Genotype-phenotype correlations in alternating hemiplegia of childhood
Masayuki Sasaki1, Atsushi Ishii, Yoshiaki Saito
1From the Department of Child Neurology (M. Sasaki, Y.S.), National Center of Neurology and Psychiatry, Kodaira; Department of Pediatrics and Central Research Institute for the Molecular Pathomechanisms of Epilepsy (A.I., S. Hirose) and Department of Biochemistry (B.Z.), Fukuoka University School of Medicine; Department of Pediatrics (N.M., K.I., S. Takada), Kobe University School of Medicine; Department of Pediatrics (A.A., Y.T.), Kansai Medical University, Osaka; Department of Neurology (H.A.), Chiba Children's Hospital; Division of Neurology (S.Y.), Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (T.O.), Nishi-Niigata Central Hospital, Niigata; Department of Pediatrics (Y. Oda, H.I.), Chigasaki Municipal Hospital; Department of Neurology (S. Hirabayashi), Nagano Children's Hospital, Azumino; Yasuhara Children's Clinic (A.Y.), Osaka; Department of Pediatrics (H.K.), Osaka City General Hospital; Division of Child Neurology (S.K.), Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi; Department of Pediatrics (M. Shimono), University of Occupational and Environmental Health, Kitakyushu; Department of Pediatrics (S.N.), Nagahama Red Cross Hospital; Department of Child Neurology (M. Suzuki), Aichi Prefectural Colony Central Hospital, Kasugai; Department of Pediatrics (T.Y.), Kyoto University School of Medicine; Department of Pediatrics (Y. Oyazato), Kakogawa-Nishi Municipal Hospital, Kakogawa; Department of Pediatrics (S. Tsuneishi), Medical and Welfare Center Kizuna, Kasai; Department of Child Development (S.O.), Faculty of Life Sciences, Kumamoto University Graduate School, Kumamoto; Department of Pediatric Neurology (K.Y.), Seirei-Mikatahara Hospital, Hamamatsu; Department of Pediatrics (S.D.), Kyoto Min-iren Chuo Hospital, Kyoto; Department of Child Neurology (T.A.), Okayama University Graduate School of Medicine; Department of Psychiatry (N.K.), Kyoto Katsura Hospital, Kyoto; Department of Pediatrics, (R.K.) Fukuo
Objective:
Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC.
Methods:
Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care.
Results:
Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations.
Conclusions:
The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.
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