Publications by authors named "Kimitoshi Nakamura"

137 Publications

Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: A nationwide survey in Japan.

Mol Genet Metab 2021 May 12. Epub 2021 May 12.

Advanced Clinical Research Center, Southern Tohoku Research Center for Neuroscience, Kanagawa, Japan.

Introduction: Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan.

Methods: A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy.

Discussion: Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan.

Conclusion: We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.
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http://dx.doi.org/10.1016/j.ymgme.2021.05.004DOI Listing
May 2021

LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα.

Blood Adv 2021 05;5(9):2305-2318

Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, and.

Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation-sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.
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http://dx.doi.org/10.1182/bloodadvances.2020003521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114557PMC
May 2021

Diagnosis and Management of Sitosterolemia 2021.

J Atheroscler Thromb 2021 Apr 28. Epub 2021 Apr 28.

Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute.

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.
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http://dx.doi.org/10.5551/jat.RV17052DOI Listing
April 2021

Variants associated with urea cycle disorders in Japanese patients: Nationwide study and literature review.

Am J Med Genet A 2021 Jul 13;185(7):2026-2036. Epub 2021 Apr 13.

Department of Pediatrics, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia with variable clinical manifestations. Using data from a nationwide study, we investigated the onset time, gene variants, clinical manifestations, and treatment of patients with UCDs in Japan. Of the 229 patients with UCDs diagnosed and/or treated between January 2000 and March 2018, identified gene variants and clinical information were available for 102 patients, including 62 patients with ornithine transcarbamylase (OTC) deficiency, 18 patients with carbamoyl phosphate synthetase 1 (CPS1) deficiency, 16 patients with argininosuccinate synthetase (ASS) deficiency, and 6 patients with argininosuccinate lyase (ASL) deficiency. A total of 13, 10, 4, and 5 variants in the OTC, CPS1, ASS, and ASL genes were respectively identified as novel variants, which were neither registered in ClinVar databases nor previously reported. The onset time and severity in patients with UCD could be predicted based on the identified gene variants in each patient from this nationwide study and previous studies. This genetic information may help in predicting the long-term outcome and determining specific treatment strategies such as liver transplantation in patients with UCDs.
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http://dx.doi.org/10.1002/ajmg.a.62199DOI Listing
July 2021

Long-term outcome of urea cycle disorders: Report from a nationwide study in Japan.

J Inherit Metab Dis 2021 Apr 11. Epub 2021 Apr 11.

Department of Pediatrics, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 μmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 μmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.
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http://dx.doi.org/10.1002/jimd.12384DOI Listing
April 2021

Expression of Lymphatic Markers in the Berger's Space and Bursa Premacularis.

Int J Mol Sci 2021 Feb 19;22(4). Epub 2021 Feb 19.

Department of Ophthalmology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-City 569-8686, Osaka, Japan.

We previously reported that the bursa premacularis (BPM), a peculiar vitreous structure located above the macula, contains numerous cells expressing markers of lymphatic endothelial cells, such as podoplanin and LYVE-1. Herein, we examined the expression of lymphatic markers in the Berger's space (BS), BPM, and vitreous core (VC). BS, BPM, and VC specimens were selectively collected in macular hole and epiretinal membrane patients during vitrectomy and were then immunostained with antibodies for podoplanin, LYVE-1, and fibrillin-1 and -2. By visualization using triamcinolone acetonide, the BS was recognized as a sac-like structure with a septum located behind the lens as well as BPM. Those tissues adhered to the lens or retina in a circular manner by means of a ligament-like structure. Immunostaining showed intense expression of podoplanin and LYVE-1 in the BS. Both BS and BPM stained strongly positive for fibrillin-1 and -2. The VC was faintly stained with antibodies for those lymph-node markers. Our findings indicate that both BS and BPM possibly belong to the lymphatic system, such as lymph nodes, draining excess fluid and waste products into lymphatic vessels in the dura mater of the optic nerve and the ciliary body, respectively, via intravitreal canals.
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http://dx.doi.org/10.3390/ijms22042086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923221PMC
February 2021

Screening for Gaucher Disease Using Dried Blood Spot Tests: A Japanese Multicenter, Cross-sectional Survey.

Intern Med 2021 1;60(5):699-707. Epub 2021 Mar 1.

