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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders Clara D.M. van Karnebeek, MD, PhD1,2,3,4
1 Division of Biochemical Diseases, Department of Pediatrics, BC
Children’s Hospital, University of British Columbia, Vancouver, Canada 2 Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), University of British Columbia, Vancouver, Canada 3 Child and Family Research Institute, University of British Columbia, Vancouver, Canada 4 Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
Address for correspondence Sylvia Stockler-Ipsiroglu, MD, PhD, MBA, FRCPC, Department of Pediatrics, University of British Columbia, Child and Family Research Institute, University of British Columbia, K3-204-4480 Oak Street, Vancouver B.C. V6H 3V4, Canada (e-mail: [email protected]).
Semin Neurol 2014;34:350–356.
Abstract
Keywords
► GATM ► guanidinoacetate methyltransferase ► SLC6A8 ► magnetic resonance spectroscopy ► treatment ► intellectual disability ► developmental delay ► autism
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 creatinemonohydrate 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.
Intellectual developmental disorders (IDDs), characterized by significant impairment of cognitive functions, with limitations of learning, adaptive behavior, and skills, are frequent (2.5% of the population affected) and present with significant comorbidity. The burden of intellectual disability (ID), in terms of emotional suffering and associated health care costs, is significant; prevention and treatment therefore are impor-
Issue Theme Neurogenetics; Guest Editor, Ali Fatemi, MD
tant. Traditionally, IDD has been considered an unchangeable fate, as causal treatments, which might prevent or reverse IDD, are not available for the majority of etiologies. Inborn errors of metabolism (IEM) currently represent the largest category of genetic IDDs, which are amenable to therapies targeting the underlying pathophysiology. We performed a systematic literature review and identified 81 such treatable
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1386772. ISSN 0271-8235.
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Sylvia Stockler-Ipsiroglu, MD, PhD1,2,3
Stockler-Ipsiroglu, van Karnebeek
Fig. 1 Creatine synthesis and metabolism. ADP, adenosine-diphosphate; AGAT, arginine: glycine amidinotransferase deficiency; ATP, adenosinetriphosphate; CK, creatine kinase; CRTR, creatine transporter (SLC6A8); GAMT, guanidinoacetate methyltransferase.
IDDs,1 recently updated to 91,2 three of which are creatine deficiency disorders (CDDs). Creatine deficiency disorders comprise two autosomal recessive disorders that affect the biosynthesis of creatine (arginine:glycine amidinotransferase deficiency [AGAT; MIM 602360] and guanidinoacetate methyltransferase deficiency [GAMT; MIM 601240]) and the X-linked creatine transporter (SLC6A8; MIM 300036) defect that affects the creatine transport into the brain and muscle. Intellectual developmental disorders are the common and predominant denominator of these conditions, ranging in severity from mild to severe. Intellectual developmental disorders are typically associated with behavioral problems, speech delay, epilepsy, and movement disorders. Myopathy and muscular hypotrophy are features of AGAT and SLC6A8 deficiency. In general, GAMT deficiency features the more severe phenotypes compared with AGAT and SLC6A8 deficiency.
Creatine Synthesis and Transport Creatine synthesis occurs mainly in the liver, kidney, and pancreas, and is facilitated by two enzymatic steps: (1) Larginine:glycine amidinotransferase (AGAT) catalyzes the formation of guanidinoacetate (GAA) from arginine and glycine; and (2) guanidinoacetate methyltransferase (GAMT) catalyzes the formation of guanidinoacetate (GAA) from GAA and S-adenosylmethionine. The formation of GAA is the rate-limiting reaction, facilitated by inhibition of AGAT activity via negative feedback through creatine and competitive inhibition through ornithine. Although the
brain is capable of producing minor amounts of creatine, the major proportion is taken up from the blood via SLC6A8. Intracellular creatine is reversibly converted into creatinephosphate by the action of creatine kinase. Creatine/creatine phosphate and ADP/ATP together with CK represent a high-energy phosphate shuttle mainly in brain and muscle. Creatine is nonenzymatically converted into creatinine, which is excreted in the urine with a constant daily turnover of 1.5% of body creatine. The daily creatinine excretion is directly proportional to total body creatine, and in particular to muscle mass (i.e., 20–25 mg/kg every 24 hours in children and adults) (►Fig. 1).
Diagnostic Markers The common biochemical denominator of all CDD is lack of creatine in the brain. Although marked reduction of the creatine signal in H-MRS (proton magnetic resonance spectroscopy) of the brain is an indicator of disorders of creatine biosynthesis and transport, determination of urinary guanidinoacetate and the urinary creatine to creatinine ratio is fundamental to their differential diagnosis. Urinary guanidinoacetate is high in GAMT deficiency and low in AGAT deficiency. An increase of urinary creatine excretion together with a low urinary creatinine excretion is characteristic for SLC6A8 deficiency. An elevated urinary creatine to creatinine ratio serves as a diagnostic marker in hemizygous males, whereas this marker is not sensitive in heterozygous females. Molecular analysis of AGAT (GATM), GAMT (GAMT), and SLC6A8 (SLC6A8) is currently used for diagnostic Seminars in Neurology
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders
Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders confirmation via the identification of mutations, insertions, deletions ,or other complex rearrangements. Available biomarker screening can yield false-negative results, particularly in AGAT and SLC6A8 deficiency. Therefore, primary molecular analysis might be the safest approach to diagnostic ascertainment of both conditions. This is especially true for detecting heterozygous SLC6A8 females, for whom there exists no reliable diagnostic marker. Functional tests, including enzymatic assays in fibroblasts, lymphoblasts, and/or in expression systems, provide diagnostic confirmation at a functional level, particularly for new mutations of unknown pathogenicity.
Guanidinoacetate Methyltransferase Deficiency In 1994, a 22-month-old boy was the first patient identified with GAMT deficiency3,4: His development had been considered normal up until the age of 4 months, when he developed hypotonia, hyperkinetic extrapyramidal movements, and head nodding. His electroencephalogram (EEG) showed slow background activity and multifocal spike slow waves. Magnetic resonance imaging (MRI) revealed bilateral abnormalities of the globus pallidus consisting of hypointensities in T1-weighted images and as hyperintensities in T2-weighted images. To date, approximately 80 patients have been diagnosed worldwide, many of them being published as either single cases or case series. In two previous overviews of 27 and 8 cases, patients had a broad clinical spectrum from mild to severe IDD.5,6 Intellectual developmental disorders in GAMTdeficient patients is mostly associated with behavioral disturbances, such as autism and aggression/hyperactivity. Expressive speech delay is also prominent in those patients who have milder degrees of IDD and is most resistant to treatment interventions. Apart from unspecific seizure types, such as absence and tonic clonic, focal, or generalized seizures, particular seizure types including head drop seizures, myoclonic seizures, infantile spasms, and myoclonic astatic seizures have been observed. Electroencephalogram changes can be nonspecific, but high amplitude theta delta background activities with multifocal spikes have been described in several cases. Basal ganglia changes are mostly confined to the globus pallidus. Neurologic findings include hypotonia in young children, and ataxia and dystonia later in the disease course. One patient has been described with intermittent ataxia occurring during episodes of febrile illness.7 Other patients have been described with chorea, new onset of choreatic storm, and hemiballism. Additionally, presentations masquerading as Leigh-like syndrome and mitochondrial disease have been reported.8 Therapy has a dual aim: Oral supplementation of creatine (administered as creatine-monohydrate) is used to restore cerebral creatine levels. To reduce GAA levels, several strategies are employed, including competitive inhibition of AGAT activity via high-dose L-ornithine supplementation and substrate deprivation via an arginine-restricted diet. Sodium benzoate has been proposed as an additional approach to reduce the production of GAA via conjugation with glycine to form hippuric acid, which is rapidly excreted by the kidneys.9 Seminars in Neurology
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Creatine is given as creatine-monohydrate at recommended dosages of 400 to 800 mg/kg/d orally/enterally. L-Ornithine supplementation is recommended at 400 to 800 mg/kg/d orally/enterally. An arginine-restricted diet, given as 0.3 to 0.4 g/kg/d of natural protein (containing 250 mg/kg/d of L-arginine) together with an arginine-free essential amino acid supplement to achieve the age-related daily recommended intake (DRI) effectively reduces GAA levels.7,9 Whether, and to what extent, a low protein diet, given as 0.8 to 1.5 g/kg/d of natural protein, with or without supplementation of an arginine-free formula, results in reduction of GAA accumulation needs to be established. Treatment is associated with a significant increase of cerebral creatine levels and reduction of urinary, plasma and cerebrospinal fluid (CSF ) GAA levels, as well as improvement or stabilization of clinical symptoms in all of the symptomatic cases.5,7 Numerous questions regarding the evidence of the described treatment modalities still remain to be answered. An observational database allowing the clinician to choose the treatment strategy most applicable to the individual patient and to longitudinally monitor a minimum set of biomarkers may bring the answers for this very rare condition. Findings in a recent international survey comprising 48 patients7 indicate that that early recognition and treatment improves outcomes. The 44 patients who were older than 9 months at initiation of treatment suffered IDD with a deteriorating degree of severity with increasing age. The four patients who were diagnosed and treated early (0–9 mo) showed normal development at most recent follow-up (ages of 14, 21, 31, and 41 mo). Robust methods have been developed to determine GAA in blood spot cards, and first pilot newborn screening projects are being performed.10 In our own center, thus far 70,000 newborns have been screened using a three-tier test employing two-tiered GAA determination, and for those with values above the cutoff, DNA is extracted from the bloodspot card for GAMT molecular analysis. Thus far, no GAMT deficiency cases have been identified, which is in keeping with the reported ultrarare incidence.11
Arginine: Glycine Amidinotransferase Deficiency Since its first description,12 less than 20 patients have been identified worldwide with this condition. The first reported family included two siblings and their cousin.13 Clinical features included mild/moderate IDD, prominent speech delay, autistic behavior, occasional seizures, and brain creatine deficiency reversible upon creatine supplementation. Recent observations indicate that myopathy is a late manifestation of AGAT deficiency. A pair of siblings, aged 21 and 14 years, from a Yemenite Jewish family has been described with a history of poor weight gain, developmental delay, and fatigability. Both siblings were subsequently found to have moderate and mild intellectual disability (IQ 47 and 60), proximal muscle weakness, moderately elevated creatine kinase levels (500–600 U/L), and myopathic electromyography. Muscle biopsy revealed tubular aggregates and decreased activity in mitochondrially encoded respiratory chain enzymes.14 Four patients from
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two additional families have been described with a similar late-onset myopathy.15,16 Oral creatine supplementation (300–400 mg/kg/d) has been effective in replenishing the cerebral creatine pool and in improvement of abnormal developmental scores.17 Early diagnosis and treatment seems to be particularly efficient in improving outcomes. A late-born sibling to the two index patients, originally described by Item et al,12 was diagnosed prenatally, and creatine supplementation was started at 4 months. Development in this child was normal at age 18 months, in contrast to his siblings, who had already shown signs of retardation at this age.18 Within the same family, a cousin of the index patients diagnosed at age 2 years had a borderline IQ at age 8 years, whereas two children out of the same family started on treatment at ages 7 and 5 years, had moderate IDD at ages 13 and 11 years. One child from an unrelated family had global developmental delay at the age of 16 months. Treatment with creatine monohydrate resulted in complete resolution of clinical symptoms and a significant increase in cerebral creatine levels.19 Treatment with oral supplementation of creatine monohydrate has also proven highly effective in the treatment of patients affected by myopathy.15,16 Overall dosages of 200 to 400 mg/kg creatine monohydrate have been employed. More systematic monitoring of clinical outcomes (muscle weakness, cognitive and behavioral function) along with cerebral creatine levels might yield the appropriate dosage for the individual patient. AGAT deficiency is biochemically characterized by reduced GAA levels in body fluids. Discrimination of low normal and low abnormal metabolite levels is a known diagnostic challenge in conditions characterized by deficiency, rather than accumulation of substrates. The absence of another specific biomarker might be the reason why so few patients have been diagnosed with AGAT deficiency thus far. Clinical observations indicate that early recognition and treatment of AGAT deficiency potentially prevents the onset of symptoms. AGAT deficiency is an ideal candidate for newborn screening, but unlike GAMT deficiency, methods suitable for newborn screening have not been developed. Primary gene sequencing and methods to determine AGAT activity directly in blood spots might be ways to explore for high throughput screening.
Cerebral Creatine Transporter Deficiency X-linked Cerebral Creatine Transporter (SLC6A8) deficiency was first described in 2001 in a 6-year-old boy with ID, speech delay, and status epilepticus.20,21 Numerous patients have been diagnosed with this condition worldwide since then. Various studies have been performed in cohorts of patients with IDD, indicating a prevalence of the disorder of up to 3.5% in males with IDD.22–24 Besides IDD, expressive speech delay and psychiatric (autistic) disturbances, numerous clinical features have been reported.25 Discrete facial dysmorphic features (broad forehead, midface hypoplasia, ptosis, short nose) and slender, poorly developed muscles seem to occur quite frequently in association with this condition. Epilepsy is also a frequent feature, varying from occasional, pharmacor-
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esponsive seizures to frequent generalized tonic clonic seizures, and therapy-resistant frontal lobe epilepsy. Additional features include hyperextensible joints and ataxic and dystonic movement disorders. Gastrointestinal (chronic constipation /ileus), urogenital, ophthalmologic and hearing abnormalities, as well as cardiomyopathy, delayed myelination, thin corpus callosum, and cerebral/cerebellar atrophy have been reported in single cases. Cerebral atrophy was progressive in two brothers.26 Mild IDD was mainly restricted to younger patients, whereas most adults had severe IDD, suggesting that patients generally develop moderate-tosevere IDD with increasing age.25 Females heterozygous for the family mutation may have mild IDD or learning disabilities. More severe presentations have also been observed.27 The most severe phenotype has been reported in a girl with mild /moderate IDD, behavioral problems, and intractable epilepsy28. SLC6A8 deficiency is typically characterized by a reduction or absence of creatine in the brain, visualized by 1H magnetic resonance spectroscopy.25 As SLC6A8 facilitates reabsorption of creatine in the renal tubular cells, in case of deficiency, creatine reabsorption is decreased and abnormally high amounts of creatine are lost via the urine.24 Together with low creatinine excretion (due to reduced creatine concentrations in muscle and brain) the increased ratio of urinary creatine to creatinine (Cr:Crn) serves as a noninvasive screening tool in males. In females, this test is not reliable and a normal Cr:Crn ratio does not exclude SLC6A8. In suspected SLC6A8 deficiency cases, diagnostic confirmation requires molecular analysis of SLC6A8. In a survey of 101 male patients,25 one third of patients had a de novo SLC6A8 mutation. Missense mutations and oneamino acid (3 bp) deletions were the most common mutation types, found in 31% and 24% of families, respectively. Mutations with residual activity were associated with milder phenotypes compared with large deletions of the SLC6A8 gene, including complex rearrangements, which presented with more severe clinical findings.29 Treatment strategies are based on the understanding that correction of cerebral creatine depletion will improve clinical outcomes. Oral supplementation of creatine (400mg/kg/d of creatine monohydrate) is intended to maximize creatine transport into the brain via residual function of the creatine transporter or by potential alternative transport mechanism.30 Creatine supplementation is administered as monotherapy or in combination with supraphysiological oral doses of precursors of creatine, such as L -arginine and/or glycine, to further enhance cerebral creatine synthesis. Apparent barriers to correction of the biochemical and clinical phenotype through these treatment strategies include the failure of creatine transport into the brain resulting from poor uptake by creatine transporters in astrocyte31; failure to synthesize sufficient cerebral creatine from precursors because of the physical separation of AGAT and GAMT enzymes in different neurons32; and failure of the neuronal reuptake of endogenously synthesized creatine, leading to increased turnover in the CSF.33 Seminars in Neurology
