Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy.

Epileptic Encephalopathy (EE) is a heterogeneous condition in which cognitive, sensory and/or motor functions deteriorate as a consequence of epileptic activity, which consists of frequent seizures and/or major interictal paroxysmal activity. There are various causes of EE and they may occur at any age in early childhood. Genetic mutations have been identified to contribute to an increasing number of children with early onset EE which had been previously considered as cryptogenic. We identified 26 patients with Infantile Epileptic Encephalopathy (IEE) of unknown etiology despite extensive workup and without any specific epilepsy syndromic phenotypes. We performed genetic analysis on a panel of 7 genes (ARX, CDKL5, KCNQ2, PCDH19, SCN1A, SCN2A, STXBP1) and identified 10 point mutations [ARX (1), CDKL5 (3), KCNQ2 (2), PCDH19 (1), SCN1A (1), STXBP1 (2)] as well as one microdeletion involving both SCN1A and SCN2A. The high rate (42%) of mutations suggested that genetic testing of this IEE panel of genes is recommended for cryptogenic IEE with no etiology identified. These 7 genes are associated with channelopathies or synaptic transmission and we recommend early genetic testing if possible to guide the treatment strategy

Schematic diagram showing the location of the identified mutations in the three encoded proteins.

<p>Schematic diagram showing the location of the identified mutations in the three encoded proteins.</p

Pathogenicity assessment of 9 missense mutations and 2 tolerated amino acid substitutions.

*<p>For conservative analysis, “+” indicates the amino acid residue is highly conserved and “−” indicated it is less conserved.</p>†<p>For SIFT analysis, “+” indicates the variant affect protein function and “−” indicated that it is tolerated.</p>‡<p>The variants were classified into 7 groups (class 0, class 15, class 25, class 35, class 45, class 55 and class 65) ranging from least likely (class 0) to most likely (class 65) to interfere the protein function (<a href="http://agvgd.iarc.fr/classifiers.php" target="_blank">http://agvgd.iarc.fr/classifiers.php</a>).</p><p>D1–D4: four homologous domains of SCN1A; S1–S6: six transmembrane segments in the four domains of SCN1A; EC: extracellular cadherin domain of PCDH19; NAP: nucleosome assembly protein domain of TSPYL4.</p

Summary of <i>SCN1A</i>, <i>PCDH19</i> and <i>TSPYL4</i> mutations found in 17 patients.

<p>D1–D4: four homologous domains of SCN1A; S1–S6: six transmembrane segments in the four domains of SCN1A; EC: extracellular cadherin domain of PCDH19; NAP: domain of nucleosome assembly protein of TSPYL4.</p

Evolutionary conservations of amino acid substitutions found in SCN1A, PCDH19 and TSPYL4.

<p>Evolutionary conservations of amino acid substitutions found in SCN1A, PCDH19 and TSPYL4.</p

Degree of intellectual disability (ID) of patients with different types of <i>SCN1A</i> mutations.

<p>The number above the bar chart indicated the number of DS patients in that group. ID: Intellectual disability; Mild ID: general/developmental quotient = 50–70; Moderate ID: general/developmental quotient = 25–50; Severe ID: general/developmental quotient<25.</p

Mutations of the <i>ARX</i>, <i>CDKL5</i>, <i>KCNQ2</i>, <i>PCDH19</i>, <i>SCN1A</i>, <i>SCN2A</i> and <i>STXBP1</i> genes found in the 10 patients and evolutionary conservation analyses for the missense mutation.

<p>Mutations of the <i>ARX</i>, <i>CDKL5</i>, <i>KCNQ2</i>, <i>PCDH19</i>, <i>SCN1A</i>, <i>SCN2A</i> and <i>STXBP1</i> genes found in the 10 patients and evolutionary conservation analyses for the missense mutation.</p

Clinical characteristics of 26 patients with infantile epileptic encephalopathies of unknown etiology.

<p>*S: spasm; M: myoclonic seizure; F: focal seizure with or without generalization; G: generalized tonic / clonic / tonic-clonic seizure; A: absence seizure; At: atonic seizure; O: other seizure type.</p><p>Clinical characteristics of 26 patients with infantile epileptic encephalopathies of unknown etiology.</p

CYP2U1: An emerging treatable neurometabolic disease with cerebral folate deficiency in 2 Chinese brothers

With the rapid advancement of medical technologies in genomic and molecular medicine, the number of treatable neurometabolic diseases is quickly expanding. Spastic paraplegia 56 (SPG56), one of the severe autosomal recessive forms of neurodegenerative disorders caused by pathogenic variants in the CYP2U1 gene, has no reported specific targeted treatment yet. Here we report 2 Chinese brothers with CYP2U1 bi-allelic pathogenic variants with cerebral folate deficiency who were treated for over a decade with folinic acid supplement. Patients have remained stable under therapy