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Background: Botulism is a rare and life-threatening disease caused by the potent botulinum neurotoxin (BoNT), which can be produced by Clostridium botulinum (C. botulinum) and related bacteria. Clinical manifestations, which include a symmetrical, descending muscular paralysis, generalized hypotonia, and potentially respiratory failure, are non-specific and diagnosis is challenging, especially when anamnesis does not reveal any typical risk factor, like honey consumption. Case Presentation: We present what is, to the best of our knowledge, the first documented case of infant botulism (IB) in Sicily and discuss its peculiarities and the challenges faced in the diagnostic-therapeutic process. The infant was exclusively breastfed and no history of consumption of possibly contaminated foods, like honey, was found. The signs observed at presentation included poor suction, hypotonia, and hyporeactivity. A detailed anamnesis motivated the suspicion of botulism, due to the occurrence of constipation and exposure to dust from home renovation works during the days before the onset of symptoms. The botulinum antitoxin was administered and the diagnosis was confirmed through fecal examination, detecting toxin-producing C. botulinum. Conclusion: IB should be considered in every infant with rapidly progressing hypotonia and a history of constipation. However rarely, transmission could occur through inhalation of dust particles containing the toxin, therefore it is important to explore all possible sources of exposure. In the case described, timely diagnosis and treatment determined the successful outcome, which highlights the importance of early intervention in managing IB. [ABSTRACT FROM AUTHOR]

ANK3 encodes ankyrin‐G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin‐G isoforms comprising different domains with distinct expression patterns. Mono‐ or biallelic ANK3 variants are associated with non‐specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self‐injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono‐ and biallelic variants appear to be localized differently across the three different ankyrin‐G isoforms, suggesting isoform‐specific pathological mechanisms. [ABSTRACT FROM AUTHOR]

Spinal Muscular Atrophy (SMA) is a neuromuscular disease due to degeneration of the anterior horn cells of the spinal cord. The estimated incidence of SMA is 1:6,000-1:10,000. The complete deletion of exon 7 of the SMN1 gene is the hallmark of 95-98% of SMA patients in most population. The first line of investigation for a child or young adult patient suspected to have SMA should be Multiplex ligation-dependent probe amplification (MLPA) testing for homozygous deletion of exons 7 and exon 8 in the SMN1 gene. In this paper, we report the results of SMN 1 exon 7 deletion tests in children who attended the Genetic clinic of a tertiary care hospital in Kerala with one or more of the symptoms especially floppy infants, hypotonia, muscle weakness, tongue fasiculations etc. SMN1 exon 7 and exon 8 deletion was confirmed in 58% cases (19) of the total 33 hypotonia patients. SMA Type I, Type II and Type III were 68.4% (13), 21% (4) and 10.5% (2) respectively among the SMA positive cases. Carrier testing of the non-consanguineous parents showed that all parents were heterozygous carriers. Until 2016, the treatment for this disease was supportive only. Recently Nusinersen, Zolgensma and Risdiplam have become available for SMA patients. The carrier testing in parents with previous SMA child history is essential for the implementation of prenatal diagnosis of this disorder in future pregnancies. The paper emphasizes the importance of this rare neuromuscular disease. [ABSTRACT FROM AUTHOR]

Pettigrew syndrome (PGS), an X‐linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe‐to‐profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1‐2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss‐of‐function alleles. The severity of ID in Pettigrew syndrome is mostly severe‐to‐profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM) is a severe type of congenital skeletal muscle disorder usually presenting at birth requiring extensive resuscitation. While having phenotypic variability, its diagnosis carries a poor prognosis due to high rates of hospitalization and mortality by early infancy. Management of patients with XLMTM should therefore be guided by shared decision-making with parents, considering the severity and progression of the disease, quality of life, and demands on caregivers. We describe a family unit of two half-siblings presenting with the severe neonatal form of XLMTM, with varying prognosis and outcomes. Furthermore, a novel maternally-derived c.343-1G > A variant in intron-5 of the MTM1 gene was identified in this family. Hereby, we propose an algorithm for the management of XLMTM, outlining important considerations during the antenatal and postnatal follow-up period.

Abstract Background Botulism is a rare and life-threatening disease caused by the potent botulinum neurotoxin (BoNT), which can be produced by Clostridium botulinum (C. botulinum) and related bacteria. Clinical manifestations, which include a symmetrical, descending muscular paralysis, generalized hypotonia, and potentially respiratory failure, are non-specific and diagnosis is challenging, especially when anamnesis does not reveal any typical risk factor, like honey consumption. Case Presentation We present what is, to the best of our knowledge, the first documented case of infant botulism (IB) in Sicily and discuss its peculiarities and the challenges faced in the diagnostic-therapeutic process. The infant was exclusively breastfed and no history of consumption of possibly contaminated foods, like honey, was found. The signs observed at presentation included poor suction, hypotonia, and hyporeactivity. A detailed anamnesis motivated the suspicion of botulism, due to the occurrence of constipation and exposure to dust from home renovation works during the days before the onset of symptoms. The botulinum antitoxin was administered and the diagnosis was confirmed through fecal examination, detecting toxin-producing C. botulinum. Conclusion IB should be considered in every infant with rapidly progressing hypotonia and a history of constipation. However rarely, transmission could occur through inhalation of dust particles containing the toxin, therefore it is important to explore all possible sources of exposure. In the case described, timely diagnosis and treatment determined the successful outcome, which highlights the importance of early intervention in managing IB.

We report the case of a Spanish pediatric patient with developmental delay, hypotonia, feeding difficulties, visual problems, and hyperkinetic movements. Whole-exome sequencing uncovered a new heterozygous de novo Synaptotagmin 1 (SYT1) missense variant, NM_005639.3:c.930T>A (p.Asp310Glu), in a female proband. This gene encodes the synaptotagmin-1 (SYT1) protein, which is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. Pathogenic SYT1 variants have been associated with Baker–Gordon syndrome (BAGOS), an autosomal dominant neurodevelopmental disorder. Although up to 30 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with mitochondrial respiratory chain deficiencies and rod–cone dysfunction. In conclusion, our data expand both the genetic and phenotypic spectrum associated with SYT1 variants. [ABSTRACT FROM AUTHOR]

Tubulinopathies are associated with malformations of cortical development but not Walker–Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker–Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker–Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker–Warburg-associated genes confirm this as not a new presentation of Walker–Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of. [ABSTRACT FROM AUTHOR]

Background: Inherited neuromuscular (NMD) and neurodegenerative diseases (NDD) belong to two distinct categories that disturb different components of the nervous system, leading to a variety of different symptoms and clinical manifestations. Both NMD and NDD are a heterogeneous group of genetic conditions. Genetic variations in the SGCA and SIL1 genes have been implicated in causing Limb Girdle Muscular Dystrophy (LGMD), a type of neuromuscular disorder, and Marinesco–Sjögren Syndrome (MSS) which is a neurodegenerative disorder. Methods: In the present study, we have investigated four patients presenting LGMD and five patients with MSS features. After collecting detailed clinical and family history, necessary laboratory investigations, including estimation of a skeletal muscle marker enzyme serum creatine kinase (CK), nerve conduction study (NCS), electromyography (EMG), echocardiography (Echo), Magnetic resonance imaging (MRI –brain), CT-brain and X-rays were performed. Whole exome followed by Sanger sequencing was employed to search for the disease-causing variants. Results: Physical examination in LGMD patients revealed poor muscle tone and facing difficulty in straightening up from the floor. Clinical history revealed frequent falls and strenuousness in climbing stairs. They started toe-walking in early childhood. Laboratory investigations confirmed elevated CK levels and abnormal NCS and EMG. The MSS patients showed abnormalities in gate and jerking movement, abnormal speech, and strabismus with cataract. MRI-brain showed cerebral atrophy in some MSS patients with elevated CK levels. Whole exome sequencing revealed a nonsense variant [c.C574T, p.(Arg192*)] in the SGCA gene and a frameshift [c.936dupG, p.(Leu313AlaFs*39)] in the SIL1 gene in LGMD and MSS patients, respectively. Conclusion: Our study emphasizes the significance of integrating clinical and genetic analyses for precise diagnosis and tailored management strategies in inherited NMD and NDD disorders. To the best of our knowledge, this is the first study documenting SGCA and SIL1 recurrent variants in subcontinent populations with few rare clinical features. The recurrent mutations expanding the global understanding of the mutation's geographic and ethnic distribution and contributing valuable epidemiological data. The study will facilitate genetic counseling for families experiencing similar clinical features, both within Pakistani populations and in other regions. [ABSTRACT FROM AUTHOR]

Striated muscle is an organized tissue that utilizes chemical energy to perform physical work, generated through muscle contraction. Proper muscle tone is essential for efficient movement and basic bodily functions. Clinical practice categorizes muscle tone alterations as hypertonia, an increase in tone in skeletal and/or smooth muscles, and hypotonia or flaccidity, a decrease in skeletal muscle tone. These terms are widely used in rehabilitation to denote decreased muscle tone. This study examined the etymological origins of the terms Hypotonia and Flaccidity and their respective definitions. Etymological research utilized the Diccionario Médicobiológico, histórico y etimológico and Diccionario Latino-Español Español-Latino. Spanish definitions were sourced in Diccionario de Términos Médicos de La Real Academia de Medicina de España; Diccionario de la Lengua española; Diccionario Panhispánico de Términos Médicos; Biblioteca Nacional Médica and Biblioteca Virtual de Salud de Centro Latinoamericano y del Caribe. The clinical use of these terms was assessed through neurology articles per authors' criteria. Consequently, Hypotonia is deemed the more suitable term for describing decreased muscle tone in rehabilitation contexts. Depending on the lesion's origin, terms like Central Hypotonia and Peripheral Hypotonia may be used when structures associated with the central or peripheral nervous systems are affected, respectively. It is suggested that these terms be adopted in clinical practice and teaching when addressing alterations in central or peripheral nervous systems resulting in reduced muscle tone. [ABSTRACT FROM AUTHOR]

Mannosyl-oligosaccharide glucosidase – congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG. [ABSTRACT FROM AUTHOR]

