Language：English   Publisher：(一社)インターナショナルハートジャーナル刊行会  

症例は18歳男性で、精神運動発達遅滞の既往があった。労作時呼吸困難を主訴に近医を受診し、急性非代償性心不全と診断された。心不全はうっ血および低灌流所見を認めるwet-cold型であった。強心剤と利尿剤が投与されたが症状が改善せず、心原性ショックを呈したため、当院に搬送された。搬送時の血圧は84/70mmHg、心拍数は134bpmであった。胸部X線で肺うっ血を認め、心胸比は69%であった。心エコー検査で左室拡張末期径は69mmで、左室駆出率は16%であった。心臓カテーテル検査で肺動脈楔入圧は28mmHg、心係数は1.8L/min/m2であった。心内膜心筋生検で心筋症を認めた。難治性心原性ショックに対して植込み型補助人工心臓(LVAD)の植込み術を施行した。4日後に意識消失し、代謝性アシドーシスと高アンモニア血症を認めた。タンデムマス法でプロピオニルカルニチン(C3)の増加を認め、遺伝学的検査でPCCA遺伝子変異が検出された。プロピオン酸血症と診断し、栄養療法とカルベジロールを含む薬物療法を開始した。心機能は徐々に改善し、118日後にLVADから離脱した。左室駆出率は45%に増加し、173日後に退院となった。

Language：Japanese   Publisher：(一社)日本遺伝カウンセリング学会  

親から子に遺伝性をどのように伝えるかということは重要なテーマである。本研究では,学生が親の遺伝情報を知ることに対する意向を性格特性との関連性を含めて明らかにすることを目的とした。九州大学学部生を対象として,遺伝情報を知ることに関するアンケート調査を実施した。326名から回答が得られ,治療法あり/なし,いずれの遺伝性疾患の場合でも,約85%が遺伝について知らせてほしいと回答したが,治療法ありの場合の方が96.0%と有意に高かった。知らされたとき,82.8%が短期的には「不安になると思う」を選択したが,80.2%は長期的には「受け入れられると思う」を選択した。86.8%は治療法のある場合には「成人するまでに」知らせてほしいと回答した。性格特性との普通～強い関連性は示されなかった。学生は性格特性に強くは関係せず,成人するまでの間に遺伝について知らせてほしいと考えていることが示唆された。(著者抄録)

Language：Japanese   Publisher：(一社)日本内分泌学会  

Publisher：Clinical and Experimental Immunology  

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2–47 years, 12 males) and 22 controls (age 4–40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, P = 0.00731) and oxidative phosphorylation (hsa00190, P = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.

DOI： 10.1093/cei/uxae048

Scopus

Publisher：Molecular Genetics and Genomic Medicine  

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

DOI： 10.1002/mgg3.2427

Scopus

Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(公社)日本小児科学会  

Language：English   Publisher：European Journal of Medical Genetics  

Predictive genetic testing (PT) for hereditary diseases that do not have effective treatment or prevention strategies places a psychological burden on parties and their families. There has been little research on the psychosocial aspects of PT in Japan, nor are there any guidelines. To address this gap, we conducted a questionnaire survey of parties at genetic risk for untreatable hereditary neuromuscular diseases, and the National Liaison Conference of Genetic Medicine Departments (GMDs). Of the 63 parties who responded to the survey, 10 (15.9%) had undergone PT. Of the 67 GMDs, only 18 facilities (26.9%) were conducting PT with written procedures. At least two of the six parties with such results felt that some follow-up would be helpful. One party had taken PT for preimplantation genetic testing for monogenic (PGT-M); four, who had no experience, provided free text responses indicating that PGT-M or prenatal genetic testing was chosen as a motivation. Eight were unaware of PT, and six were unaware of their blood relatives’ diseases being “hereditary.” The results highlighted the need to: 1) develop guidelines for PT in untreatable hereditary diseases; 2) provide access to PT information; and 3) share the “heritability” of diseases with family and relatives.

