Human Biochemical Genetics

总结： 人类生物化学遗传学研究部分选择了先天性代谢缺陷，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.该科的成员收治了约60名胱氨酸病患者作为NIH临床研究中心的住院患者或门诊患者，记录了口服半胱胺治疗对生长、肾功能和眼科异常的有益作用。他们还报告称，肝脏累及门静脉高压和冠状动脉疾病伴血管钙化是未接受口服半胱胺治疗的患者的胱氨酸病晚期并发症。该科与国家眼科研究所的同事合作，描述了胱氨酸病的眼科组织病理学，并继续向因角膜胱氨酸晶体积聚而患有眼恐惧症的患者提供半胱胺滴眼液。该合作小组继续努力使半胱胺滴眼液获得FDA的新药批准。该科是胱氨酸病方面的世界权威，每年对来自世界各地的患者和医生的大量询问作出答复。2.该科继续调查黑尿症，这是一种由于尿黑酸1，2-双加氧酶缺乏引起尿黑酸积累的疾病。与临床中心的康复医学部合作，该科的成员全面描述了黑酸尿症患者的肌肉骨骼表现和残疾进展。该科还成功招募了40名黑酸尿症受试者参加尼替西酮的随机临床试验，尼替西酮是一种产生尿黑酸的酶的强效抑制剂，使用髋关节活动度作为主要结局参数。已从FDA获得本研究的试验用新药（IND）豁免。3.该科仍然是世界上唯一的研究Hermansky-Pudlak综合征（HPS）的临床和基础方面的中心，HPS是一种罕见的眼皮肤白化病和出血疾病，由于细胞内囊泡（如黑素体和血小板致密体）的异常形成。该疾病有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，该科的成员及其合作者报告了HPS血小板中α颗粒的正常情况，已知HPS血小板缺乏致密颗粒。他们证明了HPS 3蛋白与网格蛋白相互作用;这一发现有助于解释HPS 3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HPS患者首次成功的肺移植，HPS的眼部病理学以及与特定亚型相关的HPS肉芽肿性结肠炎。该科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，并已开始入组。与本临床试验同时，科室医生正在通过研究HPS肺灌洗液中的细胞因子研究肺纤维化的病因。4.该科正在进行灰色血小板综合征的关联研究，这是一种血小板α颗粒缺失和患者具有出血素质的疾病。5.该科还开展了研究，以确定造成白色血小板综合征的基因，这是一种与血小板多个高尔基体区域有关的大血小板减少症。6.一项正在进行的临床方案研究了常染色体隐性多囊肾病和先天性肝纤维化，以确定自然史并确定未来治疗干预的结局参数。本研究对大约40名患者进行了评估，该科沿着罕见病办公室赞助并出版了由该领域国家当局参加的ARPKD/CHF研讨会的会议纪要。ARPKD/CHF影像学特征的详细描述正在准备出版。7.一项调查Hutchinson-Gilford早衰综合征自然史的临床方案已获得批准，15名患有这种早衰综合征的患者已入组。调查结果正在汇编之中。8.几名患者被发现患有Chediak-Higashi病，这是一种细胞内大颗粒的疾病，有致命感染的倾向。该章节描述了一名严重受累的婴儿和一名轻度受累的成人，确定了CHS 1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型-表型相关性。9.与代谢紊乱单位的细胞生物学合作，该科的成员一直在研究一种罕见的肌肉疾病，遗传性包涵体肌病（HIBM）。致病基因是GNE，其编码双功能酶UDP-N-乙酰葡糖胺2-差向异构酶/N-乙酰甘露糖胺激酶，负责催化唾液酸合成的前两个步骤。唾液酸作为修饰质膜和调节细胞-细胞相互作用的糖蛋白上的末端糖;肌肉蛋白如α-肌营养不良蛋白聚糖被严重唾液酸化，HIBM的肌病被归因于α-肌营养不良蛋白聚糖和其他肌肉蛋白的低唾液酸化。除了与该股合作进行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的高唾液酸含量，进行了一项静脉注射免疫球蛋白G治疗HIBM的试验研究。在四名接受治疗的患者中，肌肉力量和功能活动得到了相当大的改善，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.