Back
Clinical, ocular motor, and imaging profile of Niemann-Pick type C heterozygosity.
Journal article

Clinical, ocular motor, and imaging profile of Niemann-Pick type C heterozygosity.

  • Bremova-Ertl T From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland. Tatiana.Bremova-Ertl@insel.ch susanne.schneider@med.uni-muenchen.de.
  • Sztatecsny C From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Brendel M From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Moser M From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Möller B From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Clevert DA From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Beck-Wödl S From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Kun-Rodrigues C From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Bras J From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Rominger A From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Ninov D From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Strupp M From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland.
  • Schneider SA From the Department of Neurology (T.B.-E., C.S., M.M., M.S., S.A.S.), German Center for Vertigo and Balance Disorders (T.B.-E., D.N., M.S.), and Institute of Radiology (D.A.C.), Ludwig Maximilians University, University Hospital Grosshadern, Munich, Germany; Departments of Neurology (T.B.-E.) and Nuclear Medicine (A.R.), Inselspital, University Hospital Bern, Switzerland; Department of Nuclear Medicine (M.B., A.R.), University Hospital, LMU Munich; Department of Neurology (B.M.), University Hospital, Schleswig-Holstein, Kiel Campus; Institute for Medical Genetics and Genomics (S.B.-W.), Tübingen, Germany; Center for Neurodegenerative Science (C. K.-R., J.B.), Van Andel Research Institute, Grand Rapids, MI; Munich Cluster for Systems Neurology (SyNergy) (A.R.), Munich, Germany; and University of Bern (A.R.), Switzerland. Tatiana.Bremova-Ertl@insel.ch susanne.schneider@med.uni-muenchen.de.
Show more…
  • 2020-04-03
Published in:
  • Neurology. - 2020
Adult
Aged
Cholestanols
Cognitive Dysfunction
Eye Movement Measurements
Family
Female
Hepatomegaly
Heterozygote
Hexosaminidases
Humans
Intracellular Signaling Peptides and Proteins
Male
Middle Aged
Mutation
Niemann-Pick Disease, Type C
Ocular Motility Disorders
Olfaction Disorders
Phenotype
Positron-Emission Tomography
REM Sleep Behavior Disorder
Splenomegaly
Ultrasonography
English OBJECTIVE
To characterize subclinical abnormalities in asymptomatic heterozygote NPC1 mutation carriers as markers of neurodegeneration.


METHODS
Motor function, cognition, mood, sleep, and smell function were assessed in 20 first-degree heterozygous relatives of patients with Niemann-Pick disease type C (NPC) (13 male, age 52.7 ± 9.9 years). Video-oculography and abdominal ultrasound with volumetry were performed to assess oculomotor function and size of liver and spleen. NPC biomarkers in blood were analyzed. 18F-fluorodesoxyglucose PET was performed (n = 16) to detect patterns of brain hypometabolism.


RESULTS
NPC heterozygotes recapitulated characteristic features of symptomatic NPC disease and demonstrated the oculomotor abnormalities typical of NPC. Hepatosplenomegaly (71%) and increased cholestantriol (33%) and plasma chitotriosidase (17%) levels were present. The patients also showed signs seen in other neurodegenerative diseases, including hyposmia (20%) or pathologic screening for REM sleep behavior disorder (24%). Cognitive function was frequently impaired, especially affecting visuoconstructive function, verbal fluency, and executive function. PET imaging revealed significantly decreased glucose metabolic rates in 50% of participants, affecting cerebellar, anterior cingulate, parieto-occipital, and temporal regions, including 1 with bilateral abnormalities.


CONCLUSION
NPC heterozygosity, which has a carrier frequency of 1:200 in the general population, is associated with abnormal brain metabolism and functional consequences. Clinically silent heterozygous gene variations in NPC1 may be a risk factor for late-onset neurodegeneration, similar to the concept of heterozygous GBA mutations underlying Parkinson disease.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/247662
Statistics
Document views: 77 File downloads: