Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study

Frank Haessler, Franziska Gaese, Michael Huss, Christoph Kretschmar, Marc Brinkman, Helmut Peters, Samuel Elstner, Michael Colla, David Pittrow, Frank Haessler, Franziska Gaese, Michael Huss, Christoph Kretschmar, Marc Brinkman, Helmut Peters, Samuel Elstner, Michael Colla, David Pittrow

Abstract

Background: As data on the phenotype, characteristics and management of patients with Fragile X Syndrome (FXS) are limited, we aimed to collect such data in Germany in experienced centres involved in the treatment of such patients.

Methods: EXPLAIN-FXS is a prospective observational (non-interventional) study (registry) performed between April 2013 and January 2016 at 18 sites in Germany. Requirements for patient participation included confirmed diagnosis of FXS by genetic testing (>200 CGG repeats) and written informed consent. Patients were followed for up to 2 years.

Results: Seventy-five patients (84.0 % males, mean age 16.7 ± 14.5 years, ranging from 2 - 82 years) were analysed. The mean 6-item score, determined according to Giangreco (J Pediatr 129:611-614, 1996), was 6.9 ± 2.5 points. At least one neurological finding each was noted in 53 patients (69.7 %). Specifically, ataxia was noted in 5 patients (6.6 %), lack of fine motor skills in 40 patients, (52.6 %), muscle tonus disorder in 4 patients (5.3 %), and other neurological disorders in 39 patients (51.3 %). Spasticity was not noted in any patient. Seizures were reported in 6 patients (8.1 %), anxiety disorders in 22 patients (30.1 %), depression in 7 patients (9.6 %), ADHD/ADD in 36 patients (49.3 %), impairment of social behavior in 39 patients (53.4 %), and other comorbidities in 23 patients (31.5 %). The mean Aberrant Behaviour Checklist Community Edition (ABC-C) score on behavioral symptoms, obtained in 71 patients at first documentation, was 48.4 ± 27.8 (median 45.0, range 5-115). The mean visual analogue scale (VAS) score, obtained in 59 patients at first documentation, was 84.9 ± 14.6 points (median 90; range 50 - 100).

Conclusions: This report describes the largest cohort of patients with FXS in Europe. The reported observations indicate a substantial burden of disease for patients and their caregivers. Based on these observations, an early expert psychiatric diagnosis is recommended for suspected FXS patients. Further recommendations include multimodal and multi-professional management that is tailored to the individual patient's needs.

Trial registration: The ClinTrials.gov identifier is NCT01711606 . Registered on 18 October 2012.

Keywords: Ambulatory setting; Caregiver burden; Fragile X syndrome; Health care; Mental disorders; Outcomes; Quality of life.

