搜索结果：American journal of medical genetics. Part A

Multiple mitochondrial dysfunctions syndrome 1 (MMDS1, MIM #605711) due to NFU1 gene defects is an ultra-rare autosomal recessive inborn error of metabolism associated with reduced function of NFU1 iron-sulfur cluster (ISC) scaffold protein. This disorder demonstrates variable clinical features including hypotonia, epileptic encephalopathy, respiratory failure, lactic acidosis, hyperglycinemia, and hemodynamic instability. One unique feature of this mitochondrial disorder is the common manifestation of pulmonary arterial hypertension (PAH), for which the pathophysiologic mechanism is not well defined to date. Here, we report a case of infantile-onset lactic acidosis, refractory epilepsy with encephalopathy, hyperglycinemia, and severe PAH in a patient who underwent rapid genome sequencing (GS) which identified compound heterozygous variants in NFU1 consistent with a diagnosis of MMDS1. We additionally review the literature on published cases of MMDS1 including developments in the understanding of the intracellular impact of defective ISC proteins. Recent studies delineate a multifactorial pathogenesis including globally dysregulated energy metabolism, specific deficiencies in oxidative phosphorylation, and excess reactive oxygen species (ROS) production. A key difference between established animal models of this disorder and human cases published to date is that the previously described sex-based phenotype discrepancy in rats was not recapitulated in this review. Identification of the clinical combination of lactic acidosis, PAH, and hyperglycinemia during diagnostic evaluation should raise suspicion for a defect of the ISC pathway, and further investigations of the cellular pathophysiology of this disorder may provide insight into the phenotypic spectrum of human disease and potential therapeutic targets.

Glucocorticoid resistance syndrome (GRS) is a rare hereditary disorder caused by pathogenic variants in NR3C1, characterized by marked phenotypic heterogeneity and frequent misdiagnosis as primary aldosteronism or subclinical Cushing's syndrome. We report a family harboring a novel NR3C1 frameshift variant and provide an integrated characterization of its clinical and biochemical features. By combining structural prediction, tissue- and single-cell-level expression analyses, in silico virtual gene perturbation, and systematic literature review, we evaluated the potential functional impact and clinical relevance of this variant. Comprehensive clinical phenotyping, steroid metabolomic profiling, adrenal CT imaging, and segregation analysis were performed in the proband and his father. AlphaFold3 was used to predict the structures of wild-type and mutant GRα proteins. Variant pathogenicity was assessed following ACMG/AMP criteria. Cross-tissue and single-cell expression patterns of NR3C1 were analyzed, and in silico virtual knockout analysis was performed to generate exploratory hypotheses regarding potentially affected biological pathways. A systematic review was conducted to summarize previously reported GRS cases, their variants, and associated phenotypes. Two affected males across successive generations presented with refractory hypertension without Cushingoid features. Steroid profiling demonstrated mild hypercortisolemia with elevated ACTH, marked increases in 11-deoxycorticosterone and 11-deoxycortisol, suppressed renin, and low-to-normal aldosterone, consistent with ACTH-driven accumulation of mineralocorticoid precursors. Sequencing identified a novel NR3C1 frameshift variant, c.923dupG (p.Ala309Serfs*6), absent from population databases and co-segregating with the familial phenotype. Structural prediction indicated premature termination within the N-terminal transactivation domain, supporting loss of the downstream DNA-binding and ligand-binding domains. According to ACMG/AMP criteria, the variant was classified as pathogenic. In silico virtual perturbation analysis suggested that NR3C1 dysfunction may extend beyond a linear defect in glucocorticoid signaling, potentially influencing neuroendocrine communication, extracellular matrix regulation, protein translation, and developmental pathways. Literature review identified 66 reported GRS cases encompassing substantial phenotypic variability, with cardiovascular events documented in some carriers of N-terminal or truncating variants. We describe a novel exon 2 NR3C1 frameshift variant that co-segregates with a characteristic GRS hormonal profile and is supported by clinical, genetic, and structural evidence. This case expands the genotype-phenotype spectrum of NR3C1-related GRS. The potential relationship between N-terminal truncating variants and cardiovascular complications remains hypothesis-generating and requires validation in larger cohorts and functional studies. Our findings underscore the importance of considering NR3C1-related GRS in patients presenting with resistant hypertension accompanied by a distinctive steroid profile.

Arthrogryposis Multiplex Congenita (AMC) is a heterogeneous group of disorders characterized by multiple contractures, often associated with central nervous system (CNS) involvement. To date, advances in Next Generation Sequencing (NGS) have enabled the identification of more than 400 genes implicated in AMC. Genetic causes of AMC and CNS involvement are especially challenging due to their heterogeneous clinical presentation, overlapping phenotypes, and often uncertain etiology. Pathogenic variants in AFF3 degron motif were identified as a cause of KINSSHIP syndrome (MIM #619297) which is clinically characterized by horseshoe kidney, Nievergelt/Svarirayan type of mesomelic dysplasia, seizures, generalized hypertrichosis, intellectual disability, and pulmonary involvement. We describe a patient presenting distal contractures at birth and neurodevelopmental delay, in whom Whole Genome Sequencing (WGS) revealed a previously reported missense variant in AFF3. We also conducted a literature review of published cases associated with this gene. This case highlights the importance of recognizing and characterizing the phenotypic presence of multiple congenital contractures and neurodevelopmental impairment as a clinical pattern that may prompt consideration of AFF3-related KINSSHIP syndrome among the differential diagnoses. Our findings underscore the relevance of integrating genomic testing into the evaluation of patients with AMC and CNS involvement to support accurate diagnostic classification.

Carrier screening is a long-standing genetic testing process offered to at-risk couples, with or without a family history, who might have pregnancies affected by an autosomal recessive (AR) or X-linked (XL) disorder. A total of 276 unrelated individuals, initially referred for rare disorder screening by clinicians, were enrolled in this study and tested by Exome sequencing (ES). Expanded carrier screening (ECS) was performed for 176 disorders that met the inclusion criteria of the ACMG and ACOG. Genes with single nucleotide variants (SNVs) identified with a carrier rate > 1% for AR disorders included HBB, CFTR, PMM2, NPHS2, GJB2, ACADM, ALDOB, MEFV, MKS1, NEB, PAH, ATM, CPT2, CYP21A2, AGXT, BBS1, CAPN3, COL4A4, DHCR7, GAA, IVD, LAMA2, SLC22A5, SLC26A4, USH2A. For XL disorders, variants were detected in the RS1 gene. ECS offers a wealth of information about SNVs related to AR and XL disorders in specified populations. The information obtained from ECS provides multiple advantages: (a) it identifies the most prominent risks in health care in a given population and contributes to the prevention of genetic disorders, (b) it enriches available databases with pathogenic or likely pathogenic SNVs, and (c) it records novel targets for molecular clinical genetic testing.

ImportancePulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by alveolar surfactant accumulation leading to respiratory impairment. MARS1 mutations lead to an early onset PAP associated in a setting of multi-organ involvement and respond to high-dose methionine supplementation. While pulmonary manifestations of MARS1-related PAP and their response to methionine are well documented, its potential impact on cognitive and adaptive functioning in pediatric patients remains poorly understood. Understanding the neurodevelopmental profile of children with MARS1-related PAP is essential for optimizing comprehensive care and long-term outcomes. ObjectiveTo characterize the neurodevelopmental profile of children with MARS1-related PAP by assessing intellectual functioning and adaptive behavior using standardized neuropsychological measures and parent-reported questionnaires. DesignObservational cohort study including 16 pediatric patients with MARS1-related PAP aged 14 months to 7.3 years, followed at the Necker-Enfants Malades Hospital (Paris, France) and treated with methionine. Intellectual functioning was assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) when age-appropriate, and adaptive behavior was evaluated via the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) through parent interviews. ResultsSixteen children with MARS1-related PAP underwent the full evaluation. Methionine was started at a median age of 6 months (IQR [5, 15]). Eight of them were able to undergo the WPPSI-IV assessment. The mean Full-Scale IQ was 72.25 (SD = 16.85), indicating borderline to mild intellectual disability relative to normative data. Adaptive behavior composite scores on the VABS-II averaged 69.75 (SD = 23.58), reflecting significant deficits across communication, daily living skills, socialization, and motor domains. The neurodevelopmental impairments were relatively homogeneous across the cohort. ConclusionsChildren with MARS1-related pulmonary alveolar proteinosis exhibit marked impairments in intellectual and adaptive functioning, suggesting a consistent neurodevelopmental profile associated with the disease, and despite methionine supplementation. These findings highlight the need for routine cognitive and developmental monitoring in pediatric PAP patients and support the development of multidisciplinary interventions addressing both respiratory and neurodevelopmental outcomes.

Pathogenic variants in KIF11 are linked to autosomal dominant syndromes with microcephaly, chorioretinopathy, lymphedema, and intellectual disability (MCLID), though adult presentations remain underreported. We report a 42-year-old female presenting with a de novo single-amino acid in-frame deletion in the KIF11 gene (c.1294_1296del; p.Glu432del), who exhibited severe intellectual disability, microcephaly, hypotonia, seizures, and self-injurious behavior. There was evidence of developmental delays, ophthalmologic findings, and impairments in speech and adaptive functioning in her clinical history. Trio whole exome sequencing identified a diagnostic pathogenic variant in KIF11 and a maternally inherited SCN3A variant of uncertain significance. The presentation of the case offers an unusual longitudinal perspective of over four decades, illustrating the variable expressivity and long-term outcome of KIF11 disorders. This report calls for the consideration of KIF11 variants in the differential diagnosis of syndromic developmental delay and microcephaly in adults and underlines the diagnostic as well as the prognostic importance of detailed genetic and phenotypic analysis, particularly in cases with de novo variants.

Central conducting lymphatic anomaly (CCLA) is a devastating disorder where precision medicine can be lifesaving. Diagnosing CCLA is challenging due to its broad spectrum of symptoms, including nonimmune fetal hydrops, chylothorax, chylous ascites, or lymphedema. For that reason, genetic diagnosis is essential to uncover new genes and variants causing this debilitating disease. A patient with complex congenital heart disease presented with post-operative refractory chylothorax. Lymphatic imaging demonstrated abnormal intercostal lymphatic perfusion consistent with CCLA and suggestive of a RASopathy, a group of genetic disorders characterized by dysregulated RAS-MAPK signaling. Genetic testing showed a variant of uncertain significance (p.(Ala308Val)) in SHOC2, a scaffolding protein that regulates RAS-MAPK signaling but has not yet been described in CCLA. Trametinib, a MEK1/2 inhibitor, was trialed without improvement. A conversion/extension assay was used to evaluate pathogenicity of the VUS compared to a known pathogenic variant. Zebrafish transiently expressing the wild type human SHOC2 protein or SHOC2 p.(Ala308Val) protein in the developing lymphatic and venous endothelium were used to evaluate the effect on the vasculature. Western blot was used to explore the underlying molecular mechanisms. Major to minor axis ratio was significantly increased in developing embryos injected with SHOC2 r.923c>u mRNA, indicating pathogenicity through dysregulation of MAPK/mTOR signaling. Zebrafish transiently expressing SHOC2 p.(Ala308Val) in the lymphovenous endothelium developed pericardial edema and cystic malformations of the caudal plexus and dilation of the thoracic duct. In concordance with the lack of clinical response to trametinib, immunoblot results indicate that SHOC2 p.(Ala308Val) may be inducing lymphatic malformations through non-canonical mTOR signaling rather than dysregulated RAS-MAPK signaling. SHOC2 is a novel cause of central conducting lymphatic anomaly. Future research should investigate the cellular and molecular mechanisms as well as therapeutics.

Stüve-Wiedemann Syndrome (SWS) is a rare autosomal recessive skeletal dysplasia caused by variations in the leukemia inhibitory factor receptor (LIFR) gene. Due to its high rate of mortality in early life, current literature is largely limited to children with SWS. We present a case report of a 35-year-old female with SWS, one of the few documented adults with SWS. She was diagnosed at age 34 after clinical exome sequencing identified homozygous pathogenic variants in LIFR at c.756dup (p.Lys253*), a known pathogenic variant associated with SWS. Her past medical history consists of feeding and respiratory difficulties in infancy, recurrent fractures, a deep vein thrombosis of the upper extremity, osteoporosis, and an incidental finding of a brain aneurysm. Of note, she has undergone over 25 surgeries without complications from anesthesia. As an adult, her symptoms include heart palpitations, fatigue, restless leg syndrome, temperature dysregulation, poor dentition, and bone fragility. On physical exam, she displays short stature, blue sclera, kyphoscoliosis, significant loss of range of motion in multiple joints, and fusions in the fingers and toes. To our knowledge, she is the oldest reported individual in the literature with SWS, and her case provides insight into how symptoms evolve over time.

Cardio-facio-cutaneous (CFC) syndrome is a rare, multiple congenital anomaly disorder in which individuals commonly experience faltering growth; however, systematic analysis of growth parameters in this disorder has not been performed. We recruited 69 participants with CFC through CFC International and collected data on assessing height, weight, and body mass index (BMI). We found that the height-for-age and weight-for-age Z-scores were consistently lower in individuals with CFC than in the reference population and that children with CFC experience growth restriction from infancy to adulthood. Our findings show that as individuals age, their height Z-scores remain constant (-2 to -3 SD). However, over time, their weight shows a progressive decrease from average. There were no significant differences between the mean Z-scores of the growth parameters based on an individual's history of enteral feeding, gene associated with diagnosis, nor growth hormone deficiency status. This implies that feeding modality and severity of feeding difficulties may not be directly related to growth. Other factors could be responsible, such as malabsorption of nutrients, constitutional growth delay, hormonal deficiencies or resistance, or cardiac abnormalities. Our study is one of the first to systematically characterize growth parameters and analyze the association of clinical covariates with these parameters in individuals with CFC syndrome. Accurate assessment of growth in this rare condition will allow providers to recognize outliers of growth in their patients with CFC when compared to other individuals with CFC and make necessary referrals and recommendations, which may ultimately improve outcomes.

This cross-sectional study investigated mental health conditions, physical functioning, and health-related quality of life (HRQOL) in adults with Léri-Weill dyschondrosteosis (LWD) in Norway. Questionnaires were sent to 61 adults registered at the Norwegian Centre for Rare Diseases. The questionnaires included demographics, medical history, depression (PHQ-8), anxiety (GAD-7), pain catastrophizing, activities of daily living (HAQ), and HRQOL (RAND-36 and PROMIS-29). Results were compared with other skeletal dysplasias (SD) and Norwegian general population norms. Twenty-six participants responded. Mean age was 44 years (range 18-72). A prior psychiatric diagnosis was reported by 42%. Clinically significant symptoms of depression (PHQ-8 ≥ 10) and anxiety (GAD-7 ≥ 10) were reported by 27% and 15%, respectively. Almost all participants reported current pain, most commonly back pain (69%) and pain in the upper extremities (62%). Mental health was lower compared to adults with other SDs and general population norms. Physical functioning was the most affected HRQOL domain and was considerably lower than in the general population. This study highlights both psychological and physical burdens in LWD and underscores the importance of assessing mental health, physical function, pain and HRQOL as part of regular medical follow-up across the lifespan in patients with this condition.

Confirming the underlying molecular etiology of hereditary hypophosphatemia (HH) to provide recurrence risk counseling is highly important. Our aims were to describe the detected variants and their distribution across Argentina and to contrast them with published data. Patients with HH prospectively referred to a hypophosphatemia program for genetic testing were included. Saliva samples were evaluated by next-generation sequencing with a panel of 13 genes associated with HH. In patients with no variants detected in the HH rickets related gene panel, multiplex ligation-dependent probe amplification was performed for the PHEX gene. Cascade genetic testing was recommended for at-risk relatives of index cases (IC). One hundred and sixty participants were enrolled, including 129 ICs with suspected HH (80.62%). Among them, 114 had a positive molecular test (88.37%); 93% were variations in the PHEX gene, predominantly single-nucleotide variants. Distribution of variant types was consistent with international databases. In our sample, 12% of subjects had undetectable variants in the gene panel, highlighting the importance of complete genome sequencing. Ours is the first study in Latin America to analyze PHEX variants, which is considered crucial for the generation of regional evidence to understand the genetic variability of HH and for leading specific targeted treatment.

Genotyping in patients with vascular malformations and/or somatic overgrowth guides precision treatment and is often required for insurance approval of targeted medications. Despite commonly accepted guidelines, uniform implementation of genetic testing in this population is hindered by practical challenges in the clinical setting. Here we compare the molecular diagnostic yield as a function of biopsy source, specifics of genetic testing, and type of insurance. We conducted a retrospective chart review of patients who had genetic testing performed at various commercial or academic laboratories on a biopsy for vascular malformations and/or somatic overgrowth. Diagnostic yield was compared by specimen type, depth of coverage (DOC), and billing method. 70 genetic tests were reviewed for 56 patients. High DOC testing yielded a significantly higher diagnostic rate of 74.3% compared to 20.0% in low DOC testing (p&#x2009;<&#x2009;0.001). Core biopsies (vs. skin punch) and tests utilizing private insurance/institutional billing (vs. Medicaid) also showed a higher diagnostic yield. In the clinical setting, patients reliant on low DOC commercial testing due to insurance barriers face significantly lower diagnostic rates, underscoring a clear inequity in diagnostic outcomes and demonstrating a need for improved testing access.

Through the GeneMatcher data-sharing database, we identified five affected individuals from four unrelated families with a skeletal dysplasia who have biallelic, putatively deleterious variants in MIMS1 (formerly FAM210A). The common features included chondrodysplasia with short stature, tracheal stenosis, conical teeth and/or early tooth decay, and sparse hair suggestive of ectodermal dysplasia as a component of the phenotype. The radiographic features included platyspondyly, epiphyseal dysplasia of the long bones, short phalanges with delayed carpal ossification, lacy iliac crests, and calcaneal spurs, consistent with a form of spondyloepimetaphyseal dysplasia. Missense variants clustered within the conserved DUF1279 domain of MIMS1, while one family harbored compound heterozygous nonsense variants, collectively supporting a loss-of-function mechanism. According to the dyadic naming convention in the latest Nosology of Genetic Disorders of Bone, we suggest the name of "Spondyloepimetaphyseal dysplasia with tracheal stenosis and ectodermal dysplasia (SEMDTSED), MIMS1-related."

TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3&#x3b1;, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.

Phenylketonuria (PKU) is associated with neurocognitive and neuropsychological symptoms despite early treatment and well-controlled phenylalanine (Phe) levels. PKU impairs the conversion of Phe to tyrosine and causes excess phenylalanine to accumulate. This accumulation can competitively block some other amino acids from entering the brain. This may reduce production of key neurotransmitters like dopamine and serotonin, which can affect brain function and development. However, direct correlations between blood Phe levels and central nervous system (CNS) neurotransmitter concentrations have not been established, and reliable CNS biomarkers are lacking. Positron emission tomography (PET) enables in&#xa0;vivo assessment of brain metabolism and neurotransmitter-related processes; therefore, we aim to investigate its potential value as a biomarker. A systematic literature search was conducted in accordance with PRISMA guidelines using MEDLINE and Embase databases up to April 25, 2026. Studies evaluating brain PET imaging in individuals with PKU or hyperphenylalaninemia were included. Data on study design, patient characteristics, PET tracers, and key findings were extracted and synthesized qualitatively. A total of 380 records were screened, and 13 studies were included, with a mean sample size of 8.8 (median 6). PET tracers included 18fluorodeoxyglucose (FDG), amino acids, including tyrosine-, methionine-, leucine-, aminocyclohexanecarboxylate-based tracers, and fluorodopa-related tracers. FDG PET studies demonstrated regionally heterogeneous abnormalities in brain glucose metabolism, independent of plasma Phe levels. Amino acid PET studies demonstrated reduced cerebral protein synthesis associated with impaired large neutral amino acid transport and increased brain Phe levels. Fluorodopa-related PET studies indicated reduced dopaminergic activity, with no significant correlation between plasma Phe levels and striatal fluorodopa utilization. PET is a promising tool to bridge the gap between peripheral biochemical markers and CNS dysfunction in PKU. Further studies are needed to overcome limitations which include small sample sizes, heterogeneous metabolic control, restricted availability of tracer types, predominantly cross-sectional study designs, and lack of correlation with clinical signs and symptoms.

