Human Biochemical Genetics

人类生物化学遗传学部分研究选定的先天性代谢错误和其他遗传疾病，以深入了解细胞机制并照顾被忽视的罕见疾病患者群体。1. 在过去的一年中，该部门评估了40例肾病型胱氨酸病患者，记录了口服和局部半胱胺在生长、肾功能、晚期并发症和眼部异常方面的有益效果。他们在肾病学家和胱氨酸病倡导团体的国家和国际会议上发表了讲话，并为GeneReviews更新了关于胱氨酸病的权威综述。该科作为该疾病的国际权威机构，每年答复世界各地患者和医生提出的数十项询问。2. 本节还跟踪患有尿酸症的患者，这是由于缺乏均质酸1,2-双加氧酶导致的均质酸积累紊乱。今年，该科的成员报告了致病基因HGD的新创始突变。3. 该科仍然是世界上唯一一个研究Hermansky-Pudlak综合征（HPS）临床和基础方面的中心。HPS是一种罕见的皮肤白化病和出血疾病，由于细胞内囊泡的异常形成，包括黑素细胞中的黑素体和血小板中的致密体。今年，成员们报告了一种新的HPS6突变，并合作发表了一篇论文，证明了HPS肥大细胞的异常；肥大细胞的嗜碱性颗粒是溶酶体样细胞器。他们还描述了一名患有极其罕见的HPS-7亚型的11岁男孩，并描述了与HPS肺纤维化肺移植相关的临床问题。科专家向世界各地的医生和患者提供建议，并为倡导团体、科学家和医生的hps相关会议做出贡献。4. 一项正在进行的临床方案调查常染色体隐性多囊肾病和先天性肝纤维化（ARPKD/CHF）和其他纤毛病，以确定这些疾病的自然历史和分子基础；超过200个这样的病人在这项研究中被评估。今年，该小组描述了一名由于KIAA0586基因突变而患有两种不同纤毛病（Joubert综合征和Jeune综合征）重叠特征的儿童。另一个病例涉及囊性小脑发育不良、强迫行为和近视，这些与细胞粘附缺陷、细胞迁移受损和LAMA1双等位基因突变有关。最后，我们描述了一个在TMEM231中经历了基因转换的Joubert综合征和Meckel-Gruber综合征家族。该科成员是ARPKD/CHF和其他纤毛病临床方面的国家权威。5. 切片科学家继续研究Chediak-Higashi病（CHD），这是一种巨大细胞内颗粒的疾病。在经典疾病中，受感染的婴儿死于细菌感染；幸存者后来患上淋巴细胞组织细胞增多症，除非接受骨髓移植治疗，否则是致命的。今年，该科成员与NIAID研究人员合作，对冠心病患者自然杀伤细胞中溶解颗粒的胞吐和细胞因子的分泌进行了表征。在一项广泛的临床调查中，他们还描述了轻度非典型冠心病患者的神经系统并发症。6. 一名科研究员管理着一项临床协议，该协议跟踪了数十名白化病患者；他是处理这种疾病的国家权威。7. 鞘糖脂储存障碍单位对Tay-Sachs病和Sandhoff病以及GM1神经节脂质沉积症进行临床和转化研究。利用来自患者的iPS细胞的脑类器官作为模型系统，该小组正在测试基因疗法和小分子来减轻这些致命的溶酶体贮积病。8. 科研究者仍然是世界上唾液酸代谢紊乱的专家。唾液酸合成的限速步骤是由双功能酶GNE催化的。双等位基因GNE突变的患者会发生GNE肌病，这是一种由唾液酸缺乏引起的迟发性神经肌肉疾病，因此，n -连接糖蛋白的唾液化受损；一种这样的蛋白质是α -糖酐。该科成员进行了一项自然史研究，以确定GNE肌病中肌肉疾病的进展，作为与治疗干预措施比较的基线。第二个方案是临床试验。1b期研究确定了唾液酸前体n -乙酰甘露糖胺（ManNAc）在人体中的最佳给药方案和安全性。第二个是一项安慰剂对照的疗效和安全性研究，使用肌肉力量作为结果测量，并使用一种新的疾病进展模型进行数据分析。这项工作是与国家促进转化科学中心和一家公司合作进行的，Escala；已经与FDA进行了两次面对面的会议，以计划一项关键的注册研究。该科主任持有ManNAc的研究新药豁免。9. 该科成员还领导NIH未确诊疾病计划（UDP），该计划目前由共同基金支持，作为UDPs网络，拥有7个临床站点，一个协调中心，两个测序中心，一个生物库，一个模型系统核心和一个代谢组学核心。这一举措是精准医学的典范，旨在为患有长期无法诊断的神秘疾病的患者提供答案，并推动医学知识的发展。校内UDP由该科成员指导，根据其8年的经验，审查3500多份医疗记录，评估1000多名患者，诊断约200种罕见和新型疾病，为未确诊疾病网络（UDN）提供指导。该科成员担任联盟指导委员会联合主席、不同工作组主席和《业务手册》作者。在过去的一年里，他们举办了超过15次关于UDP的国内和国际会谈，组织了两次国际会议，并创建了一个未确诊疾病国际网络，用于共享表型和序列数据。他们还发表了一些论文，描述了由于CHST14突变导致的ehers - danlos综合征、由于AVPR2的新剪接位点突变导致的x连锁尿崩症、由于PLA2G6突变导致的神经变性、由于ALG1突变导致的蛋白质糖基化缺陷、有丝分裂基因内重组作为先天性糖基化疾病的生存机制、由于易位破坏TCF4导致的常染色体显性智力残疾、痉挛性截瘫与UNC80突变有关。过程相关的出版物描述了UDP基因型和表型信息数据库（UDPICS），这是一个新的软件程序，利用模型生物数据来帮助确定具有独特表型的患者的候选基因变异的优先级，以及UDP患者的药物基因组学发现。该部门的UDP领导人还撰写了关于该计划以及分子遗传学和代谢的国家和国际网络，美国医学会杂志和尼尔森儿科教科书的评论。该科还调查其他罕见病。今年，他们合作报道了一名伊朗患者SERPINA7突变导致的甲状腺素结合球蛋白缺乏症、DGAT1突变导致的蛋白质丧失性肠病、与组织细胞肿瘤相关的激酶基因的体突变、婴儿全身性动脉钙化患者的低磷血症佝偻病的治疗以及RAI1新生突变导致的Smith-Magenis综合征。最后，研究人员描述了世界上最大的NGLY1突变患者群体。

The Section on Human Biochemical Genetics studies selected inborn errors of metabolism and other genetic disorders to gain insight into cellular mechanisms and to care for neglected groups of rare disease patients. 1. In the past year, the Section evaluated 40 individuals with nephropathic cystinosis, documenting the beneficial effects of oral and topical cysteamine with respect to growth, renal function, late complications, and ophthalmic abnormalities. They addressed national and international meetings of nephrologists and cystinosis advocacy groups and updated the authoritative review on cystinosis for GeneReviews. The Section serves as an international authority on the disease, responding to scores of inquiries every year from patients and physicians throughout the world. 2. The Section also follows patients with alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. This year, members of the Section reported a new founder mutation in the causative gene, HGD. 3. The Section remains the only center in the world investigating the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles, including melanosomes in melanocytes and dense bodies in platelets. This year, members reported a novel HPS6 mutation and collaborated on a paper that demonstrated abnormalities in HPS mast cells; the basophilic granules of mast cells are lysosome-like organelles. They also characterized an 11 year-old boy with the extremely rare HPS-7 subtype, and described clinical issues associated with lung transplantation for HPS pulmonary fibrosis. Section experts provide advice to physicians and patients throughout the world and contribute to HPS-related meetings of advocacy groups, scientists, and physicians. 4. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF) and other ciliopathies, to define the natural history and molecular bases of these disorders; over 200 such patients have been evaluated in this study. This year, the group described a child with overlapping features of two different ciliopathies, Joubert syndrome and Jeune syndrome, due to mutations in KIAA0586. Another case involved cystic cerebellar dysplasia, obsessive-compulsive behavior, and myopia associated with defects in cell adhesion, impaired cellular migration, and biallelic mutations in LAMA1. Finally, a family with Joubert syndrome and Meckel-Gruber syndrome was described that had undergone gene conversion in TMEM231. Members of the Section serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 5. Section scientists continue to investigate Chediak-Higashi disease (CHD), a disorder of giant intracellular granules. In the classic disease, affected infants succumb to bacterial infections; survivors later suffer from a lymphocytic histiocytosis that is fatal unless treated with a bone marrow transplant. This year, members of the Section collaborated with NIAID investigators to characterize exocytosis of lytic granules and cytokine secretion in natural killer cells of CHD patients. In an extensive clinical investigation, they also described the neurological complications in patients with mild, atypical CHD. 6. One Section investigator manages a clinical protocol that follows scores of patients with albinism; he serves as the nations authority on this disorder. 7. The Unit on Glycosphingolipid Storage Disorders performs clinical and translational studies on Tay-Sachs and Sandhoff diseases and GM1 gangliosidosis. Using cerebral organoids from patient-derived iPS cells as a model system, the Unit is testing gene therapy and small molecules to mitigate these uniformly fatal lysosomal storage diseases. 8. Section investigators remain world experts in disorders of sialic acid metabolism. The rate-limiting step in sialic acid synthesis is catalyzed by GNE, a bifunctional enzyme. Patients with biallelic GNE mutations develop GNE myopathy, a late-onset neuromuscular disorder due to deficiency of sialic acid and, consequently, impaired sialylation of N-linked glycoproteins; one such protein is alpha-dystroglycan. Members of the Section conduct a natural history study to define the progression of muscle disease in GNE myopathy as a baseline for