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Brooks et al. Neurological manifestations in Fabry disease

FD and may lead to increased morbidity and mortality, as multiple sclerosis due to intermittent disseminated
with concomitant reduction in life expectancy. While sensory deficits and white matter lesions fulfilling the
[10]
the literature on the skin, kidney and cardiovascular McDonald criteria. [20-22] However, T2-FLAIR MRI of
manifestations of FD has been consistent, there have the white matter usually produces asymmetric and
been very few reports on the neurological aspects of confluent images, with little involvement of the corpus
the disease. callosum and no enhancement of the lesion through
gadolinium. There are no lesions in the spinal cord.
The aim of this article was to describe the neurological These characteristics help differentiating FD images
manifestations in FD. They may occur at any stage of from multiple sclerosis. Vertebrobasilar system
[23]
the disease, including its onset. Therefore, although ectasia, proteinuria, cardiac hypertrophy and histories
relatively rare, FD is a differential diagnosis for of death among young relatives (renal, cardiac or
young individuals with unexplained neurological cerebrovascular causes) are other frequently found
manifestations.
elements in these patients’ medical history. [24,25]

CEREBRAL VASCULOPATHY Calcification of cerebrovascular dolichoectasia
in cerebral white matter and thalamus (pulvinar
The prevalence of cerebrovascular diseases such as region) is due to dysfunction of the cerebrovascular
stroke events in FD patients is 4-6%. These events circulation and to GL-3 accumulation. Cerebrovascular
may be the first clinical manifestation of the disease hyperperfusion reflects the increased vascular
and are more often observed between the ages of 18
and 55 years, affecting both genders equally. [11] reactivity and the effect on the nitric oxide pathway,
while increased oxidative stress and formation of
Cerebral endothelial vasculopathy in FD is not fully peroxynitrite can create persistent vasodilation and
understood, but it is accepted that GL-3 accumulation increased risk of atherosclerosis. [26]
and polymorphisms of pro-thrombotic genes can
modify Virchow’s triad and create a pro-thrombotic COCHLEAR NERVE DYSFUNCTION
state. [12,13] These alterations include changes to
interleukin-6-G-174C, G894T of endothelial nitric oxide The data in the literature on the pathogenesis of cochlear
synthase, factor V G1691A mutation and protein Z dysfunction in FD are limited. It has been hypothesized
A-13G or G79A. Few studies have concentraded on that GL-3 accumulation in the cochlear nerve can
[13]
intravenous thrombolytic therapy for acute ischemic progress to hearing loss, especially at 2-3 kHz. [27]
stroke in FD patients and the outcomes are not fully
understood. [14] PSYCHIATRIC AND COGNITIVE SYMPTOMS

Although ischemic stroke and transient ischemic High prevalence of neuropsychiatric symptoms,
attacks are the main types of cerebrovascular events such as depression and neuropsychological deficits,
in FD, cerebral hemorrhage, microbleeding, cerebral reduces quality of life among FD patients. Although
venous thrombosis and cervical carotid dissection have the pathophysiological mechanisms have not been
also been reported. The main etiology of stroke comes fully elucidated, cerebral vasculopathy is involved.
from the effect of the disease on the small arteries. The Furthermore, FD patients may be chronically distressed
posterior circulation (vertebrobasilar system) is often by pain and psychosocial impairment. [28-30]
more involved than the carotid system. [15-18]

White matter lesions are a reflection of secondary AUTONOMIC DYSFUNCTION
microangiopathy involvement of the central nervous
system. As many as 80% of these patients present these Hypohidrosis, reduced saliva flow and impaired tear
abnormalities on magnetic resonance imaging (MRI), production may be present and have mechanisms
even without clinical symptoms of focal neurological that are not fully understood. GL-3 accumulation
involvement. Increased cerebral blood flow, vascular in autonomic ganglia and dysfunction of eccrine
hyper-reactivity and GL-3 deposition ultimately induce glands are found in patients with FD. Gastrointestinal
cell dysfunction and increase interstitial pressure, symptoms (which may be associated with autonomic
thus generating vulnerability of elongated perforating dysfunction) are the second most common clinical
arteries and leading to reduction of cerebral blood manifestation among children and young adults
[8]
flow. [19] with FD. During unexplained attacks of abdominal
pain, the patients may also suffer from postprandial
Brain microangiopathy in FD can be misdiagnosed flatulence and bouts of diarrhea. [31,32]
Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ October 28, 2016 229