Division of Pediatrics, Graduate School of Medical Science, Kumamoto University, Japan.

Objective For patients with Gaucher disease (GD), a rare, inherited lysosomal storage disease, obtaining a definitive diagnosis is currently time-consuming and costly. A simplified screening method to measure the glucocerebrosidase (GBA) activity using dried blood spots (DBS) on filter paper has recently been developed. Using this newly developed screening method, we evaluated real-world GD screening in patients suspected of having GD. Methods This multicenter, cross-sectional, observational study with a diagnostic intervention component evaluated real-world screening in patients suspected of having GD based on their clinical symptoms and a platelet count <120,000/μL. The endpoint was the number of patients with low GBA activity determined using DBS. Results In 994 patients who underwent initial DBS screening, 77 had low GBA activity. The assay was not repeated in 1 patient who was diagnosed as having a high possibility of GD due to clinical symptoms, and a further 21 patients completed the study without undergoing the second assay. Of the remaining 55 patients who had 2 DBS assays performed, 11 had a low GBA activity in both assays. Overall, DBS screening identified 12 (1.2%) patients with a low GBA activity, a proportion consistent with prior screening studies. Conclusion These results suggest that the simplified DBS method was less burdensome to patients, was easily utilized by many physicians, and could be a useful first-tier screening assay for GD prior to initiating burdensome genetic testing.
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http://dx.doi.org/10.2169/internalmedicine.5064-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990619PMC
April 2021

Physical, cognitive, and social status of patients with urea cycle disorders in Japan.

Mol Genet Metab Rep 2021 Jun 7;27:100724. Epub 2021 Feb 7.

Department of Pediatrics, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876628PMC
June 2021

SGLT2 inhibition alleviated hyperglycemia, glucose intolerance, and dumping syndrome-like symptoms in a patient with glycogen storage disease type Ia: a case report.

J Med Case Rep 2021 Feb 16;15(1):75. Epub 2021 Feb 16.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, Kumamoto Prefecture, 860-8556, Japan.

Background: Glycogen storage disease (GSD) type Ia is a glycogenesis disorder with long-term complications such as hepatomegaly and renal dysfunction and is caused by congenital loss of glucose-6-phosphatase (G6Pase) expression. G6Pase is essential for the final step of gluconeogenesis and glycogenolysis, and its deficiency causes clinical hypoglycemia in the fasting state during infancy. Contrastingly, patients also show blood glucose trends and glucose intolerance similar to those in type II diabetes. Owing to the contrasting presentation of hypoglycemia with glucose intolerance, glucose control in patients remains a challenge, requiring management of both fasting hypoglycemia and post-prandial hyperglycemia.

Case Presentation: The patient was a 45-year old Asian (Japanese) woman who showed disease onset at 3 years of age, when hypoglycemia and hepatomegaly were observed, and GDS type Ia was diagnosed by the lack of G6Pase activity. Over the past 45 years, she presented hyperglycemia and dumping syndrome like symptoms (a feeling of fullness, even after eating just a small amount, abdominal cramping, nausea, sweating, flushing, or light-headedness and rapid heartbeat) at 2 hours after food intake. Her liver and kidney dysfunction also worsened over time. Treatment with exercise combined with a sodium-glucose co-transporter 2 inhibitor and an alpha glucosidase inhibitor alleviated her glucose intolerance and dumping syndrome-like symptoms, without increasing hypoglycemic events.

Conclusion: This case suggests SGLT2 inhibitor as a promising candidate for treating glucose intolerance in GSD type Ia without worsening of hypoglycemia.
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http://dx.doi.org/10.1186/s13256-020-02658-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885476PMC
February 2021

Involvement of Anoikis in Dissociated Optic Nerve Fiber Layer Appearance.

Int J Mol Sci 2021 Feb 9;22(4). Epub 2021 Feb 9.

Department of Ophthalmology, Osaka Medical College, Takatsuki-City 569-8686, Osaka, Japan.