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders
Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders Until recently, the efficacy of treatment with oral creatine and/or its precursors was controversial.34,35 Reports of significant changes in brain creatine content and formal neuropsychological test performances are rare, whereas improvements in secondary, patient-reported outcomes (e.g., epilepsy, behavior, mood, attention, muscle mass)27,36 are more frequent and suggest potential benefits. In 2014, we systematically reviewed the literature, and identified seven case series/reports collectively describing the outcomes on varying treatment strategies (median duration 34.6 mo, range 3 mo–5 y).37 Ten patients (36%) demonstrated response to treatment, manifested by either a significant increase in cerebral creatine and/or improved clinical parameters (including cognitive ability, psychiatric and behavioral disturbances, and epilepsy). All seven patients with increased cerebral creatine also experienced clinical improvement, and vice versa the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. Finally, 90% of the patients who improved were initiated on treatment before 9 years of age, indicating the benefits of early
Stockler-Ipsiroglu, van Karnebeek
intervention. Acknowledging the limitations of the review, we concluded that a proportion of CTD patients show amenability to currently available treatment—particularly milder cases with residual brain creatine, and therefore probable residual protein function (evidence level IV). Systematic screening for SLC6A8 in patients with IDD is proposed to allow early initiation of treatment, which currently comprises oral creatine, arginine, and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects is required in all patients. Furthermore, the review provides effectiveness data for currently available treatments, which can be used in addition to prospective clinical trials to discern effectiveness of interventions facilitating the transport of creatine via alternative routes into brain tissues. Examples include chemically modified creatine molecules (e.g., cyclocreatine38), and coupling of creatine to molecules that have their own carrier,39,40 with preclinical trials in the SLC6A8 knockout mouse model underway.41 For an overview of clinical, biochemical features, and treatment options of CCD, see ►Table 1.
Table 1 Creatine deficiency disorders at one glance AGAT
GAMT
CTD
GAMT
SLC6A8
General information Gene
GATM
Chromosomal location
15q15.3
19p13.3
Xq28
OMIM number
612718
612736
300352
Clinical features IDD
þ
þ
þ
Speech delay
þ
þ
þ
Autism
þ
þ
Epilepsy
þ
þ
Movement disorder
þ
þ/
Basal ganglia changes
þ
Myopathy
þ
Brain creatine deficiency
þ
þ
þ
Guanidinoacetate (U, P, CSF)
low
high
normal
Creatine / Creatinine Ratio (U)
normal
normal
high
Creatine supplementation
þ
þ
þ
Biochemical features
Treatment Ornithine supplementation
þ
Arginine-restricted diet
þ
Arginine supplementation
þ
Glycine-supplementation
þ
Other
Sodium-benzoate
Abbreviations: AGAT, arginine: glycine amidinotransferase deficiency; CSF, cerebrospinal fluid; CTD, creatine transporter deficiency; GAMT, guanidinoacetate methyltransferase; IDD, intellectual developmental disorder; OMIM, Online Mendelian Inheritance in Man database; P, plasma; U, urine. Seminars in Neurology
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders
Although CDD represents a group of treatable genetic conditions, progress in understanding efficacy of treatment and development of new treatment strategies has been slow due to the rarity of the single disorders. As with other rare inborn errors of metabolism, worldwide networks and orphan disease registries are needed to facilitate progress in understanding the natural history and in the development of strategies for treatment and prevention. Given the amenability to treatment of CDD, every child with IDD of unknown origin should be systematically tested for these conditions via determination of urinary creatine/ creatinine, and guanidinoacetate. Spectroscopy should always be added to the brain MRI. If cerebral creatine levels are low, further urine and molecular analyses should be performed to identify the specific gene defect. Prevention of brain damage and thus of the phenotype is the final goal of timely diagnosis and treatment of CDD. As outlined in recent recommendations for the evaluation of IDD,2 it is mandatory that these three inborn errors of metabolism become part of the routine (or first tier) diagnostic workup in patients with IDD and/or epilepsy, and determination of marker substances (urinary GAA and the urinary creatine to creatinine ratio) need to be introduced in any selective metabolic laboratory panel.
8 Morris AA, Appleton RE, Power B, et al. Guanidinoacetate meth-
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Acknowledgments This work was supported by funding from the B.C. Children’s Hospital Foundation for TIDE-BC as the “1st Collaborative Area of Innovation.”
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders Clara D.M. van Karnebeek, MD, PhD1,2,3,4
1 Division of Biochemical Diseases, Department of Pediatrics, BC
Children’s Hospital, University of British Columbia, Vancouver, Canada 2 Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), University of British Columbia, Vancouver, Canada 3 Child and Family Research Institute, University of British Columbia, Vancouver, Canada 4 Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
Address for correspondence Sylvia Stockler-Ipsiroglu, MD, PhD, MBA, FRCPC, Department of Pediatrics, University of British Columbia, Child and Family Research Institute, University of British Columbia, K3-204-4480 Oak Street, Vancouver B.C. V6H 3V4, Canada (e-mail: [email protected]).
Semin Neurol 2014;34:350–356.
Abstract
Keywords
► GATM ► guanidinoacetate methyltransferase ► SLC6A8 ► magnetic resonance spectroscopy ► treatment ► intellectual disability ► developmental delay ► autism
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 creatinemonohydrate 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.
Intellectual developmental disorders (IDDs), characterized by significant impairment of cognitive functions, with limitations of learning, adaptive behavior, and skills, are frequent (2.5% of the population affected) and present with significant comorbidity. The burden of intellectual disability (ID), in terms of emotional suffering and associated health care costs, is significant; prevention and treatment therefore are impor-
Issue Theme Neurogenetics; Guest Editor, Ali Fatemi, MD
tant. Traditionally, IDD has been considered an unchangeable fate, as causal treatments, which might prevent or reverse IDD, are not available for the majority of etiologies. Inborn errors of metabolism (IEM) currently represent the largest category of genetic IDDs, which are amenable to therapies targeting the underlying pathophysiology. We performed a systematic literature review and identified 81 such treatable
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DOI http://dx.doi.org/ 10.1055/s-0034-1386772. ISSN 0271-8235.
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Sylvia Stockler-Ipsiroglu, MD, PhD1,2,3
Stockler-Ipsiroglu, van Karnebeek
Fig. 1 Creatine synthesis and metabolism. ADP, adenosine-diphosphate; AGAT, arginine: glycine amidinotransferase deficiency; ATP, adenosinetriphosphate; CK, creatine kinase; CRTR, creatine transporter (SLC6A8); GAMT, guanidinoacetate methyltransferase.
IDDs,1 recently updated to 91,2 three of which are creatine deficiency disorders (CDDs). Creatine deficiency disorders comprise two autosomal recessive disorders that affect the biosynthesis of creatine (arginine:glycine amidinotransferase deficiency [AGAT; MIM 602360] and guanidinoacetate methyltransferase deficiency [GAMT; MIM 601240]) and the X-linked creatine transporter (SLC6A8; MIM 300036) defect that affects the creatine transport into the brain and muscle. Intellectual developmental disorders are the common and predominant denominator of these conditions, ranging in severity from mild to severe. Intellectual developmental disorders are typically associated with behavioral problems, speech delay, epilepsy, and movement disorders. Myopathy and muscular hypotrophy are features of AGAT and SLC6A8 deficiency. In general, GAMT deficiency features the more severe phenotypes compared with AGAT and SLC6A8 deficiency.
Creatine Synthesis and Transport Creatine synthesis occurs mainly in the liver, kidney, and pancreas, and is facilitated by two enzymatic steps: (1) Larginine:glycine amidinotransferase (AGAT) catalyzes the formation of guanidinoacetate (GAA) from arginine and glycine; and (2) guanidinoacetate methyltransferase (GAMT) catalyzes the formation of guanidinoacetate (GAA) from GAA and S-adenosylmethionine. The formation of GAA is the rate-limiting reaction, facilitated by inhibition of AGAT activity via negative feedback through creatine and competitive inhibition through ornithine. Although the
brain is capable of producing minor amounts of creatine, the major proportion is taken up from the blood via SLC6A8. Intracellular creatine is reversibly converted into creatinephosphate by the action of creatine kinase. Creatine/creatine phosphate and ADP/ATP together with CK represent a high-energy phosphate shuttle mainly in brain and muscle. Creatine is nonenzymatically converted into creatinine, which is excreted in the urine with a constant daily turnover of 1.5% of body creatine. The daily creatinine excretion is directly proportional to total body creatine, and in particular to muscle mass (i.e., 20–25 mg/kg every 24 hours in children and adults) (►Fig. 1).
Diagnostic Markers The common biochemical denominator of all CDD is lack of creatine in the brain. Although marked reduction of the creatine signal in H-MRS (proton magnetic resonance spectroscopy) of the brain is an indicator of disorders of creatine biosynthesis and transport, determination of urinary guanidinoacetate and the urinary creatine to creatinine ratio is fundamental to their differential diagnosis. Urinary guanidinoacetate is high in GAMT deficiency and low in AGAT deficiency. An increase of urinary creatine excretion together with a low urinary creatinine excretion is characteristic for SLC6A8 deficiency. An elevated urinary creatine to creatinine ratio serves as a diagnostic marker in hemizygous males, whereas this marker is not sensitive in heterozygous females. Molecular analysis of AGAT (GATM), GAMT (GAMT), and SLC6A8 (SLC6A8) is currently used for diagnostic Seminars in Neurology
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders
Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders confirmation via the identification of mutations, insertions, deletions ,or other complex rearrangements. Available biomarker screening can yield false-negative results, particularly in AGAT and SLC6A8 deficiency. Therefore, primary molecular analysis might be the safest approach to diagnostic ascertainment of both conditions. This is especially true for detecting heterozygous SLC6A8 females, for whom there exists no reliable diagnostic marker. Functional tests, including enzymatic assays in fibroblasts, lymphoblasts, and/or in expression systems, provide diagnostic confirmation at a functional level, particularly for new mutations of unknown pathogenicity.
