The Section on Human Biochemical Genetics studies selected inborn errors of metabolism and other genetic disorders to provide insight into cellular mechanisms and to care for neglected groups of rare disease patients. 1. In the past year, members of the Section admitted approximately 60 individuals with cystinosis to the NIH Clinical Research Center, largely as outpatients, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. In addition, they described CTNS mutations in Thai cystinosis patients, wrote authoritative reviews on cystinosis, and addressed national and international meetings of pediatric nephrologists and cystinosis advocacy groups. In concert with the National Eye Institute, Section physicians helped a pharmaceutical company achieve New Drug Approval from the FDA for cysteamine eyedrops, which are now commercially available. The eyedrops contain the cystine-depleting drug, cysteamine, which was found by Section scientists and collaborators to inhibit the spread of pancreatic cancer using human and murine models. The Section continues to serve as an international authority on cystinosis, responding to scores of inquiries every year from patients and physicians throughout the world. 2. The Section continued its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In collaboration with NCI dermatologists, members of the Section described red-brown papules as a presenting feature of the disease. They continue to plan for the use of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, and to provide their expertise for patients and physicians throughout the world. 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, including melanosomes in melanocytes and dense bodies in platelets. In the past year, members of the Section reported only the second family in the world with HPS-8, as well as the occurrence of interstitial lung disease and hemophagocytic lymphohistiocytosis in HPS-2 patients. Section investigators also characterized the molecular interaction between the HPS1 and the HPS4 proteins, and continue to study the cause of the lung fibrosis of HPS. This year, Section experts wrote two authoritative reviews on HPS, one on the genetics and one on treatment. 4. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF), along with other ciliopathies, to define the natural history and molecular bases of these disorders. More than 200 patients with ARPKD/CHF and related ciliopathies have been evaluated in this study. The group recently described the congenital hepatic fibrosis of ARPKD and initiated an intense investigation of a related ciliopathy, Alstrom Syndrome. Members of the Section serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 5. Section scientists continue to investigate disorders of vesicle formation and trafficking such as Chediak-Higashi disease (CHD) and Griscelli syndrome, providing molecular diagnoses for patients throughout the world. Investigators have described the clinical and cellular findings in an extremely rare case of Griscelli syndrome type 3. They continue to characterize the clinical, molecular, and cellular aspects of mild CHD patients with neurological manifestations and, with NCATS investigators, pursue treatment of the neurological symptoms of CHD using small molecule therapy and a mouse model that manifests neurological findings. 6. One Section investigator manages a clinical protocol that follows scores of patients with various subtypes of albinism. The clinical and molecular investigations provided by this study make him the United States authority on this disorder, and he has written the current update on all molecular mutations in albinism genes. He is collaborating with NEI investigators on a protocol to treat partial albinism in humans with nitisinone, to increase plasma tyrosine levels and provide ocular pigment to enhance vision. 7. Section investigators have become world experts in sialic acid synthesis, whose rate-limiting step is catalyzed by GNE, a bifunctional enzyme encoded by the gene GNE. Patients with biallelic GNE mutations develop GNE myopathy, a late-onset neuromuscular disorder. Members of the Section submitted a patent for a biomarker for hyposialylation, characterized a mouse with defective sialic acid synthesis (due to mutations in GNE) as a model for glomerular disease, demonstrated that the muscle and glomerular disease of murine GNE myopathy can be reversed by oral monosaccharide therapy, and described the structural isoforms of the murine GNE enzyme. Members of the Section have also written the authoritative review on sialic acid storage diseases for the clinical genetics community. 8. In collaboration with the Office of Rare Diseases Research and the NIH Clinical Center, Members of the Section lead the NIH Undiagnosed Diseases Program (UDP). This initiative aims to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge about rare and common diseases. To date, the Program has received more than 8000 inquiries and 3000 medical records from throughout the country. The UDP uses next-generation genetic techniques and serves as a model for bringing personalized medicine to rare disease patients. The Program has accepted more than 650 patients and admitted over 600, providing state-of-the-art clinical investigations in every case, and solving approximately 150 diagnostic dilemmas, some of which are extremely rare disorders. UDP investigators have also identified candidate genes for approximately 50 new diseases, and are pursuing demonstration of the basic defects via cellular and biochemical studies. Publications emanating from the UDP include descriptions of post-viral ataxia associated with a PRF1 mutation, homozygous mutations in maltase-glucoamylase, an LMNB1 duplication causing Autosomal Dominant Leukodystrophy, Kearns-Sayre syndrome with isolated growth failure, C19orf12 mutations causing Hereditary Spastic Paraplegia Type 43, a rare amyloid myopathy, nephrolithiasis due to defective vitamin D 24-hydroxylase, and early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) diagnosed through SNP and exome sequence analysis. The UDP has also published on the systematic identification of well-characterized exons and has written 5 papers describing the workings of the UDP. UDP leaders have delivered 25 lectures and seminars on the UDP throughout the world, and have secured 7 years of funding for expansion of the Program to extramural sites. Based upon this support, Section members have organized the contracting of gene function studies of newly identified variants that may be responsible for new diseases, and have established a training course for the analysis of SNP array and exome sequencing results. 9. Miscellaneous pursuits of the Section include collaborations on in utero copper therapy for Menkes disease, discovery of the genetic defect in an autosomal recessive type of nephrocalcinosis, description of a clinical phenotype due to interaction of a protein, SATB2, with the UPF3B gene, and presentation of PET images of a patient with Erdheim-Chester disease. Section scientists also collaborated on the identification of a new congenital neutrophil defect syndrome due to biallelic mutations in VPS45, which regulates membrane trafficking through the endosomal system.
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