Ataxia and cerebellar anomalies - childhood onset

Gene: PAX6

I don't know

Early literature suspected PAX6 as the causative gene for Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation), but direct sequencing repeatedly found no PAX6 mutations in classic Gillespie cases. Linkage analysis in affected families showed the disease trait segregates independently from chromosome 11p markers flanking PAX6 (Glaser et al., 1994; PMID 8188215). |The sausative gene was identified as ITPR1.

PAX6 biallelic loss-of-function causes a severe, prenatal/neonatal-onset neurodevelopmental disorder characterised by anophthalmia/microphthalmia and major CNS malformations, including agenesis of the corpus callosum, olfactory bulb aplasia/hypoplasia, brainstem hypoplasia, cortical malformations, and cerebellar dysplasia/hypoplasia; reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities (Glaser et al., 1994, PMID: 7951315; Schmidt-Sidor et al., 2009, PMID: 20054790; Solomon et al., 2010, PMID: 19876904). Thus, biallelic PAX6-related disease is not within scope for the paediatric onset ataxia/ cerebellar anomalies panels.

Isolated reports describe heterozygous PAX6 variants associated with neurological manifestations, including ataxia or cerebellar dysfunction:

Ticho et al., 2006 (PMID: 17148041): A patient described as having "atypical Gillespie syndrome" presented with mild hand tremor and learning disability but no reported ataxia or structural cerebellar abnormalities on neuroimaging. Sequencing identified a heterozygous PAX6 splice-site variant, IVS2+2T>A.
Graziano et al., 2007 (PMID 17595013): described a 9.5-year-old girl with bilateral aniridia, ataxia, and intellectual disability; she carried a de novo heterozygous nonsense variant, PAX6 p.(Trp257Ter).
Dansault et al., 2007 (PMID 17417613): In a large family carrying the c.655A>G p.S74G variant, all affected individuals exhibited a mild but consistent cerebellar syndrome. The most severely affected individual had a clear static cerebellar syndrome. MRI findings included hypoplasia of the anterior commissure and absence of the pineal gland in one individual. Despite the consistent neurological phenotype, no specific structural cerebellar abnormalities were identified.

Conclusion: Two unrelated PAX6 families with heterozygous variants showed evidence ataxia and/or a cerebellar syndrome phenotype, the latter without any recognisable cerebellar malformation. PAX6 knockout mice delineate a primary role of PAX6 in cerebellar development, though are not known to recapitulate an ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)). An amber rating with monoallelic inheritance is proposed.

Created: 11 Sep 2026, 4:51 p.m. | Last Modified: 11 Sep 2026, 4:51 p.m.

Panel Version: 9.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Aniridia (OMIM:106210); cerebellar ataxia (MONDO:0000437)

Publications

• 17148041
• 8188215
• 7951315
• 20054790
• 19876904
• 17417613
• 8213068
• 16979618