Human Biochemical Genetics

人类生化遗传学部分研究代谢和其他遗传疾病的先天性错误，以深入了解细胞机制并照顾被忽视的罕见疾病患者。该科以各种方式实现这些目标。1. 科专家调查、诊断和治疗许多特定的疾病。在过去的一年里，该科继续为肾病胱氨酸病服务了40年，为世界各地的患者、医生和倡导团体提供咨询。Gahl博士帮助制定了关于胱氨酸骨病管理的国际共识声明，并为FGF23在胱氨酸病骨矿化调节中的作用提供了新的见解。他还参与了世界上第一个在德国进行的胱氨酸病新生儿筛查项目。Wendy Introne医生治疗尿酸症（一种由均质酸积累引起的结缔组织疾病）患者，描述了主动脉膨胀性和甲状腺功能受损。Introne博士也是chediakhigashi病（CHD）的国际权威，CHD是一种细胞内巨大颗粒，致命细菌感染和淋巴细胞组织细胞增多症的疾病。她描述了冠心病的神经心理学方面，撰写了一篇权威的综述，并参与了4个冠心病诱导多能干细胞系的创建。大卫·亚当斯博士继续通过提供专业知识、建议和合作为白化病社区服务。Juvi Estrada Veras博士是一名特殊志愿者和前科成员，他报告了一种名为Erdheim-Chester病的罕见组织细胞增生症的神经、口腔、甲状腺和肾上腺表现。特别志愿者Meral Gunay-Aygun博士分析了她在过去十年中作为该科成员收集的纤毛病数据。纤毛病，纤毛在细胞上不运动的疾病，包括Joubert综合征（JS）、Alstrom综合征和多囊肾病。Gunay博士及其同事利用小鼠模型发现了JS的一种遗传修饰因子（bartin），并利用外显子跳脱修复了JS细胞的纤毛蛋白缺陷。他们描述了纤毛病的器官特异性表现，撰写了关于Alstrom综合征的权威综述，并提供了JS的治疗建议。Carlos Ferreira博士，现在在医师科学家发展项目，发起了一项临床协议研究ENPP1酶替代疗法用于缺乏这种酶的个体；相关疾病包括婴儿期全身性动脉钙化（通常在新生儿期致命）和常染色体隐性低磷佝偻病2型。2. 先天性糖基化失调（CDGs）是一种导致蛋白质糖基化异常的生化缺陷。由于该科参与CDG联盟，与NIH未确诊疾病计划（UDP）密切互动，以及Lynne Wolfe， PNP的兴趣，该科成员合作描述了30例SLC25A2突变患者，SLC25A2编码一种UDP-半乳糖转运蛋白。与NIAID的科学家一起，他们报告了由于MAGT1突变导致的x连锁免疫缺陷与镁缺陷（XMEN）疾病的糖基化缺陷，MAGT1是合成活化聚糖前体的酶所必需的镁转运体。其他CDGs是由磷脂酰肌醇聚糖缺陷引起的，磷脂酰肌醇聚糖在细胞表面形成GPI锚点。小组成员合作报道了PIGM原聚体突变患者和神经学结果，ARV1突变导致的GPI锚点缺陷，以及40例PIGA突变患者。Lynne Wolfe帮助描述了可能从补充尿苷中获益的磷酸碳基合成酶2缺乏症患者，Carlos Ferreira博士描述了saol - wilson综合征的临床特征，其糖蛋白缺陷是由于COG4（低聚高尔基复合物4的组成部分）突变导致高尔基体网络的形态异常造成的。该部分还研究了Hermansky-Pudlak综合征（HPS），由10种罕见的遗传性皮肤病白化病和由于细胞内囊泡异常形成的出血组成。1型、2型和4型有致命性肺纤维化。Bernadette Gochuico博士与NIAAA和NCATS合作研究一种分子，该分子结合了诱导型一氧化氮合酶的抑制和内源性大麻素受体CB1的拮抗剂来治疗HPS肺纤维化。利用May Malicdan博士开发的小鼠模型，Section的合作者证明了纤维化诱导药物博来霉素也会引起肺细胞的药物外排。Marjan huzing博士和May Malicdan一起撰写了关于导致HPS的突变的评论，科的临床医生向全世界的HPS医生、患者和倡导团体提供建议。4. Drs。huzing和Nuria Carrillo及其合作者开发了一种LC-MS/MS方法来测量人类白细胞中的胞苷-5-单磷酸- n -乙酰神经氨酸，并证明了由于人类肾功能降低而导致血浆唾液酸水平升高。在倡导组织STAR （Salla Treatment and Research）的支持下，huzing和Section的研究人员成立了一个工作组来研究Salla病，这是一种溶酶体游离唾液酸分泌缺陷的疾病。本节的主要内容涉及GNE肌病，这是一种由GNE双等位基因突变引起的迟发性神经肌肉疾病，它编码唾液酸生物合成中的限速酶。Carrillo博士发起了一项多中心，随机，安慰剂对照的唾液酸前体n -乙酰甘油三胺（ManNAc）在GNE肌病中的临床试验，作为NeuroNext的一部分，这是全国神经病学中心的NINDS联盟。该试验得到了leadant Biosciences， Inc.的CRADA支持，并将于2020年秋季开始。今年，huzing博士介绍了使用ManNAc治疗肾小球疾病的基本原理。5. 该科成员还领导NIH UDP，这是由NIH共同基金支持的未诊断疾病网络（UDN）的一部分。UDN是精准医学的典范，致力于诊断患有神秘疾病的患者，并发现新的疾病和疾病机制。Gahl博士是UDN工作组的成员，Adams博士是UDN指导委员会的联合主席，UDN是一个由12个临床站点和支持核心组成的国家联盟。在过去的一年里，该部门帮助UDP开发了强大的序列分析管道，增强了颅面和口腔表型的本体论词汇表，记录了UDN对生物医学科学的独特贡献，使用机器学习识别临床术语，并描述了罕见未确诊疾病的新诊断方法。国际贡献包括呼吁对非洲罕见病采取行动，呼吁在罕见病调查中开展开放科学，以及对2014年由UDP建立的国际未确诊疾病网络（UDNI）进行5年随访。2020年，分会成员在荷兰奈梅亨组织了第八届国际UDNI会议。马利丹博士率先在UDP患者的部门内进行了转化研究。她和她的同事和合作者描述了一种由ypel3突变引起的发育障碍，与衔接蛋白PHETA1/2缺乏相关的肾脏和颅面异常，以及由于SLC12A2缺失引起的综合征性听力损失。其他部门的研究人员已经发表了HNF1B缺失导致的低镁血症、登革热病毒导致的慢性全脑炎、ARH3突变导致的发育障碍、新型SOX10突变导致的非典型Waardenburg综合征、kmt2b相关疾病的临床特征，以及与一种极其罕见的疾病——面部发病感觉和运动神经病变相关的认知改变的病例。

The Section on Human Biochemical Genetics studies inborn errors of metabolism and other genetic disorders to gain insight into cellular mechanisms and to care for neglected rare disease patients. The Section pursues these goals in various ways. 1. Section experts investigate, diagnose, and treat many specific disorders. In the past year, the Section continued its 40 years of service to nephropathic cystinosis, providing consultations to patients, physicians, and advocacy groups throughout the world. Dr. Gahl helped formulate an international consensus statement on the management of cystinotic bone disease and contributed to new insights into the role of FGF23 in the regulation of bone mineralization in cystinosis. He also collaborated on the first newborn screening program for cystinosis in the world, conducted in Germany. Dr. Wendy Introne cared for patients with alkaptonuria (a connective tissue disorder due to accumulation of homogentisic acid), describing impaired aortic distensibility and thyroid function. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis. She described the neuropsychological aspects of CHD, wrote a definitive review, and contributed to the creation of 4 CHD induced pluripotent stem cell lines. Dr. David Adams continued to serve the albinism community by providing expertise, advice, and collaborations. Dr. Juvi Estrada Veras, a Special Volunteer and former Section member, reported the neurological, oral, thyroid, and adrenal manifestations of a rare histiocytosis called Erdheim-Chester Disease. Dr. Meral Gunay-Aygun, a Special Volunteer, analyzed ciliopathy data that she had collected over the past decade as a member of the Section. Ciliopathies, disorders of immotile cilia on cells, include Joubert Syndrome (JS), Alstrom syndrome, and polycystic kidney diseases. Dr. Gunay and colleagues discovered a genetic modifier of JS (barttin) using a mouse model and rescued the ciliary protein defect of JS cells using exon skipping. They described the organ-specific manifestations of ciliopathies, wrote the definitive review on Alstrom Syndrome, and provided management recommendations for JS. Dr. Carlos Ferreira, now in the Physician Scientist Development Program, initiated a clinical protocol to study ENPP1 enzyme replacement therapy in individuals with deficiency of that enzyme; the associated disorders include Generalized Arterial Calcification of Infancy (often fatal in the neonatal period) and Autosomal Recessive Hypophosphatemic Rickets type 2. 2. Congenital Disorders of Glycosylation (CDGs) are biochemical defects that result in abnormal glycosylation of proteins. By virtue of the Sections involvement in a CDG Consortium, its close interactions with the NIH Undiagnosed Diseases Program (UDP), and the interest of Lynne Wolfe, PNP, Section members have collaborated to describe 30 patients with mutations in SLC25A2, which encodes a UDP-galactose transporter. With NIAID scientists, they reported glycosylation defects in X-linked Immunodeficiency with Magnesium Defect (XMEN) disease due to mutations in MAGT1, a magnesium transporter required for enzymes that synthesize activated glycan precursors. Other CDGs result from defects in phosphatidylinositol glycans, which form GPI anchors on the surface of cells. Section members collaborated to report patients with a PIGM protomer mutation and neurological findings, GPI anchor deficiency due to ARV1 mutations, and 40 patients with PIGA mutations. Lynne Wolfe helped describe individuals with carbomoylphosphate synthetase 2 deficiency who may benefit from supplementation with uridine and Dr. Carlos Ferreira described the clinical characteristics of Saul-Wilson Syndrome, whose glycoprotein defects result from morphological abnormalities in the Golgi network due to mutations in COG4 (Component of Oligomeric Golgi Complex 4). 3. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 10 rare genetic disorders of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles. Types 1, 2, and 4 have fatal pulmonary fibrosis. Dr. Bernadette Gochuico leads a collaboration with NIAAA and NCATS investigating a molecule that combines inhibition of inducible nitric oxide synthase and antagonism of the endocannabinoid receptor CB1 to treat HPS pulmonary fibrosis. Using mouse models developed by Dr. May Malicdan, Section collaborators demonstrated that the fibrosis-inducing drug bleomycin also causes drug efflux from lung cells. Dr. Marjan Huizing, along with May Malicdan, wrote reviews on the mutations causing HPS, and Section clinicians provided advice to HPS physicians, patients and advocacy groups throughout the world. 4. Drs. Huizing and Nuria Carrillo, with collaborators, developed an LC-MS/MS method to measure cytidine-5-monophospho-N-acetylneuraminic acid in human leukocytes and demonstrated increased plasma sialic acid levels due to reduced kidney function in humans. Huizing and Section investigators established a working group to study Salla Disease, a disorder of defective free sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). A major thrust of the Section involves GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. Dr. Carrillo initiated a multicenter, randomized, placebo-controlled clinical trial of the sialic acid precursor, N-acetylmannosamine (ManNAc) in GNE myopathy as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. The trial has CRADA support from Leadiant Biosciences, Inc., and will start in the fall of 2020. This year, Dr. Huizing described the rationale for using ManNAc in renal glomerular diseases. 5. Members of the Section also lead the NIH UDP, which is part of the Undiagnosed Diseases Network (UDN) supported by the NIH Common Fund. The UDN, a model for Precision Medicine, strives to diagnose patients with mysterious conditions and to discover new disorders and disease mechanisms. Dr. Gahl sits on the UDN Working Group and Dr. Adams co-chairs the Steering Committee of the UDN, a national consortium of 12 clinical sites and supporting cores. In the past year, the Section has helped the UDP develop a powerful sequence analysis pipeline, enhance ontological vocabularies for craniofacial and oral phenotypes, document the unique contributions of the UDN to the biomedical sciences, identify clinical terms using machine learning, and describe new diagnostic approaches to rare undiagnosed diseases. International contributions included a call to action for rare diseases in Africa, a plea for open science in the investigation of rare diseases, and the 5-year follow-up on the Undiagnosed Diseases Network International (UDNI), established by the UDP in 2014. In 2020, Section members organized the 8th international UDNI meeting in Nijmegen, the Netherlands. Dr. Malicdan has spearheaded the translational research performed within the Section on UDP patients. She and her colleagues and collaborators have described a developmental disorder due to mutations in ypel3, renal and craniofacial abnormalities associated with deficiency of the adaptor protein PHETA1/2, and syndromic hearing loss due to deletion of SLC12A2. Other Section investigators have published cases of hypomagnesemia due to deletion of HNF1B, chronic panencephalitis due to dengue virus, developmental impairment due to ARH3 mutations, atypical Waardenburg syndrome due to a novel SOX10 mutation, clinical characteristics of KMT2B-related disorders, and cognitive change related to an extremely rare disorder called Facial Onset Sensory and Motor Neuropathy.