Guanidinoacetate methyltransferase deficiency

This disorder is inherited in an autosomal recessive manner, which means the causative gene is located on an autosome, and two defective copies of the gene – one from each parent – are required to inherit the disorder. The parents both carry one pathogenic variant, however they are not affected by the disorder. As carriers, the residual activity of approximately 50% is enough to avoid clinical complications.^[3] Unaffected siblings of an affected individual have a 2/3 chance of being carriers.^[3]

Diagnosis

GAMT deficiency can be suspected from clinical findings, although clinical findings are not suggestive of a specific diagnosis. Laboratory testing of

Treatment is most effective for GAMT deficiency with early diagnosis, however the non-specific clinical findings mean there is often a delay in diagnosis. Due to the efficacy of treatment and the delay in diagnosis, GAMT deficiency has been a candidate for newborn screening programs.^[7][8] Newborn screening assays measure the amount of guanidinoacetate in a dried blood spot using tandem mass spectrometry. Abnormal results from a newborn screening test still need to be confirmed by testing in plasma or urine.^[7] GAMT deficiency was nominated to be included in the list of disorders recommended for screening in the United States in 2016. It was not recommended for inclusion, as studies completed at the time could not demonstrate that a case could be reliably identified in a newborn screening setting.^[9] Utah started screening for GAMT deficiency in all newborns in 2015. New York started screening newborns in late 2018, and Michigan planned to start in 2019.^[10]

Treatment

Treatment of GAMT deficiency focuses on restoration of depleted brain creatine with creatine supplementation in pharmacologic doses, and removal of toxic intermediates via ornithine supplementation.^[9] All patients are reported to benefit by this treatment, with improvements in muscular hypotonia, dyskinesia, social contact, alertness and behavior. Seizures appear to reduce more with dietary arginine restriction and ornithine supplementation. Despite treatment, none of the patients have been reported to return to completely normal developmental level, if significant damage had taken place before treatment. Prior to the addition of GAMT deficiency to newborn screening panels, younger siblings of affected individuals may have been tested at birth and treated early. This early treatment can result in outcomes that are very close to normal.^[9]

References