Dissociated optic nerve fiber layer (DONFL) appearance is characterized by dimpling of the fundus when observed after vitrectomy with the internal limiting membrane (ILM) peeling in macular diseases. However, the cause of DONFL remains largely unknown. Optical coherence tomography (OCT) findings have indicated that the nerve fiber layer (NFL) and ganglion cells are likely to have been damaged in patients with DONFL appearance. Since DONFL appearance occurs at a certain postoperative period, it is unlikely to be retinal damage directly caused by ILM peeling because apoptosis occurs at a certain period after tissue damage and/or injury. However, it may be due to ILM peeling-induced apoptosis in the retinal tissue. Anoikis is a type of apoptosis that occurs in anchorage-dependent cells upon detachment of those cells from the surrounding extracellular matrix (i.e., the loss of cell anchorage). The anoikis-related proteins βA3/A1 crystallin and E-cadherin are reportedly expressed in retinal ganglion cells. Thus, we theorize that one possible cause of DONFL appearance is ILM peeling-induced anoikis in retinal ganglion cells.
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http://dx.doi.org/10.3390/ijms22041724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914697PMC
February 2021

Characteristics of Neurological Symptoms in Adult Japanese Patients with Fabry Disease.

Intern Med 2021 Jan 15. Epub 2021 Jan 15.

Division of Cardiology, Nephrology, Pulmonology, and Neurology, Department of Internal Medicine, Asahikawa Medical University, Japan.

Objective Fabry disease (FD) is a hereditary lysosomal storage disease that has been highlighted as a possible etiology of stroke at a young age and presents with other various neurological symptoms. Since FD is rare, limited information is currently available on the prevalence of neurological symptoms in Japanese patients with FD. Therefore, we examined the characteristics of neurological symptoms and brain magnetic resonance imaging (MRI) findings in adult Japanese patients with FD. Methods This was a retrospective, single-center study. We reviewed neurological symptoms and brain MRI findings in the medical records of 12 adult Japanese patients with FD diagnosed by a gene analysis of the α-galactosidase gene. Results Ten out of 12 patients with FD presented with the following neurological symptoms: acroparesthesia (n=6), headache (n=5) (migraine [n=4]), hypohidrosis (n=5), and cerebral infarction (n=3). Two and three of the patients with migraine were complicated by ischemic stroke and coronary spastic angina, respectively. Five and 10 patients presented with periventricular hyperintensity and deep white matter hyperintensity, respectively, on brain MRI. Two out of eight patients had cerebral microbleeds. Seven out of 11 patients had a dilated basilar artery diameter on magnetic resonance angiography. There were no patients with the pulvinar hyperintensity sign. Conclusion Patients with FD present with various neurological symptoms. Headache, particularly migraine, might be a major neurological symptom in patients with FD. Since migraine, ischemic stroke, and coronary spastic angina might occur together in FD, caution is needed when administering triptan to FD patients with migraine.
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http://dx.doi.org/10.2169/internalmedicine.6420-20DOI Listing
January 2021

Guide for diagnosis and treatment of hyperphenylalaninemia.

Pediatr Int 2021 Jan 10;63(1):8-12. Epub 2021 Jan 10.

Department of Pediatrics, The Jikei University, Tokyo, Japan.

Importance: Sapropterin hydrochloride, a natural coenzyme (6R-tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin-responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin-responsive hyperphenylalaninemia.

Observations: It is recommended that tetrahydrobiopterin-responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels.

Conclusions And Relevance: If tetrahydrobiopterin-responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required.
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http://dx.doi.org/10.1111/ped.14399DOI Listing
January 2021

The Predictive Value of Procalcitonin and High-Sensitivity C-Reactive Protein for Early Bacterial Infections in Preterm Neonates.

Neonatology 2021 16;118(1):28-36. Epub 2020 Dec 16.

Division of Neonatology, Perinatal Center, Kumamoto University Hospital, Kumamoto, Japan,

Introduction: Evidence on the reliability of using procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP) as diagnostic markers for early-onset neonatal bacterial infections is still insufficient because of their physiological elevation during the early neonatal period. This study aimed to assess the respiratory influence of serum PCT and hs-CRP levels and evaluate their predictive value for bacterial infections during the first 72 h of life in preterm neonates.

Methods: The preterm neonates enrolled in this single-center retrospective cohort study were categorized into 3 groups: reference, infection-unlikely respiratory failure, and probable bacterial infection; their serum PCT and hs-CRP levels were assessed. Subsequently, age-specific 95th percentile curves were plotted and the median and cutoff PCT and hs-CRP levels for predicting bacterial infections at birth and 7-18, 19-36, and 37-72 h after birth were determined. Moreover, the analysis of PCT and hs-CRP with a neonatal sequential organ failure assessment (nSOFA) score was performed in very low birth weight neonates.

Results: Serum PCT levels were influenced by respiratory failure. A significant difference was found in the median PCT and hs-CRP levels among the 3 groups at each time point. PCT sensitivities for predicting bacterial infection were slightly higher than those of hs-CRP in each time frame during the first 72 h of life. In both PCT and hs-CRP, there was no significant difference between infants with nSOFA scores of >4 and those with nSOFA scores of ≤4.

Discussion/conclusion: Age-specific evaluation showed that PCT has better predictive value than hs-CRP for early-onset bacterial infections in preterm neonates.
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http://dx.doi.org/10.1159/000512523DOI Listing
December 2020

Hepatoblastoma with multiple tumors in a school-aged child.

Clin Case Rep 2020 Nov 17;8(11):2314-2315. Epub 2020 Jul 17.

Department of Pediatrics Japanese Red Cross Kumamoto Hospital Kumamoto Japan.

Clinicians need to consider hepatoblastoma in the differential even in school-aged children or adolescents presenting with multiple liver tumors.
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http://dx.doi.org/10.1002/ccr3.3138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669406PMC
November 2020

Reversal of blood flow in deep cerebral vein in preterm intraventricular hemorrhage: two case reports.

BMC Pediatr 2020 11 11;20(1):517. Epub 2020 Nov 11.

Department of Pediatrics, Graduate School of Life Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, 860-8556, Kumamoto, Japan.

Background: Intraventricular hemorrhage during the early stage is a major complication in very low birth weight infants. Elevation of venous pressure is one of the contributing factors. The internal cerebral vein receives most of the venous flow from the subependymal germinal matrix, the most common site of origin of intraventricular hemorrhage. Recently, it has been reported that pulsatile or partially interrupted internal cerebral vein waveforms might also be risk factors for intraventricular hemorrhage in extremely low birth weight infants. Here, we report two cases of partially reversed internal cerebral vein flow with intraventricular hemorrhage. There are no published reports documenting this unique flow pattern.

Case Presentation: Between 2013 and 2020, we had in our neonatal intensive care unit two cases of very low birth weight infants (27 and 25 weeks of gestational age) who showed a partially reversed internal cerebral vein waveform pattern, which was recognized as a new blood flow pattern. Their internal cerebral vein flow patterns were continuously flat early after birth. They showed an intraventricular hemorrhage on the unilateral side with partially interrupted internal cerebral vein flow at 31 and 41 hours after birth (27- and 25-week-old neonates, respectively). Consecutively, their internal cerebral vein flow changed to a partially reversed pattern with intraventricular hemorrhage on the contralateral side at 43 and 87 hours after birth (27- and 25-week-old neonates, respectively). Their flow patterns improved by day 7. These partially reversed patterns were equivalent to triphasic venous flow, and the reverse flow corresponded to A- and V-waves.

Conclusion: In the two cases, the internal cerebral vein flow patterns were normal and flat before intraventricular hemorrhage and changed to a severe flow pattern (partially interrupted or reversed flow) at the same time as the detection of intraventricular hemorrhage. After the development of intraventricular hemorrhage, they improved. These cases indicate that a partially reversed or interrupted internal cerebral vein flow pattern may be derived from central venous pressure elevation and related to intraventricular hemorrhage in very low birth weight infants, however, it is difficult to determine when this flow pattern occurs in relation to intraventricular hemorrhage.
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http://dx.doi.org/10.1186/s12887-020-02414-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656756PMC
November 2020

Adrenocorticotropic Hormone Therapy Improved Spasms and Sleep Disturbance in Smith-Magenis Syndrome: A Case Report.

Pediatr Rep 2020 Oct 24;12(3):72-76. Epub 2020 Oct 24.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

Smith-Magenis syndrome (SMS) is a complex disorder characterized by variable mental retardation, sleep disturbances, craniofacial and skeletal anomalies, self-injurious and attention-seeking behaviors, and speech and motor delays. The case of a 14-month-old girl with SMS who was experiencing spasm clusters and sleep disturbances with sleep-wake intervals of 1.5 to 2 h persisting from the neonatal period was examined. The patient's spasms stopped and interictal electroencephalography did not show epileptic discharges after undergoing a high-dose adrenocorticotropic hormone (ACTH) therapy. Moreover, the patient's sleep cycle stabilized 1 month after receiving the ACTH therapy. Dramatic reductions in the patient's self-injurious behaviors were also noted. At 1 year following ACTH treatment, the patient's improved sleep was maintained. High-dose ACTH treatment was considered to contribute to the normal adaptation of the hypothalamic-pituitary-adrenal axis by regulating the release of corticotropin-releasing hormone, resulting in improvement of the patient's infantile spasms and sleep disturbances.
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http://dx.doi.org/10.3390/pediatric12030018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717653PMC
October 2020

Effect of Flunarizine on Alternating Hemiplegia of Childhood in a Patient with the p.E815K Mutation in ATP1A3: A Case Report.

Case Rep Neurol 2020 Sep-Dec;12(3):299-306. Epub 2020 Sep 18.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Alternating hemiplegia of childhood (AHC) (MIM 104290) is characterized by transient repeated attacks of paresis on either or both sides of the body, oculomotor and autonomic abnormalities, movement disorders, and cognitive impairment. Preventing paroxysmal attacks, such as paresis and spasm, in patients with AHC is often difficult. An 8-month-old girl presented to our institution with intractable epilepsy. She developed AHC, with left-right alternating or bilateral recurrent plegia upon waking, involuntary movements, eye movement abnormalities, and psychomotor retardation. She had a heterozygous de novo p.E815K mutation in the gene. Patients with this mutation develop severe hemiplegic spells and convulsions, have a poor neuromotor developmental outcome, and are particularly difficult to treat. Flunarizine treatment has limited therapeutic effect in such patients; however, it was definitely effective for bulbar palsy in the present case. The present case further highlights the need for the development of other new treatments, such as a ketogenic diet.
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http://dx.doi.org/10.1159/000509287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548950PMC
September 2020

Newborn Screening for Pompe Disease.

Int J Neonatal Screen 2020 Jun 5;6(2):31. Epub 2020 Apr 5.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.S.); (K.N.).

Glycogen storage disease type II (also known as Pompe disease (PD)) is an autosomal recessive disorder caused by defects in α-glucosidase (AαGlu), resulting in lysosomal glycogen accumulation in skeletal and heart muscles. Accumulation and tissue damage rates depend on residual enzyme activity. Enzyme replacement therapy (ERT) should be started before symptoms are apparent in order to achieve optimal outcomes. Early initiation of ERT in infantile-onset PD improves survival, reduces the need for ventilation, results in earlier independent walking, and enhances patient quality of life. Newborn screening (NBS) is the optimal approach for early diagnosis and treatment of PD. In NBS for PD, measurement of AαGlu enzyme activity in dried blood spots (DBSs) is conducted using fluorometry, tandem mass spectrometry, or digital microfluidic fluorometry. The presence of pseudodeficiency alleles, which are frequent in Asian populations, interferes with NBS for PD, and current NBS systems cannot discriminate between pseudodeficiency and cases with PD or potential PD. The combination of gene analysis with NBS is essential for definitive diagnoses of PD. In this review, we introduce our experiences and discuss NBS programs for PD implemented in various countries.
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http://dx.doi.org/10.3390/ijns6020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423004PMC
June 2020

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II.

Mol Ther 2021 02 30;29(2):671-679. Epub 2020 Sep 30.

JCR Pharmaceuticals, Ashiya 659-0021, Japan. Electronic address:

Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.
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http://dx.doi.org/10.1016/j.ymthe.2020.09.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854283PMC
February 2021

Involvement of the Retinal Pigment Epithelium in the Development of Retinal Lattice Degeneration.

Int J Mol Sci 2020 Oct 5;21(19). Epub 2020 Oct 5.

Department of Ophthalmology, Osaka Medical College, Takatsuki-City, Osaka 569-8686, Japan.

