Cerebral Creatine Deficiency Disorders

Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders.

Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency

Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations.

Intellectual disability is a general term that describes intellectual capacity and adaptive functioning. There are many causes and many co-occurring conditions. To appreciate and respect the uniqueness of each individual and to choose appropriate interventions, it is critical that, if possible, the cause for intellectual disability be identified or the conditions that led to or sustain it be recognized. This chapter begins with an overview followed by an approach to understanding causation, a description of how etiology is determined, consideration of the neurobiological/environmental interface, a discussion of the evaluation process to determine causes and conditions related to diagnoses, and a discussion of risk factors. Intellectual disability is an intellectual, cognitive, and developmental disability that profoundly affects an individual’s functioning and adaptation to everyday life. Intellect refers to mental ability or capacity, the power of thought, and the ability to reason and solve problems. Mental capacity is distinguished from perception, emotions, and feelings. Intelligence refers to facility and quickness in understanding and problem solving. In intellectual disability, there is reduced mental capacity. Cognition refers to the use or handling of knowledge through mental activities associated with thinking, learning, and memory, which are necessary processes to acquire knowledge. In intellectual disability, there are cognitive disabilities that vary depending on the individual syndrome. The extent of intellectual disability varies among syndromes, and there may be variations within a syndrome. Both cognition and intellect are linked to cortical brain function. Intellectual disability is a developmental disability with onset during the developmental period. Thus, there are delays in meeting developmental mile stones in motor, fine motor, language, and psychosocial areas. Finally, there are difficulties in adaptive function and in the mastery of developmental tasks as a result of intellectual, cognitive, and developmental disabilities. A focus on the etiology of intellectual disability is needed for research, clinical, and administrative purposes. This chapter will review the multiple causes of intellectual disability, considering the interface between genetic, neurobiologic, and environmental factors and causation. It emphasizes the importance of a comprehensive evaluation and provides guidelines for conducting an evaluation. Associated mental, emotional, and behavioral disorders are discussed in chapter 6.

Disorders of creatine metabolism arise from genetic alterations of arginine:glycine amidinotransferase (AGAT), guanidinoacetate methyltransferase (GAMT), and the creatine transporter. We developed a strategy for the detection of AGAT and GAMT defects by measurement of guanidinoacetate (GAA) and creatine plus creatinine (Cr+Crn) in biological fluids. Three patients with AGAT deficiency from the same pedigree and their eight relatives, as well as a patient affected by a GAMT defect and his parents were analyzed by a new HPLC procedure in comparison with 90 controls. The method, which uses precolumn derivatization with benzoin, separation with a reversed-phase column, and fluorescence detection, has shown good precision and sensitivity and requires minimal sample handling. In the three AGAT patients, plasma GAA was 0.01-0.04 micro mol/L [mean (SD) for neurologically normal controls was 1.16 (0.59) micromol/L], Cr+Crn was 15-29 micro mol/L [reference limit in our laboratory, 79 (38) micromol/L]. Urinary GAA was 2.4-5.8 micro mol/L [reference, 311 (191) micromol/L], and Cr+Crn was 2.1-3.3 mmol/L [reference, 9.9 (4.1) mmol/L]. We found a smaller decrease in GAA and Cr+Crn in some carriers of an AGAT defect. In the patient with GAMT deficiency, plasma and urine GAA was increased (18.6 and 1783 micromol/L, respectively), and Cr+Crn was decreased in plasma (10.7 micromol/L) and urine (2.1 mmol/L). GAA was increased in the parents' plasmas and in the mother's urine. The assessment of GAA is a new tool for the detection of both GAMT and AGAT deficiencies.

Adolescent girl with unexplained intellectual disability in who was identified a defect in the biosynthesis of creatine by guanidinoacetate methyltransferase (GAMT) deficiency. Were identified two GAMT gene mutations: c.59G>C in exon 1 and c.521G>A in exon 5. The creatine and ornitine substitution and arginine restriction, despite initiated at 13 years old, motivated a global behaviour comportmental acceleration. The GAMT deficiency is an inborn error of metabolism with molecular and clinical heterogeneity varying from a speech delay to autistic behaviour and severe cognitive deficit. Should be considered in patients with unexplained intellec tual disability, especially in Portugal where was documented a high frequency of patients and carriers. The pertinence of the neonatal screen in our country is discussed.

