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

Fragile X syndrome (FXS) is among the most common inherited genetic disorders leading to intellectual disability and autism [1]. It is caused by expansion of a cytosine-guanine-guanine (CGG) triplet repeat in the fragile mental retardation 1 (FMR1) gene located on the X chromosome. The presence of more than 200 repeats in the full mutation - compared with 6-44 repeats in normal individuals – is associated with complete or partial absence of the fragile mental retardation protein (FMRP), which regulates neurotransmitter-activated dendritic translation and synaptic plasticity [2]. While both males and females can be affected by FXS, in females, the rates of explicit disease are much lower, and symptoms often milder, due to the inactivation of only one of the two X chromosomes in female cells (all females with FXS are mosaic by definition). A definitive diagnosis can be made via a simple blood sample test and DNA analysis by Southern blot or PCR [3].

Reduced intelligence is a major symptom of FXS, varying from learning difficulties to severe cognitive impairment [4]. Speech, language, and attention deficit occur frequently [5, 6]. Behavioral problems and mood instability often present as the most debilitating aspects of the disease and reduction in these problems are the pivotal focus of drug therapy [7]. Other psychopathological syndromes and disorders are also prevalent: up to 50 % of males with FXS have autistic spectrum disorders [8‐10]. Every sixth child with FXS suffers from seizures [11].

Therapeutic options are very limited [12]. The full spectrum of psychotropic drugs (as per label and off-label) is utilized for the treatment of attention deficit disorder, anxiety, hyperactivity, mood swings, anger, depression, seizures, self-injury, and sleep disorders [13, 14].

Further, non-pharmacological therapy such as speech-language therapy or occupational therapy is frequently indicated [15]. In a recent systematic review of 31 intervention studies of individuals with FXS, overall results suggested that a behavioral approach to intervention shows promise [16]. Preliminary experience indicates that assistive technology (i.e. optic sensors such as photocells) generally may be of use to facilitate employment and opportunities of choice [17, 18].

Based on their synaptic mechanisms, specific agents including arbaclofen, ganaxolone, acamprosate, minocycline, as well as the mGluR5 inhibitors AFQ056 (mavoglurant by Novartis) and RG7090 (basimglurant by Roche) have been investigated in FXS [19, 20]. At the time when the present study was planned and initiated, the latter two substances were under investigation in placebo controlled phase IIb/III studies. However, these were discontinued in 2014 due to lack of efficacy in the FXS indication.

In Germany and other European countries, data on the phenotype, characteristics, quality of life, caregiver burden and other aspects of the management of patients with FXS are limited. The current study aimed to fill these gaps. It was initiated as a longitudinal study to investigate changes in psychometric parameters over time.

The EXPLAIN study is the largest and the only longitudinal European observational study investigating clinical characteristics and caregiver situation of patients with FXS. It documents 75 individuals in a wide age range, from 2 to 82 years. As expected, the prevalence of neurological findings and other comorbidities was very high. Almost every patient in our study had a relevant mental or neurological disorder which required pharmacological or non-pharmacological treatment. In younger patients, externalizing symptoms prevailed; in older patients, internalizing symptoms prevailed.

The only systematic recording of data on patients with FXS is currently taking place in the USA, in the context of individual projects, namely by the Fragile X Clinical & Research Consortium (FXCRC), with its FORWARD Registry and Database, and by our Fragile X World Surveys (twice per year, also supported by the U.S. Centers for Disease Control) [14, 15, 40].

The majority of documented patients in the present study were children and adolescents; only 29 were adults. Thus, it is understandable that most patients were still living with their parents, who mostly were the main caregivers. This indicates solid family structures, and might be a finding based on patient selection. The proxy information collected in this study can be considered to be “first-hand” and very reliable.

In light of the common social and behavior problems linked with FXS, an important tool for our study was the ABC-C questionnaire. It is a sensitive instrument for rating maladaptive and inappropriate behaviors in patients with intellectual disabilities. In patients with FXS, it has also been used as an endpoint in clinical studies (in the original or a modified version) [41‐43]. For example, in the mavoglurant studies, mean total scores at first documentation were, across the placebo and treatment groups, between 40.0 and 50.6 points in adults, and between 48.3 and 58.5 points in adolescents. The corresponding scores in our study were substantially lower in adults (36.4 points), and similar in adolescents (48.5 points). During the study, we found small improvements in the ABC-C score which remained constant over time. This might represent a study artefact or a nonspecific benefit of study participation.

The study shows a high burden of comorbidities as well as mental symptoms. The rates of mental health symptoms, at least in children and adolescents, were higher than the prevalence of such symptoms in the general population of individuals with intellectual disability in this age range. The prevalence of mental health symptoms in the general population of individuals with intellectual disability has been documented as follows: 24 % with impaired social behavior; 13 % with emotional problems; and 26 % with hyperactivity [44]. In EXPLAIN, the prevalences were 53.6 %, 39.7 %, and 49.3 %, respectively. As autistic behaviors were not specifically assessed in EXPLAIN, no conclusions can be drawn about them. However, overall, 42 % of parents and other caregivers reported such symptoms in their patients without describing them in detail. This prevalence is comparable with international studies reporting a prevalence of autistic symptoms between 25 and 47 % [45].

Compared with another study in a large US American cohort (89 women and 239 men aged between 22 and 64 years) [46], affective symptoms were less frequent in the adults (71.7 % versus 43.4 %). Hyperactivity in this age range occurred in only 21.7 %. Conversely, Hartley et al. described hyperactivity in 64.3 % of adults with FXS [46].

It was an unexpected finding that the comorbid mental health symptoms and diseases usually were treated with medications. Usually the prescription of psychopharmacological drugs in individuals with impaired intelligence is between 21 and 45 % [47]. The high prescription prevalence is probably an indicator of the severity of the individual disorder. Usually, for patients with FXS, findings from other neurodevelopmental disorders such as autism or other forms of intellectual disability are extrapolated for therapy planning [48‐50]. The FXCRC has highlighted that this patient group is sensitive to psychotropic medication, and recommends low doses and cautious titration [51].

In terms of quality of life assessment, as expected, patients with FXS had limitations in terms of self-care and usual activities, but also anxiety/depression. Compared with the German reference population [52], patients with FXS reported similar values for general health (visual analog scale). The EQ-5D questionnaire is widely used in studies with adults as a source of generic health-related quality of life information and utility weights to inform resource allocation decisions. Despite methodological limitations, the EQ-5D in its “youth” form is suitable for the same aim in children [34, 53]. On the EQ-5D scale, the EQ-5D time trade off (TTO) consists of a hypothetical trade-off between a shorter lifespan and a healthier quality of life. The respective reference score for the FXS population was calculated as described by Greiner et al. [33] The utility index value (0.8) was high, but showed substantial variation between patients. It remained relatively constant across the follow-up visits.

As a limitation to this study, a number of instruments which were used in other FXS studies were not applied in our study. For example, the mavoglurant studies had applied, among others, the SRS scale to identify the presence of autistic social impairment; the TEA-Ch to test every-day attention and inhibition in children; or the widely used Clinical Global Impression (CGI) scale to assess treatment response in psychiatric patients [42]. This study might be prone to selection bias: [54] participating centres might represent a positive selection with particular interest in FXS (and research questions). Participating patients (or their caregivers) might be more likely than others to understand the disease and to contribute to the optimization of management. Finally, we did not collect information on associated non-neurological medical problems which are known to be frequent among patients with FXS (such as otitis media, gastrointestinal problems and obstructive sleep apnea), and which increase the propensity for many behavioural problems [55].

In conclusion, the findings in EXPLAIN-FXS confirm the substantial burden of psychiatric and mental problems in patients with FXS in all age groups. In these patients, an early expert psychiatric diagnosis should be initiated. The resulting management should be multimodal and multi-professional and should be tailored to the individual patient’s needs.