	842.6×	0.004	KIF5A
anterograde dendritic transport of neurotransmitter receptor complex	1	601.9×	0.005	KIF5A
nucleoside triphosphate biosynthetic process	1	526.6×	0.005	NME3
anterograde axonal protein transport	1	526.6×	0.005	KIF5A
UTP biosynthetic process	1	468.1×	0.005	NME3
regulation of lysosome size	1	468.1×	0.005	BORCS8
GTP biosynthetic process	1	421.3×	0.005	NME3
CTP biosynthetic process	1	421.3×	0.005	NME3
regulation of endosome size	1	383.0×	0.005	BORCS8
protein hexamerization	1	351.1×	0.005	NME3
organelle transport along microtubule	1	300.9×	0.006	BORCS8
mitochondrial fusion	1	210.7×	0.007	NME3
synaptic vesicle transport	1	210.7×	0.007	KIF5A
lysosome localization	1	131.7×	0.011	BORCS8
microtubule-based movement	1	73.9×	0.018	KIF5A
sodium ion transport	1	68.0×	0.019	SLC5A6
transport across blood-brain barrier	1	44.8×	0.028	SLC5A6
vesicle-mediated transport	1	24.1×	0.049	KIF5A
axon guidance	1	22.6×	0.050	KIF5A
heart development	1	19.7×	0.054	BORCS8
chemical synaptic transmission	1	19.3×	0.054	KIF5A
DNA repair	1	16.0×	0.063	NME3
apoptotic process	1	7.2×	0.132	NME3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
KIF5A	0	0
SLC5A6	0	0
BORCS8	0	0
NME3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KIF5A	8	Binding:8
SLC5A6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NME3	2.7.4.6	nucleoside-diphosphate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	NME3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	KIF5A, SLC5A6, BORCS8

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF5A	8	—
SLC5A6	1	—
BORCS8	0	—
NME3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01498263	Not specified	COMPLETED	Inherited Diseases, Caregiving, and Social Networks