X‐Linked creatine transporter deficiency in two patients with severe mental retardation and autism

Abstract

We describe the first two unrelated Spanish patients with creatine transporter deficiency initially identified by brain proton magnetic resonance spectroscopy (MRS). The clinical phenotype was characterized by severe mental retardation, epilepsy, autism, severe speech delay and absence of brain creatine by MRS. Urine creatine/creatinine ratio was increased and creatine uptake in fibroblasts was impaired in both patients. On DNA sequence analysis of the SLC6A8/creatine transporter gene, one hemizygous mutation was found in each patient: one mutation was novel and consisted of a deletion of two nucleotides c.878-879delTC in exon 5, resulting in a frameshift (p.Lys293fsX3), and in the other patient a known deletion of three nucleotides 1222-1224delTTC in exon 8 resulting in p.Phe408del. Creatine treatment for one year failed to improve the neurological symptoms and was associated with a striking increase in body weight in both patients (13 and 16 kg, respectively).

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

“…However, the pre-symptomatic treatment of AGAT-and GAMT-deficient patients appears to prevent, so far, most of the Cr-deficiency effects on their brain (Battini et al 2006;Schulze et al 2006;Schulze and Battini 2007). Oral supplementation of Cr is inefficient in replenishing brain Cr in SLC6A8-deficient patients, who remain with mental retardation, severe speech impairment and progressive brain atrophy Bizzi et al 2002;DeGrauw et al 2002;Póo-Argüelles et al 2006). Attempts to treat SLC6A8-deficient patients with arginine as precursor of Cr also failed to improve their neurological status (Fons et al 2008).…”

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

“…In patients, creatine deficiency syndromes have several common clinical manifestations, including cognitive dysfunction with mental retardation, poor language skills, and autism spectrum disorders (9)(10)(11)(12)(13)(14)(15). Proton magnetic resonance spectroscopy (MRS) of affected patients shows an absence or dramatic diminution of the creatine peak, with relatively normal levels of n-acetyl aspartate (9,16,17).…”

“…Because SLC6A8 is located on human chromosome Xq28, mutations in this gene result in a more severe syndrome in males than in female carriers. Patients with AGAT deficiency or GAMT deficiency have been successfully treated with creatine supplementation, which reverses symptoms, as well as other supplements, which manage buildup of intermediate metabolites (13-15, 21, 22); however, patients with CRT deficiency are not successfully treated with creatine supplementation (10,16,(23)(24)(25). Creatine is found in blood and cerebrospinal fluid (CSF), but is not able to enter brain cells -the cell membranes are an effective barrier to creatine transport.…”

Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes

“…In certain patients with the GAMT defect, pathological signal abnormalities have been described within the globus pallidus of the basal ganglia (29). For some patients with CTD, volume loss has been described (35,36). In the seven CTD patients followed in Cincinnati, five are noted on initial imaging studies to demonstrate mild volume loss.…”

“…There are unsuccessful treatment trials with creatine, and precursors to creatine synthesis (5,34,36,49,(56)(57)(58)(59)(60). Treatment for these patients is currently limited to supportive care, symptom management and controlling seizures.…”