Guanidinoacetate Methyltransferase Deficiency In 1994, a 22-month-old boy was the first patient identified with GAMT deficiency3,4: His development had been considered normal up until the age of 4 months, when he developed hypotonia, hyperkinetic extrapyramidal movements, and head nodding. His electroencephalogram (EEG) showed slow background activity and multifocal spike slow waves. Magnetic resonance imaging (MRI) revealed bilateral abnormalities of the globus pallidus consisting of hypointensities in T1-weighted images and as hyperintensities in T2-weighted images. To date, approximately 80 patients have been diagnosed worldwide, many of them being published as either single cases or case series. In two previous overviews of 27 and 8 cases, patients had a broad clinical spectrum from mild to severe IDD.5,6 Intellectual developmental disorders in GAMTdeficient patients is mostly associated with behavioral disturbances, such as autism and aggression/hyperactivity. Expressive speech delay is also prominent in those patients who have milder degrees of IDD and is most resistant to treatment interventions. Apart from unspecific seizure types, such as absence and tonic clonic, focal, or generalized seizures, particular seizure types including head drop seizures, myoclonic seizures, infantile spasms, and myoclonic astatic seizures have been observed. Electroencephalogram changes can be nonspecific, but high amplitude theta delta background activities with multifocal spikes have been described in several cases. Basal ganglia changes are mostly confined to the globus pallidus. Neurologic findings include hypotonia in young children, and ataxia and dystonia later in the disease course. One patient has been described with intermittent ataxia occurring during episodes of febrile illness.7 Other patients have been described with chorea, new onset of choreatic storm, and hemiballism. Additionally, presentations masquerading as Leigh-like syndrome and mitochondrial disease have been reported.8 Therapy has a dual aim: Oral supplementation of creatine (administered as creatine-monohydrate) is used to restore cerebral creatine levels. To reduce GAA levels, several strategies are employed, including competitive inhibition of AGAT activity via high-dose L-ornithine supplementation and substrate deprivation via an arginine-restricted diet. Sodium benzoate has been proposed as an additional approach to reduce the production of GAA via conjugation with glycine to form hippuric acid, which is rapidly excreted by the kidneys.9 Seminars in Neurology
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Creatine is given as creatine-monohydrate at recommended dosages of 400 to 800 mg/kg/d orally/enterally. L-Ornithine supplementation is recommended at 400 to 800 mg/kg/d orally/enterally. An arginine-restricted diet, given as 0.3 to 0.4 g/kg/d of natural protein (containing 250 mg/kg/d of L-arginine) together with an arginine-free essential amino acid supplement to achieve the age-related daily recommended intake (DRI) effectively reduces GAA levels.7,9 Whether, and to what extent, a low protein diet, given as 0.8 to 1.5 g/kg/d of natural protein, with or without supplementation of an arginine-free formula, results in reduction of GAA accumulation needs to be established. Treatment is associated with a significant increase of cerebral creatine levels and reduction of urinary, plasma and cerebrospinal fluid (CSF ) GAA levels, as well as improvement or stabilization of clinical symptoms in all of the symptomatic cases.5,7 Numerous questions regarding the evidence of the described treatment modalities still remain to be answered. An observational database allowing the clinician to choose the treatment strategy most applicable to the individual patient and to longitudinally monitor a minimum set of biomarkers may bring the answers for this very rare condition. Findings in a recent international survey comprising 48 patients7 indicate that that early recognition and treatment improves outcomes. The 44 patients who were older than 9 months at initiation of treatment suffered IDD with a deteriorating degree of severity with increasing age. The four patients who were diagnosed and treated early (0–9 mo) showed normal development at most recent follow-up (ages of 14, 21, 31, and 41 mo). Robust methods have been developed to determine GAA in blood spot cards, and first pilot newborn screening projects are being performed.10 In our own center, thus far 70,000 newborns have been screened using a three-tier test employing two-tiered GAA determination, and for those with values above the cutoff, DNA is extracted from the bloodspot card for GAMT molecular analysis. Thus far, no GAMT deficiency cases have been identified, which is in keeping with the reported ultrarare incidence.11
Arginine: Glycine Amidinotransferase Deficiency Since its first description,12 less than 20 patients have been identified worldwide with this condition. The first reported family included two siblings and their cousin.13 Clinical features included mild/moderate IDD, prominent speech delay, autistic behavior, occasional seizures, and brain creatine deficiency reversible upon creatine supplementation. Recent observations indicate that myopathy is a late manifestation of AGAT deficiency. A pair of siblings, aged 21 and 14 years, from a Yemenite Jewish family has been described with a history of poor weight gain, developmental delay, and fatigability. Both siblings were subsequently found to have moderate and mild intellectual disability (IQ 47 and 60), proximal muscle weakness, moderately elevated creatine kinase levels (500–600 U/L), and myopathic electromyography. Muscle biopsy revealed tubular aggregates and decreased activity in mitochondrially encoded respiratory chain enzymes.14 Four patients from
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two additional families have been described with a similar late-onset myopathy.15,16 Oral creatine supplementation (300–400 mg/kg/d) has been effective in replenishing the cerebral creatine pool and in improvement of abnormal developmental scores.17 Early diagnosis and treatment seems to be particularly efficient in improving outcomes. A late-born sibling to the two index patients, originally described by Item et al,12 was diagnosed prenatally, and creatine supplementation was started at 4 months. Development in this child was normal at age 18 months, in contrast to his siblings, who had already shown signs of retardation at this age.18 Within the same family, a cousin of the index patients diagnosed at age 2 years had a borderline IQ at age 8 years, whereas two children out of the same family started on treatment at ages 7 and 5 years, had moderate IDD at ages 13 and 11 years. One child from an unrelated family had global developmental delay at the age of 16 months. Treatment with creatine monohydrate resulted in complete resolution of clinical symptoms and a significant increase in cerebral creatine levels.19 Treatment with oral supplementation of creatine monohydrate has also proven highly effective in the treatment of patients affected by myopathy.15,16 Overall dosages of 200 to 400 mg/kg creatine monohydrate have been employed. More systematic monitoring of clinical outcomes (muscle weakness, cognitive and behavioral function) along with cerebral creatine levels might yield the appropriate dosage for the individual patient. AGAT deficiency is biochemically characterized by reduced GAA levels in body fluids. Discrimination of low normal and low abnormal metabolite levels is a known diagnostic challenge in conditions characterized by deficiency, rather than accumulation of substrates. The absence of another specific biomarker might be the reason why so few patients have been diagnosed with AGAT deficiency thus far. Clinical observations indicate that early recognition and treatment of AGAT deficiency potentially prevents the onset of symptoms. AGAT deficiency is an ideal candidate for newborn screening, but unlike GAMT deficiency, methods suitable for newborn screening have not been developed. Primary gene sequencing and methods to determine AGAT activity directly in blood spots might be ways to explore for high throughput screening.
Cerebral Creatine Transporter Deficiency X-linked Cerebral Creatine Transporter (SLC6A8) deficiency was first described in 2001 in a 6-year-old boy with ID, speech delay, and status epilepticus.20,21 Numerous patients have been diagnosed with this condition worldwide since then. Various studies have been performed in cohorts of patients with IDD, indicating a prevalence of the disorder of up to 3.5% in males with IDD.22–24 Besides IDD, expressive speech delay and psychiatric (autistic) disturbances, numerous clinical features have been reported.25 Discrete facial dysmorphic features (broad forehead, midface hypoplasia, ptosis, short nose) and slender, poorly developed muscles seem to occur quite frequently in association with this condition. Epilepsy is also a frequent feature, varying from occasional, pharmacor-
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esponsive seizures to frequent generalized tonic clonic seizures, and therapy-resistant frontal lobe epilepsy. Additional features include hyperextensible joints and ataxic and dystonic movement disorders. Gastrointestinal (chronic constipation /ileus), urogenital, ophthalmologic and hearing abnormalities, as well as cardiomyopathy, delayed myelination, thin corpus callosum, and cerebral/cerebellar atrophy have been reported in single cases. Cerebral atrophy was progressive in two brothers.26 Mild IDD was mainly restricted to younger patients, whereas most adults had severe IDD, suggesting that patients generally develop moderate-tosevere IDD with increasing age.25 Females heterozygous for the family mutation may have mild IDD or learning disabilities. More severe presentations have also been observed.27 The most severe phenotype has been reported in a girl with mild /moderate IDD, behavioral problems, and intractable epilepsy28. SLC6A8 deficiency is typically characterized by a reduction or absence of creatine in the brain, visualized by 1H magnetic resonance spectroscopy.25 As SLC6A8 facilitates reabsorption of creatine in the renal tubular cells, in case of deficiency, creatine reabsorption is decreased and abnormally high amounts of creatine are lost via the urine.24 Together with low creatinine excretion (due to reduced creatine concentrations in muscle and brain) the increased ratio of urinary creatine to creatinine (Cr:Crn) serves as a noninvasive screening tool in males. In females, this test is not reliable and a normal Cr:Crn ratio does not exclude SLC6A8. In suspected SLC6A8 deficiency cases, diagnostic confirmation requires molecular analysis of SLC6A8. In a survey of 101 male patients,25 one third of patients had a de novo SLC6A8 mutation. Missense mutations and oneamino acid (3 bp) deletions were the most common mutation types, found in 31% and 24% of families, respectively. Mutations with residual activity were associated with milder phenotypes compared with large deletions of the SLC6A8 gene, including complex rearrangements, which presented with more severe clinical findings.29 Treatment strategies are based on the understanding that correction of cerebral creatine depletion will improve clinical outcomes. Oral supplementation of creatine (400mg/kg/d of creatine monohydrate) is intended to maximize creatine transport into the brain via residual function of the creatine transporter or by potential alternative transport mechanism.30 Creatine supplementation is administered as monotherapy or in combination with supraphysiological oral doses of precursors of creatine, such as L -arginine and/or glycine, to further enhance cerebral creatine synthesis. Apparent barriers to correction of the biochemical and clinical phenotype through these treatment strategies include the failure of creatine transport into the brain resulting from poor uptake by creatine transporters in astrocyte31; failure to synthesize sufficient cerebral creatine from precursors because of the physical separation of AGAT and GAMT enzymes in different neurons32; and failure of the neuronal reuptake of endogenously synthesized creatine, leading to increased turnover in the CSF.33 Seminars in Neurology