comparison with therapeutic interventions. A second protocol is a clinical trial. Phase 1b determined the optimal dosing schedule and safety of the sialic acid precursor, N-acetylmannosamine (ManNAc) in humans. The second is a placebo-controlled efficacy and safety study using muscle strength as an outcome measure, and a novel Disease Progression Model for data analysis. This work is being performed in collaboration with the National Center for Advancing Translational Sciences and with a company, Escala; there have been two in-person meetings with the FDA to plan a pivotal registration study. The Section Head holds the Investigational New Drug exemption for ManNAc. 9. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), now supported by the Common Fund as a Network of UDPs with 7 Clinical Sites, a Coordinating Center, two Sequencing Centers, a biorepository, a model systems core, and a metabolomics core. This initiative, which serves as a model for Precision Medicine, aims to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge. The Intramural UDP, directed by members of the Section, provides guidance to the Undiagnosed Diseases Network (UDN) based upon its 8 years of experience reviewing more than 3500 medical records, evaluating more than 1000 patients, and diagnosing approximately 200 rare and novel disorders. Members of the Section serve as Co-Chair of the UDN Steering Committee, chairs of different working groups, and authors of the Manual of Operations. This past year they delivered more than 15 national and international talks on the UDP, organized two international meetings, and created an Undiagnosed Diseases Network International for sharing phenotypic and sequence data. They also contributed to papers describing patients with Ehlers-Danlos syndrome due to CHST14 mutations, X-linked diabetes insipidus due to a novel splice site mutation in AVPR2, neurodegeneration due to PLA2G6 mutations, protein glycosylation defects due to mutations in ALG1, mitotic intragenic recombination as a survival mechanism for Congenital Disorders of Glycosylation, autosomal dominant intellectual disability due to a translocation disrupting TCF4, and spastic paraplegia associated with mutations in UNC80. Process-related publications described the UDPs database for genotypic and phenotypic information (UDPICS), a new software program that harnesses model organism data to help prioritize candidate gene variants in patients with unique phenotypes, and pharmacogenomic findings in UDP patients. The Sections UDP leaders also wrote reviews on the Program and on the national and international Networks in Molecular Genetics and Metabolism, JAMA, and the Nelson Textbook of Pediatrics. 10. The Section also investigates other rare diseases. This year, they collaborated on a report of thyroxine-binding globulin deficiency due to a SERPINA7 mutation in an Iranian patient, protein losing enteropathy due to DGAT1 mutations, somatic mutations in kinase genes associated with histiocytic neoplasms, treatment of hypophosphatemic rickets in a patient with Generalized Arterial Calcification of Infancy, and Smith-Magenis syndrome due to a de novo mutation in RAI1. Finally, Section investigators described the largest group of patients in the world with mutations in NGLY1.