We report a new case of CRTR-D in a 5-year-old male who presented a severe epileptic phenotype. No familial history of seizure or neurological disorders was reported; delivery, birth weight, and head circumference were normal. No motor or growth delay was observed, whereas language and cognitive development was impaired as of the second year of life, together with hyperactive behavior. At 4.9 years he presented a brief febrile convulsion, with normal EEG the day after. After 2 weeks he began to manifest frequent generalized tonic–clonic seizures (≥1/day), sometimes subcontinuous, with prolonged postcritic state, both in wake and sleep, associated with intermittent fever over the following 2 months. Hyperactive and impulsive behavior became more severe with no evidence of cognitive regression. At 5 years of age the patient was admitted at our hospital. EEG recordings showed slow, high amplitude activity (Fig. 1A–B), persisting during sleep. He presented mild global hypotonia, moderate mental retardation (Griffiths's general quotient 59), hyperactivity, impulsiveness, and severe language/speech delay. Nearly 1 month after admission a segmental myoclonus with no EEG correlate on polygraphic recording appeared, while seizures became isolated, daily, generalized tonic–clonic. Inflammatory, autoimmune, and infectious investigations, both in plasma and CSF, resulted negative. AED at adequate dosage (PB, VPA, CNZ, TPM) were not effective in controlling epileptic seizures. Urine analysis showed an increased creatine/creatinine ratio (1.83; n.v. 0.03–0.92) with normal guanidinoacetate/creatinine ratio (0.024; n.v. 0.023–0.214). Brain MRI with angiography and perfusion study was normal, while 1H-MRS revealed a consistent decrease in the creatine peak (Fig. 2). DNA sequence analysis of the SLC6A8 gene highlighted a hemizygous missense mutation (c.1631C > T; p.Pro544Leu) in the patient and his healthy mother and sister. The same mutation resulted in the impairment of creatine uptake in fibroblasts of two previously described patients (Mancini et al, 2005). This mutation was not identified in a series of 276 male controls (Rosenberg et al, 2004).
Figure 1. A-B: Wake-EEG at onset (20 sec/page, 10 uV/mm, LoFilter 1Hz, HiFilter 15Hz): slow, diffuse, theta-delta activity of high amplitude; C: wake-EEG 1 year later (20 sec/page, 10 uV/mm, LoFilter 1Hz, HiFilter 15Hz): marked improvement of the background activity, intermittent theta activity more evident over the right hemisphere; D: sequence of rhythmic delta waves in the posterior right regions with no apparent clinical correlation.
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Treatment with prednisone and further association of levetiracetam (LEV) in multidrug therapy (prednisone, VPA, TPM) were effective on seizure frequency and myoclonus. One year after epilepsy onset he still presents 2–3 tonic–clonic seizures/month, with a pronounced version of the body to the left side. Recent EEG showed a clear improvement of background activity; a sequence of focal rhythmic delta waves had no apparent clinical correlate (Fig. 1C–D). Although clinical symptoms of this recently described syndrome vary in severity, they consistently include mental retardation with speech delay, behavioral disturbances, and seizures. No specific EEG pattern has been reported so far and no genotype–phenotype correlation is described, but to date only cases with a mild epileptic phenotype with infrequent and easy-to-treat seizures are reported in the literature.
On the contrary, our patient presented with abrupt onset of severe and initially refractory epilepsy with intercritic diffuse, slow, high voltage activity on EEG, similar to what has been described in some GAMT-deficient patients (Leuzzi, 2002). It is also possible that an intercurrent event has triggered or worsened the epileptic phenotype, but no definite etiologic factor was detected in our patient, despite extensive investigations.