Pontocerebellar Hypoplasia Research Articles

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.

Toe1 promotes proliferation and differentiation of neural progenitor cells

Toe1 (target of EGR1, member 1) is a 3′- exonuclease in the deadenylase family, essential for the maturation of small nuclear RNAs. Mutations in Toe1 are linked to pontocerebellar hypoplasia 7 (PCH7), a severe neurodegenerative syndrome affecting infants, characterized by progressive neurodegeneration, developmental delay, and genital abnormalities. The pathogenic mechanisms of PCH7 are unclear but are thought to involve abnormal neural stem cell (NSC) development during embryogenesis. This study investigates Toe1's role in NSC development using the C17.2 NSC line. Colony formation, EdU incorporation, and CFSE staining assays showed that Toe1 knockout inhibited C17.2 cell proliferation. Upon inducing differentiation, Toe1 knockout significantly reduced cell dendrites. Immunofluorescence, qPCR, and Western blot analyses indicated that Toe1 knockout suppressed the expression of neuronal marker βIII-tubulin and glial cell marker Gfap, thereby inhibiting C17.2 cell differentiation. Additionally, Toe1 knockout reduced the expression of Dll1 and Jag1, suggesting an inhibition of Notch signaling. High-throughput transcriptome sequencing revealed that Toe1 influenced calcium ion binding, ECM, and amino acid catabolism in undifferentiated C17.2 cells, and peptidase activity, chemotactic factors, ECM, and TNF signaling in differentiated cells. These findings underscore Toe1's critical regulatory role in NSC proliferation and differentiation, with significant implications for developing therapeutic targets for neurodegenerative diseases such as PCH7.

Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective

IntroductionTonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.MethodAfter the antenatal diagnosis of...

Severe ataxia with cognitive impairment in a young child: a case report of Pontocerebellar Hypoplasia

Adolescence is a period of rapid development and a variety of genetic disorders present during this time due to difficulties with motor and cognitive skills. A very rare group of diseases is genetic Pontocerebellar Hypoplasia, characterized by a developmentally small cerebellum that leads to ataxia and movement abnormalities. Here, we present a case of a young boy who presented with ataxia and falls.

Pontocerebellar hypoplasia caused by the TSEN54 mutation: clinical and electroencephalographic characteristics based on 3 cases

Pontocerebellar hypoplasia caused by the TSEN54 mutation: clinical and electroencephalographic characteristics based on 3 cases

Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.

Pontocerebellar hypoplasia type 2a (PCH2a) is an ultra-rare, autosomal recessive pediatric disorder with limited treatment options. Its anatomical hallmark is hypoplasia of the cerebellum and pons accompanied by progressive microcephaly. A homozygous founder variant in TSEN54, which encodes a tRNA splicing endonuclease (TSEN) complex subunit, is causal. The pathological mechanism of PCH2a remains unknown due to the lack of a model system. Therefore, we developed human models of PCH2a using regionalized neural organoids. We generated induced pluripotent stem cell (iPSC) lines from three males with genetically confirmed PCH2a and subsequently differentiated cerebellar and neocortical organoids. Mirroring clinical neuroimaging findings, PCH2a cerebellar organoids were reduced in size compared to controls starting early in differentiation. Neocortical PCH2a organoids demonstrated milder growth deficits. Although PCH2a cerebellar organoids did not upregulate apoptosis, their stem cell zones showed altered proliferation kinetics, with increased proliferation at day 30 and reduced proliferation at day 50 compared to controls. In summary, we generated a human model of PCH2a, providing the foundation for deciphering brain region-specific disease mechanisms. Our first analyses suggest a neurodevelopmental aspect of PCH2a.

Screening for TSEN54 Variants in Egyptian Patients with Pontocerebellar Malformations

Introduction: Pontocerebellar hypoplasia (PCH) represents a group of rare disorders with prenatal onset and time-dependent loss of brain parenchyma, predominantly affecting the cerebellum and pons with variable involvement of supratentorial structures. Radiologically and pathologically, they are characterized by small cerebellum and pons. Our study aimed to screen for the TSEN54 gene variants in Egyptian patients with PCH for proper counseling and to describe the brain MRI and the clinical phenotype and compare, them to those described in the literature. Methods: Thirty patients from thirty Egyptian families with a diagnosis of PCH based on neuroimaging findings were selected. Clinical evaluation, radiological findings, and genetic investigations were done for all patients. Results: The common missense variant c.919G>T (p.A307S) was identified in only 6 patients from six unrelated families (6/30; 20%) who showed different degrees of pontocerebellar malformations on brain imaging. Conclusion: The presence of a dragonfly/butterfly-like pattern in the coronal section of the cerebellum recommends genetic testing of TSEN54 as a first step. For negative cases, whole-exome sequencing is essential to reach a definite diagnosis and determine the etiology.

Anomalies of Midbrain/Hindbrain Development and Related Disabilities: Pontocerebellar Hypoplasia, Congenital Disorders of Glycosylation, and Cerebellar Hemisphere Hypoplasia

AbstractRecent progress in developmental biology, molecular genetics, and neuroimaging has enabled a more profound comprehension of developmental disorders affecting the embryonic midbrain and hindbrain, which manifest clinically. The purpose of this review is to describe anomalies of the midbrain/hindbrain such as pontocerebellar hypoplasia (PCH), congenital disorders of glycosylation (CDG), cerebellar hemisphere hypoplasia. PCH is a group of disorders that is both clinically and genetically diverse. These disorders are identified by the hypoplasia and degeneration of the cerebellum and ventral pons. A total of 18 distinct clinical subtypes of PCH, each linked to pathogenic variants in 19 different genes, have been documented, like mutations in TSEN54 (coding a subunit of tRNA splicing endonucleases complex) and TBC1D23 which display moderate-to-severe intellectual disability (ID) and microcephaly. CDG represent a set of inherited conditions marked by impaired glycosylation of proteins and lipids. The most prevalent subtype among CDG is PMM2-CDG, inherited in a recessive manner, causing reduced activity of phosphomannomutase. Its phenotype varies from mild to severe, involving the central nervous system and affecting many other organs as well. Patients who are severely affected also exhibit visceral symptoms alongside severe ID and other neurological manifestations. Cerebellar hypoplasia (CH) is characterized by a cerebellum of diminished volume while maintaining its shape. CH exhibits a diverse range of neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental involvement. Cerebello–oculo–facio–genital syndrome is linked to a recessive MAB21L1 mutation. Jubert's syndrome, associated with a rare autosomal recessive mutation, is identified on magnetic resonance imaging by cerebellar worm hypoplasia and midbrain malformations. The rhombencephalosynapsis, characterized by vermian agenesis or hypogenesis with the fusion of the cerebellar hemispheres, emerges during embryogenesis. It can manifest alone or in conjunction with other and/or extracerebral abnormalities.

Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders. Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients. These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

Anomalies of Midbrain/Hindbrain Development: Malformations of Cerebellum: Diagnosis, Classification, and Rehabilitative Hypothesis

AbstractExtensive research has been conducted on the cerebellum, making it one of the most thoroughly investigated regions of the brain. It plays a fundamental role not only in motor control but also in motor learning and cognition. The development of the cerebellum is a lengthy process, beginning during the embryonic period up to the first years of life. This slow and protracted process makes it a vulnerable organ liable to different insults, responsible for many developmental disorders such as Dandy–Walker syndrome, medulloblastoma, dystroglicanopathy, pontocerebellar hypoplasia, thubulinopathies, and Jubert syndrome. Due to several factors, the true prevalence of cerebellar malformations is not known in most cases. The cerebellum undergoes development through following four fundamental stages:(1) Identification of the cerebellar region at the boundary between the midbrain and hindbrain.(2) Establishment of two cell proliferation compartments: firstly, Purkinje cells and deep cerebellar nuclei emerge from the ventricular zone of the metencephalic alar plate; secondly, granule cell precursors are generated from a separate proliferation compartment known as the upper rhombic lip.(3) Migration of granule cells toward the interior: granule precursor cells constitute the external granular layer (EGL), and during the initial postnatal year, granule cells migrate inward to their final position in the internal granular layer.(4) Formation of cerebellar circuitry and subsequent differentiation.Based on different types of involvement of the structures detected in the brain magnetic resonance, the classification of brainstem and cerebellar anomalies is divided into three categories: (1) mainly the cerebellum, (2) mainly the brain stem, and (3) both involved. This review will outline the developmental processes of the cerebellum and delve into common developmental disorders associated with it, including the Dandy–Walker syndrome, cerebellar hypoplasia, rhomboencephalosynapsis, lissencephaly, and gray matter heterotopias.

A case report and literature review of pontocerebellar hypoplasia type 13 combined with abnormal liver function caused by VPS51 gene variation

A case report and literature review of pontocerebellar hypoplasia type 13 combined with abnormal liver function caused by VPS51 gene variation

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.

Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7.

Biallelic TOE1 variants can cause pontocerebellar hypoplasia type 7 (PCH7), a condition characterized by pontocerebellar hypoplasia with genital abnormality. TOE1 is a 3'-exonuclese for 3'-end maturation in small nuclear RNA. TOE1 pathogenic variants have been reported at the DEDD catalytic domain and zinc finger motif. Here, we describe a PCH7 patient with novel compound heterozygous TOE1 variants and a detailed clinical course. The patient was a 3-year-old female and showed developmental delay without cerebellar ataxic behavior. Head MRI revealed delayed myelination without pontocerebellar hypoplasia at 9 months of age. Progressive pontocerebellar atrophy was prominent at follow-up MRI. Cerebral abnormalities are characteristic features of PCH7 before pontocerebellar atrophy is observed. One variant, p.Arg331*, was located at the nuclear localization motif (NLM) and partially escaped from nonsense-mediated decay. This variant affected nuclear localization in mutant expressing cells, thus, the TOE1 variant at NLM leads to TOE1 dysfunction associated with nuclear mis-localization.

U1 snRNP Biogenesis Defects in Neurodegenerative Diseases.

The U1 small ribonucleoprotein (U1 snRNP) plays a pivotal role in the intricate process of gene expression, specifically within nuclear RNA processing. By initiating the splicing reaction and modulating 3'-end processing, U1 snRNP exerts precise control over RNA metabolism and gene expression. This ribonucleoparticle is abundantly present, and its complex biogenesis necessitates shuttling between the nuclear and cytoplasmic compartments. Over the past three decades, extensive research has illuminated the crucial connection between disrupted U snRNP biogenesis and several prominent human diseases, notably various neurodegenerative conditions. The perturbation of U1 snRNP homeostasis has been firmly established in diseases such as Spinal Muscular Atrophy, Pontocerebellar hypoplasia, and FUS-mediated Amyotrophic Lateral Sclerosis. Intriguingly, compelling evidence suggests a potential correlation in Fronto-temporal dementia and Alzheimer's disease as well. Although the U snRNP biogenesis pathway is conserved across all eukaryotic cells, neurons, in particular, appear to be highly susceptible to alterations in spliceosome homeostasis. In contrast, other cell types exhibit a greater resilience to such disturbances. This vulnerability underscores the intricate relationship between U1 snRNP dynamics and the health of neuronal cells, shedding light on potential avenues for understanding and addressing neurodegenerative disorders.

Expanded clinical phenotype and untargeted metabolomics analysis in RARS2-related mitochondrial disorder: a case report

BackgroundRARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE).Case presentationHere, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites.ConclusionsOur work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.

Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.

TBC1D23 mediates Golgi-specific LKB1 signaling

Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive. Here, we show that TBC1D23, a Golgi-localized protein that is frequently mutated in the neurodevelopment disorder pontocerebellar hypoplasia (PCH), is specifically required for the LKB1 signaling at the Golgi. TBC1D23 directly interacts with LKB1 and recruits LKB1 to Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Notably, Golgi-targeted expression of LKB1 rescues TBC1D23 deficiency in zebrafish models. Furthermore, the loss of LKB1 causes neurodevelopmental abnormalities in zebrafish, which partially recapitulates defects in TBC1D23-deficient zebrafish, and LKB1 sustains normal neuronal development via TBC1D23 interaction. Our study uncovers a regulatory mechanism of the LKB1 signaling, and reveals that a disrupted Golgi-LKB1 signaling underlies the pathogenesis of PCH.

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

BackgroundPontocerebellar 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.MethodsCases 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.ResultsThis 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.ConclusionsThis 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.

Sm complex assembly and 5' cap trimethylation promote selective processing of snRNAs by the 3' exonuclease TOE1.

Competing exonucleases that promote 3' end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3' exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity toward canonical snRNAs through their Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.

Prenatal diagnosis of pontocerebellar hypoplasia with postnatal follow-up.

To describe the MR features enabling prenatal diagnosis of pontocerebellar hypoplasia (PCH). This was a retrospective single monocentre study. The inclusion criteria were decreased cerebellar biometry on dedicated neurosonography and available fetal Magnetic Resonance Imaging (MRI) with PCH diagnosis later confirmed either genetically or clinically on post-natal MRI or by autopsy. The exclusion criteria were non-available MRI and sonographic features suggestive of a known genetic or other pathologic diagnosis. The collected data were biometric or morphological imaging parameters, clinical outcome, termination of pregnancy (TOP), pathological findings and genetic analysis (karyotyping, chromosomal microarray, DNA sequencing targeted or exome). PCH was classified as classic, non-classic, chromosomal, or unknown type. Forty-two fetuses were diagnosed with PCH, of which 27 were referred for decreased transverse cerebellar diameter at screening ultrasound. Neurosonography and fetal MRI were performed at a mean gestational age of 29+4 and 31+0weeks, respectively. Termination of pregnancy occurred. Pregnancy was terminated in 24 cases. Neuropathological examination confirmed the diagnosis in 24 cases and genetic testing identified abnormalities in 29 cases (28 families, 14 chromosomal anomaly). Classic PCH is associated with pontine atrophy and small MR measurements decreasing with advancing gestation. This is the first large series of prenatally diagnosed PCHs. Our study shows the essential contribution of fetal MRI to the prenatal diagnosis of PCH. Classic PCHs are particularly severe and are associated with certain MR features.