References

    1. Carter MT, Scherer SW. Autism spectrum disorder in the genetics clinic: a review. Clin Genet. 2013;83(5):399–407. doi: 10.1111/cge.12101.
    1. Wang T, Bray SM, Warren ST. New perspectives on the biology of fragile X syndrome. Curr Opin Genet Dev. 2012;22(3):256–263. doi: 10.1016/j.gde.2012.02.002.
    1. Sofocleous C, Kolialexi A, Mavrou A. Molecular diagnosis of Fragile X syndrome. Expert Rev Mol Diagn. 2009;9(1):23–30. doi: 10.1586/14737159.9.1.23.
    1. Lewis P, Abbeduto L, Murphy M, Richmond E, Giles N, Bruno L, et al. Cognitive, language and social-cognitive skills of individuals with fragile X syndrome with and without autism. J Intellect Disabil Res. 2006;50(Pt 7):532–545. doi: 10.1111/j.1365-2788.2006.00803.x.
    1. Barnes E, Roberts J, Long SH, Martin GE, Berni MC, Mandulak KC, et al. Phonological accuracy and intelligibility in connected speech of boys with fragile X syndrome or Down syndrome. J Speech Lang Hear Res. 2009;52(4):1048–1061. doi: 10.1044/1092-4388(2009/08-0001).
    1. Deshpande PS, Coffey DB. Fragile X syndrome and attention-deficit/hyperactivity disorder symptoms. J Child Adolesc Psychopharmacol. 2011;21(6):639–642. doi: 10.1089/cap.2011.2164.
    1. Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, et al. Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment. J Autism Dev Disord. 2012;42(7):1377–1392. doi: 10.1007/s10803-011-1370-2.
    1. McCary LM, Roberts JE. Early identification of autism in fragile X syndrome: a review. J Intellect Disabil Res. 2013;57(9):803–814. doi: 10.1111/j.1365-2788.2012.01609.x.
    1. Gabis LV, Baruch YK, Jokel A, Raz R. Psychiatric and autistic comorbidity in fragile X syndrome across ages. J Child Neurol. 2011;26(8):940–948. doi: 10.1177/0883073810395937.
    1. Sabaratnam M, Murthy NV, Wijeratne A, Buckingham A, Payne S. Autistic-like behaviour profile and psychiatric morbidity in Fragile X Syndrome: a prospective ten-year follow-up study. Eur Child Adolesc Psychiatry. 2003;12(4):172–177. doi: 10.1007/s00787-003-0333-3.
    1. Berry-Kravis E, Raspa M, Loggin-Hester L, Bishop E, Holiday D, Bailey DB. Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Am J Intellect Dev Disabil. 2010;115(6):461–472. doi: 10.1352/1944-7558-115.6.461.
    1. Rueda JR, Ballesteros J, Tejada MI. Systematic review of pharmacological treatments in fragile X syndrome. BMC Neurol. 2009;9:53. doi: 10.1186/1471-2377-9-53.
    1. Berry-Kravis E, Potanos K. Psychopharmacology in fragile X syndrome--present and future. Ment Retard Dev Disabil Res Rev. 2004;10(1):42–48. doi: 10.1002/mrdd.20007.
    1. Bailey DB, Jr, Raspa M, Bishop E, Olmsted M, Mallya UG, Berry-Kravis E. Medication utilization for targeted symptoms in children and adults with fragile X syndrome: US survey. J Dev Behav Pediatr. 2012;33(1):62–69. doi: 10.1097/DBP.0b013e318236c0e1.
    1. Martin GE, Ausderau KK, Raspa M, Bishop E, Mallya U, Bailey DB., Jr Therapy service use among individuals with fragile X syndrome: findings from a US parent survey. J Intellect Disabil Res. 2013;57(9):837–849. doi: 10.1111/j.1365-2788.2012.01608.x.
    1. Moskowitz LJ, Jones EA. Uncovering the evidence for behavioral interventions with individuals with fragile X syndrome: a systematic review. Res Dev Disabil. 2015;38:223–241. doi: 10.1016/j.ridd.2014.12.011.
    1. Stasolla F, Damiani R, Perilli V, Di Leone A, Albano V, Stella A, et al. Technological supports to promote choice opportunities by two children with fragile X syndrome and severe to profound developmental disabilities. Res Dev Disabil. 2014;35(11):2993–3000. doi: 10.1016/j.ridd.2014.07.045.
    1. Stasolla F, Perilli V, Damiani R, Albano V. Assistive technology to promote occupation and reduce mouthing by three boys with fragile X syndrome. Dev Neurorehabil. 2016: 1-9. Epub ahead of print.
    1. Hagerman R, Lauterborn J, Au J, Berry-Kravis E. Fragile X syndrome and targeted treatment trials. Results Probl Cell Differ. 2012;54:297–335. doi: 10.1007/978-3-642-21649-7_17.
    1. Levenga J, Hayashi S, de Vrij FM, Koekkoek SK, van der Linde HC, Nieuwenhuizen I, et al. AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. Neurobiol Dis. 2011;42(3):311–317. doi: 10.1016/j.nbd.2011.01.022.
    1. Haessler F, Gaese F, Colla M, Huss M, Kretschmar C, Brinkman M, et al. EXPLAIN Fragile-X: an explorative, longitudinal study on the characterization, treatment pathways, and patient-related outcomes of Fragile X Syndrome. BMC Psychiatry. 2013;13:339. doi: 10.1186/1471-244X-13-339.
    1. Federal Institute for Drugs and Medical Products (BfArM). Recommendations of the Federal Institute for Drugs and Medical Products and the Paul Ehrlich Institute on the planning, conduct and analysis of post marketing studies dated 7 July 2010. Internet: . Accessed 7 Mar 2016.
    1. German Association of Research-based Pharmaceutical Companies (Verband der forschenden Arzneimittelhersteller VFA). Rules for publication of post-marketing surveillance studies. Internet: . Accessed 7 Mar 2016.
    1. Giangreco CA, Steele MW, Aston CE, Cummins JH, Wenger SL. A simplified six-item checklist for screening for fragile X syndrome in the pediatric population. J Pediatr. 1996;129(4):611–614. doi: 10.1016/S0022-3476(96)70130-0.
    1. Derogatis LR, Lipman RS, Covi L. SCL-90: an outpatient psychiatric rating scale--preliminary report. Psychopharmacol Bull. 1973;9(1):13–28.
