Human Biochemical Genetics

人类生化遗传学部分研究遗传病，以更好地了解生化途径，并照顾罕见和被忽视的疾病患者。该科通过由世界专家管理的临床方案调查、诊断和治疗几种疾病来实现这些目标。1. William Gahl，医学博士，继续他42年对肾病胱氨酸病患者的服务，这是一种溶酶体贮积疾病，其基本缺陷Gahl在1982年阐明。今年，他评估了几名胱氨酸病患者，为美国和国际患者提供咨询，并在胱氨酸病研究网络会议上发表了大量报告。他的合作研究表明，早期口服半胱胺治疗可保护肾小球和小管功能，并于今年发表，同时阐明了FGF23在高磷血症中的作用。另一组方案研究先天性糖基化障碍（CDGs，即由于糖蛋白合成受损而引起的多系统疾病），由CRNP的Lynne Wolfe担任首席研究员。今年，她和她的合作者描述了由于PIGN（一种GPI锚定蛋白）双等位基因突变导致的Fryns综合征的基因型/表型相关性，并报道了CDGs中特异性脂质升高。医学博士Wendy Introne负责管理Sections患者的尿酸症，这是一种由均质酸（HGA）积累引起的骨骼和关节疾病，均质酸是酪氨酸分解代谢的一种中间体。她在她的临床方案中招募了100名患者，并正在寻求FDA批准nitisinone的新药，我们证明这种药物可以降低95%的HGA产生。Introne博士也是chediakhigashi病（CHD）的国际权威，CHD是一种由LYST基因双等位基因突变引起的巨大细胞内颗粒，致命细菌感染和淋巴细胞组织细胞增多症的疾病。在过去的一年里，Introne博士和他的同事们研究了冠心病神经损伤的机制，证明了冠心病神经元中自噬溶酶体改造的缺陷。他们还利用cDNA测序技术推进了冠心病的分子诊断，并撰写了有关该病的综述。Introne博士继续了Sections对Smith-Magenis综合征的研究，描述了一位患者的Birt-Hogg-Dube综合征。David Adams医学博士继续向白化病界提供专业知识和建议，并将Stacie Loftus博士从Pavans博士实验室调至该科。他们报告了大量1B型眼皮肤白化病（OCA）患者遗传力缺失的原因。Adams和NEI的合作者还使用人工智能来评估中央凹发育不全患者的视力。医学博士Bernadette Gochuico是该科的肺科医生，他和合作者描述了在变形综合征中成骨不全和囊性肺疾病的结构和功能肺异常。本节还研究了Hermansky-Pudlak综合征（HPS），由11种遗传性疾病组成，伴有OCA和因细胞内囊泡异常形成的出血。1型、2型和4型有致命性肺纤维化。在Gochuico博士离开NIH并将她的HPS临床方案转移给Introne博士之前，她和同事描述了HPS肺纤维化基因治疗的章节，并报告了HPS肺成纤维细胞因肌球蛋白失调而增加的细胞运动。Gochuico博士还与校外研究人员合作，阐明了HPS-1中异常免疫和炎症的因素。其他科成员报告了HPS3基因中一个独特的致病缺失，并为GeneReviews和国家罕见疾病组织（NORD）撰写了关于HPS的在线评论。该组成员继续与NIAAA科学家合作，研究内源性大麻素受体1和诱导型一氧化氮合酶的双重抑制剂，这可能会减缓HPS肺纤维化的进展。该科的成员继续与HPS网络一起照顾HPS患者。该科长期对唾液酸紊乱感兴趣。其中一种疾病是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，GNE编码唾液酸合成中的限速酶。医学博士Francis Rossignol是一项关键性临床试验的首席研究员，该试验测试了唾液酸前体n -乙酰甘露糖胺（ManNAc）对GNE肌病患者的安全性和有效性。这项多中心、随机、安慰剂对照研究是neuroonext的一部分，neuroonext是由国家神经病学中心组成的NINDS联盟，由leadant Biosciences， Inc.提供CRADA支持。2023年5月，他完成了18例NHGRI患者的入组。Marjan huzing博士和其他小组成员正在准备ManNAc在肾小球疾病中的临床研究方案。小组成员还研究游离唾液酸储存障碍（fssad）的各个方面，并在倡导组织STAR （Salla治疗和研究）的支持下，创建了一个由18名国际研究人员组成的联盟，研究溶酶体分泌唾液酸的障碍。该联盟定期召开会议，协调研究，其中包括牛津-剑桥项目的博士生玛丽亚·萨比尔。2023年，huzing博士为NORD撰写了一篇关于fssd的在线评论。4. 该科成员领导美国国立卫生研究院未确诊疾病项目（UDP），未确诊疾病网络（UDN）的创始成员，这是一个由12个临床站点和支持核心组成的国家联盟。UDP调查患有神秘疾病的患者，做出诊断并描述新的疾病和疾病机制。Drs。Gahl和Adams共同领导UDP， May Malicdan，医学博士，管理UDP的转化研究项目。今年，她和她的同事和合作者发现了一种由ATG4D双等位基因突变引起的新的神经发育疾病，以及一种与SNAPC4功能丧失变体导致的广义剪接缺陷相关的痉挛和神经退化的新疾病。Malicdan博士还报告了一个独特的，非典型的小管病的表现，由于TUBB4B突变。医学博士Camilo Toro是指导UDP成人部分的神经学专家。今年，他与Section、IRP和外部研究人员合作，描述了ROSAH综合征（功能获得性ALPK1变异）的分子基础，发表了非洲点头综合征的广泛特征，报道了一种新的HK1 （hexokinase 1）变异是bouche - neuhauser综合征的原因，描述了MYH2剪切变异引起的肌病，写了一篇关于垂体分泌过多的文章。总结UDP合并脑内钙化的遗传基础。Section和UDP研究人员与免疫学家合作，描述了一种由STAT4致病变异引起的新的自身炎症性疾病。其他小组成员报道了KMT5B单倍不足损害小鼠和人类神经发育的机制。5. 在国际罕见病领域，Gahl博士领导国际未确诊疾病网络（UDNI），这是一个由来自40个国家的130多名医生和科学家组成的联盟；2014年，他与威廉基金会（一个罕见和未确诊疾病的倡导组织）一起建立了UDNI。2022年，Gahl在维也纳协调了第11届UDNI会议，建立了一项冠军倡议，以促进发展中国家的udp，并发表了关于罕见病临床网络价值和各国未确诊患者未满足需求的论文。他与同事一起撰写了关于UDNI的文章，从UDP中收集的见解，以及UDNI与名为“稀有”的新期刊之间的关系。Gahl还发表了7次受邀的国内和国际演讲，包括世界研讨会的罗斯科·布雷迪奖演讲。

The Section on Human Biochemical Genetics studies genetic diseases to better understand biochemical pathways and to care for patients with rare and neglected diseases. The Section pursues these goals by investigating, diagnosing, and treating several disorders through clinical protocols managed by world experts. 1. William Gahl, MD, PhD, continued his 42 years of service to patients with nephropathic cystinosis, a lysosomal storage disease whose basic defect Gahl elucidated in 1982. This year, he evaluated several cystinosis patients, consulted on U.S. and international patients, and presented extensively at the Cystinosis Research Networks conference. His collaborative work showing preservation of glomerular and tubular function by early oral cysteamine therapy was published this year, along with elucidation of the role of FGF23 in hyperphosphatemia. Another Section protocol investigates Congenital Disorders of Glycosylation (CDGs, i.e., multisystemic disorders due to impaired synthesis of glycoproteins), with Lynne Wolfe, CRNP, as principal investigator. This year, she and her collaborators described genotype/phenotype correlations in Fryns syndrome due to biallelic mutations in PIGN (a GPI anchor protein) and reported specific lipid elevations in CDGs. Wendy Introne, MD, manages the Sections patients with alkaptonuria, a bone and joint disorder due to accumulation of homogentisic acid (HGA), an intermediate in tyrosine catabolism. She has enrolled >100 patients in her clinical protocol and is pursuing New Drug Approval by the FDA for nitisinone, a drug that we demonstrated lowers HGA production by 95%. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis due to biallelic mutations in the LYST gene. In the past year, Dr. Introne and colleagues pursued the mechanism of neurological impairment in CHD, demonstrating defective autophagic lysosome reformation in CHD neurons. They also advanced CHD molecular diagnostics by using cDNA sequencing and wrote a review on the disease. Dr. Introne has continued the Sections studies of Smith-Magenis syndrome, describing Birt-Hogg-Dube syndrome in a patient. David Adams, MD, PhD, continues to provide the albinism community with expertise and advice, bolstered by the transfer of Stacie Loftus, PhD, to the Section from Dr. Pavans lab. They reported the cause of missing heritability in a large number of oculocutaneous albinism (OCA) type 1B patients. Adams and NEI collaborators also employed artificial intelligence to evaluate visual acuity in patients with foveal hypoplasia. Bernadette Gochuico, MD, a pulmonologist in the Section, and collaborators described structural and functional pulmonary abnormalities in osteogenesis imperfecta and cystic lung disease in Proteus Syndrome. 2. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 11 genetic disorders with OCA and bleeding due to abnormal formation of intracellular vesicles. Types 1, 2, and 4 have fatal pulmonary fibrosis. Before Dr. Gochuico, left the NIH and transferred her HPS clinical protocol to Dr. Introne, she and colleagues described the Sections pursuit of gene therapy for HPS pulmonary fibrosis and reported increased cell motility in HPS lung fibroblasts due to dysregulated myosin. Dr. Gochuico also collaborated with extramural researchers to elucidate elements of abnormal immunity and inflammation in HPS-1. Other Section members reported a unique, disease-causing deletion in the HPS3 gene and wrote online reviews on HPS for GeneReviews and for the National Organization for Rare Disorders (NORD). Section members continue to work with NIAAA scientists on a dual inhibitor of endocannabinoid receptor 1 and inducible nitric oxide synthase that can potentially slow the progression of HPS pulmonary fibrosis. Members of the Section continue to care for HPS patients in association with the HPS Network. 3. The Section has a longstanding interest in sialic acid disorders. One such disease is GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid synthesis. Francis Rossignol, MD, is principal investigator of a pivotal clinical trial testing the safety and efficacy of the sialic acid precursor, N-acetylmannosamine (ManNAc), for patients with GNE myopathy. This multicenter, randomized, placebo-controlled study is part of NeuroNext, an NINDS consortium of national neurology centers, with CRADA support from Leadiant Biosciences, Inc. In May of 2023, he completed enrollment of the NHGRI contingent of 18 patients. Marjan Huizing, PhD, and other Section members are now preparing a clinical protocol to study ManNAc in renal glomerular diseases. Section members also investigate various aspects of Free Sialic Acid Storage Disorders (FSASD) and have created a consortium of 18 international investigators studying disorders of sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). The consortium meets regularly to coordinate research and includes an Oxford-Cambridge Program PhD student, Marya Sabir. In 2023, Dr. Huizing wrote an online review of FSASD for NORD. 4. Section members lead the NIH Undiagnosed Diseases Program (UDP), the founding member of the Undiagnosed Diseases Network (UDN), a national consortium of 12 clinical sites and supporting cores. The UDP investigates patients with mysterious conditions, making diagnoses and describing new disorders and disease mechanisms. Drs. Gahl and Adams co-direct the UDP and May Malicdan, MD, PhD, manages the UDPs translational research program. This year, she and her colleagues and collaborators discovered a new neurodevelopmental disease due to biallelic mutations in ATG4D and a new disorder of spasticity and neuroregression associated with generalized splicing defects resulting from SNAPC4 loss-of-function variants. Dr. Malicdan also reported a unique, atypical presentation of a tubulinopathy due to a TUBB4B mutation. Camilo Toro, MD, is the master neurologist who directs the adult portion of the UDP. This year, he collaborated with Section, IRP, and extramural investigators to describe the molecular basis of ROSAH syndrome (gain-of-function ALPK1 variants), publish a broad characterization of African Nodding Syndrome, report a de novo HK1 (hexokinase 1) variant as a cause of Boucher-Neuhauser syndrome, describe a myopathy due to a splice variant in MYH2, write an article on pituitary hypersecretion due to-loss of-function PAM variants, and summarize the genetic bases of UDP patients with intracerebral calcifications. Section and UDP investigators collaborated with immunologists to describe a new autoinflammatory disease due to pathogenic variants in STAT4. Other Section members reported the mechanism of haploinsufficiency of KMT5B in impairing murine and human neurodevelopment. 5. For the international rare disease community, Dr. Gahl leads the Undiagnosed Diseases Network International (UDNI), a consortium of >130 physicians and scientists from >40 nations; with the Wilhelm Foundation (a rare and undiagnosed diseases advocacy group), he established the UDNI in 2014. In 2022, Gahl coordinated the 11th UDNI conference in Vienna, established a Champions Initiative to foster UDPs in developing nations, and published papers on the value of clinical networks for rare diseases and the unmet needs of undiagnosed patients in various countries. With colleagues, he wrote articles on the UDN, insights gleaned from the UDP, and the relationship between the UDNI and a new journal entitled Rare. Gahl also delivered 7 invited national and international talks, including the Roscoe Brady Award lecture for WORLDSymposium.