Ataxia and cerebellar anomalies - childhood onset

Gene: PCLO

Green List (high evidence)

Comment on list classification: There are now at least 3 unrelated families reported in literature with biallelic PCLO variants and cerebellar atrophy / hypoplasia, plus 1 additional case with mild ataxia. There is a supportive rat model showing that pclo knock-out results in reduced brain size and impaired motor coordination. Hence, this gene can be promoted to Green at the next update.

Created: 13 Aug 2026, 4:10 p.m. | Last Modified: 13 Aug 2026, 4:12 p.m.

Panel Version: 9.26

PMID: 42038819 Baneshi et al., 2025
Report of a 38-year-old Iranian female proband with mild intellectual disability, microcephaly, muscle weakness, and a history of seizures, mild ataxia (usure on age of onset), behavioral issues, toe-walking, loss of tendon reflexes, and unilateral paralysis. First febrile seizure occurred at 1 year of age. A homozygous PCLO (NM_033026: c.458TC, p. Met153Thr) variant was detected using WES.
CRISPR-based cell model for PCH3 was developed (PCLO -/- HEK293T and REH-6 Cell Lines) - a significant reduction in CtBP1 mRNA expression was observed.

PMID: 40661989 Lertsakulbunlue et al., 2025
Report of an 8-year-old Thai girl who presented with intractable epilepsy from 2 months of age and severe global developmental delay. Seizures were resistant to medication (control eventually achieved with 4 drugs: topiramate, levetiracetam, perampanel, and carbamazepine). WES identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2) - inherited from unaffected het parents. Brain MRI showed a thin corpus callosum, small pons, thinning of the medulla oblongata, and a hypoplastic cerebellar vermis.

PMID: 30287594 Chitre et al., 2018
Cohort of 19 children from 11 UK families with Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome (7/19) or PEHO-like syndrome (12/19).
Family A - 5 affected children, 2 diagnosed with PEHO syndrome and 3 with PEHO-like syndrome. All 5 harboured comp het PCLO variants: c.2703C>T, p.(Gln901*Ter) and c.7080C>G, p.(Tyr2360*Ter).
Phenotype: Infantile hypotonia 5/5, profound psychomotor delay 5/5, Convulsive disorders presenting with myoclonias and infantile spasms 5/5, Atrophy of optic disc by 2 years 4/4; Progressive brain atrophy confirmed in 2 sibs.

PMID: 25832664 Ahmed et al., 2015
Consanguineous Omani family with Pontocerebellar hypoplasia type 3. The 4 affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. WES identified a homozygous NM_033026.5:c.10624C>T; p.Arg3542* variant.

FUNCTIONAL EVIDENCE:
PMID: 32122952 Falck et al., 2020 - Pclo gt/gt rat model. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclo wt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Behavioral studies demonstrated that adult Pclo gt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Seizures were also present in the mutated rats.

PCLO is associated with AR Pontocerebellar hypoplasia, type 3, 608027 in OMIM (accessed 13th Aug 2026).

Created: 13 Aug 2026, 4:08 p.m. | Last Modified: 13 Aug 2026, 4:14 p.m.

Panel Version: 9.26

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia, type 3, OMIM:608027; PEHO syndrome, MONDO:0009841; progressive encephalopathy with edema, hypsarrhythmia and optic atrophy

Publications

• 25832664
• 30287594
• 32122952
• 40661989
• 42038819