title: MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis.
abstract: Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding β-galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symptoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2-10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty-six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N-acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally-invasive outcome measures for clinical trials.
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Debra S
authors.initials: DS
authors.lastname: Regier
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Hyuk Joon
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jean
authors.initials: J
authors.lastname: Johnston
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.affiliation: Division of Genetics and Metabolism, Children's National Health System, Washington, District of Columbia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Yang
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Edythe
authors.initials: E
authors.lastname: Wiggs
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Latour
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Cindy
authors.initials: C
authors.lastname: Portner
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.affiliation: Department of Radiology, Children's National Health System, Washington, District of Columbia.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vezina
authors.affiliation: Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Baker
authors.affiliation: Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.|Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001284:Atrophy / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D054022:Cerebrum / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D016537:Gangliosidosis, GM1 / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051346:Mobility Limitation; D012720:Severity of Illness Index; D013060:Speech; D013064:Speech Disorders / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D001616:beta-Galactosidase / Q000172:deficiency / Q000235:genetics*
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate; C061901:GLB1 protein, human; D001616:beta-Galactosidase
keywords: GM1 gangliosidosis; MRI; MRS; lysosomal storage disease; trial readiness