Amyotrophic lateral sclerosis-parkinsonism-dementia complex

Summary

Amyotrophic lateral sclerosis-parkinsonism-dementia complex (MONDO:0007104) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis-parkinsonism-dementia complex
Mondo ID	MONDO:0007104
OMIM	105500
Orphanet	90020
DOID	DOID:0111246
UMLS	C0543859
MedGen	107775
GARD	0009239
Is cancer (heuristic)	no

Also known as: amyotrophic lateral sclerosis, Parkinsonism/dementia complex of Guam · amyotrophic lateral sclerosis-Parkinsonism/dementia Complex type 1 · Guam disease · Lytico-Bodig disease · Lytigo-Bodig disease

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › amyotrophic lateral sclerosis-parkinsonism-dementia complex

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, 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

9 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
873319	NM_007262.5(PARK7):c.133C>T (p.Gln45Ter)	PARK7	Pathogenic	criteria provided, single submitter
3367048	NM_017672.6(TRPM7):c.3868A>C (p.Lys1290Gln)	LOC126862130	Uncertain significance	criteria provided, single submitter
3577351	NM_017672.6(TRPM7):c.3+2T>A	LOC128092252	Uncertain significance	criteria provided, single submitter
1029635	NM_017672.6(TRPM7):c.2141A>C (p.Lys714Thr)	TRPM7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1683689	NM_017672.6(TRPM7):c.4928A>G (p.His1643Arg)	TRPM7	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065375	NM_017672.6(TRPM7):c.1729C>T (p.His577Tyr)	TRPM7	Uncertain significance	criteria provided, single submitter
3577350	NM_017672.6(TRPM7):c.2525C>T (p.Thr842Met)	TRPM7	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731469	NM_017672.6(TRPM7):c.2704C>T (p.Arg902Cys)	TRPM7	Uncertain significance	criteria provided, single submitter
776889	NM_017672.6(TRPM7):c.1131+3A>G	TRPM7	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
TRPM7	Limited	Unknown	amyotrophic lateral sclerosis-parkinsonism-dementia complex	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPM7	Orphanet:140957	Autosomal dominant macrothrombocytopenia
TRPM7	Orphanet:90020	Parkinson-dementia complex of Guam
PARK7	Orphanet:2828	Young-onset Parkinson disease
PARK7	Orphanet:90020	Parkinson-dementia complex of Guam

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
TRPM7	HGNC:17994	ENSG00000092439	Q96QT4	Transient receptor potential cation channel subfamily M member 7	gencc,clinvar
PARK7	HGNC:16369	ENSG00000116288	Q99497	Parkinson disease protein 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPM7	Transient receptor potential cation channel subfamily M member 7	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.
PARK7	Parkinson disease protein 7	Multifunctional protein with controversial molecular function which plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease.

Protein-family classification

Druggable: 2 · 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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPM7	Kinase	yes		a-kinase_dom, Kinase-like_dom_sf, TRPM7_a-kinase_dom
PARK7	Enzyme (other)	yes	3.5.1.124	DJ-1/PfpI, DJ-1, Class_I_gatase-like

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
calcaneal tendon	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
adult organism	1
deltoid	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPM7	247	ubiquitous	marker	left ventricle myocardium, calcaneal tendon, cardiac muscle of right atrium
PARK7	294	ubiquitous	marker	adult organism, tibia, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PARK7	5,722
TRPM7	1,995

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PARK7	Q99497	88

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRPM7	Q96QT4	69.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Chaperone Mediated Autophagy	1	248.3×	0.008	PARK7
TRP channels	1	203.9×	0.008	TRPM7
Late endosomal microautophagy	1	163.1×	0.008	PARK7
Aggrephagy	1	124.1×	0.008	PARK7
SUMOylation of transcription cofactors	1	121.5×	0.008	PARK7

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
positive regulation of acute inflammatory response to antigenic stimulus	1	8426.0×	7e-04	PARK7
cellular response to glyoxal	1	8426.0×	7e-04	PARK7
glycolate biosynthetic process	1	8426.0×	7e-04	PARK7
detoxification of mercury ion	1	8426.0×	7e-04	PARK7
detoxification of hydrogen peroxide	1	8426.0×	7e-04	PARK7
obsolete methylglyoxal catabolic process to lactate	1	8426.0×	7e-04	PARK7
guanine deglycation	1	8426.0×	7e-04	PARK7
obsolete guanine deglycation, methylglyoxal removal	1	8426.0×	7e-04	PARK7
guanine deglycation, glyoxal removal	1	8426.0×	7e-04	PARK7
cellular detoxification of methylglyoxal	1	8426.0×	7e-04	PARK7
regulation of supramolecular fiber organization	1	8426.0×	7e-04	PARK7
negative regulation of death-inducing signaling complex assembly	1	8426.0×	7e-04	PARK7
negative regulation of TRAIL-activated apoptotic signaling pathway	1	8426.0×	7e-04	PARK7
glyoxal metabolic process	1	8426.0×	7e-04	PARK7
obsolete positive regulation of L-dopa biosynthetic process	1	8426.0×	7e-04	PARK7
methylglyoxal metabolic process	1	4213.0×	1e-03	PARK7
calcium-dependent cell-matrix adhesion	1	4213.0×	1e-03	TRPM7
detection of oxidative stress	1	4213.0×	1e-03	PARK7
negative regulation of protein K48-linked deubiquitination	1	4213.0×	1e-03	PARK7
positive regulation of dopamine biosynthetic process	1	4213.0×	1e-03	PARK7
negative regulation of nitrosative stress-induced intrinsic apoptotic signaling pathway	1	4213.0×	1e-03	PARK7
lactate biosynthetic process	1	2808.7×	0.001	PARK7
positive regulation of mitochondrial electron transport, NADH to ubiquinone	1	2808.7×	0.001	PARK7
negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway	1	2808.7×	0.001	PARK7
hydrogen peroxide metabolic process	1	2106.5×	0.002	PARK7
positive regulation of autophagy of mitochondrion	1	2106.5×	0.002	PARK7
positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	1685.2×	0.002	PARK7
regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	1685.2×	0.002	PARK7
negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	1685.2×	0.002	PARK7
intracellular magnesium ion homeostasis	1	1404.3×	0.002	TRPM7

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PARK7	1	2
TRPM7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	PARK7

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PARK7	62	Binding:62
TRPM7	34	Binding:34

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PARK7	3.5.1.124, 4.2.1.130	protein deglycase, D-lactate dehydratase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	PARK7

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	1	PARK7
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TRPM7
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)
TRPM7	34	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.