Lattice degeneration involves thinning of the retina that occurs over time. Here we performed an immunohistological study of tissue sections of human peripheral retinal lattice degeneration to investigate if retinal pigment epithelium (RPE) cells are involved in the pathogenesis of this condition. In two cases of retinal detachment with a large tear that underwent vitreous surgery, retinal lattice degeneration tissue specimens were collected during surgery. In the obtained specimens, both whole mounts and horizontal section slices were prepared, and immunostaining was then performed with hematoxylin and antibodies against glial fibrillary acidic protein (GFAP), RPE-specific protein 65 kDa (RPE65), pan-cytokeratin (pan-CK), and CK18. Hematoxylin staining showed no nuclei in the center of the degenerative lesion, thus suggesting the possibility of the occurrence of apoptosis. In the degenerative lesion specimens, GFAP staining was observed in the center, RPE65 staining was observed in the slightly peripheral region, and pan-CK staining was observed in all areas. However, no obvious CK18 staining was observed. In a monkey retina used as the control specimen of a normal healthy retina, no RPE65 or pan-CK staining was observed in the neural retina. Our findings suggest that migration, proliferation, and differentiation of RPE cells might be involved in the repair of retinal lattice degeneration.
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http://dx.doi.org/10.3390/ijms21197347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583762PMC
October 2020

Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

Mol Genet Genomic Med 2020 11 5;8(11):e1502. Epub 2020 Oct 5.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Background: In Japan, newborn and high-risk screening for Fabry disease (FD), an inherited X-linked disorder caused by GLA mutations, using dried blood spots was initiated in 2006. In newborn screening, 599,711 newborns were screened by December 2018, and 57 newborns from 54 families with 26 FD-associated variants were detected. In high-risk screening, 18,235 individuals who had symptoms and/or a family history of FD were screened by March 2019, and 236 individuals from 143 families with 101 FD-associated variants were detected. Totally 3, 116 variants were detected; 41 of these were not registered in Fabry-database.org or ClinVar and 33 were definitely novel. Herein, we report the clinical outcomes and discuss the pathogenicity of the 41 variants.

Methods: We traced nine newborns and 46 individuals with the 33 novel variants, and nine newborns and 10 individuals with eight other variants not registered in the FD database, and analyzed the information on symptoms, treatments, and outcomes.

Results: Thirty-eight of the 46 individuals with the 33 novel variants showed symptoms and received enzyme-replacement therapy and/or chaperone treatment.

Conclusion: Delayed diagnosis should be avoided in patients with FD. Our results will help clinicians diagnose FD and determine the appropriate treatment for patients with these variants.
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http://dx.doi.org/10.1002/mgg3.1502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667298PMC
November 2020

Fabry disease screening in high-risk populations in Japan: a nationwide study.

Orphanet J Rare Dis 2020 08 26;15(1):220. Epub 2020 Aug 26.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto City, Kumamoto, 860-8556, Japan.

Background: Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed. Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan. A total of 601 hospitals participated in this study.

Results: Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment.

Conclusions: From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.
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http://dx.doi.org/10.1186/s13023-020-01494-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448968PMC
August 2020

Role of induced pluripotent stem cells in lysosomal storage diseases.

Mol Cell Neurosci 2020 10 21;108:103540. Epub 2020 Aug 21.

Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan. Electronic address:

Lysosomal storage diseases (LSDs) are a group of metabolism inborn errors caused by defective enzymes in the lysosome, resulting in the accumulation of undegraded substrates. Many characteristic cell features have been revealed in LSDs, including abnormal autophagy and mitochondrial dysfunction. The development of induced pluripotent stem cells (iPSCs) dramatically boosted research on LSDs, particularly regarding novel opportunities to clarify the disease etiology based on the storage of macromolecules, such as sphingolipids in lysosomes. iPSCs made from LSD patients (LSD-iPSCs) have been differentiated into neurons, endothelial cells, cardiomyocytes, hepatocytes, and macrophages, with each cell type closely resembling the primary disease phenotypes, providing new tools to probe the disease pathogenesis and to test therapeutic strategies. Abnormally accumulated substrates impaired autophagy and mitochondrial and synapse functions in LSD-iPSC-derived neurons. Reducing the accumulation with the treatment of drug candidates improved LSD-iPSC-derived neuron functions. Additionally, iPSC technology can help probe the gene expressions, proteomics, and metabolomics of LSDs. Further, gene repair and the generation of new mutations in causative genes in LSD-iPSCs can be used to understand both the specific roles of causative genes and the contributions of other genetic factors to these phenotypes. Moreover, the development of iPSC-derived organoids as disease models has bridged the gap between studies using cell lines and in vivo animal models. There are some reproducibility issues in iPSC research, however, including genetic and epigenetic abnormalities, such as chromosomal abnormalities, DNA mutations, and gene modifications via methylation. In this review, we present the disease and treatment concepts gathered using selected LSD-iPSCs, discuss iPSC research limitations, and set our future research visions. Such studies are expected to further inform and generate insights into LSDs and are important in research and clinical practice.
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http://dx.doi.org/10.1016/j.mcn.2020.103540DOI Listing
October 2020

