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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: 2.91). 09/2007; 92(8):687-9. DOI: 10.1136/adc.2006.103192
Source: PubMed

ABSTRACT 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.

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    • "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. "
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    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.
    Epilepsia 09/2010; 51(12):2406-11. DOI:10.1111/j.1528-1167.2010.02747.x · 4.58 Impact Factor
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    • "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. "
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    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.
    FEBS letters 11/2009; 584(1):181-6. DOI:10.1016/j.febslet.2009.11.055 · 3.34 Impact Factor
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    • "This case emphasizes the utility of measuring PA or AASA levels and screening ALDH7A1 for mutations in patients with preliminary diagnoses of PDS. Taken together, our data confirm that PDS is commonly the result of recessive mutations of the ALDH7A1 gene (Mills et al., 2006; Bok et al., 2007; Plecko et al., 2007), but that genetic heterogeneity is also present. One might posit that genetic causes other than ALDH7A1 mutations are more likely to be seen in later-onset cases. "
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    ABSTRACT: Pyridoxine-dependent seizure (PDS) is a rare disorder characterized by seizures that are resistant to common anticonvulsants, and that are ultimately controlled by daily pharmacologic doses of pyridoxine (vitamin B6). Mutations of the antiquitin gene (ALDH7A1) are now recognized as the molecular basis of cases of neonatal-onset PDS. Bidirectional DNA sequence analysis of ALDH7A1 was undertaken along with plasma pipecolic acid (PA) measurements to determine the prevalence of ALDH7A1 mutations in a cohort of 18 North American patients with PDS. In patients with neonatal-onset PDS, compound heterozygous or homozygous ALDH7A1 mutations were detected in 10 of 12 cases, and a single mutation was found in the remaining 2. In later-onset cases, mutations in ALDH7A1 were detected in three of six cases. In two patients with infantile spasms responsive to pyridoxine treatment and with good clinical outcomes, no mutations were found and PA levels were normal. In total, 13 novel mutations were identified. Our study advances previous findings that defects of ALDH7A1 are almost always the cause of neonatal-onset PDS and that defects in this gene are also responsible for some but not all later-onset cases. Later-onset cases of infantile spasms with good outcomes lacked evidence for antiquitin dysfunction, suggesting that this phenotype is less compelling for PDS.
    Epilepsia 11/2008; 50(5):1167-75. DOI:10.1111/j.1528-1167.2008.01816.x · 4.58 Impact Factor
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