Pyridoxine-dependent seizures in Dutch patients: Diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels

Department of Paediatrics, Máxima Medical Center, Veldhoven, The Netherlands.
Archives of Disease in Childhood (Impact Factor: 2.9). 09/2007; 92(8):687-9. DOI: 10.1136/adc.2006.103192
Source: PubMed


Pyridoxine-dependent seizures (PDS) is a rare, autosomal recessively inherited disorder. Recently alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency was identified as a major cause of PDS, which causes accumulation of both alpha-AASA and pipecolic acid (PA) in body fluids.
We studied urinary and plasma alpha-AASA and PA levels in 12 Dutch clinically diagnosed patients with PDS.
Alpha-AASA was elevated in both urine and plasma in 10 patients. In these patients plasma PA levels were also elevated but urinary PA levels were normal.
In all patients with clinically definite PDS, and in most patients with probable or possible PDS, the clinical diagnosis of PDS could be confirmed at the metabolite level. Non-invasive urinary screening for alpha-AASA accumulation provides a reliable tool to diagnose PDS and can save these patients from the classical and potentially dangerous pyridoxine withdrawal test to prove PDS.

Download full-text


Available from: Jasper V Been
  • Source
    • "Although relatively rare, with an estimated incidence up to 1:276.000 births in The Netherlands (Bok et al. 2007), this condition is treatable and early diagnosis is of utmost importance. The current knowledge about the primary defect in PDS has provided new diagnostic biomarkers, i.e., α-AASA and P6C. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The assessment of urinary α-aminoadipic semialdehyde (α-AASA) has become the diagnostic laboratory test for pyridoxine dependent seizures (PDS). α-AASA is in spontaneous equilibrium with its cyclic form Δ(1)-piperideine-6-carboxylate (P6C); a molecule with a heterocyclic ring structure. Ongoing diagnostic screening and monitoring revealed that in some individuals with milder ALDH7A1 variants, and patients co-treated with a lysine restricted diet, α-AASA was only modestly increased. This prompted us to investigate the diagnostic power and added value of the assessment of urinary P6C compared to α-AASA. Urine samples were diluted to a creatinine content of 0.1 mmol/L, followed by the addition of 0.01 nmol [(2)H(9)]pipecolic acid as internal standard (IS) and 5 μL was injected onto a Waters C(18) T3 HPLC column. Chromatography was performed using water/methanol 97/3 (v/v) including 0.03 % formic acid by volume with a flow rate of 150 μL/min and detection was accomplished in the multiple reaction monitoring mode: P6C m/z 128.1 > 82.1; [(2)H(9)]pipecolic acid m/z 139.1 > 93.1. Due to the dualistic nature of α-AASA/P6C, and the lack of a proper internal standard, the method is semi quantitative. The intra-assay CVs (n = 10) for two urine samples of proven PDS patients with only modest P6C increases were 4.7% and 8.1%, whereas their inter-assay CVs (n = 10) were 16 and 18% respectively. In all 40 urine samples from 35 individuals with proven PDS, we detected increased levels of P6C. Therefore, we conclude that the diagnostic power of the assessments of urinary P6C and α-AASA is comparable.
    Full-text · Article · Jan 2012 · Journal of Inherited Metabolic Disease
  • Source
    • "PDE was defined according to the clinical criteria of Baxter (1999) and confirmed by ALDH7A1 gene mutation analysis (Bok et al., 2007; Salomons et al., 2007). All PDE data were derived from the Dutch study cohort [until January 2010 consisting of a total of 15 PDE children; see for further description Bok et al. (2007)]. For analysis of PDE data, we selected all six neonatal (<3 months of gestation) EEG recordings that were obtained during first pyridoxine-IV Table 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pyridoxine-dependent epilepsy (PDE) is characterized by therapy-resistant seizures (TRS) responding to intravenous (IV) pyridoxine. PDE can be identified by increased urinary alpha-aminoadipic semialdehyde (α-AASA) concentrations and mutations in the ALDH7A1 (antiquitin) gene. Prompt recognition of PDE is important for treatment and prognosis of seizures. We aimed to determine whether immediate electroencephalography (EEG) alterations by pyridoxine-IV can identify PDE in neonates with TRS. In 10 neonates with TRS, we compared online EEG alterations by pyridoxine-IV between PDE (n = 6) and non-PDE (n = 4). EEG segments were visually and digitally analyzed for average background amplitude and total power and relative power (background activity magnitude per frequency band and contribution of the frequency band to the spectrum). In 3 of 10 neonates with TRS (2 of 6 PDE and 1 of 4 non-PDE neonates), pyridoxine-IV caused flattening of the EEG amplitude and attenuation of epileptic activity. Quantitative EEG alterations by pyridoxine-IV consisted of (1) decreased central amplitude, p < 0.05 [PDE: median -30% (range -78% to -3%); non-PDE: -20% (range -45% to -12%)]; (2) unaltered relative power; (3) decreased total power, p < 0.05 [PDE: -31% (-77% to -1%); -27% (-73% to -13%); -35% (-56% to -8%) and non-PDE: -16% (-43% to -5%); -28% (-29% to -17%); -26% (-54% to -8%), in delta-, theta- and beta-frequency bands, respectively]; and (4) similar EEG responses in PDE and non-PDE. In neonates with TRS, pyridoxine-IV induces nonspecific EEG responses that neither identify nor exclude PDE. These data suggest that neonates with TRS should receive pyridoxine until PDE is fully excluded by metabolic and/or DNA analysis.
    Full-text · Article · Sep 2010 · Epilepsia
  • Source
    • "Recently, the genetic defect for the majority of patients with pyridoxine dependent epilepsy (PDE) was attributed to mutations in the Antiquitin gene which results in a-AASA dehydrogenase deficiency, making PDE a disorder in L-lysine catabolism [6]. a-AASA dehydrogenase deficiency results in the accumulation of pathognomonic a-AASA (in cerebrospinal fluid (CSF), plasma and urine) and pipecolic acid (CSF and plasma) in affected patients [7] [8] [9]. Pilot experiments using fibroblasts derived from patients with a-AASA dehydrogenase deficiency verified that the defect is also expressed in these cells, based upon the accumulation of a-AASA and decreased formation of a-AAA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian degradation of lysine is believed to proceed via two distinct routes, the saccharopine and the pipecolic acid routes, that ultimately converge at the level of alpha-aminoadipic semialdehyde (alpha-AASA). alpha-AASA dehydrogenase-deficient fibroblasts were grown in cell culture medium supplemented with either L-[alpha-(15)N]lysine or L-[epsilon-(15)N]lysine to explore the exact route of lysine degradation. L-[alpha-(15)N]lysine was catabolised into [(15)N]saccharopine, [(15)N]alpha-AASA, [(15)N]Delta(1)-piperideine-6-carboxylate, and surprisingly in [(15)N]pipecolic acid, whereas L-[epsilon-(15)N]lysine resulted only in the formation of [(15)N]saccharopine. These results imply that lysine is exclusively degraded in fibroblasts via the saccharopine branch, and pipecolic acid originates from an alternative precursor. We hypothesize that pipecolic acid derives from Delta(1)-piperideine-6-carboxylate by the action of Delta(1)-pyrroline-5-carboxylic acid reductase, an enzyme involved in proline metabolism.
    Full-text · Article · Nov 2009 · FEBS letters
Show more