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X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome
G S Salomons1, S J van Dooren, N M Verhoeven
1VU Medical Center, Metabolic Unit, Department of Clinical Chemistry, 1081 HV Amsterdam, The Netherlands.
American Journal of Human Genetics
|April 28, 2001
Summary
Researchers identified a new X-linked creatine-deficiency syndrome due to a faulty creatine transporter (SLC6A8 gene). This genetic disorder causes developmental delays and neurological issues in affected males and carriers.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Creatine deficiency syndromes are rare genetic disorders affecting energy metabolism in the brain.
- The creatine transporter plays a crucial role in supplying creatine to the brain.
- X-linked inheritance patterns can affect males more severely than female carriers.
Purpose of the Study:
- To identify the genetic cause of a novel X-linked creatine-deficiency syndrome.
- To characterize the clinical and biochemical phenotype associated with the defective creatine transporter.
- To investigate the mutation's impact on creatine uptake in patient-derived cells.
Main Methods:
- Clinical evaluation of the index patient and female relatives.
- Proton magnetic-resonance spectroscopy (¹H-MRS) of the brain.
- Biochemical analysis of creatine and guanidinoacetate levels in plasma and urine.
- Genetic analysis of the SLC6A8 gene, including mutation detection and gene mapping to Xq28.
- In vitro creatine uptake studies using patient-derived fibroblasts.
Main Results:
- The male index patient exhibited developmental delay, hypotonia, and an absent creatine signal in brain ¹H-MRS.
- Elevated creatine levels in urine and plasma, with normal guanidinoacetate, were observed.
- A hemizygous nonsense mutation in the SLC6A8 gene was identified in the index patient.
- Fibroblasts from the patient showed defective creatine uptake.
- Three heterozygous female relatives presented with varying degrees of learning disabilities and biochemical abnormalities.
Conclusions:
- The study reports the first identified X-linked creatine-deficiency syndrome caused by a mutation in the SLC6A8 gene.
- Defective creatine transport leads to neurological and developmental impairments.
- The findings highlight the importance of the creatine transporter in brain function and underscore the genetic basis of creatine deficiency syndromes.