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Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

ABSTRACT: A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C?>?T and c.289C?>?T] and 1 splicing [c.391?+?15G?>?T] mutations for the GAMT gene and, 2 missense [c.1208C?>?A and c.926C?>?A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G?>?A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

SUBMITTER: Cheillan D

PROVIDER: S-EPMC3552865 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

Cheillan David D Joncquel-Chevalier Curt Marie M Briand Gilbert G Salomons Gajja S GS Mention-Mulliez Karine K Dobbelaere Dries D Cuisset Jean-Marie JM Lion-François Laurence L Portes Vincent Des VD Chabli Allel A Valayannopoulos Vassili V Benoist Jean-François JF Pinard Jean-Marc JM Simard Gilles G Douay Olivier O Deiva Kumaran K Afenjar Alexandra A Héron Delphine D Rivier François F Chabrol Brigitte B Prieur Fabienne F Cartault François F Pitelet Gaëlle G Goldenberg Alice A Bekri Soumeya S Gerard Marion M Delorme Richard R Tardieu Marc M Porchet Nicole N Vianey-Saban Christine C Vamecq Joseph J

Orphanet journal of rare diseases 20121213

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM ...[more]

PMID: 23234264

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Project description:ObjectivesTo conduct a pilot trial of a primary care Symptoms Clinic for patients with medically unexplained symptoms and evaluate recruitment and retention, and acceptability of the intervention and to estimate potential treatment effects for a full trial.Trial designRandomised parallel group pilot trial.SettingPrimary care in one locality.ParticipantsPrimary care database and postal questionnaire were used to identify patients with multiple specialist referrals and multiple physical symptoms unlikely to be explained by disease.InterventionsGeneral practitioner (GP) with special interest 'Symptoms Clinic' + usual care versus usual care alone. The Symptoms Clinic comprised one long (1 h) and three short (20 min) appointments.OutcomesNumber of patients identified and recruited; acceptability of the intervention (items from Client Satisfaction Questionnaire and interview); Medical Outcomes Survey Short Form 12 (SF-12) physical component summary.RandomisationAutomated blocked randomisation accessed by telephone.BlindingNone. NUMBERS RANDOMIZED: 16 to intervention and 16 to usual care alone.Recruitment72 patients, from seven GP practices, had repeated specialist referrals and a Patient Health Questionnaire (PHQ)-15 score of ≥10 indicating a high probability of medically unexplained symptoms. 15 were ineligible and 25 declined to participate. NUMBERS ANALYSED: 26 patients; two patients randomised to the intervention group were incorrectly included, three patients in the intervention group and one control did not complete outcome measures.OutcomeMost patients randomised to the Symptoms Clinic found the intervention acceptable: eight out of 11 reported the intervention helped them to deal with their problems. The mean difference between groups in SF-12 physical component summary, adjusted for baseline, was 3.8 points (SD 6).HarmsNo observed harms.ConclusionsPatients with multiple medically unexplained symptoms can be systematically identified in primary care; a randomised trial comparing the Symptoms Clinic with usual care is feasible and has the potential to show clinically meaningful benefit.Trial registrationISRCTN63083469.

Project description:Up to 48% of patients with medically unexplained symptoms seen in neurological practice suffer from sensory symptoms, which could be of functional nature or secondary to psychiatric disorders. These patients show high medical care utilization causing elevated healthcare costs. Despite the high prevalence, little is known about clinical characteristics and pathophysiological mechanisms. For functional disorders such as irritable bowel syndrome, a reduction of heart rate variability (HRV) has been shown, suggesting a dysfunction of the autonomic nervous system (ANS). The aim of this study was to investigate psychological data and functional changes of the ANS in patients with medically unexplained sensory symptoms (MUSS). In this exploratory pilot study, 16 patients (11 females, 31.6 ± 11.9 years) with MUSS, who were recruited at a single tertiary neurological center, underwent a structured clinical interview (SCID) to evaluate psychiatric comorbidities. Patients and age- and sex-matched healthy volunteers filled in questionnaires, and individual sensory thresholds (perception, pain) were detected by quantitative sensory testing (QST). HRV was assessed at baseline and under three different experimental conditions (tonic pain stimulus, placebo application, cold-face test). All tests were repeated after 6-8 weeks. SCID interviews revealed clinical or subclinical diagnoses of psychiatric comorbidities for 12 patients. Questionnaires assessing somatization, depression, anxiety, and perceived stress significantly discriminated between patients with MUSS and healthy controls. While there was no difference in QST, reduced ANS reactivity was found in patients during experimental conditions, particularly with regard to vagally mediated HRV. Our pilot study of neurological patients with MUSS reveals a high prevalence of psychiatric comorbidities and provides evidence for altered ANS function. Our data thus give insight in possible underlying mechanisms for these symptoms and may open the door for a better diagnostic and therapeutic approach for these patients in the future.

Dataset Information

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

Publications

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

Similar Datasets

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