Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1.

Next-generation sequencing is advancing in low- and middle-income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio-cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene-disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease-causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G > T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G > A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G > A, p.(Arg497Gln)), related to syndromic X-linked intellectual disability with epilepsy. Our small study demonstrates the promise of next-generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next-generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path.

Adult Case of Pontocerebellar Hypoplasia without the Claustrum.

We describe the case of a 63-year-old man with pontocerebellar hypoplasia without the claustrum (CL). The patient had a history of cerebral palsy, intelligent disability, cerebellar atrophy, and seizures since birth. At age 61, brain computed tomography (CT) revealed significant cerebellar and brainstem atrophy. At age 63, he was admitted to our hospital for aspiration pneumonia. Although he was treated with medications, including antibiotics, he died one month after admission. The autopsy revealed a total brain weight of 815 g, with the small-sized frontal lobe, cerebellum, and pons. The cross-section of the fourth ventricle had a slit-like appearance, rather than the typical diamond shape. In addition, bilateral CLs were not observed. Apart from CL, no other missing brain tissue or cells could be identified. Microscopic examinations disclosed neurofibrillary tangles in the hippocampus but not in the cortex; however, neither senile plaques nor Lewy bodies were detected. No acquired lesions, including cerebral infarction, hemorrhage, or necrosis, were noted. We pathologically diagnosed the patient with pontocerebellar hypoplasia without CL. As there have been no prior reports of pontocerebellar hypoplasia lacking CL in adults, this case may represent a new subtype. Congenital CL deficiency is likely associated with abnormalities in brain development. CL may play a role in seizure activity, and the loss of bilateral CLs does not necessarily result in immediate death. Further studies are needed to clarify the functions of CL.

CoA synthase plays a critical role in neurodevelopment and neurodegeneration.

Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular de novo biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The COASY gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in COASY have been identified in fetuses/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which Coasy was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the in vivo phenotype, ranging from very short survival (less than 2 weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects. Ex vivo histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably, Coasy ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms.

Pontocerebellar Hypoplasia Type 9: A New Case with a Novel Mutation and Review of Literature.

Pontocerebellar hypoplasia type 9 (PCH-9) is a very rare autosomal recessive neurodegenerative disorder. Affected infants present early with severe developmental delay, spasticity, with the unique magnetic resonance imaging picture of thin corpus callosum, atrophied pons, and cerebellum. It is caused by loss of function mutations in the AMPD2 gene, encoding for the adenosine monophosphate deaminase enzyme-paralog 2. This gene is expressed in different somatic tissues with high level of expression in cerebellum and its encoded enzyme catalyzes a critical step in de novo biosynthesis of purines and its deficiency in the developing neurons severely affects neuronal differentiation and cell viability. We clinically evaluated an Emirati patient presented with severe developmental and growth delay, as well as corpus callosum agenesis and atrophy of brainstem and cerebellum. We performed exome sequencing, Sanger sequencing, and segregation analysis to identify the genetic cause of the phenotype, followed by in silico and in vitro analysis. We identified the novel variant (NM_004037.9:c.1471G > A) in AMPD2 gene leading to a single amino acid substitution (p.Gly491Arg) in adenosine monophosphate deaminase-2 enzyme. This variant is predicted to be pathogenic using several in silico tools, and resulted in a decrease in the enzyme function in the patient's polymorphonuclear cells by 82% (95% confidence interval: 73.3-91.7%, p = 0.029) compared with the control. This data establishes that the affected child is affected by PCH-9. Furthermore, we review all reported cases in literature to summarize the main clinical features of this rare disease.

Pontocerebellar Hypoplasia Type 9: A Case Study Highlighting Distinctive Magnetic Resonance Imaging Features.

Pontocerebellar hypoplasia type 9 (PCH9) is a rare, autosomal, recessive, neurodevelopmental disorder caused by a mutation in the AMPD2 gene. Despite its rarity, it presents distinctive clinical and neuroradiological features. Diagnosing it is challenging yet crucial for appropriate management. We describe a 21-month-old boy with clinical and neuroradiological manifestations of the diagnosis, including characteristic signs such as an eight-configured midbrain and hypoplasia of the brainstem and cerebellar structures. Genetic evaluation confirmed homozygous missense mutations in the AMPD2 gene. This case highlights the pathognomonic neuroradiological features of pontocerebellar hypoplasia type 9 that point toward diagnosis.

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.

Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use mouse models of a childhood neurodegenerative disorder caused by AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that mouse models of AMPD2 deficiency exhibit predominant degeneration of the hippocampal dentate gyrus, despite a general reduction of brain GTP levels. Neurodegeneration-resistant regions accumulate micron-sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis, while these filaments are barely detectable in the hippocampal dentate gyrus. Furthermore, we show that IMPDH2 filament disassembly reduces GTP levels and impairs growth of neural progenitor cells derived from individuals with human AMPD2 deficiency. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation, opening the possibility of exploring the induction of IMPDH2 assembly as a therapy for neurodegeneration.

Long-Term Disease Course of Pontocerebellar Hypoplasia Type 10.

BACKGROUND: Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. METHODS: Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. RESULTS: Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. CONCLUSIONS: Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time.

Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

Case report: A severe clinical phenotype of pontocerebellar hypoplasia type 7 with compound heterozygous variants of TOE1.

Pontocerebellar Hypoplasia (PCH) is a rare autosomal recessive hereditary neurological degenerative disease. To elaborate upon the clinical phenotypes of PCH and explore the correlation between TOE1 gene mutations and clinical phenotype, we analyze the clinical and genetic features of a Chinese infant afflicted with pontocerebellar dysplasia accompanied by gender reversal with bioinformatics methods. The main clinical features of this infant with TOE1 gene mutation included progressive lateral ventricle widening, hydrocephalus, severe postnatal growth retardation, and hypotonia, and simultaneously being accompanied by 46, XY female sex reversal. Whole exome sequencing revealed a compound heterozygous mutation in the TOE1 gene (c.299T > G, c.1414T > G), with the protein homology modeling-generated structure predicting a pathogenic variation, which is closely related to the clinical manifestations in the patient. The new mutation sites, c.299T > G and c.1414T > G, in the TOE1 gene are pathogenic variants of pontocerebellar hypoplasia type 7.

A novel homozygous variant in SLC25A46 gene associated with pontocerebellar hypoplasia type 1E: a case report.

Neonatal encephalopathy (NE) is a complex clinical condition with diverse etiologies. Hypoxic-ischemic encephalopathy (HIE) is a major contributor to NE cases. However, distinguishing NE subtypes, such as pontocerebellar hypoplasia type 1E (PCH1E), from HIE can be challenging due to overlapping clinical features. Here, we present a case of PCH1E in a neonate with a homozygous mutation c.72delT p. (Phe24LeufsTer20) in the SLC25A46 gene. The severity of PCH1E associated NE highlighted the significance of early recognition to guide appropriate clinical management.

Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review.

BACKGROUND: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. METHODS: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. RESULTS: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. CONCLUSIONS: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH.

Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations.

OBJECTIVE: Defects in RARS2 cause cerebellopontine hypoplasia type 6 (pontocerebellar hypoplasia type 6, PCH6, OMIM: #611523), a rare autosomal recessive inherited mitochondrial disease. Here, we report two male patients and their respective family histories. METHODS: We describe the clinical presentation and magnetic resonance imaging (MRI) findings of these patients. Whole-exome sequencing was used to identify the genetic mutations. RESULTS: One patient showed hypoglycemia, high lactic acid levels (fluctuating from 6.7 to 14.1 mmol/L), and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and pons. The other patient presented with early infantile developmental and epileptic encephalopathies (EIDEEs) with an initial developmental delay followed by infantile epileptic spasm syndrome (IESS) at 5 months old, with no imaging changes. Whole-exome sequencing identified compound heterozygous RARS2 variants c.25A>G (p.I9V) with c.1261C>T (p.Q421*) and c.1A>G (p.M1V) with c.122A>G (p.D41G) in these two patients. Of these loci, c.1261C>T and c.122A>G have not been previously reported. SIGNIFICANCE: Our findings have expanded the RARS2 gene variant spectrum and present EIDEEs and IESS as phenotypes which deepened the association between PCH6 and RARS2. PLAIN LANGUAGE SUMMARY: Defects in RARS2 cause cerebellopontine hypoplasia type 6, a rare autosomal recessive inherited mitochondrial disease. Two patients with RARS2 variants were reported in this article. One patient showed hypoglycemia, high lactic acid levels, and frequent seizures after birth, with progressive atrophy of the cerebrum, cerebellum, and Page 3 of 21 Epilepsia OpenFor Review Only pons. The other patient presented with an initial developmental delay followed by refractory epilepsy at 5 months old, with no imaging changes. Our findings deepened the association between PCH6 and RARS2.

Classic "PCH" Genes are a Rare Cause of Radiologic Pontocerebellar Hypoplasia.

The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types described in OMIM, many other disorders can result in a similar imaging appearance. This study aims to review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 68% and included chromosomal (21%), monogenic (34%) and acquired (13%) causes. Only one patient had pathogenic variants in an OMIM listed PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. This cohort demonstrates that radiologic PCH has heterogenous etiologies and the "classic" OMIM-listed PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders.

Clinical and genetic characterization of a Chinese family with pontocerebellar hypoplasia type 7.

We report compound heterozygous variants in TOE1 in siblings of Chinese origin who presented with dyskinesia and intellectual disabilities. Our report provides further information regarding the etiology and pathogenesis of pontocerebellar hypoplasia type 7 syndrome (PCH7). Clinical manifestations were obtained, and genomic DNA was collected from family members. Whole-exome and Sanger sequencing were performed to identify associated genetic variants. Bioinformatics analysis was conducted to identify and characterize the pathogenicity of the heterozygous variants. Following long-term rehabilitation, both siblings showed minimal improvement, and their condition tended to progress. Whole-exome sequencing revealed two unreported heterozygous variants, NM_025077: c.C553T (p.R185W) and NM_025077: c.G562T (p.V188L), in the TOE1 gene mapped to 1p34.1. Sanger sequencing confirmed that the two variants in the proband and her brother were inherited from their parents. The NM_025077: c.C553T (p.R185W) variant was inherited from the father, and the NM_025077: c.G562T (p.V188L) variant was inherited from the mother. Although the two variants in the TOE1 gene have not been reported previously, they were associated with PCH7 based on integrated analysis. Thus, our report contributes to our knowledge regarding the etiology and phenotype of PCH 7.

ATAD3A gene variations in a family with Harel-Yoon syndrome. / Harel-Yoon综合征一家系临床表型及ATAD3AåŸºå› å˜å¼‚åˆ†æž.

An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of myocardial injury and inflammation, and high levels of acylcarnitine octanoylcarnitine and decanoylcarnitine in tandem mass spectrometry. Ultrasonography and MRI suggested cardiac insufficiency and hypertrophic cardiomyopathy. Whole exome sequencing showed that both the proband and her elderly sister had a compound heterozygous variant of c.1492dup (p.T498Nfs*13) and c.1376T>C (p.F459S) in the ATAD3A gene, inherited from their father and mother, respectively. The diagnosis of Harel-Yoon syndrome was confirmed. The proband and her sister were born with clinical manifestations of metabolic acidosis, hyperlactatemia, feeding difficulties, elevated markers of myocardial injury as well as cardiac insufficiency, and both died in early infancy.

Pontocerebellar Hypoplasia 7 with Novel Compound Heterozygous Variants of TOE1 in a Boy with Micropenis, Developmental Delay, and Ataxia: The First Korean Case Report.

Pontocerebellar hypoplasia (PCH) is a rare neurodegenerative disorder characterized by hypoplasia of the pons and cerebellum and global developmental delay. Among several PCH types, PCH7 is a characteristic type that manifests with not only brain lesions but also sexual developmental disorders. The causative gene, TOE1, encodes a protein involved in small ribonucleic acid maturation and processing. TOE1 mutation is associated with neuronal survival that causes hypoplasia of the cerebellum and pons. We report the case of a male patient with PCH7, developmental delay, ataxia, micropenis, and undescended testis. Genetic analysis revealed compound heterozygous missense variants (c.955C>T and c.533T>G) in the TOE1 gene.

Novel bi-allelic variants of CHMP1A contribute to pontocerebellar hypoplasia type 8: additional clinical and genetic evidence.

