Molecular and clinical features of KATP-channel neonatal diabetes mellitus in Japan.
BACKGROUND
There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM).


OBJECTIVE
To elucidate the characteristics of Japanese patients with KATP-NDM.


METHODS
By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts.


RESULTS
Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea.


CONCLUSIONS
Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.
Department of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.|Clinical Research Center, Osaka City General Hospital, Osaka, Japan.
Yukiko
Y
Hashimoto
Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Sumito
S
Dateki
Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan.
Masakazu
M
Hirose
Department of Pediatric Nephrology and Metabolism, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan.
Kenichi
K
Satomura
Department of Reproductive and Developmental Medicine, University of Miyazaki, Miyazaki, Japan.
Hirotake
H
Sawada
Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Haruo
H
Mizuno
Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
Shigetaka
S
Sugihara
Department of Pediatric Neurology, Aichi Prefectural Colony Central Hospital, Aichi, Japan.
Koichi
K
Maruyama
Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.
Tatsuhiko
T
Urakami
Department of Pediatrics, Yokohama City University Medical Center, Kanagawa, Japan.
Hidenori
H
Sugawara
Department of Pediatrics, Seirei-Mikatahara General Hospital, Shizuoka, Japan.
Kenji
K
Shirai
Department of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.|Clinical Research Center, Osaka City General Hospital, Osaka, Japan.
Tohru
T
Yorifuji
D019943:Amino Acid Substitution; D044903:Congenital Hyperinsulinism / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D016903:Drug Monitoring; D004351:Drug Resistance; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005905:Glyburide / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007003:Hypoglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007223:Infant; D007232:Infant, Newborn, Diseases / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000627:therapeutic use; D007564:Japan; D008297:Male; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics*; D011596:Psychomotor Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D012720:Severity of Illness Index; D064233:Sulfonylurea Receptors / Q000737:chemistry / Q000235:genetics*; D000099161:Kcnj11 Channel
D005905:Glyburide; D007004:Hypoglycemic Agents; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human

KATP
-channel; Japanese; neonatal diabetes; sulfonylurea