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders
Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders Until recently, the efficacy of treatment with oral creatine and/or its precursors was controversial.34,35 Reports of significant changes in brain creatine content and formal neuropsychological test performances are rare, whereas improvements in secondary, patient-reported outcomes (e.g., epilepsy, behavior, mood, attention, muscle mass)27,36 are more frequent and suggest potential benefits. In 2014, we systematically reviewed the literature, and identified seven case series/reports collectively describing the outcomes on varying treatment strategies (median duration 34.6 mo, range 3 mo–5 y).37 Ten patients (36%) demonstrated response to treatment, manifested by either a significant increase in cerebral creatine and/or improved clinical parameters (including cognitive ability, psychiatric and behavioral disturbances, and epilepsy). All seven patients with increased cerebral creatine also experienced clinical improvement, and vice versa the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. Finally, 90% of the patients who improved were initiated on treatment before 9 years of age, indicating the benefits of early
Stockler-Ipsiroglu, van Karnebeek
intervention. Acknowledging the limitations of the review, we concluded that a proportion of CTD patients show amenability to currently available treatment—particularly milder cases with residual brain creatine, and therefore probable residual protein function (evidence level IV). Systematic screening for SLC6A8 in patients with IDD is proposed to allow early initiation of treatment, which currently comprises oral creatine, arginine, and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects is required in all patients. Furthermore, the review provides effectiveness data for currently available treatments, which can be used in addition to prospective clinical trials to discern effectiveness of interventions facilitating the transport of creatine via alternative routes into brain tissues. Examples include chemically modified creatine molecules (e.g., cyclocreatine38), and coupling of creatine to molecules that have their own carrier,39,40 with preclinical trials in the SLC6A8 knockout mouse model underway.41 For an overview of clinical, biochemical features, and treatment options of CCD, see ►Table 1.
Table 1 Creatine deficiency disorders at one glance AGAT
GAMT
CTD
GAMT
SLC6A8
General information Gene
GATM
Chromosomal location
15q15.3
19p13.3
Xq28
OMIM number
612718
612736
300352
Clinical features IDD
þ
þ
þ
Speech delay
þ
þ
þ
Autism
þ
þ
Epilepsy
þ
þ
Movement disorder
þ
þ/
Basal ganglia changes
þ
Myopathy
þ
Brain creatine deficiency
þ
þ
þ
Guanidinoacetate (U, P, CSF)
low
high
normal
Creatine / Creatinine Ratio (U)
normal
normal
high
Creatine supplementation
þ
þ
þ
Biochemical features
Treatment Ornithine supplementation
þ
Arginine-restricted diet
þ
Arginine supplementation
þ
Glycine-supplementation
þ
Other
Sodium-benzoate
Abbreviations: AGAT, arginine: glycine amidinotransferase deficiency; CSF, cerebrospinal fluid; CTD, creatine transporter deficiency; GAMT, guanidinoacetate methyltransferase; IDD, intellectual developmental disorder; OMIM, Online Mendelian Inheritance in Man database; P, plasma; U, urine. Seminars in Neurology
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Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders
Although CDD represents a group of treatable genetic conditions, progress in understanding efficacy of treatment and development of new treatment strategies has been slow due to the rarity of the single disorders. As with other rare inborn errors of metabolism, worldwide networks and orphan disease registries are needed to facilitate progress in understanding the natural history and in the development of strategies for treatment and prevention. Given the amenability to treatment of CDD, every child with IDD of unknown origin should be systematically tested for these conditions via determination of urinary creatine/ creatinine, and guanidinoacetate. Spectroscopy should always be added to the brain MRI. If cerebral creatine levels are low, further urine and molecular analyses should be performed to identify the specific gene defect. Prevention of brain damage and thus of the phenotype is the final goal of timely diagnosis and treatment of CDD. As outlined in recent recommendations for the evaluation of IDD,2 it is mandatory that these three inborn errors of metabolism become part of the routine (or first tier) diagnostic workup in patients with IDD and/or epilepsy, and determination of marker substances (urinary GAA and the urinary creatine to creatinine ratio) need to be introduced in any selective metabolic laboratory panel.
8 Morris AA, Appleton RE, Power B, et al. Guanidinoacetate meth-
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Acknowledgments This work was supported by funding from the B.C. Children’s Hospital Foundation for TIDE-BC as the “1st Collaborative Area of Innovation.”
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