Clinical Investigations of Inborn Errors of Metabolism

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

This project supports the clinical science research conducted by the Section on Molecular Dysmorphology. It complements and synergizes with the basic/translational science conducted under project HD008988. It consolidates and extends HD008824 and HD008825. This project includes both natural history/observational and therapeutic trials genetic disorders cause by inborn errors of metabolism. The natural history/observational studies include deep phenotyping and collection of biomaterials for biomarker identification and characterization. The disorders currently being studied include Smith-Lemli-Opitz syndrome, Niemann-Pick disease, type C, CLN3 disease (Batten Disease) and Creatine Transporter Deficiency. Our goals include improving clinical care, identifying developing therapeutic interventions. 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. This is the largest SLOS cohort of well phenotyped SLOS patients in the country. Previous therapeutic trials evaluated the short-term efficacy of dietary cholesterol supplementation and simvastatin. This work has been supported by the RSH/SLOS Foundation. Niemann-Pick disease type C 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. Previous therapeutic trials evaluated safety and efficacy of n-acetyl cysteine and vorinostat. Current therapeutic trials are evaluating the efficacy of intrathecal 2-hydroxy--cyclodextrin and combined intrathecal/intravenous 2-hydroxy--cyclodextrin. Recent efforts have been focused on newborn screening and exploring opportunities for future therapeutic trials. 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. SMD is working with Amicus Therapeutics and Beyond Batten Disease Foundation on future therapeutic trials. 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. The immediate goal of this project is to obtain information on clinical outcome measures and biomarkers that could be used in a future therapeutic trial.