2. Academic Validation
  3. Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration

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

  • Brain. 2020 Jan 1;143(1):94-111. doi: 10.1093/brain/awz376.
Christina R Fagerberg 1,  Adrian Taylor 2,  Felix Distelmaier 3,  Henrik D Schrøder 4,  Maria Kibæk 5,  Dagmar Wieczorek 6,  Mark Tarnopolsky 7,  Lauren Brady 7,  Martin J Larsen 1,  Rami A Jamra 8,  Annette Seibt 3,  Eva Kildall Hejbøl 4,  Else Gade 9,  Ljubo Markovic 10,  Dirk Klee 11,  Peter Nagy 12,  Nicholas Rouse 12,  Prasoon Agarwal 13,  Vernon W Dolinsky 13,  Marica Bakovic 2
Affiliations

Affiliations

  • 1 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • 2 Department of Human Health and Nutritional Sciences, University of Guelph, Canada.
  • 3 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Düsseldorf, Germany.
  • 4 Department of Pathology, Odense University Hospital, Denmark.
  • 5 Children Hospital of H. C Andersen, Odense University Hospital, Odense, Denmark.
  • 6 Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
  • 7 Department of Pediatrics, Neuromuscular and Neurometabolic Clinic, McMaster University Medical Centre, Hamilton, Canada.
  • 8 Institute of Human Genetics, Leipzig University, Germany and Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 9 Department of Ophthalmology, Odense University Hospital, 5000 Odense C, Denmark.
  • 10 Department of Radiology, Odense University Hospital, 5000 Odense C, Denmark.
  • 11 Department of Diagnostic and Interventional Radiology, Heinrich-Heine University, Düsseldorf, Germany.
  • 12 MNG Laboratories, Atlanta Georgia, USA.
  • 13 Department of Pharmacology and Therapeutics, University of Manitoba, Canada.
PMID: 31855247 DOI: 10.1093/brain/awz376
Abstract

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.

Keywords

SLC44A1; choline transporter; neurodegeneration; phospholipids.

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