Pontocerebellar hypoplasia Type III (PCH3) is a rare, autosomal recessive neurodegenerative disorder linked to mutations in the PCLO gene, previously reported only in Omani populations. It presents with progressive microcephaly, intractable epilepsy, optic atrophy, and severe developmental delay. Here, we report the first documented case of PCH3 in an 8-year-old Thai girl with two novel PCLO truncation mutations. The patient presented with intractable epilepsy from 2 months of age and severe global developmental delay. Whole exome sequencing identified compound heterozygous mutations in the PCLO gene: c.9018_9037del (p.Tyr3007Ter) and c.8456del (p.Ala2819GlufsTer2), both of which were inherited from heterozygous parents. These mutations are predicted to result in a loss of Piccolo protein function. This case expands the mutational spectrum of PCLO-related PCH3 and highlights the importance of advanced molecular diagnostics in understanding and managing this rare neurodegenerative disorder. Given the lack of curative therapies, early genetic diagnosis is crucial in guiding patient care and genetic counseling.

Properly working synapses are one important guarantor for a functional and healthy brain. They are small, densely packed structures, where information is transmitted through the release of neurotransmitters from synaptic vesicles (SVs). The latter cycle within the presynaptic terminal as they first fuse with the plasma membrane to deliver their neurotransmitter, and afterwards become recycled and prepared for a new release event. The synapse is an autonomous structure functioning mostly independent of the neuronal soma. Dysfunction in synaptic processes associated with local insults or genetic abnormalities can directly compromise synapse function and integrity and subsequently lead to the onset of neurodegenerative diseases. Therefore, measures need to be in place counteracting these threats for instance through the continuous replacement of old and damaged SV proteins. Interestingly recent studies show that the presynaptic scaffolding protein Piccolo contributes to health, function and integrity of synapses, as it mediates the delivery of synaptic proteins from the trans-Golgi network (TGN) towards synapses, as well as the local recycling and turnover of SV proteins within synaptic terminals. It can fulfill these various tasks through its multi-domain structure and ability to interact with numerous binding partners. In addition, Piccolo has recently been linked with the early onset neurodegenerative disease Pontocerebellar Hypoplasia Type 3 (PCH3) further underlying its importance for neuronal health. In this review, we will focus on Piccolo's contributions to synapse function, health and integrity and make a connection how those may contribute to the disease pattern of PCH3.

Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3). We have characterized recently generated Piccolo KO (Pclogt/gt ) rats. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclowt/wt ) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber afferents from pontine neurons and the expression of the α6 GABAA receptor subunit at the mossy fiber-granule cell synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers. Ultrastructural and functional studies revealed a reduced size of mossy fiber boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation, and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together, these data suggest that loss of Piccolo function in patients with PCH3 could be involved in many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder.SIGNIFICANCE STATEMENT Pontocerebellar Hypoplasia Type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures, and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the PCLO gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo KO rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with Pontocerebellar Hypoplasia Type 3 are also exhibited by these Piccolo deficient animals.

The CAMK2B gene encodes the β-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in hippocampal and cerebellar neurons. Heterozygous variants in CAMK2B cause a rare neurodevelopmental disorder, with 40% of the reported cases sharing the same variant: c.416C>T, p.(P139L). This case report describes a 22-year-old patient with this recurrent variant, who presents with severe intellectual disability, absence of language, hypotonia, microcephaly, dysmorphic features, epilepsy, behavioral abnormalities, motor stereotypies, optic atrophy, and progressive cerebellar atrophy. Notably, this patient is the oldest reported so far and allows us to better delineate the clinical phenotype associated with this variant, adding clinical aspects never described before, such as epilepsy, optic atrophy, scoliosis, and neuroradiological changes characterized by progressive cerebellar atrophy.