Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency caused by an SLC6A8 mutation

Clinical Genetics (Impact Factor: 3.93). 11/2005; 68(4):379-81. DOI: 10.1111/j.1399-0004.2005.00489.x
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    • ". Their possible role in the determinism of epilepsy needs to be elucidated . Some adult cases suggest CT1 defect as a nonstationary disorder , including corticobasal dementia associated with signs of muscle and visceral involvement , such as chronic constipation , megacolon , gastric and duodenal ulcer dis - ease , ileus , and bowel perforation ( Kleefstra et al . , 2005 ) . A"
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    ABSTRACT: Creatine metabolism disorders include guanidinoacetate methyltransferase (GAMT) deficiency, arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CT1-encoded by SLC6A8 gene) deficiency. Epilepsy is one of the main symptoms in GAMT and CT1 deficiency, whereas the occurrence of febrile convulsions in infancy is a relatively common presenting symptom in all the three above-mentioned diseases. GAMT deficiency results in a severe early onset epileptic encephalopathy with development arrest, neurologic deterioration, drug-resistant seizures, movement disorders, mental disability, and autistic-like behavior. In this disorder, epilepsy and associated abnormalities on electroencephalography (EEG) are more responsive to substitutive treatment with creatine monohydrate than to conventional antiepileptic drugs. AGAT deficiency is mainly characterized by mental retardation and severe language disorder without epilepsy. In CT1 deficiency epilepsy is generally less severe than in GAMT deficiency. All creatine disorders can be investigated through measurement of creatine metabolites in body fluids, brain proton magnetic resonance spectroscopy ((1) H-MRS), and molecular genetic techniques. Blood guanidinoacetic acid (GAA) assessment and brain H-MRS examination should be part of diagnostic workup for all patients presenting with epileptic encephalopathy of unknown origin. In girls with learning and/or intellectual disabilities with or without epilepsy, SLC6A8 gene assessment should be part of the diagnostic procedures. The aims of this review are the following: (1) to describe the electroclinical features of epilepsy occurring in inborn errors of creatine metabolism; and (2) to delineate the metabolic alterations associated with GAMT, AGAT, and CT1 deficiency and the role of a substitutive therapeutic approach on their clinical and electroencephalographic epileptic patterns.
    Epilepsia 11/2012; 54(2). DOI:10.1111/epi.12020 · 4.57 Impact Factor
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    • "Few studies have described in detail the neuropsychological profile of patients affected by CRTR-D [8], in particular in terms of neuropsychological standardization tests [10,18,25,26,28,29]; the even fewer studies on adult patients, confirm the presence of mental retardation [11,30] or deterioration [12]. "
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    ABSTRACT: Background SLC6A8, an X-linked gene, encodes the creatine transporter (CRTR) and its mutations lead to cerebral creatine (Cr) deficiency which results in mental retardation, speech and language delay, autistic-like behaviour and epilepsy (CRTR-D, OMIM 300352). CRTR-D represents the most frequent Cr metabolism disorder but, differently from Cr synthesis defects, that are partially reversible by oral Cr supplementation, does not respond to Cr treatment even if precociously administrated. The precursors of Cr are the non-essential amino acids Glycine (Gly) and Arginine (Arg), which have their own transporters at the brain–blood barrier level and, therefore, their supplementation appears an attractive and feasible therapeutic option aimed at stimulating Cr endogenous synthesis and, in this way, at overcoming the block of Cr transport within the brain. However, until now the effects of Arg and/or Gly supplementation on Cr brain levels and behaviour have been controversial. Methods In this study five Italian male patients affected by CRTR-D were supplemented with oral L-Arg at a dosage of 300 mg/kg/day divided into 3 doses, for 24–36 months. Biochemical and plasmatic amino acids examinations and thyroid hormone dosages were periodically performed. Moreover, Proton and Phosphorus Magnetic Resonance Spectroscopy (MRS) was monitored during follow-up in concurrence with neuropsychological evaluations. Results During L-Arg treatment a clinical improvement in motor skills and to a lesser extent in communication and attention was observed. In addition, all patients had a reduction in the number and frequency of epileptic seizures. Daily living skills appeared also to be positively influenced by L-Arg treatment. Moreover, Total Cr and especially PhosphoCr, evaluated by proton and phosphorus spectroscopy, showed a mild increase, although well below the normal range. Conclusion This study provides information to support the effectiveness of L-Arg supplement treatment in CTRT-D patients; in fact the syndromic pattern of cognitive and linguistic deficit presented by CRTR-D patients was partially altered by L-Arg supplementation especially at a qualitative clinical level. Oral L-Arg may represent not only a protective factor towards a further cognitive decline, but can lead to the acquisition of new skills.
    Orphanet Journal of Rare Diseases 06/2012; 7(1):43. DOI:10.1186/1750-1172-7-43 · 3.36 Impact Factor
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    • "Our follow-up has been too short to decide whether the treatment might prevent complications later in life, such as myopathy and intestinal dysfunction, which have been described in adult patients (Kleefstra et al. 2005; Hahn et al. 2002). Personal observations of creatine monohydrate plus L-arginine and glycine treatment in four male adult patients aged between 17 and 54 years registered positive effects with improved behavior in all, amelioration of severe constipation in one, and achievement of urinary continence in another (Mancini, unpublished). "
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    ABSTRACT: The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated (1)H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H(1)-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect.
    Journal of Inherited Metabolic Disease 05/2011; 35(1):141-9. DOI:10.1007/s10545-011-9345-1 · 3.37 Impact Factor
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