DOI： 10.1016/j.ejmg.2022.104667

Web of Science

Scopus

PubMed

Web of Science

Language：Japanese   Publisher：(一社)日本先天代謝異常学会  

Publisher：Frontiers in Pediatrics  

Background: Juvenile myelomonocytic leukemia (JMML), which is predominantly found in infants, is a clonal abnormality of pluripotent hematopoietic stem cells and presents with the symptoms of both myeloproliferative tumors and myelodysplastic syndromes. Estimates have shown that ~20 cases of JMML occur annually in Japan. Ornithine transcarbamylase deficiency (OTCD), the most common among all urea cycle disorders (UCDs), occurs in 1 of 80,000 people in Japan. Case Presentation: A 10-month-old infant who had fever, vomiting, and diarrhea for 2 days was referred to our hospital for the following abnormalities in blood tests: white blood cell count, 48,200/μL; hemoglobin, 9.0 g/dL; and platelet count, 135,000/μL. Bone marrow examination showed a nucleated cell count of 396,000/mm³ and blast cell count of 5.0%, as well as decreased mature granulocyte count and slightly myeloperoxidase stain-negative blasts but no monoclonal cell proliferation on May–Giemsa staining. Colony assay showed the proliferation of spontaneous colony and high sensitivity to granulocyte-macrophage colony-stimulating factor. Genetic analysis of peripheral blood mononuclear cells showed that the patient was positive for neuroblastoma RAS (NRAS) mutation. The patient was ultimately diagnosed with JMML. Approximately 170 days after his first hematopoietic stem cell transplantation (HSCT), the patient's JMML relapsed. Shortly after the recurrence, nausea, vomiting, hyperventilation, and decreased vitality were observed, followed by a decrease in the level of consciousness. The patient's ammonia level was 472 μmol/L. A test for seven different genetic mutations for the UCD showed the presence of c. 119G>A (amino acid change p. Arg40His). As such, late-onset OTCD was added to his diagnosis. Administration of sodium phenylacetate, l-arginine hydrochloride, and carnitine was continued following the diagnosis of OTCD, after which hyperammonemia was not observed. Regarding JMML relapse, HSCT was performed on day 405 after the first transplantation. Conclusion: Hyperammonemia should be considered a differential diagnosis when unexplained and non-specific symptoms occur during the treatment of hematologic malignancies. Patients should be tested for UCD as a cause of hyperammonemia, and treatment for hyperammonemia should be continued until the cause is identified. The patient shows normal developmental progress, has an intact neurological status, and has not experienced another hyperammonemia attack. His JMML has remained in remission for over 3 years.

DOI： 10.3389/fped.2022.898531

Scopus

Publisher：Journal of Inherited Metabolic Disease  

Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age-dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult-onset type II citrullinemia (CTLN2). As a nationwide study to investigate the clinical manifestations, medical therapy, and long-term outcome in Japanese patients with citrin deficiency, we collected clinical data of 222 patients diagnosed and/or treated at various different institutions between January 2000 and December 2019. In the entire cohort, 218 patients were alive while 4 patients (1 FTTDCD and 3 CTLN2) had died. All patients <20 years were alive. Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. This study reports the diagnosis and clinical course in a large cohort of patients with citrin deficiency and suggests that early intervention including a low carbohydrate diet and MCT supplementation can be associated with improved clinical course and long-term outcome.

DOI： 10.1002/jimd.12483

Scopus

Web of Science

Publisher：Pediatrics International  

Background: Infantile-onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS-identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan. Methods: Acid alpha-glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next-generation followed by Sanger-method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)-amplified products (patient 2) of the GAA gene. Results: A female infant identified by NBS had a novel out-of-frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross-reactive immunological material (CRIM)-negative genotype, and developed a high titer of anti-rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT. Conclusions: Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM-negative cases may hamper turnaround time reduction.

DOI： 10.1111/ped.15286

Scopus

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese