Further delineation of phenotypic spectrum of <scp><i>SCN2A</i></scp>‐related disorder

Richardson, Ruth; Baralle, Diana; Bennett, Christopher; Briggs, Tracy A; Bijlsma, Emilia K.; Clayton‐Smith, Jill; Constantinou, Panayiotis; Foulds, Nicola; Jarvis, Joanna; Jewell, Rosalyn; Johnson, Diana; McEntagart, Meriel; Parker, Michael; Radley, Jessica A.; Robertson, Lisa; Ruivenkamp, Claudia; Rutten, Julie W.; Tellez, James O.; Turnpenny, Peter D.; Wilson, Valerie; Wright, Michael J.; Balasubramanian, Meena

doi:10.1002/ajmg.a.62595

Cited by 5 publications

(2 citation statements)

References 44 publications

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“…SCN2A -RD has been described as a severe disorder characterized by ‘encephalopathy’, which variously refers to developmental delays, movement disorders, intellectual disability and several other conditions. 6 , 7 , 12 , 13 , 18 Systematic characterization of the extent and nature of the developmental and functional impairments, however, has been inconsistent across studies. Data from the Simons Foundation Autism Research Initiative provided some of the more systematic descriptions in a relatively large group of individuals ( n = 64) with SCN2A -RD; however, the quantitative phenotyping in this study focused on developmental assessments and not on functional impairments.…”

Section: Discussionmentioning

confidence: 99%

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders

Berg,

Thompson,

Myers

et al. 2024

Brain

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SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test’s norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders

Berg,

Thompson,

Myers

et al. 2024

Brain

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“…Cognitive outcome is mostly favorable in these cases [108]. Amongst cases with a more severe intellectual disability phenotype, EA appears to be uncommon [112]. Phenotypes may vary in family members, e.g.…”

Section: Epilepsy Spectrum Disorder (Scn2a)mentioning

confidence: 99%

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches

Hassan¹

2023

Tremor and Other Hyperkinetic Movements

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Background: Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunc tion, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in KCNA1 and CACNA1A. EA3-8 are reported in rare families. Advances in genetic testing have broadened the KCNA1 and CACNA1A phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists.Methods: A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized.Results: EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accom panied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (SCA-14, SCA-27, SCA-42, AOA2, CAPOS), epilepsy syndromes (KCNA2, SCN2A, PRRT2), GLUT1, mitochondrial disorders (PDHA1, PDHX, ACO2), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxicmetabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause.Discussion: EA may be overlooked or misdiagnosed for a variety of reasons, including phenotypegenotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.

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Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder

Iezzi

Curti

Ranieri

et al. 2022

Pharmacological Research

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Further delineation of phenotypic spectrum of SCN2A‐related disorder

Cited by 5 publications

References 44 publications

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches

Acute rapamycin rescues the hyperexcitable phenotype of accumbal medium spiny neurons in the valproic acid rat model of autism spectrum disorder

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