Benign paroxysmal tonic upgaze of childhood with ataxia

Summary

Benign paroxysmal tonic upgaze of childhood with ataxia (MONDO:0008206) is a disease caused by DAGLA (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DAGLA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7
• Phenotypes (HPO): 3
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0002131	Episodic ataxia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	benign paroxysmal tonic upgaze of childhood with ataxia
Mondo ID	MONDO:0008206
MeSH	C566817
OMIM	168885
Orphanet	1179
SNOMED CT	763127004
UMLS	C1868576
MedGen	401473
GARD	0004176
Is cancer (heuristic)	no

Also known as: neuroocular syndrome 2, paroxysmal type · Ouvrier Billson syndrome · Ouvrier-Billson syndrome

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › benign paroxysmal tonic upgaze of childhood with ataxia

Related subtypes (53): cerebellar ataxia, chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

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

7 retrieved; paginated sample, class counts are floors:

5 pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3075711	NM_006133.3(DAGLA):c.2484del (p.Glu829fs)	DAGLA	Pathogenic	criteria provided, single submitter
3233425	NM_006133.3(DAGLA):c.2370C>G (p.Tyr790Ter)	DAGLA	Pathogenic	no assertion criteria provided
3233426	NM_006133.3(DAGLA):c.2485G>T (p.Glu829Ter)	DAGLA	Pathogenic	no assertion criteria provided
3233428	NM_006133.3(DAGLA):c.2440G>T (p.Glu814Ter)	DAGLA	Pathogenic	no assertion criteria provided
3391177	NM_006133.3(DAGLA):c.2401del (p.Arg801fs)	DAGLA	Pathogenic	criteria provided, single submitter
3233427	NM_006133.3(DAGLA):c.2613dup (p.Ser872fs)	DAGLA	Uncertain significance	criteria provided, single submitter
3391140	NM_006133.3(DAGLA):c.2161A>T (p.Ser721Cys)	DAGLA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 0 · 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
DAGLA	Strong	Autosomal dominant	benign paroxysmal tonic upgaze of childhood with ataxia

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
DAGLA	HGNC:1165	ENSG00000134780	Q9Y4D2	Diacylglycerol lipase-alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DAGLA	Diacylglycerol lipase-alpha	Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG).

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DAGLA	Enzyme (other)	yes	3.1.1.116	Fungal_lipase-type, AB_hydrolase_fold, DAG_Lipase-Related

Expression context

Cohort genes with no expression data: 0.

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
Brodmann (1909) area 10	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DAGLA	171	ubiquitous	yes	right frontal lobe, prefrontal cortex, Brodmann (1909) area 10

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DAGLA	726

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DAGLA	Q9Y4D2	63.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Arachidonate production from DAG	1	2284.0×	4e-04	DAGLA

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
retrograde trans-synaptic signaling by endocannabinoid	1	5617.3×	6e-04	DAGLA
cannabinoid biosynthetic process	1	5617.3×	6e-04	DAGLA
diacylglycerol catabolic process	1	2808.7×	8e-04	DAGLA
monoacylglycerol biosynthetic process	1	1532.0×	1e-03	DAGLA
regulation of neuroinflammatory response	1	1404.3×	1e-03	DAGLA
arachidonate metabolic process	1	481.5×	0.002	DAGLA
neuroblast proliferation	1	366.4×	0.003	DAGLA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DAGLA	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DAGLA	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	DAGLA
CANNABIDIVARIN	2	DAGLA
CANNABIDIOLIC ACID	2	DAGLA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DAGLA	48	Binding:48

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DAGLA	3.1.1.116	sn-1-specific diacylglycerol lipase

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

3 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)
ORLISTAT	4	DAGLA
CANNABIDIVARIN	2	DAGLA
CANNABIDIOLIC ACID	2	DAGLA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DAGLA
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	0

Undrugged target profiles

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

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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford