Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.

BACKGROUND: Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). OBJECTIVES: We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. METHODS: We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. RESULTS: Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. CONCLUSION: Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Midfacial Toddler Excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders; Midfacial Toddler Excoriation Syndrome (MiTES) - itch with normal pain sensation associated with homozygous 18 alanines (18A), and congenital insensitivity to pain (CIP) with normal itch with homozygous 19A. Knowledge of the phenotype, genotype, and disease mechanism of MiTES is incomplete. Why PRDM12 18A versus 19A can cause almost opposite phenotypes is unknown; no other poly-alanine or poly-glutamine tract expansion disease causes two such disparate phenotypes. METHODS: We assessed the genotype and phenotype of 9 new, 9 atypical, and 6 previously reported patients diagnosed with MiTES. Using cell lines with homozygous PRDM12 of 12A (normal), 18A (MiTES) and 19A (CIP) we examined PRDM12 aggregation and subcellular localisation by image separation confocal microscopy and sub-cellular fractionation western blotting. RESULTS: MiTES presents in the first year of life, and in all cases the condition regresses over the first decade leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12-CIP are rarely found. The genotype-phenotype study of PRDM12 polyalanine tract shows that 7A -15A are normal; 16A -18A are associated with MiTES; 19A leads to CIP; and no clinically atypical MiTES cases had an expansion. PRDM12 aggregation and sub-cellular localisation differ significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein aggregation disease. CONCLUSION: We provide diagnostic criteria for MiTES, and improved longitudinal data. MiTES and CIP are distinct phenotypes despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells.. We hypothesise that the developmental environment of the trigeminal ganglion is unique and critically sensitive to prenatal and postnatal levels of PRDM12.

In silico characterization and identification of compound heterozygous variants in H/ACA Ribonucleoprotein Assembly Factor (SHQ1) from Indian population.

Background: H/ACA small nucleolar ribonucleoproteins (snoRNP) form a complex with multiple proteins to accomplish the pseudouridylation of rRNA. The assembly of H/ACA small nucleolar ribonucleoproteins (snoRNP) is initiated by H/ACA ribonucleoprotein Assembly factor, that is, SHQ1. Mutations in SHQ1 have been reported to cause two disorders namely, dystonia-35 childhood onset (OMIM*619921) and neurodevelopmental disorder with seizures and dystonia (OMIM*619922), both of which are inherited in an autosomal recessive manner. Considering the high genetic and clinical diversity of SHQ1-related clinical features and the importance of SHQ1 in the assembly of the H/ACA snoRNP complex, it is important to take a systematic approach to delineate the genetic diagnosis and impact of mutations on protein structure and stability. Methods: Whole exome sequencing followed by Sanger validation was performed in an individual with the clinical features of neurodevelopmental disorder with seizures and dystonia (OMIM*619922). Protein modeling studies of all the reported SHQ1 variants to date were performed using freely available web servers Interactive Tree of Life, String, BioGrid, ShinyGO, DAVID, and Pathvix. Protein structures were visualized using Pymol. Results and Discussion: We identified compound heterozygous variants, one known frameshift deletion c. 828_831del, p.(Asp277Serfs*27) and the other novel missense variant c. 1157A>C, p.(Tyr386Ser) found in an individual with neurodevelopmental disorder, seizures, movement disorder, and hypomyelination leukodystrophy on neuroimaging. Protein-interactome studies identified potential genetic interactors that include GAR1, NAF1, TRUB1, UTP15, DKC1, NOP10, NPHOSPH 10, KRR1, NOP58, NOP56, FBL, RRP9, NHP2, RUVBL1, and RUVBL2. Ribosome biogenesis in eukaryotes, RNA polymerase, RNA transport, spliceosome, ribosome, cytosolic DNA-sensing pathway, DNA replication, mismatch repair, base excision repair, nucleotide excision repair, and basal transcription factors process were identified as the linked pathways with the prioritized genes. Conclusion: In conclusion, a sophisticated genotype and phenotype correlation followed by linking the genes to the key biological pathways opens new avenues to understand disease pathology and plan for therapeutic interventions.

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Comprehensive immunoprofiling of neurodevelopmental disorders suggests three distinct classes based on increased neurogenesis, Th-1 polarization or IL-1 signaling.

Neurodevelopmental disorders (NDDs) are a spectrum of conditions with commonalities as well as differences in terms of phenome, symptomatome, neuropathology, risk factors and underlying mechanisms. Immune dysregulation has surfaced as a major pathway in NDDs. However, it is not known if neurodevelopmental disorders share a common immunopathogenetic mechanism. In this study, we explored the possibility of a shared immune etiology in three early-onset NDDs, namely Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Intellectual Disability Disorder (IDD). A panel of 48 immune pathway-related markers was assayed in 135 children with NDDs, represented by 45 children with ASD, ADHD and IDD in each group, along with 35 typically developing children. The plasma levels of 48 immune markers were analyzed on the Multiplex Suspension Assay platform using Pro Human cytokine 48-plex kits. Based on the cytokine/chemokine/growth factor levels, different immune profiles were computed. The primary characteristics of NDDs are depletion of the compensatory immune-regulatory system (CIRS) (z composite of IL-4, IL-10, sIL-1RA, and sIL-2R), increased interleukin (IL)-1 signaling associated with elevated IL-1α and decreased IL-1-receptor antagonist levels, increased neurogenesis, M1/M2 macrophage polarization and increased IL-4 as well as C-C Motif Chemokine Ligand 2 (CCL2) levels. With a cross-validated sensitivity of 81.8% and specificity of 94.4%, these aberrations seem specific for NDDs. Many immunological abnormalities are shared by ASD, ADHD and IDD, which are distinguished by minor differences in IL-9, IL-17 and CCL12. In contrast, machine learning reveals that NDD group consists of three immunologically distinct clusters, with enhanced neurogenesis, Th-1 polarization, or IL-1 signaling as the defining features. NDD is characterized by immune abnormalities that have functional implications for neurogenesis, neurotoxicity, and neurodevelopment. Using machine learning, NDD patients could be classified into subgroups with qualitatively distinct immune disorders that may serve as novel drug targets for the treatment of NDDs.

Snijders Blok-Campeau Syndrome: Description of 20 Additional Individuals with Variants in CHD3 and Literature Review.

Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51-74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.

Biotinidase Deficiency in the Second Decade with Atypical Neuroimaging Findings.

Biotinidase deficiency is a rare autosomal recessive neurometabolic disorder resulting in biotin deficiency. Our patient presented with seizures and developmental delay since infancy and was started on megavitamin supplements. At 14 years, she presented with motor regression with encephalopathy after discontinuation of vitamins. There were no skin and hair changes. Magnetic resonance imaging (MRI) of the brain showed bilateral symmetrical posterior putamen signal changes. Tandem mass spectroscopy showed increased methyl malonyl carnitine and 3-OH isovaleryl carnitine. There was a low biotinidase level, and a pathogenic variant in the BTD gene in the next-generation sequencing was identified. Special importance is placed on the unusual symmetric posterior putamen involvement seen in MRI of the brain.