Symptoms & Screening

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Who Should be Tested?

The CCDS are inborn errors of metabolism affecting the synthesis and transport of creatine. Early diagnosis of these disorders is essential for prompt initiation of treatment and improved outcomes.

Clinical Symptoms

While there is variability in clinical severity and presentation in children with CCDS, the following symptoms are commonly observed in untreated patients.

  • Global developmental delay affects all children with these disorders. It may be the first sign, appearing before other symptoms.
  • Speech delay may be particularly severe and is present in all affected children. Many individuals develop no speech, or speak only in single words.
  • Intellectual disability of variable severity is typically present in all older children and adults.
  • Seizure disorders have a variable age of onset and severity, and are not always present.
  • Hypotonia, muscle weakness and muscle hypotrophy are common.
  • Behavior disorders including autism-like behaviors and hyperactivity
  • Movement disorder including dystonia and dyskinesia (sometimes labeled as cerebral palsy)
  • Gastrointestinal problems such as chronic constipation, vomiting
  • Failure to thrive
  • Dysmorphic features, such as mid-face hypoplasia, are more often found in people with creatine transporter deficiency.

Biochemical Testing

Testing in both urine and plasma is recommended to screen for all three disorders. At a minimum, a urine specimen should be tested.

Creatine transporter deficiency (CTD) will be missed if only plasma is screened because males with this disorder have normal creatine in plasma; urine is needed to make this diagnosis in males.

PLASMA SCREEN
GAA Creatine
CTD* Normal Normal
AGAT Deficiency Low Low/normal
GAMT Deficiency Elevated Low

Urine SCREEN*
GAA Creatine
CTD Normal Elevated
AGAT Deficiency Low Low/normal
GAMT Deficiency Elevated Low/normal

*Inclusion of urine screening is recommended because CTD can appear normal in plasma screening. Urine creatine can be normal in females heterozygous for CTD. Sequencing of the SLC6A8 gene is needed for the assessment of females for CTD. Urine metabolites are measured relative to creatinine.
Low plasma and urinary creatinine values are a diagnostic clue for AGAT and GAMT deficiency. Generalized pseudo-elevations of urine metabolites normalized to creatinine, such as amino acids and organic acids, may be observed as a result of low urinary creatinine.

Proton Magnetic Resonance Spectroscopy

Decreased or absent creatine peak is noted for all three disorders

Guanidinoacetate peak in GAMT Deficiency

Gene Sequencing & Fibroblast Assays

Gene sequencing of the GATM, GAMT, and SLC6A8 may be used to confirm a CCDS diagnosis.

Fibroblast assays may be used to measure AGAT and GAMT activity and to detect creatine uptake for CTD.

Share Your Expertise

The ACD is always looking for experienced clinicians and researchers that share our passion for Cerebral Creatine Deficiency Syndromes. If you would like to be added to our database of CCDS Centers, please submit the form below.

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    Laboratories

    1. Via Biochemical Assessment

      Biochemical Assessment for Plasma and Urine GAA/Creatine

      • ARUP Laboratories, Biochemical Genetics Laboratory
      • Baylor Miraca Genetics Laboratories
      • Greenwood Genetic Center
      • Kennedy Krieger Institute Genetics Laboratory – Biochemical Genetics Lab
      • Mayo Medical Laboratories
      • MNG Laboratories/ Atlanta Center: Medical Neurogenetics, LLC.,
      • Seattle Children’s Hospital
      • University of Alabama Birmingham, Biochemical Genetics Laboratory

    2. Via Single Gene Sequencing

      Sequencing of GAMT (GAMT Deficiency)

      • ARUP Laboratories, Molecular Genetics Laboratory
      • Baylor Miraca Genetics Laboratories
      • Cincinnati Children’s Hospital Medical Center, Molecular Genetics Laboratory
      • Fulgent Diagnostics
      • Prevention Genetics

      Sequencing of GATM (AGAT Deficiency)

      • ARUP Laboratories, Molecular Genetics Laboratory
      • Baylor Miraca Genetics Laboratories
      • Cincinnati Children’s Hospital Medical Center, Molecular Genetics Laboratory
      • Fulgent Diagnostics
      • Prevention Genetics

      Sequencing of SLC6A8 (Creatine Transporter Deficiency)

      • ARUP Laboratories, Molecular Genetics Laboratory
      • Baylor Miraca Genetics Laboratories
      • Center for Human Genetics, Inc.
      • Cincinnati Children’s Hospital Medical Center, Molecular Genetics Laboratory
      • Fulgent Diagnostics
      • Greenwood Genetic Center Diagnostic Laboratories

      *Deletions/Duplications in these genes appear to be extremely rare. However, some of the above laboratories also offer deletion/duplication testing in addition to sequencing, which may need to be ordered separately if desired.

