creatine deficiency syndromes - libreria universo

16

Creatine Deficiency Syndromes

Sylvia Stöckler-Ipsiroglu, Saadet Mercimek-Mahmutoglu, Gajja S. Salomons

16.1 Clinical Presentation – 241

16.2 Metabolic Derangement – 242

16.3 Genetics – 243

16.4 Diagnostic Tests – 243

16.5 Treatment and Prognosis – 244

References – 245

IMD_T2.indd 239IMD_T2.indd 239 28.10.2011 18:40:1228.10.2011 18:40:12

240 Chapter 16 · Creatine Deficiency Syndromes

16

Creatine Synthesis and Transport

Creatine is synthesised by two enzymatic reac-tions: (1) transfer of the amidino group from argi-nine 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) (⊡ Fig. 16.1). Creatine synthesis occurs pri-marily 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 of utilisation (mainly muscle and brain), where both the endogenous creatine and that derived from dietary

sources are taken up by a sodium- and chloride-de-pendent creatine transporter (CRTR, SLC6A8). Some of the intracellular creatine is reversibly converted into the high-energy compound creatine phosphate by the action of creatine kinase (CK). Three cytosolic isoforms, brain type (BB-CK), muscle-type (MM-CK) and the MB-CK heterodimer, and two mitochondrial isoforms exist. Creatine and creatine phosphate are nonenzymatically converted into creatinine, with a constant daily turnover of 1.5 % of body creatine. Creatinine is mainly excreted in urine, and its daily excretion is directly proportional to total-body cre-atine, and in particular to muscle mass (20-25 mg/kg/24 h in children and adults, and lower in infants younger than 2 years).

⊡ Fig. 16.1. Metabolic pathway of creatine /creatine phosphate , which mainly occurs in the organs indicated. ADP, adenosine diphosphate; ATP, adenosine triphosphate; AGAT, arginine:glycine amidinotransferase ; CK, creatine kinase ; CRTR, creatine transporter (SLC6A8); GAMT, guanidinoacetate methyltransferase


16.1 · Clinical Presentation16241

Creatine deficiency syndromes (CDS) are a group of inborn errors of creatine synthesis and transport and include auto-somal recessive arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies, and deficiency of the X-linked creatine transporter (SLC6A8). In all these disorders the common clinical hallmark is mental retardation, speech delay and epilepsy. Additional frequent manifestations include failure to thrive, growth retardation, muscular hypotonia and movement disorder (mainly extrapy-ramidal). The common biochemical hallmark is cerebral cre-atine deficiency as detected by proton magnetic resonance spectroscopy (H-MRS). Increased levels of guanidinoacetate in body fluids are pathognomonic for GAMT deficiency, whereas these levels are reduced in AGAT deficiency. In-creased urinary creatine/creatinine ratio is associated with SLC6A8 deficiency. Oral supplementation of creatine leads to partial restoration of the cerebral creatine pool and improve-ment of clinical symptoms in GAMT and AGAT deficiency. Re-duction of guanidinoacetate by additional dietary restriction of arginine (and supplementation of ornithine) appears to be of additional benefit for the long-term outcome of GAMT-deficient patients. For SLC6A8-deficient patients no effective treatment is currently available. CDS may account for a con-siderable fraction of children and adults with mental retarda-tion of unknown cause, and screening for these disorders (by urinary/plasma metabolites, brain H-MRS and/or a DNA approach) should therefore be included in the investigation of this population.

Secondary changes in creatine metabolim have been described mainly in disorders affecting arginine and orni-thine metabolism, such as ornithine aminotransferase (OAT) deficiency and deficiency of argininosuccinate synthase and argininosuccinate lyase.

16.1 Clinical Presentation

Common clinical hallmarks of CDS are mental retarda-tion, speech delay and epilepsy. Mental retardation ranges from mild to severe and is characteristically associated with hyperactive behaviour and autistic features [1, 2]. Movement disorder, mainly extrapyramidal, and basal ganglia changes have been observed as additional features in GAMT deficiency.

