Human Biochemical Genetics

摘要： 人类生化遗传学研究部分选择了先天的新陈代谢错误，以深入了解细胞机制，并为被忽视的罕见疾病患者群体提供护理。1.该组成员在NIH临床研究中心接纳了大约60名半胱氨酸病患者作为住院患者或门诊患者，记录了口服半胱胺治疗对生长、肾功能和眼部异常的有益影响。他们还报告了没有接受口服半胱胺治疗的患者的晚期并发症为肝脏受累、门脉高压和冠状动脉疾病伴血管钙化。该科与国家眼科研究所的同事合作，描述了半胱氨酸病的眼部组织病理学，并继续为因角膜半胱氨酸晶体堆积而患上畏光症的患者提供半胱胺滴眼液。该合作小组继续努力将半胱胺滴眼液带到FDA的新药审批中。该科是世界上关于胱氨酸病的权威机构，每年答复来自世界各地的患者和医生的大量询问。2.该科继续对碱尿症进行调查，这是一种由于缺乏同质性1，2-双加氧酶而导致的同功酸积聚障碍。与临床中心康复医学部合作，该组成员全面描述了尿酸尿症患者的肌肉骨骼表现和向残疾的进展。该科还成功地招募了40名尿白蛋白尿症患者参加尼替西酮的随机临床试验，尼替松是一种产生同种异构酸的酶的强大抑制剂，使用髋关节活动范围作为主要结果参数。这项研究已经从FDA获得了研究新药(IND)豁免。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是一种罕见的眼皮肤白化和出血疾病，由细胞内小泡的异常形成引起，如黑素小体和血小板致密小体。这种疾病有8种遗传亚型，该科已照顾了160多名受影响的人。在基础研究中，该部门的成员和他们的合作者报告了HPS血小板中正常的阿尔法颗粒，已知的是缺乏致密颗粒。他们证明了HPS3蛋白与笼状蛋白相互作用；这一发现有助于解释HPS3在细胞内运输中的功能。在临床研究中，该小组和合作者描述了第一例成功的HPS患者的肺移植，HPS的眼部病理，以及HPS的肉芽肿性结肠炎与特定亚型的关系。该部门的医生还启动了一项抗纤维化药物吡非尼酮的随机、安慰剂对照临床试验，以对抗HPS的致命性肺纤维化。结果参数是用力肺活量的变化。已获得IND，并已开始注册。在这项临床试验的同时，科室医生正在通过研究HPS肺灌洗液中的细胞因子来调查肺纤维化的病因。4.该科正在进行格雷血小板综合症的连锁研究，这是一种缺乏血小板α颗粒的疾病，患者患有出血素质。5.该科还开始研究导致白血小板综合症的基因，这是一种与血小板中多个高尔基区域有关的大血小板减少症。6.一项正在进行的临床方案调查常染色体隐性遗传性多囊肾病和先天性肝纤维化，以确定自然病史和为未来的治疗干预确定结果参数。在这项研究中对大约40名患者进行了评估，该科与罕见病办公室一起赞助并发表了一份关于ARPKD/CHF研讨会的会议纪要，该研讨会由该领域的国家当局参加。ARPKD/CHF的放射学特征的详细描述正在编写中，准备出版。7.一项研究Hutchinson-Gilford Progeria综合征自然病史的临床方案已获批准，已有15名患有这种早衰综合征的患者入选。调查结果正在汇编中。8.有几名患者患有Chediak-Higashi病，这是一种细胞内大颗粒的疾病，有致命感染的倾向。本部分描述了一名严重患病的婴儿和一名轻度患病的成人，确定了CHS1基因的致病突变，并在临床、分子和细胞生物学水平上提供了基因-表型相关性。9.该科成员与代谢紊乱细胞生物学股合作，研究一种罕见的肌肉疾病--遗传性包涵体肌病。致病基因是Gne，它编码双功能酶UDP-N-乙酰氨基葡萄糖2-差向异构酶/N-乙酰甘露糖氨酸激酶，负责催化唾液酸合成的前两步。唾液酸是修饰质膜和调节细胞-细胞相互作用的糖蛋白的末端糖；肌肉蛋白如α-肌营养不良聚糖被严重唾液酸化，而HIBM的肌病被认为是由于α-肌营养不良聚糖和其他肌肉蛋白的低降解所致。除了与该股合作开展HIBM基础研究项目和动物模型研究外，该科还根据免疫球蛋白中唾液酸含量高的特点，进行了静脉免疫球蛋白G治疗HIBM的试点研究。在四名接受治疗的患者中，肌肉力量和功能活动显著改善，促使进一步研究为HIBM患者提供唾液酸或前体。

Summary: The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of rare disease patients. 1. Members of the Section admitted approximately 60 individuals with cystinosis as inpatients or outpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. They also reported liver involvement with portal hypertension and coronary artery disease with vascular calcifications as late complications of cystinosis in patients not receiving oral cysteamine therapy. In collaboration with colleagues in the National Eye Institute, the Section described the ophthalmic histopathology of cystinosis, and continues to provide cysteamine eyedrops to patients suffering from photophobia due to corneal cystine crystal accumulation. The collaborative group continues to work to bring cysteamine eyedrops to New Drug Approval by the FDA. The Section serves as the world authority on cystinosis, responding to scores of inquires every year from patients and physicians throughout the world. 2. The Section continues its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In collaboration with the Clinical Center's Rehabilitation Medicine Department, members of the Section have comprehensively described the musculoskeletal manifestations and progression to disability of alkaptonuria patients. The Section has also successfully enrolled 40 alkaptonuria subjects in a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, using hip range of motion as the primary outcome parameter. An Investigational New Drug (IND) exemption has been obtained from the FDA for this study. 