Persistent elevations of alkaline phosphatase as an early indicator of GM1 gangliosidosis.
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2025-03
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GLB1-related disorders are autosomal recessive lysosomal diseases caused by enzymatic deficiency of β-galactosidase. Enzymatic deficiency of β-galactosidase may lead to one of two phenotypes, GM1 gangliosidosis or mucopolysaccharidosis IVB (MPS IVB). GM1 gangliosidosis is a neurodegenerative disorder with variable skeletal disease and involvement of other systems. The age of onset correlates with the extent of neurological involvement and established genotype/phenotype correlations. Mucopolysaccharidosis IVB is characterized by a skeletal dysplasia without neurological involvement. Diagnostic work-up for GLB1-related disorders includes enzyme analysis, biomarker analysis, molecular testing, and laboratory imaging studies. We report a patient who presented with persistent elevations of alkaline phosphatase (ALP) and subtle dysmorphic facial features. An initial skeletal survey at birth was unrevealing; however, a repeat at 3 months of age was abnormal with anterior beaking of the lumbar vertebrae and hemivertebrae of the lower cervical spine. Urinary glycosaminoglycan (GAG) analysis revealed a marked elevation of keratan sulfate (KS). Clinical exome sequencing revealed pathogenic heterozygous variants in GLB1, consistent with GLB1-related GM1 gangliosidosis. Our case demonstrates that persistent elevations of ALP may be an early indicator for GM1 gangliosidosis in an infant with progressive multisystem disease, indicating the need for early genetic consultation. This case also highlights the utility of repeat skeletal surveys with abnormalities detected at 3 months of age.
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Menkovic, Iskren, Monika Williams, Neelam Makhijani, Ruhan Wei, Sarah P Young, Areeg El-Gharbawy and Ashlee R Stiles (2025). Persistent elevations of alkaline phosphatase as an early indicator of GM1 gangliosidosis. Molecular genetics and metabolism reports, 42. p. 101191. 10.1016/j.ymgmr.2025.101191 Retrieved from https://hdl.handle.net/10161/32205.
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Scholars@Duke
Ruhan Wei
Sarah Phyllis Young
As an ABMGG-certified clinical biochemical geneticist and Co-Director of the DUHS Biochemical Genetics Laboratory, my research focuses on advancing laboratory diagnostics for rare inherited metabolic disorders. I lead efforts to develop and implement mass spectrometry–based assays to improve the detection, characterization, and monitoring of these conditions in both clinical and research settings. My work has a particular emphasis on biomarker validation for lysosomal disorders, including Pompe disease, Fabry disease, and the mucopolysaccharidoses. Through longitudinal biomarker studies, I contribute to the assessment of disease burden and therapeutic response, including enzyme replacement therapy, gene therapy, and emerging in utero interventions. I am also actively involved in translational research supporting newborn screening and diagnostic algorithms, with the goal of enabling earlier detection and more precise follow-up testing for metabolic diseases.
Ashlee R. Stiles
Dr. Stiles is a fellow of the American College of Medical Genetics and Genomics trained in clinical biochemical genetics and molecular genetics. She is co-director of the Duke University Health System Biochemical Genetics Laboratory and external Referral Laboratory. In her work with the Biochemical Genetics laboratory, her research interests focus on improving and developing laboratory diagnostics for rare inborn errors of metabolism. In her role as director of the Referral laboratory, she works closely with hospital leadership on utilization management of genetic send-out tests.
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