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IntroductionMutations in the protein WD repeat structural domain 26 (WDR26, MIM 617424) have been identified as the cause of autosomal dominant Skraban-Deardorff syndrome, a rare genetic disorder characterized by intellectual disability (ID), developmental delay (DD), hypotonia, epilepsy, infant feeding difficulties, gait abnormalities and distinctive facial features. The objective of this study is to investigate the genetic factors that may contribute to the development of Skraban-Deardorff syndrome in affected individuals.MethodsIn this study, we used whole-exome sequencing (WES) to analyze pathogenic and likely pathogenic variants in two unrelated Chinese patients with DD and ID. We confirmed the origin of the variants by conducting Sanger sequencing and classified them according to ACMG/AMP guidelines.ResultsHere, two novel de novo variants (c.1797delC(p.His599fs*11) and c.1414C>T(p.Gln472*)) in the WDR26 gene have been identified in two Chinese patients with Skraban-Deardorff syndrome. These patients exhibit a range of symptoms, including varying degrees of ID, DD, speech delay, an abnormal wide-foot and/or stiff-legged gait, facial dysmorphism, behavioural abnormalities, with or without seizures.ConclusionsIn this study, We report two unrelated Chinese patients with Skraban-Deardorff syndrome caused by novel de novo pathogenic variants of the WDR26 gene. These patients showed a clinical phenotype similar to that of patients with the WDR26 variant. Compared to reported cases with WDR26 pathogenic variants, patient 2 presented a novel complication of severe behavioural problems, including hyperactivity, social anxiety, self-mutilation, impulsivity and violent behaviour. This research broadens the range of genetic and clinical features of Skraban-Deardorff syndrome. In addition, the symptoms may become more pronounced as the patient ages. Furthermore, our report highlights the clinical diversity of Skraban-Deardorff syndrome. The findings may assist healthcare professionals in providing more accurate genetic testing and counselling to affected families and improving the overall management of the condition.

Background: Congenital myopathies may be a cause of prolonged and persistent hypotonia and weakness in a newborn, which may be overlooked as a neurological consequence of hypoxic-ischemic encephalopathy. We report such a neonate which turned out to be a case of central core myopathy. Clinical Description: A female neonate born at 38 weeks of gestation suffered birth asphyxia and was referred at 25 days of life due to a persistent need for respiratory support. A review of history revealed that the mother had decreased fetal movements during the third trimester and polyhydramnios. On examination, the baby had a frog-like posture with a paucity of proximal movements with preserved distal movements. Considering the possibility of a congenital myopathy, investigations were carried out. The whole-exome sequencing revealed heterozygous nonsense variation in exon 20 of the RyR1 gene, thus diagnosing the infant as a case of congenital core myopathy. Management and Outcome: The baby was managed with supportive care including ventilatory and nutritional support. Baby remained ventilator dependent, but ultimately succumbed to complications by 2 months of age. Conclusions: A high index of suspicion is required in a newborn with birth asphyxia having unusually persistent hypotonia, thorough clinical examination and appropriate genetic testing can help in identifying an underlying congenital myopathy.

Abstract Background Congenital muscular dystrophies (CMDs) are genetically and clinically heterogeneous inherited conditions. Onset is typically within the first year of life. Most CMDs are autosomal recessive, except for de novo dominant mutations in LMNA‐related muscular dystrophy and some collagen‐6‐associated disorders. Results CMD is characterized by progressive muscular weakness, hypotonia, multiple contractures with a variable degree, spinal stiffness, delay in motor milestones acquisition, and histologically dystrophic lesions. Also, some forms of CMD may feature structural and myelination abnormalities on brain magnetic resonance imaging, intellectual impairment, and structural abnormalities of the eye. Muscle biopsy specimens exhibit a dystrophic pattern, but the appearance is quite variable depending on the different stages and severity of the disorder. The prevalence of CMD is estimated to be one in 100 000 people. Over the last few years, with advances in molecular genetic diagnostics, knowledge about neuromuscular disorders, particularly CMDs, has increased dramatically. Thus, the incidence may be higher than originally thought. Conclusion This article reviews the recent achievements related to the clinical, diagnostic, pathogenic, and therapeutic aspects of CMDs.

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder. SEPHS1 is in the selenocysteine biosynthetic pathway. We report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Our findings provide insight into the molecular pathogenesis of this neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism. We describe a cohort of 18 individuals with germline variants in ZFX , which encodes a transcription factor not previously associated with a human disease. In addition to identifying recurrent clinical features, molecular characterization of variants in cultured cells, in silico modeling, and a zebrafish model suggest potential modes of pathogenicity. [ABSTRACT FROM AUTHOR]

Calmodulin‐binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long‐term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift‐7, nonsense‐6, splicing‐1, initiation codon‐1, missense‐5, and intragenic deletions‐3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under‐reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals. [ABSTRACT FROM AUTHOR]

Milena Barbosa Porto,1 Geovanna da Mata e Castro,1 Samara Socorro Silva Pereira,2 Elza Maria Gonçalves Santos Uchoa,2 Raffael Zatarin,3 Lysa Bernardes Minasi,1 Aparecido D da Cruz1– 3 1Graduate Program in Genetics, School of Medical and Life Sciences, Pontifical Catholic University of Goiás, Goiânia, GO, Brazil; 2Federal University of Goiás, Graduate Program in Genetics and Molecular Biology, Goiânia, GO, Brazil; 3Clinical Genetics Service, Center for Rehabilitation and Readaptation Dr. Henrique Santillo, State Health Secretary of Goiás, Goiânia, GO, BrazilCorrespondence: Aparecido D da Cruz, Email acruz@pucgoias.edu.brAbstract: Baker-Gordon Syndrome (BAGOS) is a genetically determined 4 (NDD), represented by a phenotypic spectrum of moderate to severe intellectual disability, resulting from mutations in the synaptotagmin 1 (SYT1) gene. Its prevalence is estimated at 1:1,000,000 and the known gene variants have indicated complete penetrance with variable expressivity. SYT1 is a membrane trafficking protein in presynaptic vesicles, which exerts a complex influence on synaptic transmission, with fundamental roles in the release of neurotransmitters and facilitators of endocytosis, impacting both neurotransmission and neuron plasticity. The current case report describes the first Brazilian male patient diagnosed at 17-year-old, and the 39th reported case globally using whole-exome sequencing. A de novo heterozygous missense mutation at chr12q:79448958 (NM_005639.2; c.1103T>C; p.Ile368Thr) in the SYT1 was found and classified as a pathogenic variant. The proband’s clinical phenotype was compatible with BAGOS, involving behavioral changes such as irritability and severe intellectual disability. Knowledge about the mechanism of action and the extent of the genotypic and phenotypic presentations of the mutations in the SYT1 is still unfolding. Thus, we aimed to describe additional genotype–phenotype correlation for BAGOS, contributing to the expansion of the existing knowledge of such a heterogeneous ultra-rare syndrome, and, therefore, improve its diagnostic yield, case management, and therapeutic journey for future patients. Keywords: SYT1, hypotonia, congenital malformations, NDD, WES

BackgroundGLI3 encodes a zinc finger transcription factor that plays a role in the sonic hedgehog pathway. Germline pathogenic GLI3 variants are associated with Greig cephalopolysyndactyly and Pallister-Hall syndromes, two syndromes involving brain malformation and polydactyly.MethodsWe identified patients with pathogenic GLI3 variants and brain malformations in the absence of polydactyly or other skeletal malformation.ResultsTwo patients were identified. Patient #1 is a 4-year-old boy with hypotonia and global developmental delay. Brain MRI showed a focal cortical dysplasia, but he had no history of seizures. Genetic testing identified a de novo likely pathogenic GLI3 variant: c.4453A>T, p.Asn1485Tyr. Patient #2 is a 4-year-old boy with hypotonia, macrocephaly, and global developmental delay. His brain MRI showed partial agenesis of the corpus callosum, dilatation of the right lateral ventricle, and absent hippocampal commissure. Genetic testing identified a de novo pathogenic GLI3 variant: c.4236_4237del, p.Gln1414AspfsTer21. Neither patient had polydactyly or any apparent skeletal abnormality.ConclusionsThese patients widen the spectrum of clinical features that may be associated with GLI3 pathogenic variants to include hypotonia, focal cortical dysplasia, and other brain malformations, in the absence of apparent skeletal malformation. Further study is needed to determine if GLI3 pathogenic variants are a more common cause of focal cortical dysplasia or corpus callosum agenesis than presently recognized.

Key Clinical Message: Congenital myotonic dystrophy should be considered in hypotonic infants with polyhydramniotic mothers with a positive history of myotonia. Congenital myotonic dystrophy (CDM) is a predominantly maternally inherited disease and results from increased numbers of cytosine, thymine, and guanine (CTG) repeats in the unstable DNA regions and presents as hypotonia in the neonatal period and myotonia in adulthood. This report aims to present two cases of CDM. A first‐cousin couple was born and hospitalized due to hypotonia at birth and a maternal history of polyhydramnios during this pregnancy. The first‐born baby girl was admitted to the NICU with tachypnea and hypotonia, clubfoot, and frog‐like posture. The pregnancy was complicated by polyhydramnios. Interestingly, her first cousin was born the next day with a similar picture and history. Myotonia was detected in their mothers. The concurrent presence of hypotonia and polyhydramnios as well as maternal myotonia in a first cousin should be considered CDM until proven otherwise and this was confirmed by the EMG‐ NCV test. [ABSTRACT FROM AUTHOR]

Vissers‐Bodmer Syndrome (VIBOS) is an autosomal dominant disorder caused by variants in the CNOT1 gene. It is characterized by systemic developmental and language‐motor delay, intellectual disabilities, growth and behavioral abnormalities, hypotonia, and distal skeletal defects, such as deformities of the hands and feet. This syndrome becomes evident during infancy and can display a highly variable phenotype. Thirty‐nine individuals with heterozygous de novo CNOT1 variants were first reported in 2019. Herein, we report a child with VIBOS who exhibited delayed motor development for over 4 years, along with hypotonia and atypical facial features. Notably, the patient developed short stature as the primary characteristic without any intellectual disability or organic nervous system lesions. Genetic testing revealed a de novo base duplication variant in exon 5 of the CNOT1 gene, NM_016284.5(CNOT1):c.316_317dup(p.Pro107Serfs*10). Importantly, the pathogenicity of this specific variant has not been reported in relevant literature. This study reports a new variant, thereby enriching the variant spectrum of CNOT1 associated with VIBOS, and contributes to the genetic counseling of affected families. [ABSTRACT FROM AUTHOR]

Background: Peroxisome biogenesis disorders (PBDs) are caused by variants in PEX genes that impair peroxisome function. Zellweger spectrum disorders (ZSDs) are the most severe and common subtype of PBDs, affecting multiple organ systems due to peroxisomal involvement in various metabolic functions. PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported worldwide and none in China. Methods: We describe an infant with biochemically and molecularly confirmed ZSDs due to variants in the PEX13 gene, identified by whole exome sequencing and validated by Sanger sequencing. The patient's treatment and prognosis were followed up. We also reviewed the literature on previously reported cases with PEX13 variants. Results: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features. Serum analysis revealed elevated levels of very long‐chain fatty acids (VLCFA), phytanic acid, and pipecolic acid. We detected a novel homozygous missense variant c.493G>C (p. Ala165Pro) in the PEX13 gene (NM_002618.3), which caused severe clinical manifestations and was inherited from the consanguineous parents. The patient died at the age of 14 months. Conclusion: We report the first case of ZSDs due to the PEX13 variant in China. Our findings broaden the mutational spectrum of the PEX13 gene and indicate that missense variants can lead to severe ZSDs phenotypes, which has implications for genotype–phenotype correlations and genetic counseling. [ABSTRACT FROM AUTHOR]

BackgroundCongenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (OMIM #616266) is an autosomal dominant hereditary disease that can lead to the congenital contracture of the limbs and face, hypotonia, and developmental delay. In addition, it may result in growth retardation and present various clinical symptoms, such as brain atrophy, a small pituitary gland, musculoskeletal abnormalities, abnormal breathing, abdominal hernia, and abnormal facial features. Herein, we describe a novel de novo missense genetic variant in the sodium leak channel, non-selective (NALCN) gene that is associated with CLIFAHDD syndrome.Case descriptionThis study describes a patient with varus deformities in both feet, deviation of the ulnar side of the fingers, and severe hypotonia. This patient was subsequently confirmed to have CLIFAHDD syndrome through genetic testing, which also revealed a novel missense de novo genetic variant in the NALCN gene (c.3553G > A, p.Ala1185Thr).ConclusionsOur findings further enrich the known variant spectrum of the NALCN gene and may expand the range of clinical options for treating NALCN-related disorders.

Glycosylation is the most common protein and lipid post-translational modification in humans. Congenital disorders of glycosylation (CDG) are characterized by both genetic and clinical heterogeneity, presenting multisystemic manifestations, and in most cases are autosomal recessive in inheritance. The PIGN gene is responsible for the addition of phosphoethanolamine to the first mannose in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, a highly conserved process that enables proteins to bind to the cell surface membrane. Here, we report a family with two siblings pediatric cases with the exact same compound heterozygous variants in PIGN. The (c.776T > C) variant of uncertain significance (VUS) together with a known pathogenic variant (c.932T > G), resulting in clinical features compatible with PIGN-related conditions, more specific the CDG. This is the first time that PIGN variant c.776T > C is reported in literature in individuals with PIGN-congenital disorder of glycosylation (PIGN-CDG), and the current submission in ClinVar by Invitae® is specifically of our case. Detailed clinical information and molecular analyses are presented. Here, we show for the first time two affected siblings with one pathogenic variant (c.932T > G) and the c.776T > C VUS in trans. In honor of the family, we propose the name Bella-Noah Syndrome for disorder.

Background: Autosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients. Methods: We described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene. Results: The patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database. Conclusions: This study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.

Pentasomy X syndrome is a very rare sex chromosome numerical anomaly of unknown frequency. The karyotype consists of 49,XXXXX. Musculoskeletal, craniofacial, cardiac, and kidney anomalies accompany psychomotor developmental delays. This report describes, a 16-month-old girl who presented to the pediatric neurology outpatient clinic with complaints of joint laxity and inability to hold her head upright from the age of 3-4 months. The patient exhibited dysmorphic facial features and hand-foot deformities. Genetic consultation was requested, and cytogenetic examination revealed a 49,XXXXX chromosomal anomaly. The most prominent clinical feature of 49,XXXXX patients with pentasomy is severe hypotonia. This article emphasizes the importance of cytogenetic analysis in the evaluation of hypotonicity.

Key Clinical Message Congenital myotonic dystrophy should be considered in hypotonic infants with polyhydramniotic mothers with a positive history of myotonia. Abstract Congenital myotonic dystrophy (CDM) is a predominantly maternally inherited disease and results from increased numbers of cytosine, thymine, and guanine (CTG) repeats in the unstable DNA regions and presents as hypotonia in the neonatal period and myotonia in adulthood. This report aims to present two cases of CDM. A first‐cousin couple was born and hospitalized due to hypotonia at birth and a maternal history of polyhydramnios during this pregnancy. The first‐born baby girl was admitted to the NICU with tachypnea and hypotonia, clubfoot, and frog‐like posture. The pregnancy was complicated by polyhydramnios. Interestingly, her first cousin was born the next day with a similar picture and history. Myotonia was detected in their mothers. The concurrent presence of hypotonia and polyhydramnios as well as maternal myotonia in a first cousin should be considered CDM until proven otherwise and this was confirmed by the EMG‐ NCV test.

