Parental perspectives of episodic irritability in an ultra-rare genetic disorder associated with NACC1

Abstract Background A recurrent de novo variant (c.892C>T) in NACC1 causes a neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM). An unusual and consistently reported feature is episodic extreme irritability and inconsolability. We now characterize these episodes, their impact on the family, and ascertain treatments that may be effective. Parents of 14 affected individuals provided narratives describing the irritability episodes, including triggers, behavioral and physiological changes, and treatments. Simultaneously, parents of 15 children completed the Non-communicating Children’s Pain Checklist-Revised (NCCPC-R), a measure to assess pain in non-verbal children. Results The episodes of extreme irritability include a prodromal, peak, and resolving phase, with normal periods in between. The children were rated to have extreme pain-related behaviors on the NCCPC-R scale, although it is unknown whether the physiologic changes described by parents are caused by pain. Attempted treatments included various classes of medications, with psychotropic and sedative medications being most effective (7/15). Nearly all families (13/14) describe how the episodes have a profound impact on their lives. Conclusions NECFM caused by the recurrent variant c.892C>T is associated with a universal feature of incapacitating episodic irritability of unclear etiology. Further understanding of the pathophysiology can lead to more effective therapeutic strategies

The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt

Summary: Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2–3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7–11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine

Thinner Retinal Nerve Fiber Layer in Very Preterm Versus Term Infants and Relationship to Brain Anatomy and Neurodevelopment

PURPOSE: To assess retinal nerve fiber layer (RNFL) thickness at term-equivalent age in very preterm (<32 weeks gestational age) versus term-born infant cohorts, and compare very preterm infant RNFL thickness with brain anatomy and neurodevelopment. DESIGN: Cohort study. METHODS: RNFL was semi-automatically segmented (one eye per infant) in 57 very preterm and 50 term infants with adequate images from bedside portable, handheld spectral domain optical coherence tomography (Bioptigen, Inc., Research Triangle Park, NC) imaging at 37-42 weeks postmenstrual age. Mean RNFL thickness was calculated for the papillomacular bundle (−15° to + 15°) and temporal quadrant (−45° to +45°) relative to the fovea-optic nerve axis. Brain magnetic resonance imaging (MRI) scans clinically obtained in 26 very preterm infants were scored for global structural abnormalities by an expert masked to data except for age. Cognitive, language, and motor skills were assessed with Bayley Scales of Infant and Toddler Development-III (Pearson, San Antonio, TX) in 33 of the very preterm infants at 18-24 months corrected age. RESULTS: RNFL was thinner for very preterm versus term infants at the papillomacular bundle ([mean ± standard deviation] 61 ± 17 versus 72 ± 13 μm, p<0.001) and temporal quadrant (72 ± 21 versus 82 ± 16 μm, p=0.005). In very preterm infants, thinner papillomacular bundle RNFL correlated with higher global brain MRI lesion burden index (R(2)=0.35, p=0.001) and lower cognitive (R(2)=0.18, p=0.01) and motor (R(2)=0.17, p=0.02) scores. Relationships were similar for temporal quadrant. CONCLUSIONS: Thinner RNFL in very preterm infants relative to term-born infants may relate to brain structure and neurodevelopment

Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

International audienceDevelopmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders