Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome

Summary

Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome (MONDO:0014419) is a disease caused by LAMA1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LAMA1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 193
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0002198	Dilated fourth ventricle	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0002350	Cerebellar cyst	Very frequent (80-99%)
HP:0007033	Cerebellar dysplasia	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000646	Amblyopia	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001105	Retinal atrophy	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002363	Abnormal brainstem morphology	Frequent (30-79%)
HP:0007068	Inferior vermis hypoplasia	Frequent (30-79%)
HP:0011933	Elongated superior cerebellar peduncle	Frequent (30-79%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000556	Retinal dystrophy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0002599	Head titubation	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome
Mondo ID	MONDO:0014419
OMIM	615960
Orphanet	370022
UMLS	C4014821
MedGen	863258
GARD	0017597
Is cancer (heuristic)	no

Also known as: ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome · PORETTI-Boltshauser syndrome · Poretti-Boltshauser syndrome · PTBHS

Data availability: 193 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome

Related subtypes (53): craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, Aase-Smith syndrome, arachnoid cyst, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dandy-Walker malformation-postaxial polydactyly syndrome, cervical hypertrichosis-peripheral neuropathy syndrome, Joubert syndrome with oculorenal defect, NPHP3-related Meckel-like syndrome, orofaciodigital syndrome type 6, X-linked intellectual disability-cerebellar hypoplasia syndrome, syndromic X-linked intellectual disability Najm type, X-linked cerebral-cerebellar-coloboma syndrome syndrome, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, aprosencephaly cerebellar dysgenesis, Gomez-Lopez-Hernandez syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, pontine tegmental cap dysplasia, cerebellar-facial-dental syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal recessive spinocerebellar ataxia 20, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, isolated cerebellar vermis hypoplasia, cerebral gigantism-jaw cysts syndrome, holoprosencephaly-caudal dysgenesis syndrome, Joubert syndrome with ocular defect, macrocephaly-short stature-paraplegia syndrome, glioependymal/ependymal cyst, isolated cerebellar vermis agenesis, isolated unilateral hemispheric cerebellar hypoplasia, isolated bilateral hemispheric cerebellar hypoplasia, Hoyeraal-Hreidarsson syndrome, neural tube defect, partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, tubulinopathy-associated dysgyria, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, Ritscher-Schinzel syndrome, spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome, cystic malformation of the posterior fossa, pontocerebellar hypoplasia, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, hereditary cerebral malformation, isolated arhinencephaly

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

193 retrieved; paginated sample, class counts are floors:

73 uncertain significance, 37 pathogenic, 26 likely pathogenic, 21 benign, 18 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 6 benign/likely benign, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027444	NM_005559.4(LAMA1):c.1404_1405del (p.Gly469fs)	LAMA1	Pathogenic	criteria provided, single submitter
1027445	NM_005559.4(LAMA1):c.184C>T (p.Arg62Ter)	LAMA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075978	NM_005559.4(LAMA1):c.8737del (p.Asp2913fs)	LAMA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098868	NM_005559.4(LAMA1):c.494del (p.Ile165fs)	LAMA1	Pathogenic	no assertion criteria provided
1098869	NM_005559.4(LAMA1):c.3053del (p.Pro1018fs)	LAMA1	Pathogenic	no assertion criteria provided
1098918	NM_005559.4(LAMA1):c.2962del (p.Tyr988fs)	LAMA1	Pathogenic	no assertion criteria provided
1098919	NM_005559.4(LAMA1):c.1281C>A (p.Cys427Ter)	LAMA1	Pathogenic	no assertion criteria provided
1210079	NM_005559.4(LAMA1):c.3099G>A (p.Trp1033Ter)	LAMA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1284926	NM_005559.4(LAMA1):c.8761C>T (p.Arg2921Ter)	LAMA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323157	NM_005559.4(LAMA1):c.2480G>A (p.Trp827Ter)	LAMA1	Pathogenic	criteria provided, single submitter
1323159	NM_005559.4(LAMA1):c.6489+1G>C	LAMA1	Pathogenic	criteria provided, single submitter
144107	NM_005559.4(LAMA1):c.588+2T>G	LAMA1	Pathogenic	criteria provided, single submitter
144108	NM_005559.4(LAMA1):c.7965-15_7965-3del	LAMA1	Pathogenic	criteria provided, single submitter
144109	NM_005559.4(LAMA1):c.2986del (p.Thr996fs)	LAMA1	Pathogenic	criteria provided, single submitter
144110	NM_005559.4(LAMA1):c.2816_2817del (p.Tyr939fs)	LAMA1	Pathogenic	criteria provided, single submitter
144111	NM_005559.4(LAMA1):c.555T>G (p.Tyr185Ter)	LAMA1	Pathogenic	criteria provided, single submitter
1675304	NM_005559.4(LAMA1):c.3919C>T (p.Arg1307Ter)	LAMA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1675305	NM_005559.4(LAMA1):c.7009dup (p.Ser2337fs)	LAMA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709400	NM_005559.4(LAMA1):c.4807-2A>G	LAMA1	Pathogenic	criteria provided, single submitter
1804139	NM_005559.4(LAMA1):c.2932_2933delinsG (p.Lys978fs)	LAMA1	Pathogenic	criteria provided, single submitter
1805047	NM_005559.4(LAMA1):c.6333dup (p.Gln2112fs)	LAMA1	Pathogenic	criteria provided, single submitter
209987	NM_005559.4(LAMA1):c.6701del (p.Pro2234fs)	LAMA1	Pathogenic	criteria provided, single submitter
209990	NM_005559.3:c.2988_2989delA	LAMA1	Pathogenic	criteria provided, single submitter
209991	NM_005559.4(LAMA1):c.6345+3G>C	LAMA1	Pathogenic	criteria provided, single submitter
209992	Single allele	LAMA1	Pathogenic	criteria provided, single submitter
2444495	NM_005559.4(LAMA1):c.5235_5236del (p.Leu1746fs)	LAMA1	Pathogenic	criteria provided, single submitter
2444624	NM_005559.4(LAMA1):c.4075delinsCTA (p.Leu1359_Glu1360insTer)	LAMA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2506318	NM_005559.4(LAMA1):c.1078del (p.Val360fs)	LAMA1	Pathogenic	criteria provided, single submitter
2506484	NM_005559.4(LAMA1):c.4171_4172del (p.Arg1391fs)	LAMA1	Pathogenic	criteria provided, single submitter
2582654	NM_005559.4(LAMA1):c.5700dup (p.Ser1901fs)	LAMA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
LAMA1	Definitive	Autosomal recessive	ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMA1	Orphanet:370022	Ataxia-intellectual disability-oculomotor apraxia-cerebellar cysts syndrome