Background: Prader-Willi Syndrome (PWS) is a multisystemic disorder characterized by dysmorphic facies, hypotonia, developmental delay, cognitive impairment, hypogonadism, and obesity. It is caused by the absence of expression of paternally derived genes on chromosome 15. Here, we report the diagnostic journey of a case with severe neonatal hypotonia. Case Report: A neonatal patient was referred for the prediagnosis of spinal muscular atrophy (SMA). During the SMA Multiplex Ligation-dependent Probe Amplification (MLPA) analysis, a diminished signal of a reference probe on the 15q11.2 was revealed. Later, it was confirmed that she had a deletion confined to 15q11.2-q13.1, with a methylation pattern compatible with PWS. Conclusion: Since hypotonia might be the only finding in newborns with PWS, this case was presented to emphasize the importance of a comprehensive approach to such patients. [ABSTRACT FROM AUTHOR]

Congenital hypotonia and neuropathy caused by SPTBN4 mutation are the core findings of a newly defined rare syndrome: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness. Although hearing loss secondary to auditory neuropathy, dysmorphic findings, and epilepsy are distinctive features, they are not present in every patient, leading to a wide range of phenotypic spectrum. We report here a male patient with the SPTBN4 gene mutation presenting with core symptoms but not hearing loss and epilepsy. There were also previously unreported dysmorphic findings such as prominent eyebrows, bilateral constant esotropia, microphthalmia, bitemporal narrowing, low hairline, low-set ears, broad nasal bridge, bulbous nose, anteverted nares, and high-arched palate, broadening the phenotypic spectrum even further. In conclusion, both genetic background and phenotypic features of the SPTBN4 mutations were expanded in our report. After exclusion of spinal muscular atrophy in patients with congenital hypotonia and areflexia, the SPTBN4 mutations should be considered. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case report presents a child with PURA‐related neurodevelopmental disorder, caused by the heterozygous pathogenic variant c.175C>T (p.Gln59*). The clinical symptoms included microcephaly, brachygnathia, central and peripheral hypotonia, and developmental delay (non‐verbal), among others. On comparison with published literature, even patients with the same mutation present different clinical symptoms. This case report presents a child with PURA‐related neurodevelopmental disorder, caused by the heterozygous pathogenic variant c.175C>T (p.Gln59*), whose symptoms included microcephaly, brachygnathia, the development of a high anterior hairline, hip dysplasia, strabismus, severe hypotonia, developmental delay (non‐meaningful verbal), feeding difficulties, and respiratory difficulties. His development ceased with age, such that his development at 10 years corresponded to an infant of 6 months. Moreover, even patients with the same variant can have different clinical symptoms, such as the presence or absence of epilepsy or congenital malformations. Therefore, we should follow his long‐term clinical course and provide medical support as necessary. [ABSTRACT FROM AUTHOR]

Pentasomy X syndrome is a very rare sex chromosome numerical anomaly of unknown frequency. The karyotype consists of 49,XXXXX. Musculoskeletal, craniofacial, cardiac, and kidney anomalies accompany psychomotor developmental delays. This report describes, a 16-month-old girl who presented to the pediatric neurology outpatient clinic with complaints of joint laxity and inability to hold her head upright from the age of 3-4 months. The patient exhibited dysmorphic facial features and hand-foot deformities. Genetic consultation was requested, and cytogenetic examination revealed a 49,XXXXX chromosomal anomaly. The most prominent clinical feature of 49,XXXXX patients with pentasomy is severe hypotonia. This article emphasizes the importance of cytogenetic analysis in the evaluation of hypotonicity. [ABSTRACT FROM AUTHOR]

Key Clinical Message This case report presents a child with PURA‐related neurodevelopmental disorder, caused by the heterozygous pathogenic variant c.175C>T (p.Gln59*). The clinical symptoms included microcephaly, brachygnathia, central and peripheral hypotonia, and developmental delay (non‐verbal), among others. On comparison with published literature, even patients with the same mutation present different clinical symptoms. Abstract This case report presents a child with PURA‐related neurodevelopmental disorder, caused by the heterozygous pathogenic variant c.175C>T (p.Gln59*), whose symptoms included microcephaly, brachygnathia, the development of a high anterior hairline, hip dysplasia, strabismus, severe hypotonia, developmental delay (non‐meaningful verbal), feeding difficulties, and respiratory difficulties. His development ceased with age, such that his development at 10 years corresponded to an infant of 6 months. Moreover, even patients with the same variant can have different clinical symptoms, such as the presence or absence of epilepsy or congenital malformations. Therefore, we should follow his long‐term clinical course and provide medical support as necessary.

Autism spectrum disorder (ASD) is a developmental disorder characterized by deficits in social interaction/communication, restricted interests, and repetitive behaviors. Recent discussions have emerged worldwide regarding the heterogeneity around presentation/etiology and comorbidities. This study aimed to determine the frequency and characteristics of comorbidities among children diagnosed with ASD in Manitoba and to evaluate differences in presentation between those with and without medical comorbidities. We conducted a retrospective chart review of >1900 electronic charts at the only publicly funded referral site for children ≤6 years requiring evaluation for ASD in Manitoba. All children aged 0–6 years diagnosed with ASD at this site between May 2016 and September 2021 were identified. χ2 and t-tests were used to compare groups. Of the total of 1858 children identified, 1452 (78.1%) were boys, 251 (13.5%) were prematurely born, and 539 (29.0%) had ≥1 medical comorbidity. Global developmental delay (GDD) was diagnosed in 428 (23.0%). The age of referral and diagnosis did not differ between groups. Comorbidities were more common among premature children (16.0% vs. 12.5%, p: 0.005) and children with comorbid GDD (34.9% vs. 18.2%, p < 0.001). Neurological comorbidities were most common (37.1%). No sex difference in the overall presence of comorbidities was found (boys = 77.1% vs. 78.5%, p: 0.518); however, girls had a higher incidence of neurological comorbidities, e.g., cerebral palsy, seizures, hypotonia (14.8% vs. 9.64%, p: 0.009), as well as genetic comorbidities (4.92% vs. 2.75%, p: 0.04). The high rates of associated neurological conditions, GDD, and prematurity add heterogeneity to this group leading to potential difficulties with prognosis and service allocation. Primary vs. secondary ASD can be a way of separating individuals based on relevant medical comorbidities. [ABSTRACT FROM AUTHOR]