    1. Kuhl HC, Hartwig I, Petitjean S, Muller-Spahn F, Margraf J, Bader K. Validation of the Symptom Checklist SCL-27 in psychiatric patients: Psychometric testing of a multidimensional short form. Int J Psychiatry Clin Pract. 2010;14(2):145–149. doi: 10.3109/13651501003660484.
    1. Kubinger K. The intelligence test-battery AID 2 as a prototypical globalized test. Test Int. 2008;19:13–14.
    1. Petermann F, Petermann U. HAWIK-IV. 3. Bern: Huber Verlag; 2010.
    1. Melchers P, Preuß U. Kaufman Assessment Battery for Children. Eights. Frankfurt/Main: Pearson Assessment; 2009.
    1. Harris S. An evaluation of the Snijders-Oomen nonverbal intelligence scale for young children. J Pediatr Psychol. 1982;7(3):239–251. doi: 10.1093/jpepsy/7.3.239.
    1. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985;89(5):485–491.
    1. Newton JT, Sturmey P. The Aberrant Behaviour Checklist: a British replication and extension of its psychometric properties. J Ment Defic Res. 1988;32(Pt 2):87–92.
    1. Greiner W, Claes C, Busschbach JJ, von der Schulenburg JM. Validating the EQ-5D with time trade off for the German population. Eur J Health Econ. 2005;6(2):124–130. doi: 10.1007/s10198-004-0264-z.
    1. Wille N, Badia X, Bonsel G, Burstrom K, Cavrini G, Devlin N, et al. Development of the EQ-5D-Y: a child-friendly version of the EQ-5D. Qual Life Res. 2010;19(6):875–886. doi: 10.1007/s11136-010-9648-y.
    1. Loyd BH, Abidin RR. Revision of the parenting stress index. J Pediatr Psychol. 1985;10(2):169–177. doi: 10.1093/jpepsy/10.2.169.
    1. Honigfeld G. NOSIE--30: history and current status of its use in pharmacopsychiatric research. Mod Probl Pharmacopsychiatry. 1974;7:238–263. doi: 10.1159/000395079.
    1. Honigfeld G, Gillis RD, Klett CJ. NOSIE-30: a treatment-sensitive ward behavior scale. Psychol Rep. 1966;19(1):180–182. doi: 10.2466/pr0.1966.19.1.180.
    1. Linden M, Baron S, Muschalla B. Mini-ICF-Rating für Aktivitäts- und Partizipationsstörungen bei psychischen Erkrankungen. Bern: Hans Huber Verlag; 2009.
    1. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453–1457. doi: 10.1016/S0140-6736(07)61602-X.
    1. Hartley SL, Wheeler AC, Mailick MR, Raspa M, Mihaila I, Bishop E, et al. Autism symptoms across adulthood in men with Fragile X syndrome: a cross-sectional analysis. J Autism Dev Disord. 2015;45(11):3668–3679. doi: 10.1007/s10803-015-2513-7.
    1. Gomez-Mancilla B, Berry-Kravis E, Hagerman R, von Raison F, Apostol G, Ufer M, et al. Development of mavoglurant and its potential for the treatment of fragile X syndrome. Expert Opin Investig Drugs. 2014;23(1):125–134. doi: 10.1517/13543784.2014.857400.
    1. Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, et al. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med. 2016;8(321):321ra5. doi: 10.1126/scitranslmed.aab4109.
    1. Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med. 2012;4(152):152ra27. doi: 10.1126/scitranslmed.3004214.
    1. Emerson E, Einfeld S, Stancliffe RJ. The mental health of young children with intellectual disabilities or borderline intellectual functioning. Soc Psychiatry Psychiatr Epidemiol. 2010;45(5):579–587. doi: 10.1007/s00127-009-0100-y.
    1. Gallagher A, Hallahan B. Fragile X-associated disorders: a clinical overview. J Neurol. 2012;259(3):401–413. doi: 10.1007/s00415-011-6161-3.
    1. Hartley SL, Seltzer MM, Raspa M, Olmstead M, Bishop E, Bailey DB. Exploring the adult life of men and women with fragile X syndrome: results from a national survey. Am J Intellect Dev Disabil. 2011;116(1):16–35. doi: 10.1352/1944-7558-116.1.16.
    1. Habetaler F, Thome J, Reis O. Polypharmacy in the treatment of subjects with intellectual disability. J Neural Transm (Vienna) 2015;122(Suppl 1):S93–S100. doi: 10.1007/s00702-014-1219-x.
    1. Young NJ, Findling RL. An update on pharmacotherapy for autism spectrum disorder in children and adolescents. Curr Opin Psychiatry. 2015;28(2):91–101.
    1. Hässler F, Reis O. Pharmacotherapy of disruptive behavior in mentally retarded subjects: A review of the current literature. Dev Disabil Res Rev. 2010;16(3):265–272. doi: 10.1002/ddrr.119.
    1. Wang H, Pati S, Pozzo-Miller L, Doering LC. Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes. Front Cell Neurosci. 2015;9:55.
    1. Fragile X Foundation. Consensus of the Fragile X Clinical & Research Consortium on Clinical Practices. Medication for Individuals with Fragile X Syndrome. Washington DC, USA. Updated version October 2012. Internet: . Accessed 11 Mar 2016.
    1. Morfeld M, Bullinger M, Nantke J, Brahler E. The version 2.0 of the SF-36 Health Survey: results of a population-representative study. Soz Praventivmed. 2005;50(5):292–300. doi: 10.1007/s00038-005-4090-6.
    1. Noyes J, Edwards RT. EQ-5D for the assessment of health-related quality of life and resource allocation in children: a systematic methodological review. Value Health. 2011;14(8):1117–1129. doi: 10.1016/j.jval.2011.07.011.
    1. Delgado-Rodriguez M, Llorca J. Bias. J Epidemiol Community Health. 2004;58(8):635–641. doi: 10.1136/jech.2003.008466.
    1. Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, et al. Fragile X syndrome: a review of associated medical problems. Pediatrics. 2014;134(5):995–1005. doi: 10.1542/peds.2013-4301.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner