Guanidinoacetate methyltransferase deficiency: differences of creatine uptake in human brain and muscle

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Abstract

Deficiency of guanidinoacetate methyltransferase (GAMT), the first described creatine biosynthesis defect, leads to depletion of creatine and phosphocreatine, and accumulation of guanidinoacetate in brain. This results in epilepsy, mental retardation, and extrapyramidal movement disorders. Investigation of skeletal muscle by proton and phosphorus magnetic resonance spectroscopy before therapy demonstrated the presence of considerable amounts of creatine and phosphocreatine, and accumulation of phosphorylated guanidinoacetate in a 7-year-old boy diagnosed with GAMT deficiency, suggesting separate mechanisms for creatine uptake and synthesis in brain and skeletal muscle. The combination of creatine supplementation and a guanidinoacetate-lowering therapeutic approach resulted in improvement of clinical symptoms and metabolite concentrations in brain, muscle, and body fluids.

Introduction

Guanidinoacetate methyltransferase (GAMT, EC 2.1.1.2) catalyzes the formation of creatine by methylation of its precursor guanidinoacetate (GAA) (Fig. 1). After transport from the liver, pancreas, and kidney into nerve and muscle tissue, creatine is converted into phosphocreatine by the creatine kinase reaction. Phosphocreatine is re-utilized to generate ATP whenever needed. Following the first characterization of a GAMT-deficient patient in 1994, [1] seven patients have been reported so far [2], [3], [4], [5], [6], [7]. Whereas affected patients present with mental retardation and epilepsy, a few patients also exhibited signs of an extrapyramidal movement disorder [1], [2], [5], [7]. In vivo proton magnetic resonance spectroscopy (1H-MRS) revealed an almost complete depletion of brain creatine/phosphocreatine and an accumulation of GAA in all patients. Treatment with creatine monohydrate has been shown to increase brain creatine concentration leading to partial clinical improvement. Dietary arginine restriction in combination with ornithine supplementation has been proposed to lower the concentration of potentially neurotoxic GAA [8].

In contrast to the severe brain involvement, affected patients show no or only mild muscular symptoms [5], [7]. This remains poorly understood, considering that skeletal muscle is another tissue with significant energy demands. Skeletal muscle has not been investigated in newly diagnosed GAMT-deficient patients prior to therapy except for one adult [7]. To study muscle creatine uptake, we performed 1H-MRS and phosphorus magnetic resonance spectroscopy (31P-MRS) of both brain and skeletal muscle before and on treatment of a 7-year-old child diagnosed with GAMT deficiency.

Section snippets

Case report

The 7-year-old male, the product of an uncomplicated 38-week gestation, is the first child of consanguineous healthy Turkish parents. Neonatal hypothermia and feeding difficulties were observed. He sat at 10 months, crawled at 12 months, and walked without support at 18 months. During the following years, severe mental retardation with speech impairment became evident. He developed autistic features with increasing aggressiveness towards individuals and objects. Moderate generalized hypotonia

Metabolite, enzymatic, and molecular genetic analyses

GAA concentrations in plasma, urine, and CSF were markedly elevated (Table 1). Creatinine in serum was in the low normal range, and creatinine excretion during 24 h was decreased (Table 1). When calculated in relation to the initial urinary creatinine excretion, the elevation of the urine GAA concentration before treatment was more drastic (1007 mmol/mol creatinine; controls 10–308). The diagnosis of GAMT deficiency was confirmed by enzyme analysis in cultured fibroblasts (<0.1 nmol/h/mg protein;

Discussion

In a 7-year-old boy with marked developmental delay and epilepsy, GAMT deficiency was suspected by a positive Sakaguchi reaction and subsequent quantitative measurements of GAA. The diagnosis was confirmed by 1H-and 31P-MRS in brain showing an almost complete absence of total creatine and a marked accumulation of GAA, absent GAMT activity in fibroblasts and detection of homozygosity for a new frameshift mutation.

In this patient, MRS of skeletal muscle was performed prior to treatment to

Acknowledgements

We are grateful to Dr. H. Korall, Klinik für Kinder-und Jugendmedizin Reutlingen, School of Medicine, University of Tübingen, Reutlingen, Germany, for analysis of creatine in CSF.

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