To calculate growth charts for pontocerebellar hypoplasia (PCH) type 2A (PCH2A) and compare them to German reference charts, especially with regard to nutritional aspects. Data were gathered from a cohort of patients with genetically confirmed PCH2A, who were predominantly recruited through the German PCH patient network (65 patients [33 female, 32 male] at a mean age of 8 years 7 months). We collected data retrospectively using a parent questionnaire, and from medical records (December 2020-September 2022). Disease-specific growth charts were prepared from predominantly longitudinal data using the gamlss package implemented in R. Sex-disaggregated growth charts for PCH2A were compared to German reference data from the Kinder- und Jugendgesundheitssurvey (German Health Interview and Examination Survey for Children and Adolescents). The height and weight of participants with PCH2A were within the reference range at birth. Mean height was significantly lower at 6 months of age, weight at 3 months, and body mass index at 4 months. These deviations were also mostly significant later on. Head circumference in individuals with PCH2A was significantly below average at birth; all participants showed severe and progressive microcephaly in the further course. Caloric intake was within or above reference values. Participants with PCH2A exhibited progressive microcephaly and frequently failed to thrive. Disease-specific growth charts are a helpful tool to monitor those with PCH2A.

Biallelic pathogenic variants in PNKP are associated with microcephaly and early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4 and Charcot-Marie-Tooth disease type 2B2. We describe the clinical and neuroimaging features of 27 new patients with PNKP variants. All patients presented with early-onset seizures, congenital microcephaly and intellectual disability. In addition, we compared our results with data in the literature. Twenty-five patients presented with the classic MCSZ phenotype, while two showed a more severe clinical phenotype. The brain imaging features of the 25 patients varied significantly, but widening of the frontal lobe gyri with frontal hypoplasia and prominent cerebellar folia (consistent with atrophy) could point to PNKP-related microcephaly . In contrast, the two patients with severe phenotype showed additional brain MRI features of white matter loss and pontocerebellar hypoplasia fulfilling the criteria of microlissencephaly. Exome sequencing identified seven different PNKP variants, including two novel ones. The c.1253_1269dup p.(Thr424GlyfsTer49) and c.1381_1383dup p.(Asn461dup) variants, each was recurrent in 10 patients (37%), while the c.1381_1383del p.(Asn461del) variant was recurrent in four patients (14.8%). Haplotype analysis confirmed that the p.Asn461dup variant has a founder effect in our population. No genotype-phenotype correlation was observed in our cohort. Our results provide 'microlissencephaly' as an emerging distinct phenotype linked to PNKP variants. As such, PNKP variants could be associated with four overlapping subgroups that lie along a unifying phenotypic continuum.

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.

To explore the genetic etiology of Pontocerebellar Hypoplasia Type 2D (PCH2D) due to compound heterozygous variants of the SEPSECS gene and to conduct a literature review. A child with PCH2D diagnosed at the Children's Hospital of Nanjing Medical University due to "motor and cognitive retardation" in June 2022 was selected as the study subject. Clinical and imaging data were collected. Genomic DNA was extracted from the peripheral blood samples of the child and her parents. Whole-exome sequencing (WES) was conducted using capture-based high-throughput sequencing technology. Candidate variants were confirmed by Sanger sequencing and bioinformatics analysis. The pathogenicity of variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by American College of Medical Genetics and Genomics (ACMG). Additionally, relevant literature on PCH2D caused by SEPSECS gene variants was reviewed to assess the genotype-phenotype correlation. This study was approved by the Medical Ethics Committee of the hospital (Ethical No.: 202402022-1). The child, a 1-year-and-3-month-old girl, had presented with global developmental delay, progressive microcephaly, hypotonia, elevated blood lactic acid, feeding difficulties, and absent tendon reflexes. Cranial MRI indicated thinning of the splenium of the corpus callosum. Electromyography suggested peripheral neurogenic changes primarily affecting sensory nerves. WES revealed the she has harbored compound heterozygous variants of the SEPSECS gene, namely c.194A>G (p.N65S) and c.896_c.897insA (p.N299fs*2) (NM_016955), which were inherited from her father and mother, respectively. Neither of her parents had related clinical manifestations. According to the ACMG guidelines, the c.194A>G (p.N65S) variant was classified as pathogenic (PM1+PM2_Supporting+PM3+PP3), and the c.896_c.897insA (p.N299fs*2) variant was as likely pathogenic (PVS1+PM2_Supporting). A total of 18 relevant literature were retrieved, which have involved 32 patients (including this case). The p.N65S variant has been reported previously, while the p.N299fs*2 variant is novel. Compound heterozygous variants in the SEPSECS gene probably underlay the pathogenesis of PCH2D in this child. Above finding has expanded the mutational and phenotypic spectrum of the SEPSECS gene.

Pontocerebellar hypoplasia type 11 (PCH11) is an autosomal recessive disorder caused by variants in TBC1D23. The molecular basis for its clinical heterogeneity remains poorly understood. Here, we identified a novel TBC1D23 variant in a Chinese family, investigated its underlying pathogenic mechanisms, and systematically reviewed the clinical phenotypes of all reported cases of PCH11. We identified a novel homozygous frameshift variant, c.511_512delTT (p.F171Qfs*8), in TBC1D23. The patient exhibited a severe phenotype, including marked pontocerebellar hypoplasia, a thinned corpus callosum, global developmental delay, and severe language and motor impairments. Mechanistic studies in a zebrafish model revealed that the mutant transcript partially escaped nonsense-mediated decay (NMD), with expression levels at approximately 50% of the wild-type. In vitro, the resultant truncated protein showed enhanced stability and aberrant cytoplasmic distribution instead of its normal Golgi localization. Furthermore, its expression significantly inhibited cell proliferation. Our study identifies c.511_512delTT as a novel pathogenic variant in TBC1D23. We propose the severe phenotype stems from a primary loss-of-function (LoF), which is likely exacerbated by the cytotoxic effect of the truncated protein produced via partial NMD escape. Our findings suggest this mutant protein exhibits increased stability. This model provides a novel explanation for the phenotypic heterogeneity in PCH11 and expands the mutational spectrum of this disorder.