Retrospective evaluations revealed pre-symptomatic citrulline concentrations measured by newborn screening were significantly low in late-onset ornithine transcarbamylase deficiency patients.

Clin Chim Acta 2020 Nov 20;510:633-637. Epub 2020 Aug 20.

Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan.

Introduction: Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Late-onset OTCD manifests after the neonatal period; therefore, if pre-symptomatic diagnosis and treatment are performed, it can improve the prognosis by preventing hyperammonemia. However, pre-symptomatic diagnosis is unreliable as the specific screening marker of OTCD has not been established yet. This retrospective study aimed to evaluate the pre-symptomatic blood citrulline levels in patients with late-onset OTCD.

Methods: Patients with late-onset OTCD who were born after the newborn screening based on tandem mass spectrometry (MS/MS-NBS) was started and were referred to Hyogo College of Medicine Hospital between 2014 and 2018 were included. Pre-symptomatic blood citrulline levels measured by MS/MS-NBS were retrospectively evaluated.

Results: Four patients were included in this study. The pre-symptomatic blood citrulline levels were 2.02, 4.50, 4.97, and 3.75 µmol/l, respectively. Compared with the citrulline levels in all newborns in Hyogo prefecture, these values were significantly low.

Conclusions: These results suggest the possibility that hypocitrullinemia detected by the MS/MS-NBS can be used as a screening marker for some patients with late-onset OTCD. Further retrospective evaluation of pre-symptomatic citrulline levels in patients with late-onset OTCD, as well as prospective monitoring of hypocitrullinemia on the MS/MS-NBS should be conducted.
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http://dx.doi.org/10.1016/j.cca.2020.08.027DOI Listing
November 2020

Successful Artery Embolization in a Patient with Autoimmune Lymphoproliferative Syndrome Associated with Splenic Rupture.

J Clin Immunol 2020 07 25;40(5):780-782. Epub 2020 Jun 25.

Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

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http://dx.doi.org/10.1007/s10875-020-00809-3DOI Listing
July 2020

Pharmacokinetics and pharmacodynamics of JR-051, a biosimilar of agalsidase beta, in healthy adults and patients with Fabry disease: Phase I and II/III clinical studies.

Mol Genet Metab 2020 07 1;130(3):215-224. Epub 2020 May 1.

Advanced Clinical Research Centre & Asian Lysosome Storage Disorder Centre, Institute of Neurological Disorders, Japan.

Fabry disease is a rare X-linked lysosomal disease, in which mutations in the gene encoding α-galactosidase A result in progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs including the skin, kidney, and heart, often leading to life-threatening conditions. Enzyme replacement therapy is currently the standard therapy for the disease, to which two α-galactosidase A formulations have been approved: agalsidase α (Replagal®, Shire) and agalsidase β (Fabrazyme®, Sanofi). We have recently developed a biosimilar of agalsidase β, JR-051, and investigated its pharmacokinetics and pharmacodynamics to assess its bioequivalence to agalsidase β. In a randomized phase I study, healthy adult male volunteers were treated with JR-051 or agalsidase β and the pharmacokinetics of the drugs were compared. The ratio of geometric means (90% confidence interval [CI]) of the AUC and C for JR-051 over agalsidase β were 0.91 (0.8294, 1.0082) and 0.90 (0.7992, 1.0125), respectively. In a 52-week, single-arm, phase II/III study, patients with Fabry disease switched therapy from agalsidase β to JR-051 to evaluate its pharmacodynamics. The mean (95% CI) plasma GL-3 concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.03 (0.91, 1.15) and 0.96 (0.86, 1.06), respectively, which were within the pre-determined bioequivalence acceptance range (0.70, 1.43). The mean (95% CI) plasma globotriaosylsphingosine (lyso-GL-3) concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.07 (0.92, 1.23) and 1.13 (1.03, 1.22), respectively. Estimated glomerular filtration rate and left ventricular mass index, as renal and cardiac function indicators, showed no notable changes from baseline throughout the study period, and no new safety concerns were identified. In conclusion, these studies demonstrated bioequivalence of JR-051 to agalsidase β in terms of its pharmacokinetics and pharmacodynamics. JR-051 offers a potential new treatment option for patients with Fabry disease.
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http://dx.doi.org/10.1016/j.ymgme.2020.04.003DOI Listing
July 2020

