Abstracts

Rationale: Succinic Semialdehyde Dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with elevated GHB, is associated with predominantly generalized epilepsy with high SUDEP risk, heretofore in the adult cohort. We report SUDEP cases at ages 14 and 19, and a genotype-phenotype correlation study. Methods: Longitudinal study with periodic six month follow-up data from patients in the SSADH registry; assignment of gene variant pathogenicity based on in silico testing and metabolic profile.  Results: There are 61 subjects enrolled in the longitudinal study with 23 participating in an SSADHD natural history study. Epilepsy is present in 50%, and more prevalent in the adolescent/adult cohorts: 69% (22/32) >12 vs 28% (8/29) <12 (p=0.004). A new case of probable SUDEP recently occurred in an adolescent subject, age 14, with escalating seizures. Autopsy-confirmed SUDEP occurred in two subjects, ages 19 and mid-20s. Additional cases of possible and probable SUDEP occurred in adult subjects ages 37 and 63, respectively. SUDEP has occurred in 5 of 30 (17%) SSADHD patients with epilepsy. Over 45 pathologic ALDH5A1 variants have been reported in SSADHD patients, the majority being missense mutations. Duplication/insertion/deletion mutations have been reported in only a handful of patients. Of the subjects participating in the natural history study (n=23), 25 different variants are represented. In silico analysis and the metabolic profiles indicate a number of new pathological variants not previously reported. Novel missense variants discovered are: c.416C>A (p. Ala139Asp), c.508G>A (p.Gly268Glu), c.842G>A (p.Gly281Glu), Intron 6 c.1015-2A>C, Intron 6 c.1015-3C>G, c.1044 C>A (p. Asn348Lys), Intron 8 c.1054-2A>C, c.1265G>A (p. Gly422Asp), c.1306G>A (p.Gly454Arg), and Exon 10 c.1441+2T>C. In addition, our cohort contains the following novel pathological duplication/insertion/deletion variants: c.909+3delA, c.967_968dupCA, and c.1253delpAsn418llefs*39. A previously reported variant (classified as of unknown significance) c.1306G>A (p.Gly454Arg) caused disease in a subject confirmed by consistently increased urine GHB by CLIA-approved during clinical testing. Three variants were identified in multiple unrelated families, c.612G>A (p.Trp204Ter) (9 families/10 subjects, one homozygous), Intron 7 c.1054-2A>C (4 families/5 subjects), and Intron 6 c.1015-2A>C (two families/2 subjects). The c.1054-2A>C variant was discovered in the 14-year-old SUDEP patient. The 19-year-old SUDEP subject was homozygous for c.1226G>A (p.Gly409Asp). These variants are also seen in other (unrelated) families, of which all the adolescent and adult patients have epilepsy. Conclusions: Epilepsy is a co-morbid diagnosis in half of patients with SSADH deficiency and increases in incidence during adolescence and adulthood. There appears to be a striking incidence of SUDEP in this population. Novel pathologic variants are described, with three variants of high incidence. Specific variants may suggest an increased predisposition to epilepsy and SUDEP, to be further analyzed in the larger cohort. Funding: No funding