Creatine Deficiency Syndrome (CDS). X-linked creatine transporter deficiency. SLC6A8 Deficiency.
Incidence
Prevalence of SLC6A8 deficiency is relatively high and may be responsible for about 2% of males with X-linked MR and for 1.4 % of males with sporadic MR. 78 families with a total of about 170 patients have been diagnosed. SLC6A8 deficiency is an X-linked disorder, affecting mainly males. However, heterozygous females may have a variable clinical phenotype.
Clinical Characteristics
SLC6A8 deficiency is caused by a gene defect involved in transport of creatine resulting in almost complete lack of cerebral creatine, though creatine levels are only slightly reduced in the skeletal muscle of patients with CDS. Clinical hallmarks include mental retardation (MR), speech delay and epilepsy. MR may range from mild to severe and is characteristically associated with hyperactive behavior and autistic features. Epilepsy is frequently present and the spectrum ranges from occasional, drug-responsive seizures to frequent generalized tonic-clonic seizures and therapy resistant frontal lobe epilepsy.
Additional frequent manifestations include failure to thrive (FTT), growth retardation, short stature, hypotonia, hyperextensible joints, movement disorder (mainly extrapyramidal), brain atrophy, discrete facial dysmorphic features and intestinal manifestations. Cardiac arrhythmia, including PVC’s has also been observed in association with SLC6A8 deficiency. Females heterozygous for the family mutation in SLC6A8 can have learning problems or mild MR. The most severe phenotype reported in a girl included mild intellectual disability, behavioral problems and intractable epilepsy. Neurological and psychiatric problems can be progressive in adulthood. The SLC6A8 gene has been mapped to Xq28. SLC6A8 deficiency is an X-linked disorder, males are mainly affected, while according to the X-inactivation pattern heterozygous females may have a variable clinical phenotype. The X-linked pattern of inheritance will not be observed in the case of de novo mutation. To date many different types of mutations have been identified without a clear phenotype-genotype correlation. In SLC6A8 gene, c.319_321delCTT, and c.1221_1223delTTC are the most frequently found and at present 36 different pathogenic mutations have been reported. Analysis of urinary guanidinoacetate and the creatine to creatinine ratio is an important screening test for all CDS. Inborn errors of creatine metabolism can be recognized by the marked reduction of the creatine signal in H-MRS of the brain. In patients with SLC6A8 deficiency, the increase of urinary creatine excretion together with the inherently low urinary creatinine excretion results in an elevation of the urinary creatine to creatinine ratio which serves as a valuable diagnostic marker in males. In heterozygous females this biochemical trait is not sufficiently sensitive to serve as a diagnostic marker. Even in symptomatic patients the creatine to creatinine ratio can be within the control range. (A random urine sample is sufficient for the diagnosis of CDS). False positive values can be detected as the results of a protein-rich diet. In SLC6A8 deficiency, guanidinoacetic acid levels are normal. Mutation analysis for SLC6A8 is currently used to confirm the diagnosis. The common biochemical hallmark is cerebral creatine deficiency as detected by proton magnetic resonance spectroscopy (H-MRS). Enzyme activity levels in fibroblasts (GAMT) and lymphoblasts (GATM) can be measured. No effective treatment is currently available. Treatment with creatine monohydrate has not proved successful. Supplementation with high doses of arginine and glycine along with high dose creatine is being investigated. Supplementation of arginine alone has resulted in developmental progress in one patient but failed to show improvement in intellectual outcomes in other patients.
Combined treatment with creatine arginine and glycine has resulted in a significant improvement of intractable seizures in a female patient.
Precipitants
None
Provocation Tests
None
Diagnostic Procedures
Analysis of urinary guanidinoacetate and the creatine to creatinine ratio is an important screening test for all CDS. Urinary creatine to creatinine ratio may be elevated in males. Guanidinoacetic acid levels are normal. Mutation analysis for SLC6A8 is currently used to confirm the diagnosis. The common biochemical hallmark is cerebral creatine deficiency as detected by proton magnetic resonance spectroscopy (H-MRS). Enzyme activity levels in fibroblasts (GAMT) and lymphoblasts (GATM) can be measured.