    3. Via Multigene Panel

      Sequencing Panels that include GAMT

      • Ambry Genetics – Comprehensive Epilepsy Testing (EpiNext)
      • Courtagen Life Sciences – epiSEEK Focus
      • Emory University – Epilepsy and Seizure Disorders Panel
      • Emory University – Neurology: Sequencing Panel
      • Fulgent Diagnostics – Epilepsy NGS Panel
      • Fulgent Diagnostics – Intellectual Disability NGS Panel
      • Fulgent Diagnostics – Lysosomal Disorders NGS Panel
      • GeneDx – Comprehensive Epilepsy Panel
      • GeneDx – Infantile Epilepsy Panel
      • Gene Dx – Childhood Onset Epilepsy Panel
      • Greenwood Genetic Center Diagnostic Laboratories – NGS Epilepsy/Seizure Panel
      • Prevention Genetics – Early Infantile Epileptic Encephalopathy, Recessive NextGen Sequencing (NGS) panel
      • Prevention Genetics – Early Infantile Epileptic Encephalopathy NextGen Sequencing (NGS) Panel

      Sequencing Panels that include GATM

      • Ambry Genetics – Comprehensive Epilepsy Testing (EpiNext)
      • Courtagen Life Sciences – epiSEEK Focus
      • Courtagen Life Sciences – nucSEEK Comprehensive Sequence Analysis of the Nuclear Mitochondrial Exome
      • Emory University – Epilepsy and Seizure Disorders Panel
      • Emory University – Neurology: Sequencing Panel
      • Fulgent Diagnostics – Epilepsy NGS Panel
      • Fulgent Diagnostics – Nuclear-Mito NGS Panel
      • GeneDx – Comprehensive Epilepsy Panel
      • GeneDx – Childhood Onset Epilepsy Panel
      • Greenwood Genetic Center Diagnostic Laboratories – NGS Epilepsy/Seizure Panel

      Sequencing Panels that include SLC6A8

      • ARUP – X-Linked Intellectual Disability Panel
      • Courtagen Life Sciences – devSEEK Sequence Analysis for Neurodevelopmental Disorders, Developmental Delay, Intellectual Disability, Autism Spectrum Disorders
      • Courtagen Life Sciences – nucSEEK Comprehensive Sequence Analysis of the Nuclear Mitochondrial Exome
      • Fulgent Diagnostics – Intellectual Disability NGS Panel
      • Fulgent Diagnostics –Nuclear-Mito NGS Panel
      • InVitae – Early Infantile Epileptic Encephalopathy Panel
      • Transgenomic – Autism Spectrum Disorder/Intellectual Disability/Multiple Congenital Anomalies NGS Panel
      • University of Chicago – Comprehensive Non-Specific ID Sequencing Panel

      Sequencing Panels that include all three (GAMT, GATM and SLC6A8)

      • Courtagen Life Sciences – epiSEEK Infancy and Childhood Epilepsy Panel
      • Courtagen Life Sciences – devACT Clinical Management Panel, Developmental Delay, Intellectual Disability, Autism Spectrum Disorders
      • GeneDx – Comprehensive Mitochondrial Nuclear Gene Panel
      • GeneDx – Combined Mito Genome Plus Mito Nuclear Gene Panel
      • InVitae – Epilepsy Panel
      • Transgenomic – NuclearMitome
      • Transgenomic – Comprehensive Epilepsy Evaluation NGS Panel
      • University of Chicago – Epilepsy Exome Panel

      *Whole Exome Sequencing (WES) is also available through many labs, and this test should also detect all three creatine deficiency syndromes.

    References

    Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M. Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet. 157C:72-8, 2011.

    Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S, Salomons GS. Creatine Deficiency Syndromes. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. 2009 Jan 15.

    Rosenberg EH, Almeida LS, Kleefstra T, deGrauw RS, et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 75:97-105, 2004

    Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, et al. Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab. 2015 Oct 17. [Epub ahead of print]

    Stockler-Ipsiroglu S, van Karnebeek C, Longo N, Korenke GC, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 111:16-25, 2014

    van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 50:463-72, 2013

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