Pontocerebellar hypoplasia type 8(PCH8) is a rare neurodegenerative disorder, reportedly caused by pathogenic variants of the CHMP1A in autosomal recessive inheritance, and CHMP1A variants have also been implicated in other diseases, and yet none of the prenatal fetal features were reported in PCH8. In this study, we investigated the phenotype and genotype in a human subject with global developmental delay, including clinical data from the prenatal stage through early childhood. Prenatally, the mother had polyhydramnios, and the bilateral ventricles of the fetus were slightly widened. Postnatally, the infant was observed to have severely delayed psychomotor development and was incapable of visual tracking before 2 years old and could not fix on small objects. The young child had hypotonia, increased knee tendon reflex, as well as skeletal malformations, and dental crowding; she also had severe and recurrent pulmonary infections. Magnetic resonance imaging of the brain revealed a severe reduction of the cerebellum (vermis and hemispheres) and a thin corpus callosum. Through whole exome sequencing and whole genomics sequencing, we identified two novel compound heterozygous variations in CHMP1A [c.53 T > C(p.Leu18Pro)(NM_002768.5) and exon 1 deletion region (NC_000016.10:g.89656392_89674382del)]. cDNA analysis showed that the exon1 deletion region led to the impaired expression, and functional verification with zebrafish embryos using base edition indicated variant c.53 T > C (p.Leu18Pro), causing dysplasia of the cerebellum and pons. These results provide further evidence that CHMP1A variants in a recessive inheritance pattern contribute to the clinical characteristics of PCH8 and further expand our knowledge of the phenotype and genotype spectrum of PCH8.

FAM91A1-TBC1D23 complex structure reveals human genetic variations susceptible for PCH.

Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1-TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes.

Advanced Optical Microscopy: Unveiling Functional Insights Regarding a Novel PPP2R1A Variant and Its Unreported Phenotype.

The number of genes implicated in neurodevelopmental conditions is rapidly growing. Recently, variants in PPP2R1A have been associated with syndromic intellectual disability and a consistent, but still expanding, phenotype. The PPP2R1A gene encodes a protein subunit of the serine/threonine protein phosphatase 2A enzyme, which plays a critical role in cellular function. We report an individual showing pontocerebellar hypoplasia (PCH), microcephaly, optic and peripheral nerve abnormalities, and an absence of typical features like epilepsy and an abnormal corpus callosum. He bears an unreported variant in an atypical region of PPP2R1A. In silico studies, functional analysis using immunofluorescence, and super-resolution microscopy techniques were performed to investigate the pathogenicity of the variant. This analysis involved a comparative analysis of the patient's fibroblasts with both healthy control cells and cells from an individual with the previously described phenotype. The results showed reduced expression of PPP2R1A and the presence of aberrant protein aggregates in the patient's fibroblasts, supporting the pathogenicity of the variant. These findings suggest a potential association between PPP2R1A variants and PCH, expanding the clinical spectrum of PPP2R1A-related neurodevelopmental disorder. Further studies and descriptions of additional patients are needed to fully understand the genotype-phenotype correlation and the underlying mechanisms of this novel phenotype.

Differentiating Genetic Forms of Pontocerebellar Hypoplasia From Acquired Lesions Resembling Pontocerebellar Hypoplasia: Clinical, Neurodevelopmental, and Imaging Insight From 19 Extremely Premature Patients.

It is well established that extreme prematurity can be associated with cerebellar lesions potentially affecting the neurologic prognosis. One of the commonly observed lesions in these cases is pontocerebellar hypoplasia resulting from prematurity, which can pose challenges in distinguishing it from genetically caused pontocerebellar hypoplasia. This confusion leads to unacceptable and prolonged diagnostic ambiguity for families as well as difficulties in genetic counseling. Therefore, it is crucial to identify the clinical and neuroradiologic features allowing to differentiate between acquired and genetic forms of pontocerebellar hypoplasia in order to guide clinical practices and improve patient care. In this regard, we report in the present manuscript the clinical, developmental, and radiologic characteristics of 19 very premature children (gestational age <28 weeks, now aged 3-14 years) with cerebellar lesions and discuss the causal mechanisms. Our findings support the notion that a combination of specific clinical and radiologic criteria is essential in distinguishing between acquired and genetic forms of pontocerebellar hypoplasia.