title: Variable White Matter Atrophy and Intellectual Development in a Family With X-linked Creatine Transporter Deficiency Despite Genotypic Homogeneity.
abstract: The X-linked creatine transporter deficiency (CRTD) caused by an SLC6A8 mutation represents the second most common cause of X-linked intellectual disability. The clinical phenotype ranges from mild to severe intellectual disability, epilepsy, short stature, poor language skills, and autism spectrum disorders. The objective of this study was to investigate phenotypic variability in the context of genotype, cerebral creatine concentration, and volumetric analysis in a family with CRTD.
  
  
  
  The clinical phenotype and manifestations of epilepsy were assessed in a Caucasian family with CRTD. DNA sequencing and creatine metabolism analysis confirmed the diagnosis. Cerebral magnetic resonance imaging (cMRI) with voxel-based morphometry and magnetic resonance spectroscopy was performed in all family members.
  
  
  
  An SLC6A8 missense mutation (c.1169C>T; p.Pro390Leu, exon 8) was detected in four of five individuals. Both male siblings were hemizygous, the mother and the affected sister heterozygous for the mutation. Structural cMRI was normal, whereas voxel-based morphometry analysis showed reduced white matter volume below the first percentile of the reference population of 290 subjects in the more severely affected boy compared with family members and controls. Normalized creatine concentration differed significantly between the individuals (P < 0.005).
  
  
  
  There is a broad phenotypic variability in CRTD even in family members with the same mutation. Differences in mental development could be related to atrophy of the subcortical white matter.
authors.affiliation: Department of Pediatrics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. Electronic address: Nicole.heussinger@klinikum-ab-alz.de.
authors.forename: Nicole
authors.initials: N
authors.lastname: Heussinger
authors.affiliation: Department of Radiology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Saake
authors.affiliation: Department of Neuroradiology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Mennecke
authors.affiliation: Department of Pediatrics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Helmuth-Günther
authors.initials: HG
authors.lastname: Dörr
authors.affiliation: Department of Pediatrics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Trollmann
mesh_terms: D000293:Adolescent; D001284:Atrophy / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics / Q000523:psychology; D020739:Brain Diseases, Metabolic, Inborn / Q000097:blood / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000523:psychology; D002648:Child; D003401:Creatine / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000097:blood / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000523:psychology; D008297:Male; D038901:X-Linked Intellectual Disability / Q000097:blood / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000523:psychology; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D066127:White Matter / Q000000981:diagnostic imaging* / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C094770:SLC6A8 protein, human; D003401:Creatine
keywords: CRTD; SLC6A8 gene mutation; epilepsy; genotype–phenotype correlation; intellectual disability; magnetic resonance spectroscopy; white matter atrophy