Pyridoxine-Dependent Seizures Caused by Alpha Amino Adipic Semialdehyde Dehydrogenase Deficiency: The First Polish Case with Confirmed Biochemical and Molecular Pathology

Abstract

Pyridoxine-dependent seizures are a rare condition recognized when numerous seizures respond to pyridoxine treatment and recur on pyridoxine withdrawal. For decades the diagnosis was confirmed only with pyridoxine treatment withdrawal trial. Recently described biochemical and molecular pathology improved the diagnostic process for those cases in which seizures are caused by alpha amino adipic semialdehyde dehydrogenase deficiency. This article presents a girl with recurrent status epilepticus episodes resistant to phenobarbital and phenytoin and partly responding to midazolam. Eventually the seizures were completely controlled with pyridoxine; however, due to the severe condition of this child when seizing, no trial of withdrawal has been performed. The diagnosis of pyridoxine-dependent seizures was confirmed with biochemical and molecular testing revealing elevated alpha-AASA excretion and the presence of 2 different mutations in the antiquitin ( ALDH7A1) gene. Due to the availability of reliable laboratory testing, confirmation of the diagnosis was made without the life-threatening trial of pyridoxine withdrawal.

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

“…Seventeen of these were novel mutations and included missense, nonsense and splice site mutations as well as deletions and a single-base insertion. All other mutations have been published previously (Mills et al ., 2006; Kanno et al ., 2007; Plecko et al ., 2007; Salomons et al ., 2007; Kaczorowska et al ., 2008; Bennett et al ., 2009; Gallagher et al ., 2009; Kluger et al ., 2009; Striano et al ., 2009). The novel missense mutations P169S, P78L, W175G, S289L, Q300R and S448L were not found in ethnically matched controls (Caucasian; n  = 96).…”

“…These children accumulated α-AASA in their body fluids and P6C was shown to inactivate the active form of pyridoxine (pyridoxal phosphate) by the formation of a Knoevenagel condensation product. Mutations in the ALDH7A1 gene in other children with PDE have been reported subsequently (Kanno et al ., 2007; Plecko et al ., 2007; Salomons et al ., 2007; Kaczorowska et al ., 2008; Bennett et al ., 2009; Gallagher et al ., 2009; Kluger et al ., 2009; Striano et al ., 2009), including in patients who had been previously diagnosed as having ‘folinic acid responsive seizures’. To characterize further the phenotypic spectrum of this disorder we investigated individuals with clinically proven or suspected PDE by measurement of urinary α-AASA and mutational analysis of the ALDH7A1 gene.…”

The genotypic and phenotypic spectrum of pyridoxine‐dependent epilepsy due to mutations in ALDH7A1

“…1 and previously reported mutations are referenced in Table 1 (Mills et al 2006; Plecko et al 2007; Salomons et al 2007; Kanno et al 2007; Kluger et al 2008; Kaczorowska et al 2008; Striano et al 2009; Bennett et al 2009; Gallagher et al 2009; Schmitt et al 2010; Millet et al 2010). There are 26 missense mutations, 13 of which cluster in exons 14, 15, and 16.…”

Disorders of Pyridoxine Metabolism

“…12,23,[25][26][27][29][30][31]40,[57][58][59][60][61][62] Of these, 50-60% are missense mutations, resulting in an altered amino acid sequence. 12,23,[25][26][27][29][30][31]40,[57][58][59][60][61][62] Of these, 50-60% are missense mutations, resulting in an altered amino acid sequence.…”