Tuesday, November 17, 2015

Cerebral creatine deficiency syndrome 1

Inspired by the recent diagnosis of cerebral creatine deficiency syndrome 1 in a patient with speech and language delay, accomplished through whole exome sequencing, showing a pathogenic alteration in the SLC6A8 gene

Comeaux MS, Wang J, Wang G, Kleppe S, Zhang VW, Schmitt ES, Craigen WJ, Renaud
D, Sun Q, Wong LJ. Biochemical, molecular, and clinical diagnoses of patients
with cerebral creatine deficiency syndromes. Mol Genet Metab. 2013


Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing.

From the article:
Treatment for CCDS is limited. Creatine supplementation is used for patients with AGAT or GAMT deficiencies and has been shown to improve patient symptoms. Dietary restriction of arginine using protein restriction and supplementation with ornithine to reduce the available substrate for AGAT and provide product feedback inhibition has been reported for several GAMT patients. However, while GAA levels decreased, the long term benefits remain to be established. Effective treatment for CT1 deficiency remains elusive. l-Arginine and l-glycine supplementation, creatine precursors that cross the blood brain barrier without a functional CT1 transporter, has been used to stimulate creatine synthesis in the brain; however, the results to date have not been shown to improve cerebral 1H-MRS-detectable levels of creatine. Additionally, it has been reported that supplementation with arginine and glycine in CT1 patients causes hyperhomocysteinemia.
Thus, while CT1 deficiency does not respond well to creatine supplementation, early treatment is somewhat effective for both AGAT and GAMT deficiencies. Therefore, early diagnosis confirmation followed by treatment implementation is important to prevent worsening of the neurological symptoms. So, when CCDS is suspected, especially in patients with neurologic signs, language/speech defects, and growth delay, biochemical screening of plasma GAA and urine creatine:creatinine ratio should be performed. Gene sequencing of AGAT and GAMT should be considered in patients with multiple abnormal plasma GAA levels. SLC6A8 sequencing should be performed in male patients with multiple elevated creatine:creatinine ratios and when female patients are suspected of having CT1 deficiency.
Clark JF, Cecil KM. Diagnostic methods and recommendations for the cerebral
creatine deficiency syndromes. Pediatr Res. 2015 Mar;77(3):398-405.


Primary care pediatricians and a variety of specialist physicians strive to define an accurate diagnosis for children presenting with impairment of expressive speech and delay in achieving developmental milestones. Within the past two decades, a group of disorders featuring this presentation have been identified as cerebral creatine deficiency syndromes (CCDS). Patients with these disorders were initially discerned using proton magnetic resonance spectroscopy of the brain within a magnetic resonance imaging (MRI) examination. The objective of this review is to provide the clinician with an overview of the current information available on identifying and treating these conditions. We explain the salient features of creatine metabolism, synthesis, and transport required for normal development. We propose diagnostic approaches for confirming a CCDS diagnosis. Finally, we describe treatment approaches for managing patients with these conditions.

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