3. The Section remains the only center in the world investigating both 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 such as melanosomes and platelet dense bodies. There are 8 genetic subtypes of this disease, and the Section has cared for more than 160 affected individuals. In basic studies, members of the Section and their collaborators reported a normal contingent of alpha granules in HPS platelets, which are known to lack dense granules. They demonstrated that the HPS3 protein interacts with clathrin; this finding helps explain the function of HPS3 in intracellular trafficking. In clinical studies, the group and collaborators described the first successful lung transplantation in an HPS patient, the ocular pathology of HPS, and the granulomatous colitis of HPS in relation to the particular subtypes. Physicians in the Section have also initiated a randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. The outcome parameter is change in forced vital capacity. An IND has been obtained, and enrollment has begun. In parallel with this clinical trial, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokines in HPS pulmonary lavage fluid. 4. The Section is performing linkage studies of Gray Platelet Syndrome, a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. 5. The Section has also initiated studies to identify the gene responsible for White Platelet Syndrome, a macrothrombocytopenia associated with multiple Golgi regions in platelets. 6. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis to define the natural history and determine outcome parameters for future therapeutic intervention. Approximately 40 patients have been evaluated in this study, and the Section, along with the Office of Rare Diseases, sponsored and published a summary of the proceedings of a workshop on ARPKD/CHF attended by national authorities in the field. Detailed descriptions of the radiographic features of ARPKD/CHF are being prepared for publication. 7. A clinical protocol investigating the natural history of Hutchinson-Gilford Progeria Syndrome has been approved, and 15 patients with this premature aging syndrome have been enrolled. The findings are being compiled. 8. Several patients were seen with Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. The Section described a severely affected infant and a mildly affected adult, identifying the causative mutations in the CHS1 gene and providing genotype-phenotype correlations on clinical, molecular, and cell biological levels. 9. In collaboration with the Cell Biology of Metabolic Disorders Unit, members of the Section have pursued a rare muscle disease, Hereditary Inclusion Body Myopathy (HIBM). The causative gene is GNE, which encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, responsible for catalyzing the first two steps in sialic acid synthesis. Sialic acid serves as the terminal sugar on glycoproteins that decorate plasma membranes and modulate cell-cell interactions; muscle proteins such as alpha-dystroglycan are heavily sialylated, and the myopathy of HIBM has been attributed to hyposialylation of alpha-dystroglycan and other muscle proteins. In addition to collaborating on HIBM basic research projects and animal model studies with the Unit, the Section has performed a pilot study of intravenous immune globulin G for treating HIBM, based upon the high sialic acid content of immune globulin. In four treated patients, muscle strength and functional activity improved considerably, prompting further investigations into providing sialic acid or a precursor to HIBM patients.