Dhamija, Radhika

Hartsfield syndrome has been recently reported to be associated with mutations in FGFR1 however, to this date; no familial cases have been reported. In this report, we describe two siblings with Hartsfield syndrome and a novel de novo FGFR1 mutation suggesting gonadal mosaicism. The proband presented at our institution at age 6 years with a clinical diagnosis of Hartsfield syndrome and requesting further genetic evaluation. Previous studies included a normal karyotype, oligonucleotide array, and single gene testing for nonsyndromic holoprosencephaly (SHH, SIX3, ZIC2, TGIF). At the age of 6 years, exome sequencing was performed and a de novo novel missense variant was identified in FGFR1 (coding for fibroblast growth factor‐1) on chromosome 8p12: c.1880G>C (p.R627T). Subsequently, a younger sibling was born with the same phenotype (holoprosencephaly, ectrodactyly of bilateral hands and feet and bilateral cleft lip and palate). Targeted sequencing of FGFR1 revealed the identical variant that was previously identified in the proband. To our knowledge this observation is the first documentation of familial recurrence of Hartsfield syndrome. As both parents were negative for the sequence variant in FGFR1 gene by testing peripheral blood samples, this suggests gonadal mosaicism. The frequency of gonadal mosaicism in Hartsfield syndrome is not known however given our case, this possibility should be taken in to consideration for recurrence risk estimation in children of clinically unaffected parents. © 2014 Wiley Periodicals, Inc.

Seizures are often the first manifestation of central nervous system dysfunction and are common in many inborn errors of metabolism, especially in neonates, infants, and children. A high index of suspicion is required to diagnose inborn errors of metabolism as the cause of seizures. It is also important to recognize these metabolic disorders early, as specific disease-modifying treatments are available for some with favorable long-term outcomes. This review discusses the classification of metabolic disorders as a cause of seizures based on pathogenesis and age and proposes a tiered approach for cost-effective diagnosis of metabolic disorders.

The role of surgery in continuous spike wave in slow-wave sleep has not been robustly explored. The authors present a case of an 11-year-old boy with refractory partial seizures and continuous spike wave in slow-wave sleep who was treated with an anterior temporal lobectomy. His presurgical brain magnetic resonance imaging revealed right basal ganglia and thalamic infarcts and right mesial temporal sclerosis. Following surgery, he achieved seizure freedom, cessation of continuous spike wave in slow-wave sleep, and improved cognition. This case provides further evidence that epilepsy syndromes with generalized electrographic discharges can be secondary to focal pathology and potentially cured with resective surgery. The normalization of his sleep electroencephalogram following the anterior temporal lobectomy suggests that temporal lobe structures may be involved in the seizure network needed to generate continuous spike wave in slow-wave sleep.

The use of valproate sodium as an antiepileptic is not advised in children with an undiagnosed metabolic condition because of the increased risk of hepatotoxicity and encephalopathy. Here the authors describe a 2.5-year-old girl with a history of developmental delay, failure to thrive, and a seizure disorder whose seizures worsened after the introduction of valproate sodium. This led to a search for an underlying metabolic disorder, and after extensive investigations, a diagnosis of nonketotic hyperglycinemia was made. In this report, the authors discuss the metabolic conditions that can be worsened by valproate sodium. Valproate sodium interferes with the glycine cleavage enzyme synthesis in the mitochondria, hence increasing glycine levels. The increased glycine levels are responsible for worsening of the underlying metabolic condition and increased seizure frequency.