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. 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. In addition, they collaborated on publications describing toxic side effects of oral cysteamine therapy. They also wrote authoritative reviews on cystinosis for European Nephrology, Pediatric Nephrology, and the Netter Collection of Medical Illustrations, addressed national and international meetings of cystinosis advocacy groups, and continued to assist the National Eye Institute in the provision of cysteamine eyedrops to the cystinosis community. The Section serves as the world 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 cardiologists in the NHLBI, members of the Section described the frequency of aortic stenosis and arterial calcifications in alkaptonuria. 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 a ninth subtype of HPS in a single male infant due to bi-allelic mutations in the gene pallidin. The gene product encodes a component of Biogenesis of Lysosome-related Organelles Complex-1, a protein complex responsible for intracellular vesicle formation. Members of the Section also described the clinical and molecular manifestations of HPS in non-Puerto Rican Hispanic individuals and the second family in the world with HPS-8. The Sections pulmonary group reported interstitial lung disease in three HPS-2 patients, documenting this complication as part of the HPS-2 phenotype. Section investigators continue to pursue the etiology of the lung fibrosis of HPS, through studies of surface glycoproteins such as galectin-3 in blood and pulmonary lavage fluid. In collaboration with NIAID investigators, Section scientists are studying mast cell function in HPS, since the basophilic granules of these cells are lysosome-like organelles. The Section also collaborated on a project to demonstrate that KXD1, a blos1 interacting protein, functions in the formation of lysosome-related organelles. 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 published papers describing hepatorenal findings in obligate heterozygotes for ARPKD/CHF and portal hypertension in Autosomal Dominant Polycystic Kidney Disease. 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. In collaborative efforts, they reported the platelet dense body results of CHD patients with and without bone marrow transplantation, and are extensively characterizing the clinical, molecular, and cellular aspects of mild CHD patients with neurological manifestations. In collaboration with NCATS investigators, basic scientists in the Section are pursuing treatment of the neurological symptoms of CHD using small molecule therapy and a mouse model that manifests neurological findings. 6. One Section investigator has established 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. He and his NEI collaborators have shown that nitisinone increases plasma tyrosine levels and improves ocular and skin pigmentation abnormalities in a mouse model of oculocutaneous albinism, paving the way for possible treatment in humans. 7. In miscellaneous collaborative pursuits, Section investigators have provided the GNE gene, defective in Hereditary Inclusion Body Myopathy, to a patient intravenously. Other Section members have reported an unusual patient with Smith-Magenis syndrome and an isolated RAI1 mutation, the different isoforms of UDP-GlcNac 2-epimerase/ManNAc kinase in various tissues, the renal pathology of the Gne mouse, the role of cysteamine in suppressing cancer metastases, and the fact that the lysosomal membrane sialic acid transporter sialin serves as a nitrate transporter in the plasma membrane. 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 6800 inquiries and 2500 sets of 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 530 patients and admitted over 450, providing state-of-the-art clinical investigations in every case, and solving approximately 100 diagnostic dilemmas, some of which are extremely rare disorders. UDP investigators have also identified 20 new diseases associated with genetic variants, and are pursuing demonstration of the basic defects via cellular and biochemical studies. Publications emanating from the UDP include descriptions of a new spastic ataxia-neuropathy syndrome due to homozygous AFG3L2 mutations, a very rare compound heterozygous case of fatty acid hydroxylase deficiency and neurodegeneration, a case of IgG4 sclerosing disease with mastoiditis, a girl with juvenile onset GM1 gangliosidosis, and neurotransmitter deficiency in the CSF of patients with spastic paraplegia and gait abnormalities (SPG11). The UDP has also advanced the field of next generation sequencing analysis by publishing papers that describe whole exome sequencing filters and tools for analyzing variants in small Mendelian pedigrees, lists of false positive variants and of exons that behave well in exome sequencing platforms, variants in genes associated with muscle disease and spastic paraplegia, the use of SNP genotyping in whole exome sequence analysis, and quantification of mosaicism using a cumulative distribution function to analyze SNP arrays. Finally, UDP leaders have written a review and an editorial about the Program in the past year. Recently, Section leaders secured 7 years of support for expansion of the Program to extramural sites.
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