Chapter 188 - Creatine deficiency syndromes
Introduction
The creatine deficiency syndromes (CDS) are inborn errors of metabolism that compromise the synthesis and transport of creatine (Cr). Their hallmark is the virtually complete absence of Cr and phosphocreatine (PCr) in the brain, causing a predominantly neurological disease. Patients with CDS present with global developmental delay, mental retardation, speech impairment especially affecting active language, seizures, extrapyramidal movement disorder, and autism spectrum disorder (Schulze, 2003).
The CDS have been discovered only recently. The three diseases, AGAT (arginine:glycine amidinotransferase) deficiency, GAMT (guanidinoacetate methyltransferase) deficiency, and CrT (creatine transporter) defect might together represent the most frequent metabolic disorders with a primarily neurological phenotype. Treatable, but easy to miss through standard diagnostic workup, this group of diseases warrants consideration in the workup for genetic mental retardation syndromes, for intractable seizure disorders, and for neurological diseases with a predominant lack of active speech.
Section snippets
Metabolism and function of creatine
Cr metabolism plays essential roles in energy homeostasis especially in tissues with high or fluctuating energy demands, such as muscle and brain (Wallimann et al., 1992, Wyss and Kaddurah-Daouk, 2000). The system of Cr, PCr, and Cr kinases serves as a spatial and temporal buffer in the intracellular energy metabolism taking up ATP at its production sites and delivering it at its sites of consumption. In addition, it represents the most important intracellular pH buffer system. More recently,
Creatine metabolism in the brain
Due to the limited permeability of the blood–brain barrier for peripheral Cr, the brain relies to some extent on its own de novo Cr synthesis. Recent research in rat brain provides interesting insights into the particular situation of the Cr metabolism in the brain. Ubiquitous expression of AGAT and GAMT indicates that the brain is capable to synthesize Cr from arginine (Braissant et al., 2001). Though, in many brain structures only a small proportion of cells are coexpressing AGAT + GAMT. Less
AGAT
AGAT deficiency is an autosomal recessive disorder. The AGAT gene (official nomenclature GATM) has been mapped to chromosome 15q15.3. It is 16.8 kb in size and contains nine exons. Two mutations, both null mutations, have been reported so far.
GAMT
GAMT deficiency is an autosomal recessive disorder. The GAMT gene has been mapped to chromosome 19p13.3. It is 4.46 kb in size and contains six exons. To date, 20 different mutations have been reported; 65% of them are null mutations and 35% are missense
Clinical presentation
Developmental delay, severe speech disturbance, mental retardation, and, with varying degrees, muscular hypotonia and autistic behavior are common symptoms in all CDS (Table 188.1). Symptoms may be noticed first at 6–12 months of age, becoming more evident in the second and third year.
Neuroimaging
Considering the severity of neurological symptoms in CDS, structural abnormalities of the brain as assessed by MRI are rather infrequent, not pronounced, not progressive in nature and may resolve in subsequent investigations.
AGAT
Except for mild febrile seizures in one patient, seizures or EEG abnormalities have not been observed so far.
GAMT
Seizures usually develop after the first year of life (10 months to 3 years). These include myoclonic, generalized tonic-clonic, and sporadic partial complex seizures, head nodding, and drop attacks (Mercimek-Mahmutoglu et al., 2006a). In severe cases, the seizures are refractory to anticonvulsant treatment. EEG findings have been described as diffuse or multifocal epileptic activity,
Diagnosis
The diagnosis of CDS is feasible by biochemical analysis of Cr and its metabolites, GAA and creatinine, in urine, plasma, and CSF. Each CDS reveals a characteristic biochemical pattern (Schulze, 2003). In AGAT, Cr and GAA are decreased, in GAMT, Cr is decreased and GAA is increased, in CrT, the urinary Cr-to-creatinine ratio is increased, but can be normal in females. In all CDS, MR spectroscopy of the brain is diagnostic revealing the virtually complete absence of Cr and PCr (Schulze, 2003) (
Treatment
The restoration of cerebral Cr and PCr is the primary target of the treatment in CDS. In AGAT and GAMT deficiency, Cr supplementation successfully increases the brain Cr and leads to the improvement of neurological symptoms. However, in CrT patients, Cr supplementation is not effective (Stoeckler-Ipsiroglu et al., 2006). Due to the accumulation of GAA, the neurotoxic precursor of Cr, in GAMT deficiency, the patients require additional treatment (Schulze, 2005). Both the treatment with
Selective screening for creatine deficiency syndromes
Although screening is technically possible, the few reported series show that it is only in cases where there are associated symptoms that either mental retardation or autism can reveal CDS: a thorough search for epilepsy, dystonic movements, active speech impairment, and evidence for X-linked inheritance is required to justify such investigation (Sempere et al., 2010).
Conclusion
CDS represent frequent causes of cognitive and neurological impairment that are treatable. CDS are underdiagnosed because they are easy to miss in the standard diagnostic workup, although they warrant consideration in the workup for genetic mental retardation syndromes, intractable seizure disorders, and neurological diseases with a predominant lack of active speech.
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