Considerable advances have been made in our understanding of Bardet-Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framework. Using a rigorous, evidence-based, and consensus-driven process, a multidisciplinary group of international experts and patient-led organizations developed an updated diagnostic algorithm. This algorithm provides practical, updated guidance for clinicians, including a pathway for accurately incorporating genetic findings into the diagnostic process. We recommend that a clinical diagnosis requires either 4 major criteria or 3 major and 2 minor criteria. Revised major criteria are retinal dystrophy, obesity (or overweight in individuals <&#x2009;2&#x2009;years old), congenital anomalies of the kidney and urinary tract or chronic kidney disease, hypogonadism/genital anomalies, neurodevelopmental/neurocognitive manifestations, and postaxial polydactyly. The diagnosis can also be established with a positive genetic testing result in patients exhibiting &#x2265;&#x2009;1 major criterion, provided that genetic findings should be interpreted in the context of the patient's clinical presentation, age, family history, and overlap with related ciliopathies. These consensus criteria offer a simple algorithm incorporating updated definitions for major and minor criteria and genetic testing to support a timely and accurate diagnosis of patients with BBS, inform genetic counseling, and potentially facilitate earlier access to treatment. Trial Registration: CRIBBS Registry; ClinicalTrials.gov: NCT02329210.

Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder involving self-resolving joint contractures that are present since birth. Because of characteristic facial features, clinical diagnosis may be suspected by experienced clinicians or identified using facial recognition-based software. Confirmation by identification of disease-causing biallelic variants in SCARF2 can be helpful to definitively provide a clinico-molecular diagnosis to differentiate VDEGS from other disorders with overlapping phenotypes with blepharophimosis, arachnodactyly, and camptodactyly. Most affected individuals do not have major malformations or intellectual disability. However, occasional patients with ophthalmological, genitourinary, or laryngeal abnormalities are reported, indicating the need for a detailed evaluation. The causative gene, SCARF2, is located within the region of the 22q11.2 microdeletion syndrome. Two cases with microdeletion of the region on one chromosome and a SCARF2 variant on the other chromosome have been reported. Two cases resembling the phenotype but with no causative variants in SCARF2 have been reported, supporting the possibility of another causative gene with overlapping phenotype. Though prognosis can often be positive, there is a need for better long-term outcome data.

Acute confusional migraine (ACM) is an uncommon pediatric migraine variant characterized by transient confusion and agitation, nonspecific electroencephalographic changes, and normal bloodwork and neuroimaging. We present the first case of ACM in a child with Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM: 617140), a rare multisystem disorder caused by a pathogenic variant in the SON gene, clinically characterized by global developmental delay, intellectual disability, hypotonia, distinctive craniofacial dysmorphic features, and structural brain anomalies. Emerging evidence suggests that SON haploinsufficiency may contribute to a broader neuroinflammatory phenotype, potentially increasing susceptibility to cortical excitability, which is one of the proposed causes of ACM. We hypothesize a direct mechanistic link whereby SON-related splicing defects lower the cortical excitability threshold, predisposing individuals to episodic hyperexcitability syndromes such as ACM. This report expands the known neurological phenotype of ZTTK syndrome. Given the nature of the communication impairments among patients with ZTTK syndrome, ACM symptoms may be underreported or mistaken for epileptic events. Future studies are needed to validate this association and elucidate the underlying molecular pathways.

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