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l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation.

Abstract：

:Creatine and creatine phosphate provide storage and transmission of phosphate-bound energy in muscle and brain. Of the three inborn errors of creatine metabolism causing brain creatine depletion, l-arginine:glycine amidinotransferase (AGAT) deficiency has been described in only two families. We describe clinical and biochemical features, magnetic resonance spectroscopy (MRS) findings and response to creatine supplementation in two siblings with a novel mutation in the AGAT-encoding GATM gene. The sister and brother were evaluated at age 12 and 18years, respectively, because of mild mental retardation, muscle weakness and low weight. Extensive work-up had previously yielded negative results. Electron microscopy of the muscle revealed tubular aggregates and the activity of respiratory chain complexes was decreased in the muscle. Urine organic acid concentrations normalized to urine creatinine concentration were all increased, suggesting a creatine metabolism disorder. Brain MRS was remarkable for absence of creatine. Urine guanidinoacetate levels by tandem mass spectrometry were low, suggesting AGAT deficiency. GATM sequencing revealed a homozygous single nucleotide insertion 1111_1112insA, producing a frame-shift at Met-371 and premature termination at codon 376. Eleven months after commencing treatment with oral creatine monohydrate 100mg/kg/day, repeat MRI/MRS showed significantly increased brain creatine in the sister and a slight increase in the older brother. The parents' impression of improved strength and stamina was substantiated by increased post-treatment versus pre-treatment scores in the Vineland Adaptive Behavior Scale, straight-arm raising and timed up-and-go tests. Similarly, there was an apparent improvement in cognitive function, with significantly increased IQ-scores in the sister and marginal improvement in the brother.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Edvardson S,Korman SH,Livne A,Shaag A,Saada A,Nalbandian R,Allouche-Arnon H,Gomori JM,Katz-Brull R

doi

10.1016/j.ymgme.2010.06.021

subject

Has Abstract

pub_date

2010-10-01 00:00:00

pages

228-32

issue

2-3

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(10)00256-8

journal_volume

101

pub_type

杂志文章

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l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation.