Publications by authors named "Kiyoshi Hayasaka"

115 Publications

ALOX12 mutation in a family with dominantly inherited bleeding diathesis.

J Hum Genet 2021 Feb 10. Epub 2021 Feb 10.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

The arachidonic acid (AA) cascade plays a significant role in platelet aggregation. AA released from membrane phospholipids is metabolized by cyclooxygenase (COX) pathway to thromboxane A (TXA) or by 12S-lipoxygenase (ALOX12) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE). In contrast to a well-known role of the COX pathway in platelet aggregation, the role of ALOX12 is not well understood. Platelets of ALOX12-deficient mice exhibit increased sensitivity for ADP-induced aggregation. However, recent evidence strongly suggests a significant role of ALOX12 in platelet aggregation and calcium signaling. 12-HPETE potentiates thrombin- and thromboxane-induced platelet aggregation, and calcium signaling. Inhibition experiments of ALOX12 demonstrated decreased platelet aggregation and calcium signaling in stimulated platelets. We studied a family with a dominantly inherited bleeding diathesis using next-generation sequencing analysis. Platelet aggregation studies revealed that the proband's platelets had defective aggregation responses to ADP, TXA mimetic U46619, collagen, and AA, normal affinity of TXA receptor for U46619, and normal induction of GTPase activity upon stimulation with U46619. However, the production of inositol 1,4,5-triphosphate (IP) was only increased up to 30% of the control upon U46619 stimulation, suggesting a defect in phospholipase C-β2 (PLCB2) activation downstream from TXA receptors. Affected family members had no mutation of PLCB2, but had a heterozygous c.1946A > G (p.Tyr649Cys) mutation of ALOX12. ALOX12 activity in platelets from the affected members was decreased to 25-35% of the control. Our data strongly suggested that a heterozygous c.1946A > G ALOX12 mutation was a disease-causing mutation; however, further experiments are required to confirm the pathogenesis of ALOX12 mutation in platelet aggregation.
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http://dx.doi.org/10.1038/s10038-020-00887-6DOI Listing
February 2021

Adult cases of late-onset congenital central hypoventilation syndrome and paired-like homeobox 2B-mutation carriers: an additional case report and pooled analysis.

J Clin Sleep Med 2020 11;16(11):1891-1900

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Study Objectives: Congenital central hypoventilation syndrome (CCHS) is caused by the paired-like homeobox 2B (PHOX2B) mutation and predominantly diagnosed during the neonatal period. Although late-onset CCHS and PHOX2B mutation carriers have been reported, the features of these disease states in adults remain uncertain. This study aimed to identify the characteristics of adult-onset CCHS and PHOX2B-mutation carriers in adult.

Methods: We mainly searched the PubMed/Medline and Cochrane Databases and classified our target patients into 2 groups: group A, symptomatically diagnosed with late-onset CCHS in adulthood; group B, adult PHOX2B-mutation carriers. Then, clinical characteristics, including the onset, treatment, long-term course, and pattern of the PHOX2B mutation in both groups were analyzed. Additionally, a new adult-case of late-onset CCHS was added to the analysis.

Results: Group A was comprised of 12 patients. The onset triggers of illness included a history of respiratory compromise following general anesthesia and respiratory tract infections. All patients in group A had 20/25 polyalanine repeat mutations and required some chronic ventilatory support at least during sleep, including portable positive pressure ventilator via tracheostomy or noninvasive positive pressure ventilation. In these patients with ventilatory support during sleep, sudden death or poor prognosis was not reported. Group B was comprised of 33 adults from 24 families with PHOX2B mutations. Nine patients in group B were confirmed with the diagnosis of CCHS. Although polyalanine repeat mutations 20/25 represented the most common gene mutation, diverse mutations, including mosaicism, were observed. Hypoventilation of several cases in group B were underdiagnosed by overnight polysomnography without monitoring for CO₂.

Conclusion: Alveolar hypoventilation with unknown origin can be caused by the PHOX2B mutation even in adult cases. Both the identification of the PHOX2B mutation and the incorporation of capnography in polysomnography are important for adult cases with unexplained alveolar hypoventilation or asymptomatic mutation carriers.
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http://dx.doi.org/10.5664/jcsm.8732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034226PMC
November 2020

Metabolic basis and treatment of citrin deficiency.

