Variable White Matter Atrophy and Intellectual Development in a Family With X-linked Creatine Transporter Deficiency Despite Genotypic Homogeneity

• Published in: Pediatric neurology Vol. 67; pp. 45 - 52
• Main Authors: Heussinger, Nicole, Saake, Marc, Mennecke, Angelika, Dörr, Helmuth-Günther, Trollmann, Regina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017
• Subjects: Adolescent; Atrophy - blood; Atrophy - diagnostic imaging; Atrophy - genetics; Atrophy - psychology; Brain Diseases, Metabolic, Inborn - blood; Brain Diseases, Metabolic, Inborn - diagnostic imaging; Brain Diseases, Metabolic, Inborn - genetics; Brain Diseases, Metabolic, Inborn - psychology; Child; Creatine - blood; Creatine - deficiency; Creatine - genetics; CRTD; epilepsy; Female; Genotype; genotype–phenotype correlation; Humans; intellectual disability; Intellectual Disability - blood; Intellectual Disability - diagnostic imaging; Intellectual Disability - genetics; Intellectual Disability - psychology; magnetic resonance spectroscopy; Male; Mental Retardation, X-Linked - blood; Mental Retardation, X-Linked - diagnostic imaging; Mental Retardation, X-Linked - genetics; Mental Retardation, X-Linked - psychology; Middle Aged; Mutation, Missense; Nerve Tissue Proteins - genetics; Neurology; Pediatrics; Phenotype; Plasma Membrane Neurotransmitter Transport Proteins - blood; Plasma Membrane Neurotransmitter Transport Proteins - deficiency; Plasma Membrane Neurotransmitter Transport Proteins - genetics; SLC6A8 gene mutation; White Matter - diagnostic imaging; White Matter - metabolism; white matter atrophy; CRTD; epilepsy; genotype–phenotype correlation; SLC6A8 gene mutation; magnetic resonance spectroscopy; white matter atrophy; intellectual disability; Hamburger-Wechsler- Intelligenztests für Erwachsene; tCr; MRI; Normalized total creatine; Electroencephalography; genotype-phenotype relation; MRS; Cr; HAWIE; tNAA; NRXI; Voxel based morphometry; androgen receptor; WM; total N-acetylaspartate; X-linked creatine transporter deficiency; polymerase chain reaction; VBM; Creatinine; Magnetic Resonance Spectroscopy; EEG; GAA; White matter; Guanidinoacetate; non-random X-inactivation; Kaufmann Assesment Battery for Children; AR; Magnetic resonance imaging; HAWIK; creatine; K-ABC; Hamburger-Wechsler- Intelligenztests für Kinder; nCr; total Cr; Crn; PCR
• ISSN: 0887-8994; 1873-5150
• DOI: 10.1016/j.pediatrneurol.2016.10.007

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.