Glycosylphosphatidylinositol biosynthesis defect 15 is a rare autosomal recessive disorder due to biallelic loss of function of GPAA1. At the moment, less than twenty patients have been reported, usually compound heterozygous for GPAA1 variants. The main clinical features are intellectual disability, hypotonia, seizures, and cerebellar atrophy. We describe a 4-year-old male with a novel, homozygous variant. The patient presents with typical features, such as developmental delay, hypotonia, seizures, and atypical features, such as macrocephaly, preauricular, and cheek appendages. When he was 15 months, the cerebellum was normal. When he was 33 months old, after the molecular diagnosis, magnetic resonance imaging was repeated, showing cerebellar atrophy. This case extends the clinical spectrum of the GPAA1-related disorder and helps to delineate phenotypic differences with defects of other subunits of the transamidase complex. [ABSTRACT FROM AUTHOR]

• Expanding the phenotype of DNMT3A associated with Tatton-Brown Syndrome (TBRS) to cause a congenital myopathy. • DNMT3A is associated with episodes of rhabdomyolysis and myalgias. • DNA methylation profile matching other haploinsufficient TBRS cases, consistent with the loss of methyltransferase activity, provides functional evidence for variant pathogenicity. Pathogenic variants in DNMT3A are most commonly associated with Tatton-Brown-Rahman Syndrome (TBRS), but includes other phenotypes such as Heyn-Sproul-Jackson syndrome and acute myeloid leukemia (AML). We describe a patient presenting to the neuromuscular clinic with a de novo missense variant in DNMT3A where the striking clinical feature is that of a congenital myopathy with associated episodes of rhabdomyolysis, severe myalgias and chest pain along with phenotypic features associated with TBRS. Muscle biopsy showed minor myopathic features and cardiac investigations revealed mildly impaired bi-ventricular systolic function. We confirmed the DNA methylation profile matched haplo-insufficient TBRS cases, consistent with a loss of methyltransferase activity. Our report emphasizes the phenotypic overlap of patients with syndromic disorders presenting to neuromuscular clinics and limitations of gene panels in establishing a molecular diagnosis. [ABSTRACT FROM AUTHOR]

Transient neonatal myasthenia gravis (TNMG) is a neuromuscular disorder that occurs in infants born from mothers with myasthenia gravis (MG) due to transplacental transfer of antibodies against the acetylcholine receptor. TNMG is a rare form occurring in 10-15% of infants born from mothers with MG. We present a case of a newborn with TNMG with generalized hypotonia and respiratory distress. The newborn shows symptoms of hypotonia, weakened reflexes, poor crying, difficult sucking and potentiated tachydyspnea after 24 hours of birth and needs of assisted mechanical ventilation. Based on the mother's positive history of MG and the high titer of mother's (8.43nmol/l) and newborn's (9.088nmol/l) anti-AChR antibodies, TNMG was diagnosed. The baby was treated with assisted mechanical ventilation and neostig-mine until the anti-AChR antibody titer was negative. Adequate management of the newborn resulted in a positive outcome and evident withdrawal of the symptoms. Although TNMG is one of the rare neuromuscular disorders in newborns that can be treated, a multidisciplinary approach in the management of pregnant women with MG and newborns through timely diagnosis and early appropriate treatment, results in successful resolution of this condition. [ABSTRACT FROM AUTHOR]

In the process of neuronal development, the protein Purα (encoded by the PURA gene) is essential for neuronal proliferation, dendritic maturation, and the transportation of mRNA to translation sites. Mutations in the PURA gene may alter normal brain development and impair neuronal function, contributing to developmental delays and seizures. Recently, PURA syndrome is described as developmental encephalopathy with or without epilepsy, neonatal hypotonia, feeding difficulties, global developmental delay, and severe intellectual disability. In our study, we aimed to perform a genetic analysis by whole exome sequencing (WES) in a Tunisian patient presented with developmental and epileptic encephalopathy to provide a molecular explanation for the developed phenotype. We collected, also, clinical data of all PURA p.(Phe233del) patients reported yet and compared the clinical features with those of our patient. Results revealed the presence of the known PURA c.697_699del, p.(Phe233del) variant. Our studied case shares some clinical features including hypotonia, feeding difficulties, severe developmental delay, epilepsy, and language delay (nonverbal) but presents a radiological finding undescribed before. Our finding defines and expands the phenotypic and genotypic spectrum of the PURA syndrome supporting the absence of reliable genotype–phenotype correlations and the existence of a highly variable, wide‐ranging clinical spectrum. [ABSTRACT FROM AUTHOR]

Congenital myopathies (CMs) are a group of diseases that primarily affect the muscle fiber, especially the contractile apparatus and the different components that condition its normal functioning. They present as muscle weakness and hypotonia at birth or during the first year of life. Centronuclear CM is characterized by a high incidence of nuclei located centrally and internally in muscle fibers. Clinical case: a 22-year-old male patient with symptoms of muscle weakness since early childhood, with difficulty in performing physical activity according to his age, with the presence of a long face, a waddling gait, and a global decrease in muscle mass. Electromyography was performed, showing a neurogenic pattern and not the expected myopathic one, neuroconduction with reduced amplitude of the motor potential of the peroneal nerve and axonal and myelin damage of the posterior tibial nerves. The microscopic study of the studied striated muscle fragments stained with hematoxylin–eosin and Masson's trichrome showed the presence of fibers with central nuclei, diagnosing CM. The patient meets most of the description for CM, with involvement of all striated muscles, although it is important to note the neurogenic pattern present in this case, due to the denervation of damaged muscle fibers, which contain terminal axonal segments. Neuroconduction shows the involvement of motor nerves, but with normal sensory studies, axonal polyneuropathy is unlikely, due to normal sensory potentials. Different pathological findings have been described depending on the mutated gene in this disease, but all coincide with the presence of fibers with central nuclei for diagnosis by this means, which is so important in institutions where it is not possible to carry out genetic studies, and allowing early specific treatment, according to the stage through which the patient passes. [ABSTRACT FROM AUTHOR]

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

Background: Multisystem inflammatory syndrome in children (MIS-C) has been described as an illness consisting of inflammation of more than one system of the body with raised inflammatory biomarkers following an infection of COVID-19. There is growing literature regarding the clinical spectrum of the condition. We report an unusual presentation of optic nerve demyelination in a child diagnosed with MIS-C. Clinical Description: A 3 years, 10-month-old boy presented with fever, generalized maculopapular rash, conjunctivitis, and bilateral palmar erythema. On examination, the child was febrile with tachypnea, tachycardia, and engorged jugular veins. Chest auscultation revealed basal crepitation. The cardiovascular examination was unremarkable. He had tender hepatomegaly. He developed photophobia and poor vision on the fourth day of admission with weakness of limbs. Ophthalmological examination showed a loss of visual acuity (perception of light only), while the fundoscopy examination was normal. Management: Inflammatory biomarkers and COVID-19 antibody titers were elevated. Echocardiography (ECHO) showed dilatation of the coronary arteries and poor ejection fraction. Magnetic resonance imaging of the brain showed bilateral optic nerve demyelination. Thus, the diagnosis was consistent with MIS-C with optic neuritis. Treatment was initiated with intravenous immunoglobulin (IVIG) and intravenous methylprednisolone with other supportive measures. At the 3-week follow-up, the child's vision, power in all four limbs, and echo parameters improved. Conclusion: This case creates awareness regarding optic neuritis as a rare presentation of MIS-C with cardiorespiratory and neurological involvement, successfully managed with IVIG and steroids.

Kabuki syndrome (KS) is a rare genetic disorder associ- ated with unique facial features, developmental delay, and multiple end-organ abnormalities. Specific pheno- typic findings include long palpebral fissures, eversion of the lateral third of the lower eyelid, arched eyebrows with sparseness of the lateral one-third, a short columella with a depressed nasal tip, and prominent ears. Patients with KS frequently have associated skeletal deformities, short stature, cleft lip and palate, dental anomalies, joint laxity, cardiovascular abnormalities, renal malformations, re- current pneumonia, recurrent otitis media, and hearing loss. Given the potential for end-organ involvement and congenital malformations, surgical intervention may be required to address these concerns. We present a patient with Kabuki syndrome who required anesthetic care dur- ing two operative interventions: laryngoscopy and supra- glottoplasty at 5 months of age and open reduction for hip dislocation at 9 months of age. Previous reports of anes- thetic care for patients with Kabuki syndrome are re- viewed with discussion of perioperative concerns and op- tions for anesthesia.

Aromatic L‑amino acid decarboxylase (AADC) deficiency is rare autosomal recessive neurometabolic disorder. It caused by generalized combined deficiency of serotonin, dopamine, norepinephrine and adrenaline. This disorder is characterized by muscular hypotonia, motor development delay, oculogyric crises and impairment of the autonomic nervous system.Laboratory diagnostic of AADC deficiency in Russian Federation includes determination of the concentration of 3‑O‑methyldophamine in dried blood spots by tandem mass spectrometry and molecular analysis of the DDC gene by Sanger sequencing or next generation sequencing.Therapy of AADC deficiency includes combination of drugs which increase the formation of dopamine, inhibit its reuptake and increase the residual activity of the enzyme. The first‑line drugs are selective dopamine agonists, monoamine oxidase inhibitors of type B and vitamin B6 supplements.We present the case of management and treatment of patients with AADC deficiency. The patient’s condition was improved by using of combination therapy with pyridoxal‑5‑phosphate, pramipexole and selegiline. Significant positive dynamics was achieved on pyridoxal‑5‑phosphate therapy for the first time.

A 7-month-old boy presented to our hospital with complaints of epistaxis. Pancytopenia was found on a blood test, and physical examination was significant for hepatosplenomegaly, acral hyperpigmentation of hands and feet, and hypotonia, along with mild delayed milestones. The infant underwent extensive investigations including metabolic workup and bone marrow aspiration, which revealed abundant megalocytes. Vitamin B12 was deficient (result 82 pg/mL, reference range 187–883 pg/mL); therefore, vitamin B12 therapy was commenced. Following the initiation of vitamin B12 therapy, blood cell lines normalized, neurological symptoms improved, hepatosplenomegaly regressed, and milestones were achieved.