16.1.1 Guanidinoacetate Methyltransferase Deficiency

The first patient with GAMT deficiency was described in 1994 [3, 4]. This boy was considered to be normal until 4 months of age, when he was noted to have developmen-

tal arrest, hypotonia, hyperkinetic extrapyramidal move-ments 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, more than 50 patients are known to the au-thors, and many of them have been published as single or groups of cases. An overview of 27 cases showed a broad clinical spectrum from mild to severe mental retarda-tion, occasional to drug-resistant seizures and, in the most severe cases, extrapyramidal movement disorder and pathological signal intensities in the basal ganglia [5]. Findings were widely confirmed in a more recent report of a series including 8 new patients [6]. Presentations masquerading as Leigh-like syndrome and mitochondrial disease [7] or late-onset ballistic and dystonic movement disorder [8] have been reported.

16.1.2 Arginine: Glycine Amidinotransferase Deficiency

So far patients from only three unrelated families have been identified with AGAT deficiency. The first reported family includes three siblings and their cousin. Clinical features included developmental delay/intellectual dis-ability, speech delay, autistic behaviour, occasional sei-zures and brain creatine deficiency that was reversible upon creatine supplementation [9-11]. One sibling diag-nosed at birth and treated with creatine within the first few weeks remained asymptomatic until the age of 18 months [12]. The second family includes a 14-month-old American girl of Chinese descent, who presented with psychomotor delay, severe language impairment, failure to thrive and autistic behaviour [13]. Recently a 21- and 14-year-old pair of siblings belonging to a Yemenite Jew-ish family has been reported with AGAT deficiency. Both presented with a history of developmental delay, fatigabil-ity and poor weight gain. They had moderate and mild intellectual disability (IQ 47 and 60), proximal muscle weakness, moderately elevated CK levels (500-600 U/l) and myopathic electromyography. Muscle biopsy showed tubular aggregates and decreased activities of mitochon-drially encoded respiratory chain enzymes [14].

16.1.3 SLC6A8 Deficiency

The first patient with SLC6A8 deficiency was reported in 2001 [15, 16]. He had mental retardation, autistic behav-



16

iour and speech delay. Since then at least 78 families with a total of about 170 patients (including affected males/heterozygous females) have been diagnosed [17] (www.LOVD.nl/SLC6A8). Mental retardation, speech delay, autistic behaviour and hyperactive attention deficit are the leading clinical features [18, 19]. Additional features can include muscular hypotonia, hyperextensible joints, movement disorder, short stature, and brain atrophy, dis-crete facial dysmorphic features and intestinal manifesta-tions [19-21]. Neurological and psychiatric problems can be progressive in adulthood [22]. Cardiac arrhythmia, including multiple premature ventricular contractions, has also been observed in association with SLC6A8 de-ficiency [23]. Epilepsy is frequently present [24], and the spectrum ranges from occasional, drug-responsive seizures [19] to frequent generalised tonic clonic seizures [25] and therapy-resistant frontal lobe epilepsy [26].

Females heterozygous for the family mutation in SLC6A8 can have learning problems/mild mental retarda-tion [27] The most severe phenotype has been reported in a girl with mild intellectual disability, behavioural problems and intractable epilepsy [26].

The prevalence of SLC6A8 deficiency is relatively high and may be responsible for about 2% of males with X-linked mental retardation [28-32] and for 1.4% of males with sporadic mental retardation [32].

16.2 Metabolic Derangement

CDS are caused by three gene defects involved in ei-ther synthesis or transport of creatine. All three defects result in an almost complete lack of cerebral creatine (⊡ Fig. 16.2). The prominent CNS involvement in all CDS patients indicates that creatine is essential for proper brain function. Apart from its role in energy storage and transmission, creatine may have an additional role as a neuromodulator [2, 33]. Although creatine plays an im-portant metabolic role in muscle tissue, creatine levels are only slightly reduced in skeletal muscle of patients with CDS [34, 35]. Creatine has not been measured in heart muscle, but none of the reported patients had cardio-myopathy. Plasma creatine levels are largely influenced by individual nutritional facts. Thus, normal plasma creatine levels do not exclude the presence of CDS. Urinary cre-atine excretion is expected to be low in patients with de-fects in creatine synthesis, but in SLC6A8 deficiency the urinary creatine-to-creatinine ratio is high [36]. Impaired function of SLC6A8 in renal tubular cells and subse-quent reduced tubular (re)uptake of creatine is the most likely reason for this. Moreover, low intracellular creatine and creatine phosphate results in reduced production of

creatinine. Thus, plasma creatinine concentrations, and in particular urinary creatinine excretion, are low in pa-tients with CDS [37].

Guanidinoacetate is the second metabolite that plays a role in CDS. In GAMT deficiency, guanidinoacetate accumulates in tissues and body fluids [2, 5]. In the CSF levels up to more than 100-fold normal are found [5]. In AGAT deficiency guanidinoacetate is low [2, 9, 11]. In SLC6A8 deficiency, guanidinoacetic acid levels are nor-mal [36, 37].

S-Adenosylmethionine is methyldonor for creatine synthesis. Although one might speculate that S-adeno-sylmethionine accumulates in creatine synthesis defects, S-adenosylmethionine and S-adenosylhomocysteine lev-els were unremarkable in one patient with GAMT defi-ciency (unpublished).

Secondary (cerebral) creatine deficiencies have been observed in argininosuccinate lyase deficiency (arginino-succinic aciduria), argininosuccinate synthase deficiency

⊡ Fig. 16.2 a, b. In vivo proton magnetic resonance spectroscopy (1H MRS) of the brain of a patient with cerebral creatine deficiency due to GAMT deficiency. a Complete lack of creatine resonance; b partial normalisation of creatine spectrum after 6 months of treatment with oral creatine monohydrate

a

b


16.4 · Diagnostic Tests16243

(citrullinaemia type 1) [38], and ornithine aminotrans-ferase (OAT) deficiency (gyrate atrophy of the choroid and retina) [39]. Secondary changes in creatine metabo-lism seem also to occur in disorders of remethylation, such as in cobalamin C deficiency [40].

16.3 Genetics

The genes encoding for GAMT and AGAT (GAMT and GATM) are mapped on chromosome 19p13.3 and 15q15.3, respectively. Both disorders are inherited auto-somal recessively, and many of the reported patients are the products of consanguineous marriages [5, 10].

The SLC6A8 gene has been mapped to Xq28. As SLC6A8 deficiency is an X-linked disorder, males are mainly affected, while according to the X-inactivation pattern heterozygous females may have a variable clinical phenotype [27]. Moreover, it should be noted that the X-linked pattern of inheritance will not be observed in the case of a de novo mutation. Therefore, diagnostic screen-ing of males with sporadic mental retardation (prevalence of 1.4%; CI: 0-3.30 [31] and females (prevalence data un-known) should include screening for SLC6A8 deficiency [41].

To date, in the GAMT and SLC6A8 genes many differ-ent mutations have been identified, including nonsense, missense, splice error, insertion, deletion and frameshift mutations without a clear phenotype-genotype correla-tion [2, 5, 6, 42]. In the GATM gene three mutations have been found in three unrelated families; a nonsense mutation [9, 11], a splice error [12] and single nucle-otide insertion [13]. There is no evidence for a hotspot region in any of these genes; however, certain mutations appear to occur more frequently. In GAMT, c.327G>A and c.59G>A occur in more than 50% of alleles. While c.327G>A occurs in all ethnicities [5, 6], c.59G>A has been found in patients from Southern Europe and Turkey only. This mutation is particularly prevalent in Portu-gal [43]; in the SLC6A8 gene, c.319_321delCTT, and c.1221_1223delTTC) are the most frequently found [2], and at present 36 different pathogenic mutations have been reported [17] (www.LOVD.nl/SLC6A8).

16.4 Diagnostic Tests

16.4.1 MRS of Brain

Inborn errors of creatine metabolism (biosynthesis and transport) can be recognised by the marked reduction of the creatine signal in H-MRS of the brain. However, me-

tabolite screening and molecular analysis remain neces-sary, to unravel the underlying defect in particular. More-over, MRS in infants and children often requires general anaesthesia and is not generally available as a routine method. Therefore, H-MRS of the brain is not a conve-nient primary screening tool, even though it is increas-ingly becoming a part of current practice for investigating mental retardation and neurological syndromes.

16.4.2 Metabolite Screening

Analysis of urinary guanidinoacetate and the creatine-to-creatinine ratio is an important screening test for all CDS [37]. Various methods have been developed for the determination of these compounds [44]. Stable isotope gas chromatography-mass spectrometry (SID GC–MS) is a highly sensitive technique suitable for detection of low guanidinoacetate levels characteristic of AGAT deficiency and those required for analysis of this compound in the CSF. Liquid chromatography tandem mass spectrometry (LC-MS-MS) allows the rapid, simultaneous determi-nation of urinary analytes including guanidinoacetate, creatine and creatinine [45, 46]. High guanidinoacetate levels characteristic of GAMT deficiency can be detected with all these methods.

In patients with SLC6A8 deficiency, the increase of urinary creatine excretion together with the inherently low urinary creatinine excretion results in an elevation of the urinary creatine-to-creatinine ratio, which serves as a valuable diagnostic marker in males [36, 47]. In heterozy-gous females this biochemical trait is not sufficiently sensitive to serve as a diagnostic marker [27]. Even in symptomatic patients the creatine-to-creatinine ratio can be within the control range [26].

Variation of these compounds during the day is not significant, indicating that a random urine sample is suf-ficient for the diagnosis of CDS [36]. On the other hand, false-positive values can be detected as the result of a protein-rich diet [32].

Age-dependent normal values have been established [36, 47, 48]. The urinary creatine-to-creatinine ratio de-creases after the age of 3 years, while it increases during the first 3 years of life [47]. It is of note that in metabolic urine screening, an overall increased concentration of amino acids and organic acids, expressed as millimoles per mole of creatinine, may be a result of a decreased creatinine excretion and thus represent a suggestive hint for the presence of CDS [37].

Guanidinoacetate can also be measured in dried blood spots [49, 50], thus allowing newborn screening for GAMT deficiency.



16

16.4.3 DNA Diagnostics

Mutation analysis for the three genes (GAMT, GATM and SLC6A8) involved in CDS is currently used to confirm the diagnosis. Denaturing gradient gel electrophoresis (DGGE) and denaturing high-performance liquid chro-matography (HPLC) methods [51, 52] were applied in the past, allowing screening of larger sample numbers. Most patients, however, have been diagnosed individually via direct gene sequencing. New technologies such as high-throughput sequencing, will allow direct gene testing as a screening tool. This might help to diagnose more patients with AGAT deficiency and SLC6A8 deficiency, for which the currently available biomarkers are not very sensi-tive. This is especially true for detection of heterozygous SLC6A8 females [27].

16.4.4 Functional Tests/Enzymatic Diagnostics

Functional tests and/or enzymatic diagnostics in fibro-blasts and/or lymphoblasts or in expression systems facil-itate confirmation of a diagnosis at a functional level, in particular if new mutations with unknown pathogenicity are detected [53-55].

16.4.5 Prenatal Diagnosis

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family for all three creatine deficiency syndromes [1]. In addition, GAMT deficiency can be prenatally diagnosed by guanidinoac-etate measurement in the amniotic fluid in pregnancies at risk for GAMT deficiency if the underlying disease-causing mutations have not been identified in the index patient [56].

16.5 Treatment and Prognosis

16.5.1 GAMT Deficiency

Oral creatine substitution has been effective in replen-ishing the cerebral creatine pool to approximately 70% of normal in all patients [5, 57]. Most received creatine monohydrate at 300-400 mg/kg/day in three to six di-vided doses. The clinical response to oral creatine supple-mentation alone included resolution of extrapyramidal signs and symptoms, and in most patients considerable

improvement of their epilepsy [4, 5]. Additional di-etary restriction of arginine helps to reduce accumulated guanidinoacetate [58], which in high concentrations is neurotoxic. Arginine is restricted to 15-25 mg/kg/day (corresponding to 0.4-0.7 g/kg/day protein intake), and supplementation with an arginine-free aminoacid mix-ture is necessary to provide an adequate nutritional amino acid supply [59]. Supplementation with high dos-ages of ornithine has the potential to reduce guani-dinoacetate synthesis by competitive inhibition of AGAT activity in vitro; however, this approach did not result in reduction of guanidinoacetate in one patient [60]. A combination of arginine restriction and ornithine sup-plementation might be more effective. This approach has led to an impressive improvement of epileptic seizures, mental capabilities and behaviour in a severely affected adult patient [34]. In this patient, sodium benzoate was given in addition to prevent ammonia accumulation due to possible lack of arginine as the essential amino acid in the urea cycle.

Initiation of combined therapy at an early age, prefer-ably in the neonatal period, might improve the long-term outcome. As an example, a sibling of one index patient was identified by positive mutation analysis in the neo-natal period. Treatment was initiated at age 3 weeks in the presymptomatic stage of the disease. The child had a normal neurodevelopmental outcome at age 14 months compared in contrast to the older, symptomatic sibling at the same age [61]. This finding raises the question of adding GAA to the routine derivatised MS/MS newborn screen, as it is simple and adds little to the cost [62].

16.5.2 AGAT Deficiency

Oral creatine supplementation (300-400 mg/kg/day) has been effective in replenishing the cerebral creatine pool and in improving abnormal developmental scores [10-12]. Early diagnosis and treatment seem to be par-ticularly efficient in improving outcomes. One child with global developmental delay at the age of 16 months had achieved normal developmental scores at the age of 40 months, after 23 months of treatment with creatine [13]. Another child diagnosed at age 2 years had a borderline IQ at age 8 years, whereas two children in the same family who started treatment at ages 7 and 5 years had moderate intellectual deficit at the ages of 13 and 11 years [11]. An additional patient from the same family was diagnosed prenatally, and creatine supplementation was started at 4 months. This child showed normal development in at age 18 months, in contrast to his siblings, who had already shown signs of retardation at this age [12].


16245References

16.5.3 SLC6A8 Deficiency

SLC6A8 deficiency appears not to be treatable by any of the approaches described above. Treatment of both males and females affected with SLC6A8 deficiency with cre-atine monohydrate has not proved successful [18]. Only one heterozygous female patient with learning disability and a mildly decreased creatine concentration on brain MRS showed mild improvement on neuropsychological testing after 18 weeks of treatment with creatine mono-hydrate (250-750 mg/kg/day) [16]. Supplementation with high doses of l-arginine and l-glycine, which are the pri-mary substrates for creatine biosynthesis, combined with high doses of creatine monohydrate, are currently being investigated. The rationale behind this protocol is based on an increased cerebral uptake of both amino acids with the aim of enhancing intracerebral creatine synthesis [63]. Supplementation of l-arginine alone has resulted in developmental progress in one male patient [64]. In four male patients this treatment has failed to improve intel-lectual outcomes [65]. Additional supplementation of l-glycine might enhance the therapeutic effect. Com-bined treatment with creatine, arginine and glycine has resulted in a significant improvement of intractable sei-zures in a female patient with SLC6A8 deficiency [26]. In addition, alternative strategies may be developed that facilitate creatine transport into the brain (e.g. by modi-fied transport via carrier peptides/molecules).

References

[1] Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S (Updated 2009) Creatine deficiency syndromes. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copy-right, University of Washington, Seattle. 1997-2011. Available at http://www.genetests.org

[2] Stöckler S, Schutz PW, Salomons GS (2007) Cerebral creatine defi-ciency syndromes: clinical aspects, treatment and pathophysiol-ogy. Subcell Biochem 46:149-166

[3] Stöckler S, Holzbach U, Hanefeld F et al. (1994) Creatine defi-ciency in the brain: a new treatable inborn error of metabolism. Pediatr Res 36:409-413

[4] Stöckler S, Isbrandt D, Hanefeld F et al. (1996) Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 58:914-922

[5] Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S, Adami A et al. (2006) Clinical, biochemical and molecular features of guanidinoacetate methyltransferase deficiency. Neurology 67:480-484

[6] Dhar SU, Scaglia F, Li FY, Smith L et al. (2009) Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 96:38-43

[7] Morris AA, Appleton RE, Power B et al. (2007) Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. J Inherit Metab Dis 30:100

[8] O’Rourke DJ, Ryan S, Salomons G et al. (2009) Guanidinoacetate methyltransferase (GAMT) deficiency: late onset of movement disorder and preserved expressive language. Dev Med Child Neurol 51:404-407

[9] Bianchi MC, Tosetti M, Fornai F et al. (2002) Reversible brain cre-atine deficiency in two sisters with normal blood creatine level. Ann Neurol 47: 511-513

[10] Item CB, Stöckler-Ipsiroglu S, Stromberger C et al. (2001) Arginine:glycine amindinotransferase (AGAT) deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69:1127-1133

[11] Battini R, Leuzzi V, Carducci C et al. (2002) Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 77:326-331

[12] Battini R, Alessandri MG, Leuzzi V et al.i (2006) Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treat-ment can prevent phenotypic expression of the disease. J Pediatr 148:828-830

[13] Johnston K, Plawner L, Cooper L et al. (2005) The second family with AGAT deficiency (creatine biosynthesis defect): diagnosis, treatment and the first prenatal diagnosis (abstract). In: Proceed-ings of the Annual Meeting of the American Society of Human Genetics, Salt Lake City, Utah, p 58

[14] Edvardson S, Korman SH, Livne A et al. (2010) l-Arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Mol Genet Metab 101:228-32

[15] Salomons GS, Dooren v SJ, Verhoeven NM et al. (2001) X-Linked creatine-transporter gene (SLC6A8) defect: a new creatine-defi-ciency syndrome. Am J Hum Genet 68:1497-1500

[16] Cecil KM, Salomons GS, Ball WS Jr et al. (2001) Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol 49:401-404

[17] Betsalel OT, Rosenberg EH, Almeida LS et al. (2011) Characteriza-tion of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database. Eur J Hum Genet 19:56-63

[18] DeGrauw TJ, Salomons GS, Cecil KM et al. (2002) Congenital cre-atine transporter deficiency. Neuropediatrics 33:232-238

[19] DeGrauw TJ, Cecil KM, Byars AW et al. (2003) The clinical syn-drome of creatine transporter deficiency. Mol Cell Biochem 244:45-48

[20] Mancini GM, Catsman-Berrevoets CE, de Coo IF et al. (2004) Two novel mutations in SLC6A8 cause creatine transporter defect and distinctive X-linked mental retardation in two unrelated Dutch families. Am J Med Genet 132:288-295

[21] Hahn KA, Salomons GS, Tackels-Horne D et al. (2002) X-Linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. Am J Hum Genet 70:1349-1356

[22] Kleefstra T, Rosenberg EH, Salomons GS et al. (2005) Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency caused by an SLC6A8 mu-tation. Clin Genet 68:379-381

[23] Anselm IA, Coulter DL, Darras BT (2008) Cardiac manifestations in a child with a novel mutation in creatine transporter gene SLC6A8. Neurology 29/70:1642-1644

[24] Fons C, Sempere A, Sanmartí FX et al. (2009) Epilepsy spectrum in cerebral creatine transporter deficiency. Epilepsia 50:2168-2170

[25] Mancardi MM, Caruso U, Schiaffino MC et al. (2007) Severe epi-lepsy in X-linked creatine transporter defect (CRTR-D). Epilepsia 48:1211-1213



16

[26] Mercimek-Mahmutoglu S, Connolly MB, Poskitt K et al. (2010) Treatment of intractable epilepsy in a female with SLC6A8 defi-ciency. Mol Genet Metab 101:409-12

[27] Kamp v d JM, Mancini GM, Pouwels PJ et al. (2011) Clinical fea-tures and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79:264-72

[28] Rosenberg EH, Almeida LS, Kleefstra T et al. (2004) High preva-lence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 75:97-105

[29] Newmeyer A, Cecil KM, Schapiro M, Clark JF, Degrauw TJ (2005) Incidence of brain creatine transporter deficiency in males with developmental delay referred for brain magnetic resonance im-aging. J Dev Behav Pediatr 26:276-282

[30] Clark AJ, Rosenberg EH, Almeida LS et al. (2006) X-Linked cre-atine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet 119:604-610

[31] Lion-Francois L, Cheillan D, Pitelet G et al. (2006) High frequency of creatine deficiency syndromes in patients with unexplained mental retardation. Neurology 67:1713-1714

[32] Arias A, Corbella M, Fons C et al. (2007) Creatine transporter defi-ciency: prevalence among patients with mental retardation and pitfalls in metabolite screening. Clin Biochem 40:1328-1331

[33] Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN (2006) Exocytotic release of creatine in rat brain. Synapse 60:118-123

[34] Schulze A, Bachert P, Schlemmer H et al. (2003) Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neu-rol 53:248-251

[35] Ensenauer R, Thiel T, Schwab KO et al. (2004) Guanidinoacetate methyltransferase deficiency: differences of creatine uptake in human brain and muscle. Mol Genet Metab 82:208-213

[36] Almeida LS, Verhoeven NM, Roos B et al. (2004) Creatine and guanidinoacetate: diagnostic markers for inborn errors in cre-atine biosynthesis and transport. Mol Genet Metab 82:214-219

[37] Stöckler-Ipsiroglu S, Stromberger C, Item CB et al. (2003) In: Blau N, Duran M, Blaskovics ME, Gibson KM (eds). Physician’s guide to the laboratory diagnosis of metabolic diseases. Springer, Heidel-berg Berlin New York, pp 467-480

[38] Spronsen v FJ, Reijngoud DJ, Verhoeven NM et al. (2006) High ce-rebral guanidinoacetate and variable creatine concentrations in argininosuccinate synthetase and lyase deficiency: implications for treatment. Mol Genet Metab 89:274-276

[39] Nanto-Salonen K, Komu M, Lundbom N et al. (1999) Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 53:303-307

[40] Bodamer OA, Sahoo T, Beaudet AL et al. (2005) Creatine metabo-lism in combined methylmalonic aciduria and homocystinuria. Ann Neurol 57:557-560

[41] Betsalel OT, Kamp v d JM, Martínez-Muñoz C et al. (2008) Detec-tion of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency. Neurogenetics 9:183-190

[42] Salomons GS, Dooren v SJ, Verhoeven NM et al. (2003) X-Linked creatine transporter defect: an overview. J Inherit Metab Dis 26:309-318

[43] Almeida LS, Vilarinho L, Darmin PS et al. (2007) A prevalent pathogenic GAMT mutation (c.59G>C) in Portugal. Mol Genet Metab 91:1-6

[44] Arias A, Ormazabal A, Moreno J et al. (2006) Methods for the di-agnosis of creatine deficiency syndromes: a comparative study. J Neurosci Methods 156:305-309

[45] Young S, Struys E, Wood T (2007) Quantification of creatine and guanidinoacetate using GC-MS and LC-MS/MS for the detection of cerebral creatine deficiency syndromes. Curr Protoc Hum Genet, chap 17, Unit 17.3

[46] Carling RS, Hogg SL, Wood TC, Calvin J (2008) Simultaneous de-termination of guanidinoacetate, creatine and creatinine in urine and plasma by un-derivatized liquid chromatography-tandem mass spectrometry. Ann Clin Biochem 45:575-584

[47] Mercimek-Mahmutoglu S, Muehl A, Salomons GS et al. (2009) Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry. Mol Genet Metab 96:273-275

[48] Valongo C, Cardoso ML, Domingues P et al. (2004) Age related reference values for urine creatine and guanidinoacetic acid con-centration in children and adolescents by gas chromatography-mass spectrometry. Clin Chim Acta 348:155-161

[49] Bodamer OA, Bloesch SM, Gregg AR, Stöckler-Ipsiroglu S, O’Brien WE (2001) Analysis of guanidinoacetate and creatine by isotope dilution electrospray tandem mass spectrometry. Clin Chim Acta 308:173-178

[50] Carducci C, Santagata S, Leuzzi V et al. (2006) Quantitative deter-mination of guanidinoacetate and creatine in dried blood spot by flow injection analysis-electrospray tandem mass spectrom-etry. Clin Chim Acta 364:180-187

[51] Item CB, Mercimek-Mahmutoglu S, Battini R et al. (2004) Charac-terization of seven novel mutations in seven patients with GAMT deficiency. Hum Mutat 23:524

[52] Item CB, Stöckler-Ipsiroglu S, Willheim C, Mühl A, Bodamer OA (2005) Use of denaturing HPLC to provide efficient detection of mutations causing guanidinoacetate methyltransferase defi-ciency. Mol Genet Metab 86:328-334

[53] Verhoeven NM, Schor DS, Roos B et al. (2003) Diagnostic enzyme assay that uses stable-isotope-labeled substrates to detect l-arginine:glycine amidinotransferase deficiency. Clin Chem 49:803-805

[54] Verhoeven NM, Roos B, Struys EA et al. (2004) Enzyme assay for diagnosis of guanidinoacetate methyltransferase deficiency. Clin Chem 50:441-443

[55] Rosenberg EH, Martínez Muñoz C, Betsalel OT et al. (2007) Func-tional characterization of missense variants in the creatine trans-porter gene (SLC6A8): improved diagnostic application. Hum Mutat 28:890-896

[56] Cheillan D, Salomons GS, Acquaviva C et al. (2006) Prenatal diagnosis of guanidinoacetate methyltransferase deficiency: increased guanidinoacetate concentrations in amniotic fluid. Clin Chem 52:775-777

[57] Stöckler S, Hanefeld F, Frahm J (1996) Creatine replacement ther-apy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 348: 789-790

[58] Schulze A, Ebinger F, Rating D, Mayatepek E (2001) Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab 74:413-419

[59] Stöckler-Ipsiroglu S, Battini R, de Grauw T, Schulze A (2005) Disor-ders of creatine metabolism. In: Blau N, Hoffmann GF, Leonard J, Clarke JTR (eds) Physician’s guide to the treatment and follow up of metabolic diseases. Springer-Verlag, Heidelberg, Berlin New York, pp 255-265

[60] Stöckler S, Marescau B, De Deyn PP et al. (1997) Guanidino com-pounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis. Metabolism 46:1189-1193


16247References

[61] Schulze A, Hoffmann GF, Bachert P et al. (2006) Presymptomatic treatment of neonatal guanidinoacetate methyltransferase defi-ciency. Neurology 67:719-721

[62] Sweetman L, Ashcraft P (2010) Newborn screening for GAMT deficiency: experience with guanidinoacetate by FIA-MS/MS and UPLC-MS/MS second tier testing. J Inherit Metab Dis 33 [Suppl 1]:S98

[63] Braissant O, Bachmann C, Henry H (2007) Expression and func-tion of AGAT, GAMT and CT1 in the mammalian brain. Subcell Biochem 46:67-81

[64] Chilosi A, Leuzzi V, Battini R et al. (2008) Treatment with l-arginine improves neuropsychological disorders in a child with creatine transporter defect. Neurocase 14:151-161

[65] Fons C, Sempere A, Arias A et al. (2008) Arginine supplementa-tion in four patients with X-linked creatine transporter defect. J Inherit Metab Dis 31:724-728


http://www.springer.com/978-3-642-15719-6

creatine deficiency syndromes - libreria universo

Documents