CEREBRAL CREATINE DEFICIENCY SYNDROME

HISTORY, PATHOPHYSIOLOGY, AND TREATMENTS

BY: TENZIN KELSANG
Cerebral Creatine Deficiency Syndromes (CCDS) are a group of inborn errors of

creatine metabolism. A deficiency intervenes the proteins involved transportation in

creatine biosynthesis. Creatine is necessary to increase adenosine triphosphate (ATP),

which provides energy to all the cells in the body. Creatine is essential to sustain the high

energy levels needed for muscle and brain development. CCDS is divided into three

groups, Creatine Transport Deficiency (CTD, SLC6A8, CRTR), Guanidinoacetate

Methyltransferase Deficiency (GAMT) and Arginine: Glycine Amidinotransferase

Deficiency (AGAT).

Creatine is synthesised by two enzymatic reactions: (1) transfer of the amidino

group from arginine to glycine, yielding guanidinoacetate and catalysed by L-arginine:

glycine amidinotransferase (AGAT); (2) methylation of the amidino group in the

guanidinoacetate molecule by S-adenosyl-L- methionine: N-guanidinoacetate

methyltransferase (GAMT). Creatine synthesis happens mainly in the kidney and

pancreas, which have high AGAT activity, and in liver, which has high GAMT activity.

From these organs of synthesis, creatine is transported via the bloodstream to the organs;

mainly muscle and brain, where both the endogenous creatine and that derived from

dietary sources are taken up by a sodium- and chloride-dependent CRTR.

In all three disorders, the common symptoms include expressive speech delay,

development delay, hypotonia, and movement disorder, feeding intolerance,

hyperactivity, seizure and autistics-like behaviours. The creatine deficiency is not only

limited to these symptoms as there can be more depending on the severity. Movement

disorder is an additional symptom of GAMT; about 40% of the patients have this

symptom. Only 14 individuals have been reported with AGAT as of 2009. The phenotype

of CRTR deficiency in affected male’s range from mild intellectual disability and speech

delay to severe intellectual disability, seizures, movement disorder and behaviour

disorder. The age at diagnosis range from two to 66years. Females who have CCDS have

more acute symptoms and show less signs of intellectual disability, as females have two

X chromosomes.

All three defects result in almost complete lack of cerebral creatine. It has been known

that creatine is essential for proper brain functions. As they do have roles in energy

storage and transmission, creatine may have an additional role as a neuromodulator.

Creatine plays an important role in muscle tissue, but creatine levels are not affected as

much in patients with CDS. Urinary creatine excretion levels also differ as patients with

defects in creatine synthesis, levels are low, whereas in CRTR, the levels are high. Then

there’s also guanidinoacetate, which is the second metabolite that plays a role in CDS. In

GAMT deficiency, guanidinoacetate gather in tissues and body fluids. In the

cerebrospinal fluid levels, more than 100-fold normal are found. In AGAT deficiency,

guanidinoacetate is low, while in CRTR the acid levels are normal.

Diagnosis/Testing & Treatments

Diagnoses of CCDS depend on measurement of guanidinoacetate, creatine, and creatinine

in urine and plasma and molecular genetic testing, which involve GAMT and SCL6A8. If
the molecular genetic test results are inconclusive, then GAMT enzyme activity or

creatine uptake in cultures fibroblasts can be assessed. Then there is also prenatal

diagnosis and preimplantation genetic diagnosis for at-risk pregnancies. They require

prior identification of the disease causing mutation in the family for all three creatine

deficiency syndromes. GAMT deficiency can also be prenatally diagnosed by

guanidinoacetate measurement in the amniotic fluid in pregnancies at risk, only if the

underlying disease causing mutations have not been identified.

Currently there has been no effective treatment for CRTR and it is estimated that

this deficiency is the second largest cause of X-linked mental disability. For GAMT and

AGAT, treatment with oral supplementation is available and effective, if it has been

initiated early in patients. Supplements may include Creatine Monohydrate, L-ornithine

and sodium benzoate for GAMT. For AGAT, supplements include Creatine

Monohydrate. Dosing and supplement vary from patient to patients, as there are different

levels of severity.
Reference:
Mercimek-Mahmutoglu, S. (2015, December 10). Creatine Deficiency Syndromes.
Retrieved April 06, 2018, from https://www.ncbi.nlm.nih.gov/books/NBK3794/

Stockler, S., Schutz, P. W., & Salomons, G. S. (1970, January 01). Cerebral Creatine
Deficiency Syndromes: Clinical Aspects, Treatment and Pathophysiology. Retrieved
April 06, 2018, from https://link.springer.com/chapter/10.1007/978-1-4020-6486-9_8

Overview of Cerebral Creatine Deficiency Syndromes. (n.d.). Retrieved April 06, 2018,
from https://creatineinfo.org/overview-of-creatine-deficiency-syndromes/

Mercimek-Mahmutoglu, S., Salomons, G. S., Adam, M. P., Ardinger, H. H., Pagon, R.

A., Wallace, S. E., Amemiya, A. (n.d.). Creatine Deficiency Syndromes. Retrieved April
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