Exome sequence identified a c.320A &gt; G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: Review of the literature

Hamici, Sana; Bastaki, Fatma; Khalifa, Mohamed M.

doi:10.1016/j.ejmg.2017.07.014

Cited by 18 publications

(20 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Epilepsy is a common finding in patients with glycosylation deficiencies, with a wide spectrum of severity and semiology (Freeze et al 2015). Severe epilepsy, often beginning as Ohtahara syndrome (early infantile epileptic encephalopathy) or West syndrome (hypsarrhythmia, clinical spasms, and developmental arrest) and sometimes developing into multifocal hard-to-treat epilepsy, has been reported for many CDG types, including ALG1-CDG (Fiumara et al 2016;Barba et al 2016), ALG3-CDG (Fiumara et al 2016;Barba et al 2016), ALG6-CDG (Fiumara et al 2016), ALG13-CDG (Hamici et al 2017), ALG14-CDG (Schorling et al 2017), DPM2-CDG (Fiumara et al 2016), DOLK-CDG (Helander et al 2013), RFT1-CDG (Barba et al 2016), SLC35A2-CDG (Ng et al 2013), and SLC35A3-CDG (Marini et al 2017). In the published cohort of DPAGT1-CDG patients including this report, 4/24 patients have had the diagnosis West syndrome, and 9 more have a definitive diagnosis of epilepsy, whereas only 3 were negated to have epilepsy.…”

Section: Discussionmentioning

confidence: 99%

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Underhill

Palm

et al. 2018

JIMD Reports

View full text Add to dashboard Cite

Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.

show abstract

Section: Discussionmentioning

confidence: 99%

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Underhill

Palm

et al. 2018

JIMD Reports

View full text Add to dashboard Cite

show abstract

“…Brain Sci. 2021, 11, 904 of 14 often have mild intellectual disability, while males may develop mild to severe intellectual disability, including PPM-X syndrome marked by psychosis and bipolar disorder, parkinsonism, increased muscle tone, exaggerated reflexes, and abnormal enlargement of the testes [12]. The disease severity and variability of the phenotype is influenced both by the location and type of the variant as well as by genetic background and cellular environment [13].…”

Section: Mecp2mentioning

confidence: 99%

The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders

2021

View full text Add to dashboard Cite

Nearly 20% of genes located on the X chromosome are associated with neurodevelopmental disorders (NDD) due to their expression and role in brain functioning. Given their location, several of these genes are either subject to or can escape X-chromosome inactivation (XCI). The degree to which genes are subject to XCI can influence the NDD phenotype between males and females. We provide a general review of X-linked NDD genes in the context of XCI and detailed discussion of the sex-based differences related to MECP2 and FMR1, two common X-linked causes of NDD that are subject to XCI. Understanding the effects of XCI on phenotypic expression of NDD genes may guide the development of stratification biomarkers in X-linked disorders.

show abstract

“…As a consequence, heterozygous females typically have a milder disease phenotype or are not affected. Despite this, there is a growing list of X-chromosome genes which are subject to X-inactivation or escape X-inactivation, including, for example, PHF6, CLCN4, ALG13, ARX, or USP9X, DDX3X , which display distinct phenotypes in males and females depending on the functional severity of the variant, as well as manifesting in a more severe female phenotype than the heterozygous state would predict (4, 5, 6, 7, 8, 9, 10). We contend that the IQ motif and Sec7 domain 2 protein ( IQSEC2 ) (NM_001111125) (MIM 300522) is another X-chromosome disease gene in which we see a severe female phenotype because of heterozygous loss-of-function mutation.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

et al. 2019

View full text Add to dashboard Cite

Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9–edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.

show abstract

Exome sequence identified a c.320A > G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: Review of the literature

Cited by 18 publications

References 34 publications

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

Contact Info

Product

Resources

About