New reference ranges of procalcitonin excluding respiratory failure in neonates.

Pediatr Int 2020 Oct 30;62(10):1151-1157. Epub 2020 Sep 30.

Division of Neonatology, Perinatal Center, Kumamoto University Hospital, Kumamoto, Japan.

Background: Existing reference data on serum procalcitonin (PCT) in neonates include the effects of respiratory disorders commonly occurring during birth. We aimed to determine new 95% reference intervals in neonates after excluding the influence of respiratory failure at birth, and to investigate the effects of gestational age (GA) and respiratory condition at birth on postnatal transient serum PCT elevation.

Methods: Samples were obtained from term and preterm neonates during the first 3 days of life. Neonates were classified into reference, respiratory failure, and bacterial infection groups. In the reference group, the correlation between PCT level and GA was investigated.

Results: The median PCT level within the 95% range 12-36 h after birth was 1.05 ng/mL (0.14-4.39) in term neonates (143 samples) and 1.01 ng/mL (0.15-4.44) in preterm neonates (95 samples). There was no correlation between GA and serum PCT level during 1-48 h after birth. There was a significant difference in median serum PCT level during 12-36 h after birth between the respiratory failure (9.56 ng/mL) and bacterial infection (49.82 ng/mL) groups in preterm neonates but no difference between term neonates (respiratory failure 6.83 ng/mL, and bacterial infection 7.43 ng/mL).

Conclusions: Respiratory failure is the main effector for the transient elevation in serum PCT levels at 3 days of life. After excluding the influence of respiratory failure, the chronological pattern and range were very similar between term and preterm neonates. Procalcitonin can be useful for clinicians in distinguishing bacterial infection from respiratory failure, aiding decisions on appropriate antibiotic use.
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http://dx.doi.org/10.1111/ped.14282DOI Listing
October 2020

The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago.

J Hum Genet 2020 Jul 3;65(7):619-625. Epub 2020 Apr 3.

Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.
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http://dx.doi.org/10.1038/s10038-020-0745-7DOI Listing
July 2020

Carglumic Acid Contributes to a Favorable Clinical Course in a Case of Severe Propionic Acidemia.

Case Rep Pediatr 2020 9;2020:4709548. Epub 2020 Mar 9.

Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Propionic acidemia (PA) is manifested as an abnormal accumulation of propionic acid and its metabolites, including methylcitrate, 3-hydroxypropionic acid, and propionylglycine, and is caused by a defect of propionyl-CoA carboxylase. PA is complicated by acute life-threatening metabolic crises, which are precipitated by a catabolic state and result in multiple organ failure or even death, if untreated. A neonate with PA recovered from the first metabolic crisis 3 days after birth but developed a second metabolic crisis during the recovery phase. This patient was considered to have severe PA and was accordingly given carglumic acid treatment in combination with carnitine supplementation and protein restriction, which was expected to prevent a recurrent metabolic attack. The patient did not develop hyperammonemia after receiving carglumic acid and was never hospitalized. Moreover, she did not present with acidosis even during viral infection. At 26 months of age, she led a stable life while receiving carglumic acid and regular rehabilitation. Carglumic acid treatment in combination with carnitine supplementation and protein restriction prevented metabolic decompensation, which would have otherwise required hospitalization, and resulted in improved quality of life and developmental outcomes.
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http://dx.doi.org/10.1155/2020/4709548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085357PMC
March 2020