Human Biochemical Genetics

人类生化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和照顾被忽视的患者群体。1.该科的成员将大约85名胱氨酸病患者作为住院患者送入NIH临床研究中心，记录了口服半胱胺治疗对生长、肾功能、吞咽能力和眼后段异常的有益作用。他们还报告了胱氨酸病的并发症特发性颅内高压，并与国家眼科研究所的同事合作，向因角膜晶体积聚而患有眼恐惧症的患者提供半胱胺眼药水。该小组继续努力使半胱胺滴眼液获得FDA的新药批准。2.该科加强了对黑尿症的调查，这是一种由于尿黑酸1，2-双加氧酶缺乏而引起尿黑酸积累的疾病。在一项初步研究中，7名患者通过每天服用2毫克的药物nitisinone（一种产生尿黑酸的酶的强效抑制剂），使尿黑酸的产生减少了约95%。该科目前已启动了一项尼替西酮治疗黑尿症的随机临床试验，使用髋关节活动度作为主要结局参数。FDA已批准本研究的研究性新药（IND）豁免。3.该科已成为研究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，由于黑素体和血小板致密体的异常形成。该疾病有7种遗传亚型，该科已照顾了140多名受影响的人。在基础研究中，该科的成员及其合作者描述了HPS-1、HPS-2和HPS-3黑素细胞中的异常蛋白质运输，以及由于调节褐黑素产生的转运蛋白缺乏而导致的小鼠HPS样疾病。该部分还报告了一种定量实时PCR方法，用于检测HPS-1患者的半合子性，并证明HPS 3蛋白与网格蛋白相互作用;这一重要发现解释了HPS 3在细胞内运输中的功能。在临床研究中，该小组及其同事描述了HPS患者首次成功的肺移植，与HPS相关的特定眼球运动异常，以及与特定亚型相关的HPS肉芽肿性结肠炎。该科的医生已经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，入组正在进行中。该小组继续确定HPS临床参与的自然史，并对细胞内囊泡的运动进行细胞生物学研究。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。5.一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。在这项研究中对25名患者进行了评估，该科沿着罕见病办公室主办了一次由该领域国家当局参加的ARPKD/CHF讲习班。6.一项新的临床方案调查了Hutchinson-Gilford早衰综合征的自然史。迄今为止，已经招募了10名患有这种早衰综合征的患者，正在考虑进行治疗试验。7.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。该章节详细描述了一名受影响的儿童，确定了LYST基因中的致病突变，并提供了基因型-表型相关性。

The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of patients. 1. Members of the Section admitted approximately 85 individuals with cystinosis as inpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, swallowing ability, and abnormalities of the posterior segment of the eye. They also reported idiopathic intracranial hypertension as a complication of cystinosis and, in collaboration with colleagues in the National Eye Institute, provided cysteamine eyedrops to patients suffering from photophobia due to corneal crystal accumulation. The group continues to work to bring cysteamine eyedrops to New Drug Approval by the FDA. 2. The Section has intensified its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In a pilot study, seven patients achieved a reduction of approximately 95% of their homogentisic acid production by taking 2 mg per day of the drug nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid. The Section has now initiated a randomized clinical trial of nitisinone in alkaptonuria, using hip range of motion as the primary outcome parameter. An Investigational New Drug (IND) exemption has been granted by the FDA for this study. 3. The Section has become a center for investigating the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of melanosomes and platelet dense bodies. There are 7 genetic subtypes of this disease, and the Section has cared for more than 140 affected individuals. In basic studies, members of the Section and their collaborators described abnormal protein trafficking in HPS-1, HPS-2, and HPS-3 melanocytes and an HPS-like disease in mice due to deficiency of a transporter regulating pheomelanin production. The Section also reported a quantitative real-time PCR method to detect hemizygosity in an HPS-1 patient, and demonstrated that the HPS3 protein interacts with clathrin; this important finding explains the function of HPS3 in intracellular trafficking. In clinical studies, the group and colleagues described the first successful lung transplantation in an HPS patient, the specific eye movement abnormalities associated with HPS, and the granulomatous colitis of HPS in relation to particular subtypes. Physicians in the Section have 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 is underway. The group continues to define the natural history of clinical involvement in HPS, and to perform cell biological studies of the movement of intracellular vesicles. 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. 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. Twenty-five patients have been evaluated in this study, and the Section, along with the Office of Rare Diseases, sponsored a workshop on ARPKD/CHF attended by national authorities in the field. 6. A new clinical protocol investigates the natural history of Hutchinson-Gilford Progeria syndrome. To date, 10 patients with this premature aging syndrome have been enrolled, and therapeutic trials are under consideration. 7. Several patients were seen with Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. The Section described one affected child in detail, identifying the causative mutations in the LYST gene and providing genotype-phenotype correlation.