Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration

Christina R Fagerberg, Adrian Taylor, Felix Distelmaier, Henrik D Schrøder, Maria Kibæk, Dagmar Wieczorek, Mark Tarnopolsky, Lauren Brady, Martin J Larsen, Rami A Jamra, Annette Seibt, Eva Kildall Hejbøl, Else Gade, Ljubo Markovic, Dirk Klee, Peter Nagy, Nicholas Rouse, Prasoon Agarwal, Vernon W Dolinsky, Marica Bakovic*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

TidsskriftBrain : a journal of neurology
Udgave nummer1
Sider (fra-til)94-111
StatusUdgivet - jan. 2020


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© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email:


Fagerberg, C. R., Taylor, A., Distelmaier, F., Schrøder, H. D., Kibæk, M., Wieczorek, D., Tarnopolsky, M., Brady, L., Larsen, M. J., Jamra, R. A., Seibt, A., Hejbøl, E. K., Gade, E., Markovic, L., Klee, D., Nagy, P., Rouse, N., Agarwal, P., Dolinsky, V. W., & Bakovic, M. (2020). Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration. Brain : a journal of neurology, 143(1), 94-111.