3 - Creatine deficiency syndromes

Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of the metabolism of creatine that leads to depleted levels of creatine and excessive concentrati...

Intellectual disability is sub-average intellectual functioning with impaired adaptive functioning. The limitations in their adaptive skill hampers the ability to cope with stressful life events. There are many issues which require attention while dealing with them like parental level, peer groups, schools, presence of comorbid conditions, etc. Interventions at right stage under efficient supervision can lead to healthy and smooth functioning of cases with ID and with good outcomes. Difficulties like lack of human resources, quality training of clinical psychologists in India, scarcity of effective clinical guidelines, conflicts among the team approach, acceptance in the family and society requires attention in current scenario. There are many things that can be offered but what we need is their acceptance in our society and awareness towards Intervention. This chapter aims at acknowledging these issues to create awareness amongst the responsible caregivers. Timely recognition of treatable causes of intellectual disability can be very rewarding and prevent a lifelong disability.

Creatine deficiency syndromes are a newly described group of inborn errors of creatine synthesis (arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency) and of creatine transport (creatine transporter (CRTR) deficiency). The common clinical feature of creatine deficiency syndromes is mental retardation and epilepsy suggesting main involvement of cerebral gray matter. The typical biochemical abnormality of creatine deficiency syndromes is cerebral creatine deficiency, which is demonstrated by in vivo proton magnetic resonance spectroscopy. Measurement of guanidinoacetate in body fluids may discriminate between the GAMT (high concentration), AGAT (low concentration) and CRTR (normal concentration) deficiencies. Further biochemical characteristics include changes in creatine and creatinine concentrations in body fluids. GAMT and AGAT deficiency are treatable by oral creatine supplementation, while patients with CRTR deficiency do not respond to this type of treatment. The creatine deficiency syndromes are underdiagnosed, so their possibility should be considered in all children affected by unexplained mental retardation, seizures and speech delay.

Chapter 9 - Intellectual disability

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis that results in intellectual disability, epilepsy, expressive language delay, and dystonia. We report data from two siblings with an uncommon GAMT deficiency phenotype and their clinical, biochemical, imaging, and treatment findings. The older sibling had intellectual disability, epilepsy, and generalized dystonia. The younger sibling had intellectual disability and generalized dystonia. After treatment with creatine, verbal fluency improved, as well as dystonia and aggression. This study confirms that in patients with unexplained intellectual disability, epilepsy, and/or movement disorders, GAMT deficiency should be considered. GAMT-associated cerebral creatine deficiency syndrome is a potentially treatable condition and can be identified by elevated levels of guanidinoacetate in plasma or urine or by a significantly decreased creatine peak on magnetic resonance spectroscopy.

Editorial: Introduction to Special Section on Evidence-Based Practices for Persons With Intellectual and Developmental Disabilities

The epigenetic machinery in conjunction with the transcriptional machinery is responsible for maintaining genome-wide chromatin states and dynamically regulating gene expression. Mendelian disorders of the epigenetic machinery (MDEMs) are genetic disorders resulting from mutations in components of the epigenetic apparatus. Though individually rare, MDEMs have emerged as a collectively common etiology for intellectual disability (ID) and growth disruption. Studies in model organisms and humans have demonstrated dosage sensitivity of this gene group with haploinsufficiency as a predominant disease mechanism. The epigenetic machinery consists of three enzymatic components (writers, erasers and chromatin remodelers) as well as one non-enzymatic group (readers). A tally of the entire census of such factors revealed that although multiple enzymatic activities never coexist within a single component, individual enzymatic activities often coexist with a reader domain. This group of disorders disrupts both the chromatin and transcription states of target genes downstream of the given component but also DNA methylation on a global scale. Elucidation of these global epigenetic changes may inform our understanding of disease pathogenesis and have diagnostic utility. Moreover, many therapies targeting epigenetic marks already exist, and some have proven successful in treating cancer. This, along with the recent observation that neurological dysfunction in these disorders may in fact be treatable in postnatal life, suggests that the scientific community should prioritize this group as a potentially treatable cause of ID. Here we summarize the recent expansion and major characteristics of MDEMs, as well as the unique therapeutic prospects for this group of disorders.