Phenotype and genotype in 101 males with X-linked creatine transporter deficiency

Kamp, Jiddeke M. van de; Betsalel, O.T.; Mercimek-Mahmutoglu, Saadet; Abulhoul, Lara; Grünewald, Stéphanie; Anselm, Irina; Azzouz, Hatem; Bratkovic, Drago; Brouwer, Arjan de; Hamel, B.C.J.; Kleefstra, Tjitske; Yntema, Helger G.; Campistol, Jaume; Vilaseca, M. A.; Cheillan, David; D’Hooghe, Marc; Diogo, Luísa; Garcia, Paula; Valongo, Carla; Fonseca, Maria José; Frints, Suzanna G.M.; Wilcken, Bridget; Haar, Sigrun von der; Meijers-Heijboer, Hanne; Hofstede, Floris C.; Johnson, Diana; Kant, S. G.; Lion‐François, Laurence; Pitelet, G.; Longo, Nicola; Maat-Kievit, J.A.; Monteiro, João; Münnich, Arnold; Muntau, Ania C.; Nassogne, Marie‐Cécile; Osaka, Hitoshi; Õunap, Katrin; Pinard, Jean-Marc; Quijano‐Roy, Susana; Poggenburg, I; Poplawski, Nicola; Abdul‐Rahman, Omar; Ribes, Antònia; Arias, Ángela; Yaplito‐Lee, Joy; Schulze, Andreas; Schwartz, Charles E.; Schwenger, S; Soares, Gabriela; Sznajer, Yves; Valayannopoulos, Vassili; Esch, Hilde Van; Waltz, Stephan; Wamelink, Mirjam M. C.; Pouwels, Petra J. W.; Errami, Abdellatif; Knaap, Marjo S. van der; Jakobs, Cornelis; Mancini, Grazia M.S.; Salomons, Gajja S.

doi:10.1136/jmedgenet-2013-101658

Cited by 125 publications

(150 citation statements)

References 67 publications

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“…True positive samples were diagnosed with either AGAT (n ϭ 3), GAMT (n ϭ 32), or CRT deficiency (n ϭ 120). At least 84 of these cases have been reported previously in peer- reviewed publications (13)(14), and all were confirmed by combinations of molecular analysis, magnetic resonance spectroscopy, and enzymatic analysis. The specimens included in this study were collected before treatment.…”

Section: Study Population and Analytical Methodsmentioning

confidence: 64%

Continuous Age- and Sex-Adjusted Reference Intervals of Urinary Markers for Cerebral Creatine Deficiency Syndromes: A Novel Approach to the Definition of Reference Intervals

et al. 2015

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Section: Study Population and Analytical Methodsmentioning

confidence: 64%

Continuous Age- and Sex-Adjusted Reference Intervals of Urinary Markers for Cerebral Creatine Deficiency Syndromes: A Novel Approach to the Definition of Reference Intervals

et al. 2015

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“…Mutation in CRT1 leads to an X-linked cellular creatine-deficiency syndrome with mental retardation, increased plasma and urinary creatine levels, and resistance to creatine supplementation. 9,10 Blood and urine levels of the creatine precursor guanidinoacetate are normal in patients with CRT1 mutations.…”

mentioning

confidence: 99%

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

Dhayat

Simonin

Anderegg

et al. 2015

JASN

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A heterozygous mutation (c.643C.A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo. However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G.A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.

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“…In CRTR deficiency, creatine concentrations in CSF are normal to mildly elevated, suggesting that creatine in the brain is lost because of a reuptake failure. 29 In general, specific enzyme activity assays and/or DNA testing should be used to confirm biochemical (metabolite) findings.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, these disorders are among the most important known metabolic causes of intellectual impairment and autistic behaviors. CRTR deficiency is the most common creatine deficiency syndrome, with over 150 patients reported, 29,41 accounting for approximately 2% of males with nonsyndromic, X-linked intellectual disability (after fragile X has been ruled out [47][48][49] ) and 0.3 to 2.2% of males with an IQ less than 70. 36,50 GAMT deficiency is the second most common creatine disorder, with approximately 110 patients reported worldwide.…”

Section: Prevalencementioning

confidence: 99%

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

Sharer

Bodamer

Longo

et al. 2017

Genetics in Medicine

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Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.

show abstract

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency

Cited by 125 publications

References 67 publications

Continuous Age- and Sex-Adjusted Reference Intervals of Urinary Markers for Cerebral Creatine Deficiency Syndromes: A Novel Approach to the Definition of Reference Intervals

Continuous Age- and Sex-Adjusted Reference Intervals of Urinary Markers for Cerebral Creatine Deficiency Syndromes: A Novel Approach to the Definition of Reference Intervals

Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

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