The NeuroFab Study: Two year follow-up of Cognitive and Psychological functioning in patients with Fabry Disease.

Fabry Disease (FD) is a rare, progressive, X-linked metabolic disorder, that
belongs to the group of lysosomal storage diseases. GLA gene abnormalities
cause absence or deficiency of lysosomal *-galactosidase A (*-GalA) leading to
accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3).
Progressive accumulation of Gb3 is prominent in vascular endothelium, brain,
kidneys and heart. FD has a wide range of symptoms and is usually divided into
the classic phenotype, most often seen in male patients without residual enzyme
activity, and the non-classical phenotype. In untreated FD renal disease,
cardiac events and transient ischaemic attacks (TIA) or cerebrovascular
accidents (CVA) occur frequently. In contrast, patients with non-classical FD
usually have a less progressive disease course and symptoms may be restricted
to one organ.

Since 2001 enzyme replacement therapy (ERT) is available for patients with FD.
Studies on the long therm effect of ERT have shown that ERT can postpone
complications on heart and kidneys and might improve quality of life (QoL),
gastrointestinal symptoms and pain, primarily when started in the early course
of FD.

Cerebral involvement is common in patients with FD. The prevalence of white
matter lesions (WMLs) increases with age and is present in all patients above
54 years of age. The prevalence of often premature CVA/TIA is up to 24% in
males with classic phenotype, while the two largest Fabry registries report a
prevalence of 6.9%-25% in male patients and 4.3%-21% in female patients.

The effect of ERT on cerebrovascular manifestation of FD is unclear. Evidence
shows mixed results. Some studies showed halt or reverse of WMLs, while other
studies demonstrated progression of WMLs and occurrence of stroke and/or TIAs
during ERT in Fabry patients.
Research in non-Fabry populations shows that dysfunction of cerebral blood
flow, microvascular brain damage and WMLs increase the risk of cognitive
impairment and dementia. These abnormalities are all present in FD. In
addition, it has become clear from personal clinical experience that some males
with end stage classical FD may develop severe cognitive impairment. Indeed,
the results of a systematic review suggested an association between FD and
cognitive impairment (executive functioning, information processing speed and
attention). However, definite conclusions could not be drawn due to the limited
amount of available evidence.

This review also summarized the available evidence on the prevalence of
depression in FD and discussed their relationship. The largest included study
reported a depression prevalence of 46% of which a significant part was
undiagnosed. It is still under debate whether depression is a result of
difficulties in coping with symptoms of FD, especially chronic pain, or a
result of cerebrovascular disease. It is important to realize that depression
or depressive symptoms may impair performance on neuropsychological tests.
Several studies on neuropsychological functioning have been carried out since
the abovementioned systematic review, and these showed variable outcomes.
Altogether, the extent of cognitive impairment in FD remains unclear.

Previous studies have suggested an association between FD and cognitive
impairment but these were flawed either by lack of power, used variable
assessment of cognitive functioning and/or merged results of different
phenotypes and sexes. It is of great importance to gain more insight into the
debilitating cognitive problems in FD and the occurrence of psychological
distress and its influence on cognitive functioning.

In summary, FD is a severe and debilitating disease which affects cognitive and
psychological functioning, with unclear effect of ERT. We hypothesize that
Fabry patients have decreased cognitive functioning measured by standardized
neuropsychological instruments, compared to Dutch normative data, which is
attributable to cerebrovascular manifestations of FD. These cognitive
complications are probably most prominent in males with classical FD.

The Academic Medical Centre (AMC) in Amsterdam is the only referral center for
Fabry patients in the Netherlands. Fabry patients are frequently monitored,
with intervals ranging from once every three months immediately after start of
ERT to once every four years in asymptomatic female patients. During follow-up
visits Fabry patients undergo routine clinical care including MRI-brain,
testing and follow-up of biomarkers and physical examination. All Fabry
patients have been asked for informed consent to use their clinical data for
research. These data have been prospectively entered into a clinical database
which will be used in our study.
In this prospective cohort study, data on cognitive and psychological
functioning will be gathered using standardized neuropsychological tests and
questionnaires. These tests and questionnaires are not included in the routine
clinical care for Fabry patients. For all neuropsychological tests and most of
the questionnaires extensive Dutch normative data are available. These data are
adjusted for age, gender and education. All Fabry patients known in this center
will be screened by telephone for eligibility, according to inclusion and
exclusion criteria. Included patients will be followed for two years after
inclusion. Excluded patients and patients unwilling to participate will be
compared to included patients for possible differences in demographic and
disease characteristics, collected through our clinical database. In the two
years follow up period the included patients will be evaluated three times.
There will be three visits to the AMC: at baseline, after one year and after
two years, each visit lasting around three hours. If possible, study visits
will be scheduled on the same day as their routine appointments to minimize
patient inconvenience.

There will be no invasive tests during this study. Patients will fill in
questionnaires at home and complete neuropsychological tests at the AMC.
Filling in questionnaires and completing a neuropsychological test battery
costs time and can be experienced as exhausting. If performance on
questionnaires and cognitive tests is worse than expected by the Fabry patients
or controls this can be experienced as a burden.
Benefits of this study can be: establishing the presence or absence of
neuropsychological problems. If any problems are present they can be addressed.
In case of neuropsychological problems with impact on wellbeing, Fabry patients
or controls will be informed and advised to consult their general practitioner.
If there are no evident problems this can be seen as a reassurance of their
health status.