Case report: Clinical and genetic characterization of a novel ALDH7A1 variant causing pyridoxine-dependent epilepsy, developmental delay, and intellectual disability in two siblings

BackgroundPathogenic variants in ALDH7A1 are associated with pyridoxine-dependent epilepsy (PDE), a rare autosomal recessive disorder characterized by epileptic seizures, unresponsiveness to standard antiseizure medications (ASM), and a response only to pyridoxine. Here, we report two patients (from a consanguineous family) with neonatal seizures and developmental delay.Case presentationPatient 1 (a 13-year-old girl) was born normally at term. Her pregnancy was complicated by antiphospholipid syndrome, and persistent vomiting was managed with several medications, including pyridoxine (40 mg daily). Seizures occurred 6 h after birth and did not respond to antiseizure medications. However, they ceased 2 days later when pyridoxine (40 mg daily) was administered. She continued her medications and had delayed early milestones. Phenobarbitone was discontinued at 18 months, and pyridoxine was increased to 100 mg daily at 8 years of age. She was able to join a regular school and performed well. Patient 2, a 12-year-old boy, was delivered normally at term. Seizures started 10 h after birth, and he immediately received 40 mg of pyridoxine. Seizures have been controlled since then, and he experienced delayed milestones. Pyridoxine was increased to 100 mg daily at 7 years of age. He is currently in fifth grade and has dyslexia. Whole exome sequencing (WES) revealed that both patients 1 and 2 harbor a novel homozygous missense variant in ALDH7A1 (NM_001202404: exon 12: c.1168G>C; (p.Gly390Arg)).ConclusionThe present study reports a novel ALDH7A1 variant causing PDE and highlights the associated developmental delay and intellectual disability, despite early seizure control treatment

Health Information Exchange in Relation to Long-Term Follow-Up Data System in Newborn Screening Program: General Overview and the Saudi Status

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Newborn screening program (NBS) is a vital public health service aiming to prevent morbidity, mortality, and disability through early detection and intervention. The service is a complex system that requires proper communication between its different constituents. The advent of technology in this field represented by the existence of robust analytical diagnostic tools which allow for rapid analysis of many rare congenital disorders along with the accelerated revolution of health information technology is a capstone towards improvement of an individual’s life quality and patient safety enhancement. &lt;b&gt;&lt;i&gt;Summary:&lt;/i&gt;&lt;/b&gt; Effective screening program requires an effective system that delivers results in timely manner, tracks those who are affected, and shares long-term outcomes at population level. Recently, more focus has been placed on the implementation of long-term follow-up (LTFU) data systems as an effective tool for continuous evaluation of the efficacy of NBS program. The ability to communicate health information using health information exchange system (HIE) is very essential to effective implementation of any LTFU plan. &lt;b&gt;&lt;i&gt;Key Messages:&lt;/i&gt;&lt;/b&gt; This review explores other programs’ experience in the impact of implementing HIE system in relation to LTFU data system in the era of NBS program and the importance of having a well-established collaboration infrastructure. Also, and at a glance, the current status of the Saudi National NBS program in the context of health informatics and barriers faced towards implementation of successful LTFU data system in relation to HIE is highlighted. Future trends may involve incorporating genomic data to LTFU system allowing for the application of the newly emerged personalized medicine era. </jats:p

Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature

BackgroundSLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as “developmental and epileptic encephalopathy 25 with amelogenesis imperfecta.”ResultsHere, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients’ conditions were poorly controlled by multiple antiepileptics as they needed constant care.ConclusionConsidering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.</jats:sec

Table1_Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature.xlsx

BackgroundSLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as “developmental and epileptic encephalopathy 25 with amelogenesis imperfecta.”ResultsHere, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients’ conditions were poorly controlled by multiple antiepileptics as they needed constant care.ConclusionConsidering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.</p

The composition of plasmalogen molecular species (%) in testes and epididymides.

<p>Plasmalogen levels of whole testes and epididymides of <i>Tysnd1</i>^+/+ (white bars) and <i>Tysnd1^−/−</i> (black bars) mice were measured by LC/ESI-MS/MS. Each error bar represents the mean ± SE in n = 5. * <i>p</i><0.05, **<i>p</i><0.01 and *** <i>p</i><0.001.</p