Human Biochemical Genetics

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

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 nephropathic cystinosis to the NIH Clinical Research Center, largely as outpatients, documenting the beneficial effects of oral and topical cysteamine therapy with respect to growth, renal function, late complications, and ophthalmic abnormalities. In addition, they addressed national and international meetings of pediatric nephrologists and cystinosis advocacy groups and published an article showing that compliance with oral cysteamine therapy correlates with maintenance of renal glomerular function but not improvement in renal Fanconi syndrome. The Section continues to serve as an international authority on the disease, responding to scores of inquiries every year from patients and physicians throughout the world. 2. The Section continues to follow approximately 20 patients with alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. Members of the Section 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 published a paper that demonstrated a correlation between the number of circulating fibrocytes and the pulmonary disease prognosis in HPS patients, one that showed correction of the HPS phenotype in HPS cells by lentivirus-mediated transfer of the HPS1 gene, and another that found a correlation between chitinase-3-like 1 protein and pulmonary fibrosis in HPS patients. Section experts continue to provide advice to physicians and patients throughout the world and to contribute to HPS-related meetings of advocacy groups, scientists, and physicians. 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, now including Alstrom syndrome, have been evaluated in this study. This year, the group described a rare pregnancy in an ARPKD patient, and they continue to serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 5. Section scientists continue to investigate Chediak-Higashi disease (CHD), recently describing the first Indian patients with molecularly documented CHD. 6. One Section investigator manages a clinical protocol that follows scores of patients with various subtypes of albinism; he serves as the nations authority on this disorder. 7. Section investigators remain world experts in disorders of sialic acid metabolism. The rate-limiting step in sialic acid synthesis is catalyzed by GNE, a bifunctional enzyme. Patients with biallelic GNE mutations develop GNE myopathy, a late-onset neuromuscular disorder. This past year, members of the Section described a unique patient with asymmetric hand weakness, and developed a new, hydrophilic interaction chromatography-mass spectrometry method for assaying sialic acid and N-acetylmannosamine (ManNAc) in human plasma. In collaboration with the National Center for Advancing Translational Sciences, they continued phase 1b studies of dose determination and safety for ManNAc, a sialic acid precursor, in the treatment of GNE myopathy; the Section Head holds the Investigational New Drug exemption for this compound. 8. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), now supported by the Common Fund as a Network of UDPs with 7 Clinical Sites, a Coordinating Center, two Sequencing Centers, a model systems core, and a metabolomics core. 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. The NIH Intramural Research Programs UDP, directed by members of the Section on Human Biochemical Genetics, is providing guidance to the Undiagnosed Diseases Network (UDN) based upon its 7 years of experience handling more than 10,000 inquiries and 3500 medical records from throughout the country and the world. The UDP uses next-generation genetic techniques and serves as a model for bringing precision medicine to rare disease patients. The Program has accepted more than 900 patients, providing state-of-the-art clinical investigations in every case, and solving more than 150 diagnostic dilemmas, most of which represent extremely rare disorders. UDP investigators have also identified candidate genes for approximately 50 new diseases, and are pursuing the basic defects via cellular and biochemical studies. Members of the Section serve as Co-Chair of the UDN Steering Committee, chairs of different working groups, and writers of the Manual of Operations. This past year they delivered more than 15 national and international talks on the UDP and they have organized two international meetings to create an Undiagnosed Diseases Network International for sharing phenotypic and sequence data. In the past year, publications emanating from the UDP include descriptions of a patient with mutations in the DNA excision repair gene ERCC6 presenting with brain hypomyelination and progressive neurologic deficits, and a child with intellectual disability associated with biallelic MED23 mutations. UDP and Section investigators showed that a bleeding disorder called York Platelet syndrome is due to mutations in the gene STIM1 that increases the activity of a calcium release activated channel (CRAC). They reported another new disease characterized by multisystem involvement and developmental delays, due to biallelic mutations in the CAD gene, which encodes a cytoplasmic carbamylphosphate synthetase; the group showed that the failure to synthesize pyrimidines such as uridine causes deficiency of uridine diphosphate sugars, creating a Congenital Disorder of Glycosylation. Other Section and UDP scientists and physicians showed that a patient with Snyder-Robinson syndrome, an extremely rare X-linked neurological disorder with polyamine abnormalities due to spermine synthetase deficiency, exhibit impaired osteoblast and osteoclast function to account for their bone disease. Two other UDP siblings had hypotonia, global developmental delays, seizures, and endocrine, ophthalmologic, skeletal, hearing and cardiac anomalies, determined to be due to mutations in PIGT, which encodes a glycosylphosphatidylinositol anchor protein. For another family with ablepharon (absent eyelids), UDP and Section scientists organized an international effort to identify the causative gene, i.e., TWIST2, demonstrating that the helix-loop-helix transcription factor encoded by TWIST2 is defective in Ablepharon Macrostomia and Barber-Say syndromes. The UDP also contributed to articles that advance the methods by which rare and undiagnosed diseases are investigated. One paper describes a database and portal that allows for matchmaking of similarly affected patients based upon their phenotypes and genotypes. Another reports on the use of an automated, high-throughput system to derive induced pluripotent stem cells, and then characterize and differentiate them. Finally, Program authors wrote a chapter for the Nelson Textbook of Pediatrics on genetic approaches to rare and undiagnosed diseases.