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Guide to Understanding CCDS Brochure

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Guide to Understanding CCDS Brochure Diagnostic Testing This is Creatine A Guide to Proper diagnosis and early intervention is critical to establish treatments needed to im- Creatine is formed in the liver and prove life quality and longevity for CCDS patients. Understanding kidneys. It is also found in some of the METABOLITE SCREENING Metabolite Screening foods we eat, such as fish, meat, and Test Results: dairy. Creatine is necessary for energy Testing of both urine and plasma is necessary to screen usage in all cells of the body and is for all three disorders. AGAT crucial for brain development . The concentration of creatine (CR), guanidinoacetate Plasma CCDS (GAA), and creatinine (Crn) are measured. GAA: Low Cerebral Creatine Deficiency Syndromes Gene sequencing should be considered if there is a suspi- Creatine: Low/normal cion of CTD in a female with normal metabolite screening. Urinea GAA: Low Our Bodies PROTON MAGNETIC RESONANCE Creatine: Low/normal SPECTROSCOPY (1H-MRS) OF THE BRAIN Need Creatine Can be requested at the same time as brain MRI. GAMT Useful for measuring creatine levels in the brain. Production and transportation of creatine are essential to its use in the body. Two Decreased/absent creatine peak in the brain for all Plasma three disorders. Creatine level is low in females het- enzymes make creatine, AGAT (L-Argi- GAA: Elevated erozygous for CTD, but may overlap with unaffected Creatine: Low nine:glycine amidinotransferase) and GAMT individuals. Urinea (guanidinoacetate methyltranserase). GAA: Elevated Brain MRI may show non-specific findings such as Creatine: Low/normal delayed myelination, hyperintensities of the globus pallidus, and cerebral atrophy. GENE SEQUENCING CTD Sequencing of the genes GATM, GAMT, and SLC6A8 Plasma It Requires a GAA: Normal ENZYME ASSAYS Creatine: Normalb Transporter Cultured skin fibroblasts are not usually required for diagno- Urinea sis, but may be helpful when metabolite and gene sequencing GAA: Normal Creatine: Elevated in males; The CrT transporters allow creatine to be test results are unclear. This includes measurement of AGAT may be normal in femalsc transported into the cells of the body. and GAMT activity and creatine uptake studies for CTD. Without this transporter, creatine can’t aUrine metabolites are measured rela- get into the brain and muscles. LABORATORY TESTING tive to creatinine. bUrine is needed to diagnose creatine transporter deficiency (CTD) in males, Resources offering CCDS testing information: CTD will be missed in males if only plasma is screened. Association for Creatine Deficiencies: creatineinfo.org/screening/ cUrine creatine can be normal in females ScreenCreatine: screencreatine.org/labs/ who are heterozygous for CTD. Se- quencing of the SLC6A8 gene is need- Genetic Testing Registry (GTR): www.ncbi.nlm.nih.gov/gtr/ ed for assessment of females for CTD. Association for Creatine Deficiencies 6965 El Camino Real, Suite 105-598 Carlsbad, CA 92009 www.creatineinfo.org NORMAL CREATINE PRODUCTION EARLY DIAGNOSES It is encouraged that all individuals with Global Developmental Delay, CEREBRAL CREATINE DEFICIENCY Speech Delay, Hypotonia, Autism, or Epilepsy be screened for CCDS as SYNDROMES (CCDS) are three rare, early as possible. inborn errors of creatine metabolism, = = Speech Delay may be particularly severe and is present in all affected GAA children. Many individuals develop no speech, or speak only in single words. in which the body’s production or AGAT GAMT CREATINE transportation of creatine is impaired. Intellectual Disability of variable severity is typically present in all affected TRANSPORTER older children and adults. CCDS CLINICAL SYMPTOMS AGAT DEFICIENCY 97% SPEECH DELAY Arginine: Glycine Amidinotransferase Deficiency is an 92% GROSS MOTOR DELAY impairment of the first enzyme necessary for creatine pro- 73% SEIZURES duction. Glycine and Arginine in the diet cannot combine NO 73% HYPOTONIA to form guanidinoacetate (GAA). No creatine is produced. CREATINE 64% AUTISM AGAT GAMT MUTATED GENE: GATM 62% EATING DIFFICULTIES INHERITANCE: Autosomal Recessive (Two copies of an abnormal 41% FAILURE TO THRIVE gene are present. Typically one from each parent.) GAMT DEFICIENCY Guanidinoacetate Methyltransferase Deficiency is an im- pairment of the second enzyme necessary for metabolizing NO guanidinoacetate into creatine, resulting in a buildup of *Results from ACD 2017 unused guanidinoacetate (GAA). No creatine is produced. CREATINE survey of CCDS families. Additional GAA references for this brochure can be AGAT GAMT found at: creatineinfo.org/acd-resources MUTATED GENE: GAMT INHERITANCE: Autosomal Recessive (Two copies of an abnormal gene are present. Typically one from each parent.) TREATMENTS: Treatment with oral supplementation is effective, if initiated early for AGAT CTD and GAMT deficiencies. To date, supplementation has not been proven to Creatine Transporter Deficiency is a mutation in the be effective in individuals with CTD. creatine transporter gene. This results in a blockage in the Oral creatine monohydrate is given to replenish creatine levels in the transportation of creatine to the brain. No creatine is utilized. brain and other tissues in individuals with AGAT and GAMT deficiencies. MUTATED GENE: SLC6A8 = Low arginine/protein diet, l-ornithine supplementation, and sodium INHERITANCE: X-linked (Mutated gene is located on the X chromo- benzoate are used to reduce toxic levels of guanidinoacetate in GAA some. Typically inherited from the mother or a “de novo mutation” that AGAT GAMT CREATINE individuals with GAMT deficiency. is not inherited, but is the first occurrence in a family.) There may be some clinical benefit to a subset of individuals with CTD FEMALES: About half of females with one mutated copy of the SLC6A8 gene (heterozygous) have intellectual disability, learning difficul- CTD when treated with creatine monohydrate, l-arginine, and glycine. ties, or behavioral problems. The other half are unaffected carriers. Additional treatments for CTD are under investigation. FIND SUPPORT, CCDS RESOURCES, AND JOIN OUR PATIENT REGISTRY AT: CREATINEINFO.ORG.
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