Authors:
Kiyoshi Hayasaka

J Inherit Metab Dis 2021 Jan 26;44(1):110-117. Epub 2020 Aug 26.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

Citrin deficiency is a hereditary disorder caused by SLC25A13 mutations and manifests as neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Citrin is a component of the malate-aspartate nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, an essential shuttle for hepatic glycolysis. Hepatic glycolysis and the coupled lipogenesis are impaired in citrin deficiency. Hepatic lipogenesis plays a significant role in fat supply during growth spurt periods: the fetal period, infancy, and puberty. Growth impairment in these periods is characteristic of citrin deficiency. Hepatocytes with citrin deficiency cannot use glucose and fatty acids as energy sources due to defects in the NADH shuttle and downregulation of peroxisome proliferator-activated receptor α (PPARα), respectively. An energy deficit in hepatocytes is considered a fundamental pathogenesis of citrin deficiency. Medium-chain triglyceride (MCT) supplementation with a lactose-restricted formula and MCT supplementation under a low-carbohydrate diet are recommended for NICCD and CTLN2, respectively. MCT supplementation therapy can provide energy to hepatocytes, promote lipogenesis, correct the cytosolic NAD /NADH ratio via the malate-citrate shuttle and improve ammonia detoxification, and it is a reasonable therapy for citrin deficiency. It is very important to administer MCT at a dose equivalent to the liver's energy requirements in divided doses with meals. MCT supplementation therapy is certainly promising for promoting growth spurts during infancy and adolescence and for preventing CTLN2 onset. Intravenous administration of solutions containing fructose is contraindicated, and persistent hyperglycemia should be avoided due to glucose intoxication for patients receiving hyperalimentation or with complicating diabetes.
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http://dx.doi.org/10.1002/jimd.12294DOI Listing
January 2021

Diabetes mellitus exacerbates citrin deficiency via glucose toxicity.

Diabetes Res Clin Pract 2020 Jun 23;164:108159. Epub 2020 Apr 23.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan; Department of Pediatrics, Miyukikai Hospital, Kaminoyama, Japan. Electronic address:

Aims: Citrin is an aspartate/glutamate carrier that composes the malate-aspartate reduced nicotinamide adenine dinucleotide (NADH) shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD) and adult-onset type II citrullinemia (CTLN2). Hepatic glycolysis is essentially impaired in citrin deficiency and a low-carbohydrate diet was recommended. The lethal effect of infusion of glycerol- and fructose-containing osmotic agents was reported in these patients. Hyperalimentation was also reported to exacerbate CTLN2; however, glucose toxicity was unclear in citrin deficiency.

Methods: We studied two CTLN2 patients complicated with type 2 diabetes mellitus (DM), Case 1 presented with hyperammonemic encephalopathy accompanied with DM, while Case 2 presented with hyperammonemic encephalopathy relapse upon the onset of DM after several years' remission following supplementation with medium-chain triglycerides (MCT) and adherence to a low-carbohydrate diet.

Results: Insulin therapy with MCT supplementation and a low-carbohydrate diet improved hyperammonemia and liver function in Case 1. Additional insulin therapy improved hyperammonemia in Case 2.

Conclusion: Glucose is not toxic for citrin deficiency in normoglycemia because glucose uptake and metabolism by hepatocytes are limited in normoglycemia. However, glucose becomes toxic during persistent hyperglycemia and antidiabetic therapy is indispensable for CTLN2 patients with DM.
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http://dx.doi.org/10.1016/j.diabres.2020.108159DOI Listing
June 2020

Expression of NUP93 and Its Alteration by Mutations Causing Focal Segmental Glomerulosclerosis.

Kidney Int Rep 2019 Sep 31;4(9):1312-1322. Epub 2019 May 31.

Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.

Introduction: Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as , have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which mutations cause this renal phenotype, remain unclear.

Methods: The expression of NUP93 in normal control kidney and in a patient with FSGS carrying mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis.

Results: Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient's kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient's podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient.

Conclusion: NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by mutations may underlie the pathogenic mechanism of SRNS or FSGS.
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http://dx.doi.org/10.1016/j.ekir.2019.05.1157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732778PMC
September 2019

Novel PHOX2B mutations in congenital central hypoventilation syndrome.

Pediatr Int 2019 Apr 17;61(4):393-396. Epub 2019 Apr 17.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata City, Japan.

Background: Congenital central hypoventilation syndrome (CCHS) is caused by mutation of paird-like homeobox 2B (PHOX2B). Approximately 90% of patients were found to carry polyalanine repeat expansion mutation (PARM), and the remaining 10% had non-PARM (NPARM). In PARM, the length of the polyalanine expansion correlates with clinical disease severity. Most patients with NPARM have hypoventilation symptoms in the neonatal period and complications of Hirschsprung disease, dysregulation of autonomic nervous system, and tumors of neural crest origin. Data on the genotype-phenotype association may contribute to the clinical management of the disease.

Methods: We studied the genetic background of Japanese CCHS patients according to PHOX2B sequencing.

Results: Of 133 Japanese CCHS patients we identified 12 patients carrying 11 different NPARM (approx. 9% of the patients) and described the clinical manifestations in seven of them with the following novel mutations: c.941-945del5, c.678_693dup16, c.609_616del8, c.620_633del14, c.663_711del 49, c.448C>G and c.944G>C. All patients had hypoventilation in the neonatal period and also had Hirschsprung disease, with the exception of two patients carrying c.620_633del14 and c.663_711del49 mutations. The patient carrying the c.609_616del8 mutation also had a benign mediastinal tumor.

