233 Efficient and effective newborn screening (NBS) for early infantile Krabbe diseases (KD) Dietrich Matern a , Dimitar Gavrilov a , Devin Oglesbee a , Kimiyo Raymond a , Silvia Tortorelli a , Jeremy Hart b , Lea Mott b , Joanne Kurtzberg c , Vinod Prasad c , Piero Rinaldo a , a Mayo Clinic, Rochester, MN, United States, b Kentucky Department for Public Health, Frankfort, KY, United States, c Duke University Medical Center, Durham, NC, United States NBS for KD has been conducted primarily by measuring galactocerebrosidase (GALC) activity and employing molecular genetic analysis of the GALC gene as a 2 nd tier test. This has led to the detection of many (N 1:6,000) infants with reduced GALC activity and genotypes of uncertain significance subjected to follow up testing. Our approach to NBS for KD employs measurement of Psychosine (PSY) as a 2 nd tier test when post-analytical interpretive tools created using Collaborative Laboratory Integrated Reports suggests a possible diagnosis of KD. Among more than 80,000 newborns screened, we identified one case with reduced GALC activity (0.18 nmol/mL/hr; 1 st percentile of controls: 1.16), a high CLIR score for Krabbe disease (788; informative N 30), and signifi- cantly elevated PSY (61 nM; controls b 10). The NBS specimen was received in the laboratory on the 4 th day of life (a Saturday), the report was released on the 6 th day of life, the patient was admitted to the Pediatric Blood and Marrow Transplant Program at Duke University Medical Center at 7 days old, received a hematopoietic stem cell transplant at 23 days old, and was discharged to home at 104 days old. At now 10 months old the patient has no neurological problems. Some expected transplant related complications are being managed as an outpatient. We postulate that precision NBS for early infantile KD is possible with minimal false positive results and without the need for molecular genetic testing in the NBS laboratory. As our case illustrates, 7-day- operation of the NBS laboratory is required to achieve best outcomes. Whether a biochemical-genetics-only approach is sufficient to detect all cases with later onset variants of KD remains to be determined. doi:10.1016/j.ymgme.2017.12.242 234 Precision newborn screening for three lysosomal disorders in Kentucky Dietrich Matern a , Silvia Tortorelli a , Devin Oglesbee a , Dimitar Gavrilov a , Kimiyo Raymond a , Jeremy Hart b , Lea Mott b , Piero Rinaldo a , a Mayo Clinic, Rochester, MN, United States, b Kentucky Department for Public Health, Frankfort, KY, United States Since February 2016, more than 80,000 infants born in the Commonwealth of Kentucky have been screened for Krabbe disease, mucopolysaccharidosis type I, and Pompe disease using a 6 plex MS/MS method combined with covariate-adjusted reference inter- vals, post-analytical interpretive tools created using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu), a novel multivariate pattern recognition software, and 2 nd tier tests (Minter Baerg MM et al. Genet Med. in press). Specimens collected before 24 hours and after 1 week of age were 1,913 (2.2%) and 4,126 (4.7%), respectively. Age at collection and birth weight were provided for 99.5% of the specimens. With only a single repeat sample requested since screening began, the false positive rate currently is 0.0012% and the positive predictive value is 86%. Of seven cases referred as abnormal, one was affected with infantile Krabbe disease, four were affected with (late onset) Pompe disease, and one was affected with Mucopolysaccharidosis type I. The remaining case was a heterozygote for Mucopolysaccharidosis type I, a false positive outcome. Our testing and post-analytical protocol can improve performance for conditions recently included in the recommended uniform screening panel, and likely for all others as well. Downstream savings in health care expenditures and decrease in psychosocial harm experienced by caregivers could be realized if this freely available software was employed and supported through greater collaboration and data sharing among programs. doi:10.1016/j.ymgme.2017.12.243 235 The importance of astrocytes in the pathophysiology of GBA1-associated Parkinson disease Benjamin McMahon, Elma Aflaki, Ellen Sidransky, National Institutes of Health, Bethesda, MD, United States Astrocytes, the most abundant cells in the human central nervous system, play a multitude of roles in neuronal homeostasis and the regulation of synaptic plasticity. Despite these vital functions, few studies have focused on the role of astrocytes in specific neurode- generative diseases, including neuronopathic Gaucher disease (GD) and Parkinson disease (PD). Astrocytes provide critical support for neuronal function by providing antioxidant protection, clearing glutamate, developing and/or maintaining the blood-brain barrier, and releasing gliotransmitters and cytokines. Mutations in GBA1, the gene encoding glucocerebrosidase (GCase), which is mutated in GD, are the most common known genetic risk factor for PD. We generated astrocytes from induced pluripotent stem cells from the fibroblasts of eight patients. Six of the patients had type 1 GD (GD1), three with (GD1-PD) and three without parkinsonism, including two siblings discordant for PD and two with type 2 GD. The patient astrocytes exhibited decreased GCase activity and stored the substrates glucosylceramide and glucosylsphingosine compared to those from a healthy control. Moreover, astrocytes from patients with GD2 and GD1 with PD had increased glutamate uptake and decreased intracellular calcium in response to ATP. We then studied the role of monomeric and aggregated α-synuclein on astrocyte neuroinflammation. When astrocytes from patients with GD1-PD or GD2 were treated with α-synuclein, they had increased GFAP expression (a marker for active astrocytes) and secreted significant amounts of inflammatory cytokines, as confirmed by a proteome profiler. Studying the trafficking of α-synuclein in intravesicular bodies, we found that astrocytes from patients with GD1-PD and GD2 accumulate α-synuclein in the late-endosome and in mature cathepsin-D positive lysosomes. This results in astrogliosis, as con- firmed by elevated levels of Ki67 positive cells. These cells therefore provide an excellent model to explore the potential role of astrocytes in the pathogenesis of GBA1-associated PD and neuronopathic forms of GD. doi:10.1016/j.ymgme.2017.12.244 236 Multimorbidity in type 1 Gaucher disease patients under miglustat therapy Blanca Medrano Engay a , Ana Roy b , Koldo Atutxa c , Vicente Diaz- Morant d , Javier García-Frade e , Roberto Hernández-Martín f , Elisa Luño g , Soledad Noya h , Javier de la Serna i , Lucía Villalón j , Pilar Giraldo k , Abstracts / Molecular Genetics and Metabolism 123 (2018) S15–S153 S93