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
LAMA1	HGNC:6481	ENSG00000101680	P25391	Laminin subunit alpha-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMA1	Laminin subunit alpha-1	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAMA1	Other/Unknown	no		Laminin_IV, EGF, Laminin_G

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMA1	171	broad	marker	ventricular zone, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMA1	1,405

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMA1	P25391

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
MET promotes cell motility	1	601.0×	0.009	LAMA1
Attachment of bacteria to epithelial cells	1	496.5×	0.009	LAMA1
Laminin interactions	1	380.7×	0.009	LAMA1
MET activates PTK2 signaling	1	380.7×	0.009	LAMA1
Signaling by MET	1	317.2×	0.009	LAMA1
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.009	LAMA1
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.010	LAMA1
Non-integrin membrane-ECM interactions	1	154.3×	0.012	LAMA1
ECM proteoglycans	1	150.3×	0.012	LAMA1
L1CAM interactions	1	120.2×	0.013	LAMA1
Extracellular matrix organization	1	63.1×	0.023	LAMA1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.026	LAMA1
Axon guidance	1	45.1×	0.027	LAMA1
Nervous system development	1	42.9×	0.027	LAMA1
Developmental Biology	1	14.5×	0.074	LAMA1
Signal Transduction	1	10.2×	0.098	LAMA1

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
negative regulation of muscle cell apoptotic process	1	4213.0×	0.002	LAMA1
regulation of basement membrane organization	1	2808.7×	0.002	LAMA1
retinal blood vessel morphogenesis	1	2407.4×	0.002	LAMA1
morphogenesis of an epithelial sheet	1	1685.2×	0.002	LAMA1
branching involved in salivary gland morphogenesis	1	1404.3×	0.002	LAMA1
positive regulation of integrin-mediated signaling pathway	1	1296.3×	0.002	LAMA1
positive regulation of muscle cell differentiation	1	1123.5×	0.002	LAMA1
establishment of epithelial cell apical/basal polarity	1	1053.2×	0.002	LAMA1
epithelial tube branching involved in lung morphogenesis	1	842.6×	0.002	LAMA1
positive regulation of Rac protein signal transduction	1	648.1×	0.003	LAMA1
regulation of embryonic development	1	330.4×	0.005	LAMA1
positive regulation of cell adhesion	1	271.8×	0.005	LAMA1
regulation of cell migration	1	157.5×	0.008	LAMA1
neuron projection development	1	122.1×	0.010	LAMA1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.014	LAMA1
cell surface receptor signaling pathway	1	64.1×	0.017	LAMA1
cell adhesion	1	37.5×	0.027	LAMA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
LAMA1	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
LAMA1	2	Binding:2

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

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	1	LAMA1

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)
LAMA1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.