Conclusion: Most patients carrying NPARM had severe symptoms with frequent complications, as in previous reports, and should be carefully monitored for various complications, including neural crest-derived tumor.
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http://dx.doi.org/10.1111/ped.13812DOI Listing
April 2019

Growth impairment in individuals with citrin deficiency.

J Inherit Metab Dis 2019 05 4;42(3):501-508. Epub 2019 Feb 4.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Owing to a defect in the NADH-shuttle, citrin deficiency impairs hepatic glycolysis and de novo lipogenesis leading to hepatic energy deficit. To investigate the physiological role of citrin, we studied the growth of 111 NICCD-affected subjects (51 males and 60 females) and 12 NICCD-unaffected subjects (five males and seven females), including the body weight, height, and genotype. We constructed growth charts using the lambda-mu-sigma (LMS) method. The NICCD-affected subjects showed statistically significant growth impairment, including low birth weight and length, low body weight until 6 to 9 months of age, low height until 11 to 13 years of age, and low body weight in 7 to 12-year-old males and 8-year-old females. NICCD-unaffected subjects showed similar growth impairment, including low birth weight and height, and growth impairment during adolescence. In the third trimester, de novo lipogenesis is required for deposition of body fat and myelination of the developing central nervous system, and its impairment likely causes low birth weight and length. The growth rate is the highest during the first 6 months of life and slows down after 6 months of age, which is probably associated with the onset and recovery of NICCD. Adolescence is the second catch-up growth period, and the proportion and distribution of body fat change depending on age and sex. Characteristic growth impairment in citrin deficiency suggests a significant role of citrin in the catch-up growth via lipogenesis.
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http://dx.doi.org/10.1002/jimd.12051DOI Listing
May 2019

Adult-onset type II citrullinemia: Current insights and therapy.

Appl Clin Genet 2018 12;11:163-170. Epub 2018 Dec 12.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan,

Citrin deficiency is a recessively inherited metabolic disorder with age-dependent clinical manifestations. It causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Patients with NICCD present with intrahepatic cholestasis in the neonatal period and usually respond to the treatment with medium-chain triglyceride (MCT) supplement and lactose-restricted formula. In adulthood, CTLN2 develops in <10 % of the patients showing hyperammonemic encephalopathy. Patients with CTLN2 required liver transplantation for the most promising prognosis; however, they were successfully treated with MCT supplement with a low carbohydrate formula. Citrin deficiency is caused by mutations in on chromosome 7q21.3, with a high frequency in East Asia, including Japan. Citrin is aspartate/glutamate transporter in mitochondria, a component of malate-aspartate nicotinamide adenine dinucleotide hydrogen shuttle, and is essential for the hepatic glycolysis. Although the precise pathophysiology of citrin deficiency remains unclear, recent reports for the effective MCT supplement therapy and downregulation of peroxisome proliferator-activated receptor α suggest that citrin deficiency impairs hepatic de novo lipogenesis coupled with glycolysis leading to the energy deficit of hepatocytes. Herein, we review the current therapeutic and pathological understanding of CTLN2.
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http://dx.doi.org/10.2147/TACG.S162084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296197PMC
December 2018

A novel PHOX2B gene mutation in an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease.

Eur J Med Genet 2019 Sep 15;62(9):103541. Epub 2018 Sep 15.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

Congenital central hypoventilation syndrome is a disorder of respiratory control caused by mutations in the paired-like homeobox 2B gene. Mutations in the paired-like homeobox 2B gene are also responsible for Hirschsprung's disease. Variant Hirschsprung's disease is a rarer disorder that does not meet the diagnostic criteria of Hirschsprung's disease, although severe functional bowel obstruction persists. We present a case of an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease. A male infant who was diagnosed to have fetal growth restriction and polyhydramnios was delivered by emergency cesarean section at 30 weeks and 3 days of gestational age due to non-reassuring fetal status. The birth weight was 979 g, and intensive care was started immediately following delivery. The patient exhibited refractory apnea and was diagnosed with congenital central hypoventilation syndrome by genetic testing of the paired-like homeobox 2B gene. The patient also exhibited refractory functional bowel obstruction and was diagnosed to have variant Hirschsprung's disease through pathological examination of his intestinal specimens. The patient grew slowly but surely with intensive care including mechanical ventilation and parenteral nutrition. However, the patient repeatedly suffered from sepsis and died of fungemia at 197 days of age. This is the first congenital central hypoventilation syndrome case that was accompanied with variant Hirschsprung's disease, and the paired-like homeobox 2B mutation detected in this case (NM_003924.3: c.441G > C; p.(Gln147His)) is novel. This case suggests that the paired-like homeobox 2B mutation causes not only congenital central hypoventilation syndrome and Hirschsprung's disease, but also variant Hirschsprung's disease in humans. It also highlights the extreme difficulty in treating premature infants with severe and prolonged functional bowel obstruction.
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http://dx.doi.org/10.1016/j.ejmg.2018.09.008DOI Listing
September 2019

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

J Inherit Metab Dis 2018 09 12;41(5):777-784. Epub 2018 Apr 12.

