Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients

Authors

  • Craig L. Bennett,

    1. Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, and Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A.
    2. Center on Human Development and Disability, University of Washington, Seattle, Washington, U.S.A.
    3. Center for Neurogenetics and Neurotherapeutics, University of Washington School of Medicine, Seattle, Washington, U.S.A.
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  • Yingzhang Chen,

    1. Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, and Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A.
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  • Sihoun Hahn,

    1. Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, and Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A.
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  • Ian A. Glass,

    1. Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, and Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A.
    2. Center on Human Development and Disability, University of Washington, Seattle, Washington, U.S.A.
    3. Center for Neurogenetics and Neurotherapeutics, University of Washington School of Medicine, Seattle, Washington, U.S.A.
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  • Sidney M. Gospe Jr

    1. Center on Human Development and Disability, University of Washington, Seattle, Washington, U.S.A.
    2. Center for Neurogenetics and Neurotherapeutics, University of Washington School of Medicine, Seattle, Washington, U.S.A.
    3. Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, Washington, U.S.A.
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Address correspondence to Craig L. Bennett, Ph.D., Division of Genetics and Developmental Medicine, Department of Pediatrics, University of Washington, Box 356320, Seattle, WA 98195-6320, U.S.A. E-mail: cbenet@u.washington.edu

Summary

Purpose: 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.

Methods: 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.

Results: 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.

Discussion: 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.

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