Quantitative sensory testing and intraepidermal nerve fibre density for improved diagnosis of Fabry disease.

Fabry disease is an X-linked inherited multisystem lysosomal storage disorder
with an estimated birth prevalence of classically affected patients of
~1:40,000. Deficient activity of the lysosomal hydrolase alfa-galactosidase A
is the primary cause of the disease and as a consequence glycosphingolipids,
primarily globotriaosylceramide (Gb3, also named GL-3 or CTH) accumulate. In
hemizygous males the first signs or symptoms usually occur during childhood and
adolescence. These include acroparesthesia, intolerance to heat, inability to
sweat and micro-albuminuria. Later in life cerebrovascular disease, cardiac
hypertrophy and progressive kidney disease may develop. Fabry disease may
manifest itself in carrier females in a more variable and in general a more
attenuated course.
The rarity of the disorder and variability of disease signs and symptoms often
cause important diagnostic delays. Although many ethical, legal and social
issues remain, several studies on the feasibility of screening for Fabry
disease have already been executed. These initiatives included screening of
high risk groups as well as neonatal screening. Surprisingly, the birth
prevalence of Fabry disease as diagnosed by newborn screening is around 10
times higher than birth prevalence based upon traditional diagnostic
trajectories. This may be explained by a high incidence of individuals with
mutations associated with late onset and mild disease manifestations. Whether
such individuals will develop Fabry related complications has not been
investigated sufficiently.
Sometimes, individuals are identified with a decreased alfa-galactosidase A
activity or a genetic variation in the GLA gene. These patients often only
present with a single -otherwise unexplained- symptom such as albuminuria, left
ventricular hypertrophy, pain in hands or feet, early stroke and/or atypical
white matter lesions, *red spots*, fatigue, gastrointestinal symptoms etc.
Oligosymptomatic patients are increasingly subjected to screening studies for
Fabry disease. These symptoms need not necessarily be causally related to the
genetic variations. Thus, there is an increasing need to specify whether in
positively sreened patients, specific signs and symptoms are actually caused by
Fabry disease or not. Biopsies from affected organ(s), to establish actual
storage of GB3, may in those cases be essential for a definite diagnosis.
The aim of the current study is to evaluate the added value of quantitative
sensory testing and intraepidermal nerve fiber density in individuals with a
AGAL deficiency and/or variation in the GLA gene of unknown clinical
significance. These assessments will be incorporated in a general Fabry disease
diagnostic algorithm that will explore all organ systems involved in Fabry
disease.

The aim of the current study is to evaluate the added value of quantitative
sensory testing and intraepidermal nerve fiber density in individuals with a
AGAL deficiency and/or variation in the GLA gene of unknown clinical
significance. These assessments will be incorporated in a general Fabry disease
diagnostic algorithm that will explore all organ systems involved in Fabry
disease.

Patients with a mutation or variant of undetermined clinical significance in
the AGAL gene or a decreased enzyme activity of *-galactosidase A are eligible
for the study; The AMC is the national referral center for Fabry disease.
Eligible patients are selected from the AMC Fabry patient cohort. .Quantitative
sensory testing and Skin biopsy for intraepidermal nerve fiber density are
performed and scheduled with other clinical assessments for Fabry disease after
informed consent is obtained.

The aim of the study is to delineate the added value of QST and intraepidermal
nerve fiber density in the establishment of Fabry disease. This is of extreme
importance for adequate counseling and support of patients and especially for
appropriate installation of costly treatment. The project has high potential to
lead to important clinical benefit when treatment can be more appropriately
timed. When patients are better diagnosed, we expect that those who need it can
be treated earlier and more effectively. On the other hand individuals may be
identified who carry a polymorphism or mild mutation who are asymptomatic or
have symptoms that suggest Fabry disease but are in fact caused by another
condition. In these cases, burdensome and anxiety causing procedures can be
avoided, such as unnecessary counseling, treatment and problems related to
eligibility for life insurance or disability insurance.
Fabry disease is one of the first genetic disorders for which the question of
disease versus non-disease will be studied in depth, with clear consequences
for patients and society.
A general public health goal will be served by avoiding unnecessary treatment
and interventions as well as to promote more timely initiation of therapy.
Harmonizing the approach to individuals with suspected Fabry disease within the
Netherlands supports the principles of equity, evidence and efficiency.
All procedures will be conducted by trained medical professionals only,
resulting in a low complication risk.