Department of Pediatrics, Tsuruoka Municipal Shonai Hospital, Tsuruoka, Japan.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.
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http://dx.doi.org/10.1007/s10545-018-0176-1DOI Listing
September 2018

Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties.

Hum Mutat 2017 07 20;38(7):805-815. Epub 2017 Apr 20.

Department of Immunoregulation, Research Institute for Microbial Diseases Osaka University, Suita, Osaka, Japan.

Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.
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http://dx.doi.org/10.1002/humu.23219DOI Listing
July 2017

Effectiveness of Medium-Chain Triglyceride Oil Therapy in Two Japanese Citrin-Deficient Siblings: Evaluation Using Oral Glucose Tolerance Tests.

Tohoku J Exp Med 2016 12;240(4):323-328

Department of Pediatrics, Graduate School of Medicine, Gifu University.

Citrin deficiency, an inherited defect of the liver-type mitochondrial aspartate/glutamate carrier isoform (citrin), may cause impairment of glycolysis because of an increase in the cytosolic NADH/NAD ratio. We report a Japanese boy whose main complaint was recurrent hypoglycemic episodes. He was suspected as having citrin deficiency because of his peculiar preference for protein- and fat-rich food. His young sister also had a similar food preference. Both siblings were diagnosed with citrin deficiency by genetic analysis. The brother and sister underwent an oral glucose tolerance test (OGTT) at 10 and 7 yr of age, respectively. Blood glucose, ammonia, lactic acid, pyruvic acid, and insulin levels were monitored before starting the test, and then every 30 min. During this test, they maintained blood glucose levels until 180 min. At 210 min, they experienced vomiting, feeling ill, and decreased blood glucose levels (2.9 and 2.8 mmol/l in the brother and sister, respectively). The sister and brother recovered uneventfully by intravenous glucose injection. In a second OGTT, 4 months after medium-chain triglyceride (MCT) oil supplementation, they had no major symptoms and normal glucose levels were maintained, even after 240 min. Additionally, after MCT oil therapy, their food preference slightly changed as they started eating more carbohydrates. Our OGTT data suggest excess carbohydrate intake has adverse consequences in patients with citrin deficiency, including hypoglycemia after a few hours. MCT oil therapy may be effective in preventing such hypoglycemia and improving metabolic derangement, even during the so-called apparently healthy period.
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http://dx.doi.org/10.1620/tjem.240.323DOI Listing
December 2016

Unique food-entrained circadian rhythm in cysteine414-alanine mutant mCRY1 transgenic mice.

Sleep Biol Rhythms 2016;14:261-269. Epub 2016 Jan 29.

Research Center for Molecular Genetics, Institute for Promotion of Medical Science Research, Faculty of Medicine, Yamagata University, Yamagata, 990-9585 Japan.

Food availability is a potent environmental cue that directs circadian locomotor activity in rodents. Daily scheduled restricted feeding (RF), in which the food available time is restricted for several hours each day, elicits anticipatory activity. This food-anticipatory activity (FAA) is controlled by a food-entrainable oscillator (FEO) that is distinct from the suprachiasmatic nucleus (SCN), the master pacemaker in mammals. In an earlier report, we described generation of transgenic (Tg) mice ubiquitously overexpressing cysteine414-alanine mutant mCRY1. The Tg mice displayed long locomotor free-running periods (approximately 28 h) with rhythm splitting. Furthermore, their locomotor activity immediately re-adjusted to the advance of light-dark cycles (LD), suggesting some disorder in the coupling of SCN neurons. The present study examined the restricted feeding cycle (RF)-induced entrainment of locomotor activity in Tg mice in various light conditions. In LD, wild-type controls showed both FAA and LD-entrained activities. In Tg mice, almost all activity was eventually consolidated to a single bout before the feeding time. The result suggests a possibility that in Tg mice the feeding cycle dominates the LD cycle as an entrainment agent. In constant darkness (DD), wild-type mice exhibited robust free-run activity and FAA during RF. For Tg mice, only the rhythm entrained to RF was observed in DD. Furthermore, after returning to free feeding, the free-run started from the RF-entrained phase. These results suggest that the SCN of Tg mice is entrainable to RF and that the mCRY1 mutation alters the sensitivity of SCN to the cycle of nonphotic zeitgebers.
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http://dx.doi.org/10.1007/s41105-016-0050-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932127PMC
January 2016

Effects of heat stress on production, somatic cell score and conception rate in Holsteins.

Anim Sci J 2017 Jan 25;88(1):3-10. Epub 2016 Apr 25.

Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

We examined the effects of heat stress (HS) on production traits, somatic cell score (SCS) and conception rate at first insemination (CR) in Holsteins in Japan. We used a total of 228 242 records of milk, fat and protein yields, and SCS for the first three lactations, as well as of CR in heifers and in first- and second-lactation cows that had calved for the first time between 2000 and 2012. Records from 47 prefectural weather stations throughout Japan were used to calculate the temperature-humidity index (THI); areas were categorized into three regional groups: no HS (THI < 72), mild HS (72 ≤ THI < 79), and moderate HS (THI ≥ 79). Trait records from the three HS-region groups were treated as three different traits and trivariate animal models were used. The genetic correlations between milk yields from different HS groups were very high (0.91 to 0.99). Summer calving caused the greatest increase in SCS, and in the first and second lactations this increase became greater as THI increased. In cows, CR was affected by the interaction between HS group and insemination month: with summer and early autumn insemination, there was a reduction in CR, and it was much larger in the mild- and moderate-HS groups than in the no-HS group.
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http://dx.doi.org/10.1111/asj.12617DOI Listing
January 2017

Analysis of the genes responsible for steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis in Japanese patients by whole-exome sequencing analysis.

J Hum Genet 2016 Feb 15;61(2):137-41. Epub 2015 Oct 15.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

Steroid-resistant nephrotic syndrome (SRNS) represents glomerular disease resulting from a number of different etiologies leading to focal segmental glomerulosclerosis (FSGS). Recently, many genes causing SRNS/FSGS have been identified. These genes encode the proteins associated with the formation and/or maintenance of glomerular filtration barrier. Next-generation sequencing is used to analyze large numbers of genes at lower costs. To identify the genetic background of Japanese patients, we studied 26 disease-causing genes using whole-exome sequencing analysis in 24 patients with SRNS and/or FSGS from 22 different Japanese families. We finally found eight causative gene mutations, four recessive and four dominant gene mutations, including three novel mutations, in six patients from five different families, and one novel predisposing mutation in two patients from two different families. Causative gene mutations have only been identified in ~20% of families and further analysis is necessary to identify the unknown disease-causing gene. Identification of the disease-causing gene would support clinical practices, including the diagnosis, understanding of pathogenesis and treatment.
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http://dx.doi.org/10.1038/jhg.2015.122DOI Listing
February 2016

Genotype-phenotype relationship in Japanese patients with congenital central hypoventilation syndrome.

J Hum Genet 2015 Sep 11;60(9):473-7. Epub 2015 Jun 11.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

Examine the genotype-phenotype relationship in Japanese congenital central hypoventilation syndrome (CCHS) patients and estimate the incidence of CCHS in Japan. Subjects were 92 Japanese patients with PHOX2B mutations; 19 cases carried 25 polyalanine repeat expansion mutations (PARMs); 67 cases carried 26 or more PARMs; and 6 had non-PARMs (NPARMs). We collected clinical data in all patients and estimated the development or intelligent quotients only in the patients carrying 25 PARM. The estimated incidence of CCHS was greater than one case per 148 000 births. Polyhydramnios was observed in three cases. Twelve infants exhibited depressed respiration at birth. In 19 cases carrying 25 PARM, the male-to-female ratio was ~3, no cases had Hirschsprung disease; 7 cases (37%) developed hypoventilation after the neonatal period, and 8 cases (42%) had mental retardation. In other 73 cases carrying 26 or more PARMs or NPARMs, male-to-female ratio was equal; patients frequently complicated with Hirschsprung disease and constipation, and all patients presented with hypoventilation in the neonatal period. Clinical symptoms were severe in most patients carrying long PARMs and NPARMs. In 25 PARM, additional genetic and/or epigenetic factors were required for CCHS development and male sex is likely a predisposing factor. The patients carrying 25 PARM frequently had mental retardation likely because they were not able to receive appropriate ventilation support following a definitive diagnosis owing to subtle and or irregular hypoventilation. Molecular diagnosis provides a definitive diagnosis and enables to receive appropriate ventilator support.
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http://dx.doi.org/10.1038/jhg.2015.65DOI Listing
September 2015

[Treatment and Pathomechanism of Citrin Deficiency].

Brain Nerve 2015 Jun;67(6):739-47

Department of Pediatrics, Yamagata University School of Medicine.

Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, a small number of adults with citrin deficiency develop adult-onset type II citrullinemia (CTLN2), which causes hyperammonemic encephalopathy leading to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. Hepatic glycolysis is coupled with hepatic lipogenesis via the NADH shuttles composed of the malate-aspartate shuttle and malate-citrate shuttle. Citrin deficiency is expected to impair glycolysis and lipogenesis in hepatocytes. We noticed that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. We extended this therapy for CTLN2 and found that an MCT supplementation therapy under a low-carbohydrate formula prevented the relapse of hyperammonemic encephalopathy, normalized the liver dysfunction (including the Fisher ratio), and gradually improved the level of plasma citrulline and fatty liver. An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to improvement of the cytosolic NAD+/NADH ratio via the malate-citrate shuttle. MCT supplementation could be a promising therapy for citrin deficiency.
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http://dx.doi.org/10.11477/mf.1416200211DOI Listing
June 2015

Two patients with HNF4A-related congenital hyperinsulinism and renal tubular dysfunction: A clinical variation which includes transient hepatic dysfunction.

Diabetes Res Clin Pract 2015 Jun 13;108(3):e53-5. Epub 2015 Mar 13.

Department of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.

The HNF4A p.R76W mutation causes congenital hyperinsulinism with Fanconi syndrome. Here, we report two cases who also presented with increased urinary calcium excretion and one had a transient hepatic dysfunction with hepatomegaly. Clinical variations including transient liver dysfunction is a likely mutation-specific clinical characteristic.
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http://dx.doi.org/10.1016/j.diabres.2015.03.005DOI Listing
June 2015

A novel ETFB mutation in a patient with glutaric aciduria type II.

Hum Genome Var 2015 18;1:15016. Epub 2015 Jun 18.

Department of Pediatrics, Yamagata University School of Medicine , Yamagata, Japan.

Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth.
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http://dx.doi.org/10.1038/hgv.2015.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785565PMC
April 2016

Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms.

J Hum Genet 2015 Jan 13;60(1):35-40. Epub 2014 Nov 13.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

Neonates have physiologically increased bilirubin production and immature bilirubin metabolism, and present hyperbilirubinemia in association with genetic and or epigenetic factors. We previously reported that maximal body weight loss (inadequate feeding) is an independent risk factor for the development of hyperbilirubinemia in breast-fed Japanese neonates, and the UGT1A1 211G>A genotype becomes a risk factor under conditions of inadequate feeding. We extended the study to the association of other genetic factors, the UGT1A1 (TA)7 and solute-carrier organic anion transporters (SLCOs) polymorphisms with neonatal hyperbilirubinemia. We enrolled 401 full-term Japanese infants who were exclusively breastfeeding and classified them into two groups based on the degree of maximal body weight loss. We analyzed the clinical characteristics and UGT1A1 and SLCOs genotypes. Statistical analysis revealed that maximal body weight loss is the only independent risk factor for the development of neonatal hyperbilirubinemia. UGT1A1, SLCO1B1 and SLCO1B3 polymorphisms become risk factors in neonates showing 10% or greater body weight loss during the neonatal period. Inadequate feeding may increase the bilirubin burden and cause apparent hyperbilirubinemia in neonates, who have a polymorphic change in the genes involved in the transport and/or metabolism of bilirubin.
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http://dx.doi.org/10.1038/jhg.2014.98DOI Listing
January 2015

A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.

Am J Hum Genet 2014 Sep 21;95(3):294-300. Epub 2014 Aug 21.

Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata 990-9585, Japan. Electronic address:

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.
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http://dx.doi.org/10.1016/j.ajhg.2014.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157141PMC
September 2014

Identification of novel ALK rearrangement A2M-ALK in a neonate with fetal lung interstitial tumor.

Genes Chromosomes Cancer 2014 Oct 26;53(10):865-74. Epub 2014 Jun 26.

Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan; Department of Immunology, Yamagata University Faculty of Medicine, Yamagata, Japan.

Fetal lung interstitial tumor (FLIT) is a recently reported type of congenital lung lesion comprising solid and cystic components. The pathological features include unique interstitial mesenchyme-based cell proliferation, and differ from other neoplasms represented by pleuropulmonary blastoma or congenital peribronchial myofibroblastic tumor. FLIT is extremely rare and its gene expression profile has not yet been reported. We provide the first report of a novel chromosomal rearrangement resulting in α-2-macroglobulin (A2M) and anaplastic lymphoma kinase (ALK) gene fusion in a patient with FLIT. The tumor cells contained a t(2;12)(p23;p13) and were mesenchymal in origin (e.g., inflammatory myofibroblastic tumors), suggesting the involvement of ALK in this case of FLIT. Break apart fluorescence in situ hybridization demonstrated chromosomal rearrangement at ALK 2p23. Using 5'-rapid amplification of cDNA ends, we further identified a novel transcript fusing exon 22 of A2M to exon 19 of ALK, which was confirmed by reverse-transcription polymerase chain reaction. The corresponding chimeric gene was subsequently confirmed by sequencing, including the genomic break point between intron 22 and 18 of A2M and ALK, respectively. Discovery of A2M as a novel ALK fusion partner, together with the involvement of ALK, provides new insights into the pathogenesis of FLIT, and suggests the potential for new therapeutic strategies based on ALK inhibitors.
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http://dx.doi.org/10.1002/gcc.22199DOI Listing
October 2014

Cellular expression and localization of DGKζ-interacting NAP1-like proteins in the brain and functional implications under hypoxic stress.

Histochem Cell Biol 2014 Nov 4;142(5):461-71. Epub 2014 Jun 4.

