Basic and Translational Studies of Inborn Errors of Metabolism

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

This project supports the basic and translational science research conducted by the Section on Molecular Dysmorphology. This project complements and synergizes with the clinical science conducted under project HD008989. It consolidates and extends work previously done under project HD000139. The rare genetic disorders being studied in the Section on Molecular Dysmorphology (SMD) currently Smith-Lemli-Opitz syndrome, Niemann-Pick disease, type C, CLN3 disease (Batten Disease) and Creatine Transporter Deficiency. The goal of SMD is to use model systems to understand pathological processes contributing to these disorders to identify, develop and test potential biomarkers and therapeutic interventions. These model systems include mouse models, zebrafish models, patient fibroblasts and induced pluripotent stem cells. Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis with an incidence on the order of 1/50,000. SLOS is an autosomal recessive multiple congenital anomaly/cognitive impairment syndrome characterized by facial dysmorphology, growth retardation and variable structural anomalies of the heart, lungs, brain gastrointestinal tract, genitalia, kidneys, and limbs. Mutations of DHCR7, the gene that encodes an enzyme that converts 7-dehydrocholesterol to cholesterol underly SLOS. Individual with SLOS manifest variable cognitive impairment ranging from mild learning difficulties to profound mental dysfunction. SLOS has a distinct behavior phenotype which includes self-injurious, obsessive compulsive and autistic features. SMD has evaluated over 120 individuals with SLOS in a natural history trial. SMD has developed multiple SLOS mouse models and a zebrafish model of SLOS. We also have produced and studied induced pluripotent stem cells. This work has been supported by the RSH/SLOS Foundation. Niemann-Pick disease type C (NPC) is a lysosomal disease caused by impaired intracellular cholesterol transport. NPC can be caused by mutation of either NPC1 or NPC2, and its incidence is on the order of 1/100,000. This is a lethal neurodegenerative disorder characterized by progressive cerebellar dysfunction and dementia. While most of the patients are children, the participants range in age from infants to adults. SMD has enrolled approximately 130 individuals in our ongoing, longitudinal natural history/observational trial. This clinical protocol provides for deep phenotyping and biomaterial collection. Significant effort has been invested in using the mouse model to identify potential lipid and protein biomarkers that can then be evaluated in human samples. This work has led to development of a blood-based diagnostic test and a newborn screen. Recently we have obtained cerebellar lobule specific and cerebellar single cell transcriptomic data from control and mutant NPC1 mice. These databases provide insight into disease pathology and potential therapeutic interventions that can subsequently be tested in the laboratory. In addition to utilizing NPC1 mouse models, SMD has developed and characterized zebrafish models of both NPC1 and NPC2. SMD has also been involved in the development of multiple induced multipotent stem cell lines for the study of NPC1. This work has been supported and facilitated by collaboration with the Ara Parseghian Medical Research Foundation, National Niemann-Pick Disease Foundation, SOAR-NPC and Firefly Fund. CLN3-disease, or juvenile Batten disease, is a recessive lysosomal disease characterized by progressive blindness, seizures, dementia, and behavioral issues. CLN3-disease is due to mutations of CLN3, a gene that encodes a protein of unknown function. SMD has initiated a longitudinal natural history trial which includes deep phenotyping and biomaterial collection for biomarker identification. As part of a NCATS project, SMD is participating in a multicenter natural history trial sponsored by Ultragenyx which is enrolling individuals with Creatine Transported Deficiency (CTD). CTD is an X-linked disorder causing severe cognitive impairment and seizures in affected boys. After identification of cardiac issues in the natural history trial, SMD has been studying a mouse model of CTD to further characterize the abnormal cardiac function.