Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene
Sara Matricardi1, Paola De Liso2, Elena Freri3
1Department of Child Neuropsychiatry, Children's Hospital, Ancona, Italy.
Insights
Variants in the SLC13A5 gene cause severe neonatal epilepsy and developmental issues. While seizures often improve in childhood, tooth abnormalities persist, highlighting the gene
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Autosomal recessive pathogenic variants in the SLC13A5 gene are linked to severe neonatal epilepsy, developmental delay, and tooth abnormalities.
- This disorder presents a unique challenge in early diagnosis and management.
Purpose of the Study:
- To identify the clinical hallmarks of SLC13A5-related disorder by analyzing 14 new patients and comparing them to previously reported cases.
- To understand the evolutionary trajectory of seizures and developmental milestones in affected individuals.
Main Methods:
- Clinical data from 14 patients with biallelic SLC13A5 variants were collected.
- A comprehensive PubMed search identified and analyzed previously published patient data.
- Phenotypic features were compared between the new cohort and literature cases.
Main Results:
- All patients experienced neonatal seizures, with 57% developing status epilepticus.
- Seizure frequency decreased over time, with a significant portion becoming seizure-free by late childhood/adulthood.
- Most patients exhibited mild to severe developmental impairment and hypotonia, with tooth hypoplasia/hypodontia being a consistent feature.
Conclusions:
- SLC13A5 variants cause a distinct neonatal epileptic encephalopathy with evolving cognitive and motor impairments.
- Seizures tend to resolve in late childhood, but dental anomalies remain a hallmark.
- Screening the SLC13A5 gene in neonatal epileptic encephalopathies is crucial, with implications for genetic counseling due to its recessive inheritance pattern.
Objective:
Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder.
Methods:
We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients.
Results:
All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3 years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12 years, 60% become seizure-free; in the following years, up to age 18 years, 57% were seizure-free. After the age of 18 years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients.
Significance:
Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.
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