Department of Anatomy and Cell Biology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.

Diacylglycerol kinase (DGK) catalyzes conversion of a lipid second messenger diacylglycerol to another messenger molecule phosphatidic acid. Consequently, DGK plays a pivotal role in cellular pathophysiology by regulating the levels of these two messengers. We reported previously that DGKζ translocates from the nucleus to cytoplasm in hippocampal neurons under ischemic/hypoxic stress. In addition, we also identified nucleosome assembly protein 1 (NAP1)-like proteins NAP1L1 and NAP1L4 as novel DGKζ-interacting partners using a proteomic approach and revealed that these NAP1-like proteins induce cytoplasmic translocation of DGKζ in overexpressed cells because NAP1-like proteins associate with the nuclear localization signal of DGKζ and block its nuclear import via importin α. In the present study, we examined whether NAP1-like proteins are expressed in the brain and whether the molecular interaction of DGKζ and NAP1-like proteins would be changed in the brain after hypoxic stress. Immunohistochemistry revealed that NAP1L1 and NAP1L4 are widely expressed in neurons and glial cells in the brain with some differences. After 3 days of transient whole-body hypoxic stress, DGKζ translocated from the nucleus to cytoplasm in hippocampal pyramidal neurons, whereas NAP1-like proteins remained in the cytoplasm. Contrary to our expectations, NAP1-like proteins showed no change in their expression levels. The molecular interaction between DGKζ and NAP1-like proteins was attenuated after hypoxic stress. These results suggest that DGKζ cytoplasmic translocation in neurons under hypoxic stress is regulated by some mechanism which differs from that mediated by NAP1-like proteins.
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http://dx.doi.org/10.1007/s00418-014-1226-xDOI Listing
November 2014

Characterization of age-associated alterations of islet function and structure in diabetic mutant cryptochrome 1 transgenic mice.

J Diabetes Investig 2013 Sep 26;4(5):428-35. Epub 2013 Apr 26.

Research Laboratory for Molecular Genetics Yamagata Japan.

Aims/introduction: In earlier reports, we described that transgenic (Tg) mice ubiquitously expressing cryptochrome1 (CRY1) with a mutation in cysteine414 (CRY1-AP Tg mice) show an early-onset insulin-secretory defect of diabetes mellitus resembling human maturity-onset diabetes of the young (MODY). To clarify the yet undiscovered molecular pathogenesis of diabetes mellitus in which the mutant of CRY1 is involved, we examined age-dependent characteristics of islets of CRY1-AP Tg mice.

Materials And Methods: Immunohistochemical analyses of islets were carried out for 2-, 4- and 19-week-old mice. Insulin contents in the pancreas and glucose-stimulated insulin secretion of isolated islets of mice were measured at 4 weeks. Real-time polymerase chain reaction analyses using pancreases of mice at 4 and 21 weeks-of-age were carried out.

Results: Already at a young stage, the proliferation of β-cells was reduced in CRY1-AP Tg mice. Insulin contents and the levels of glucose-stimulated insulin secretion were lower than those of wild-type controls in CRY1-AP Tg mice at the young stage. The expression of insulin and glucose-sensing genes was reduced at the young stage. At the mature stage, altered distribution and hyperplasia of α-cells were observed in the islets of CRY1-AP Tg mice.

Conclusions: Architectural abnormality in islets progressed with age in CRY1-AP Tg mice. The reduced expression of insulin and glucose-sensing genes, along with the lowered proliferation of β-cells from an early stage, is a possible primary cause of early-onset insulin-secretory defect in CRY1-AP Tg mice. Our results suggest that CRY1 is crucial for the maintenance of β-cell function.
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http://dx.doi.org/10.1111/jdi.12080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025103PMC
September 2013

PIGA mutations cause early-onset epileptic encephalopathies and distinctive features.

Neurology 2014 May 4;82(18):1587-96. Epub 2014 Apr 4.

From the Department of Pediatrics (M.K., K.H.), Yamagata University Faculty of Medicine, Yamagata; Department of Human Genetics (H.S., C.O., M.N., Y.T., N. Miyake, N. Matsumoto), Yokohama City University Graduate School of Medicine, Yokohama; Department of Immunoregulation (Y.M., T.K.), Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, Suita; Division of Neurology (K.K., R.M., S.-i.H.), Saitama Children's Medical Center, Saitama; Division of Neurology (S.W.), Miyagi Children's Hospital, Sendai; Division of Neurology (M.I., H.O.), Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama; Department of Pediatrics (K.M.), Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama; Department of Pediatrics (R.T.), Aomori Prefectural Central Hospital, Aomori; and Department of Pediatrics (H.O.), Jichi Medical School, Tochigi, Japan.

Objective: To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs).

Methods: Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated.

Results: We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism.

Conclusions: Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.
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http://dx.doi.org/10.1212/WNL.0000000000000389DOI Listing
May 2014

A case of congenital central hypoventilation syndrome with a novel mutation of the PHOX2B gene presenting as central sleep apnea.

