Linkage Analysis and Disease Models in Benign Familial Infantile Seizures: A Study of 16 Families

Abstract

Summary:Purpose: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis.Methods: Sixteen families were examined. Probands underwent neurologic examination, at least one EEG recording, and, when possible, brain CT and MRI. Clinical information about relatives was collected. Families with SCN2A or ATP1A2 mutations were excluded from the study. Chromosome 16p and 19q loci were examined by linkage analysis using two models that differed in penetrance rate. Genetic heterogeneity was evaluated with both models.Results: Clinical information was available for 124 members of affected families. BFIS was diagnosed in 69 subjects. One patient without BFIS had a single febrile seizure, and another had rare episodes of paroxysmal dystonia. Evidence of linkage was obtained only for chromosome 16. Moreover, the high penetrance allowed the identification of genetic heterogeneity.Conclusions: Our data confirm the relevance of the chromosome 16 locus in BFIS and suggest the presence of an additional locus. This study shows that the genetic model used affects the outcome of linkage analysis.

The epileptic and nonepileptic spectrum of paroxysmal dyskinesias: Channelopathies, synaptopathies, and transportopathies

“…Currently, PRRT2 is the major gene responsible for PKD, with a frequency ranging from about 40% to over 90%, depending on case ascertainment [6,7,14,17,20–23]. Almost all PRRT2 cases have a clear kinesigenic trigger, and in up to 40% anxiety or prolonged exercise can also induce them [6].…”

“…PRRT2 consists of two transmembrane helices in the C-terminal region, a long N-terminal intra-cytoplasmic region that includes a proline-rich domain, an intracellular loop linking the two transmembrane helices, and a very short C-terminal end [17]. Subsequent to alternative splicing at the 3′ terminus, there are recognized six splice variants and three different isoforms (www.ensemble.org; ENSG00000167371).…”

“…For instance, ictal SPECT demonstrated that a network including both basal ganglia and cortical motor areas was involved in patients with SLC2A1 mutations manifesting with epilepsy and PxD, [34]. The age-dependent expression of clinical features in patients with PRRT2 mutations is likely to be explained by the particular temporal pattern of the protein at both cerebral and spinal level [17], which is in accordance with the observation that mutations in this gene more likely lead to epilepsy in infancy and PKD in childhood or adolescence, with a tendency to spontaneous remission later in life. Moreover, this temporal pattern implicates PRRT2 in neurodevelopment, as also suggested by the fact that biallelic PRRT2 mutations cause mental retardation [76].…”

Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes

“…Genetic heterogeneity has been demonstrated and several BFIS genes have been mapped (fig 1) at chromosome 19q in five Italian families,47 chromosome 16p12-q12 in more than 30 families worldwide,48 – 51 and chromosome 2q24 in four additional Italian families 52. The locus at chromosome 16 seems to be by far the most frequently linked.…”

Infantile Convulsions with Paroxysmal Dyskinesia (ICCA Syndrome) and Copy Number Variation at Human Chromosome 16p11

“…Since then, numerous studies have confirmed linkage of ICCA pedigrees[3], [9]–[11] to the same ICCA genomic area, strongly suggesting genetic homogeneity of the ICCA syndrome. Indeed, no ICCA family has ever been excluded for linkage to the ICCA genomic area amongst the 27 families that have been genotyped so far[2], [3], [9]–[14]. Noteworthingly, a majority of pure BFIS families[14]–[17] also showed linkage to the same ICCA genomic area.…”