J Clin Sleep Med 2014 Mar 15;10(3):327-9. Epub 2014 Mar 15.

Department of Pediatrics, Fukuoka National Hospital, Fukuoka, Japan.

Unlabelled: Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by abnormal autonomic control of breathing resulting in hypoventilation. We report an infant girl with CCHS who presented with central sleep apnea, which was first demonstrated by polysomnography when the infant was 5 months old. She was heterozygous for the novel 590delG mutation of PHOX2B, which is classified as a non-polyalanine repeat mutation (NPARM). This mutation is considered to be associated with a relatively mild phenotype.

Citation: Amimoto Y; Okada K; Nakano H; Sasaki A; Hayasaka K; Odajima H. A case of congenital central hypoventilation syndrome with a novel mutation of the PHOX2B gene presenting as central sleep apnea.
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http://dx.doi.org/10.5664/jcsm.3542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927440PMC
March 2014

Effects of a breeding scheme combined by genomic pre-selection and progeny testing on annual genetic gain in a dairy cattle population.

Anim Sci J 2014 Jun 26;85(6):639-49. Epub 2014 Feb 26.

NARO Hokkaido Agricultural Research Center, Sapporo, Japan.

The effectiveness of the incorporation of genomic pre-selection into dairy cattle progeny testing (GS-PT) was compared with that of progeny testing (PT) where the fraction of dam to breed bull (DB) selected was 0.01. When the fraction of sires to breed bulls (SB) selected without being progeny tested to produce young bulls (YB) in the next generation was 0.2, the annual genetic gain from GS-PT was 13% to 43% greater when h(2)  = 0.3 and 16% to 53% greater when h(2)  = 0.1 compared with that from PT. Given h(2)  = 0.3, a selection accuracy of 0.8 for both YB and DB, and selected fractions of 0.117 for YB and 0.04 for DB, GS-PT produced 40% to 43% greater annual genetic gain than PT. Given h(2)  = 0.1, a selection accuracy of 0.6 for both YB and DB, and selected fractions of 0.117 for YB and 0.04 for DB, annual genetic gain from GS-PT was 48% to 53% greater than that from PT. When h(2)  = 0.3, progeny testing capacity had little effect on annual genetic gain from GS-PT. However, when h(2)  = 0.1, annual genetic gain from GS-PT increased with increasing progeny testing capacity.
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http://dx.doi.org/10.1111/asj.12186DOI Listing
June 2014

[Congenital central hypoventilation syndrome: paradigm shifts and future prospects].

Nihon Rinsho 2014 Feb;72(2):363-70

Department of Pediatrics, Yamagata University School of Medicine.

Congenital central hypoventilation syndrome (CCHS) is characterized by a failure of the automatic control of breathing during sleep, and is caused by the dominant PHOX2B mutation. PHOX2B encodes a highly conserved homeobox transcription factor with two short polyalanine tracts. More than 90% of patients carry polyalanine expansion mutations (PARM) in the polyalanine tract of 20 residues and less than 10% of the patients have missense, nonsense, or frameshift mutations(non-PARM). Approximately 25% of the patients with PARM inherited the mutation from asymptomatic parents with somatic mosaicism or few affected parents. Molecular analysis can provide the definite diagnosis and clinically useful information. Model mouse experiments and MRI study of the patients will contribute to understanding the pathogenesis and development of new treatment strategy.
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February 2014

Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia.

Mol Genet Metab Rep 2014 14;1:42-50. Epub 2014 Jan 14.

Dept. of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Background: Citrin, encoded by , is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, small numbers of adults with citrin deficiency develop hyperammonemic encephalopathy, adult-onset type II citrullinemia (CTLN2), which leads to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. We previously reported that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. Citrin deficiency may impair the glycolysis in hepatocytes because of an increase in the cytosolic NADH/NAD ratio, leading to an energy shortage. MCT administration can provide energy to hepatocytes and was expected to have a good effect on CTLN2.

Methods: An MCT supplementation therapy under a low-carbohydrate formula was administered to five patients with CTLN2. Four of the patients had episodes of hyperammonemic encephalopathy, and one patient had postprandial hyperammonemia with no symptoms.

Results: One of the patients displaying hyperammonemic encephalopathy completely recovered with all normal laboratory findings. Others notably improved in terms of clinical and or laboratory findings with no hyperammonemic symptoms; however, the patients displayed persistent mild citrullinemia and occasionally had postprandial mild hyperammonemia most likely due to an irreversible change in the liver.

Conclusions: An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to a reduction in the cytosolic NADH/NAD ratio. MCT supplementation under a low-carbohydrate formula could be a promising therapy for CTLN2 and should also be used to prevent CTLN2 to avoid irreversible liver damage.
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http://dx.doi.org/10.1016/j.ymgmr.2013.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121258PMC
January 2014