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LESSON OF THE MONTH

Neurological presentation of Fabry’s disease in a 52
year old man
R Mohanraj, J P Leach, J C Broome, D F Smith
.............................................................................................................................

J Neurol Neurosurg Psychiatry 2002;73:340–342

Fabry’s disease is an X linked inborn error of metabolism
due to deficient activity of the lysosomal enzyme α
galactosidase A. Previously unrecognised Fabry’s disease
presenting in a 52 year old man being investigated for progressive dysarthria and ataxia is discussed. Brain magnetic
resonance imaging suggested the presence of small vessel
disease but skin biopsy (done to exclude cerebral autosomal
dominant arteriopathy with subcortical infarcts and leucencephalopathy) showed typical changes of Fabry’s disease.
This diagnosis was confirmed by subsequent enzyme
assays. The authors contend that Fabry’s disease should be
excluded, at least on clinical grounds, in patients with
otherwise unexplained cerebrovascular disease.

A

52 year old man presented with a two year history of
progressive slurring of speech, memory problems, and
unsteadiness of gait. He also complained of involuntary
twitches in both legs and occasional paraesthesiae in the fingers of one hand. On direct questioning, he admitted to
urinary incontinence and erectile dysfunction. He suffered
from asthma, for which he took regular inhaled salbutamol,
fluticasone, salmeterol, and ipratropium bromide. Congenital
lymphoedema had been diagnosed when the patient was in
his 20s and he had since been on long term diuretic treatment.
He had recently been started on paroxetine for depression.
The patient was a non-smoker and was drinking a maximum
of three units of alcohol a day. There was a family history of cerebrovascular disease: his mother and one of his sisters had both
had a non-fatal cerebrovascular accident in their 50s. Another
sister was being investigated for “visual problems”. The patient
had one healthy brother, but the patient’s 30 year old daughter
suffered from unexplained limb pains.
On examination the patient was normotensive and mildly
dysarthric. No organomegaly was noted. His ocular fundi were
normal and pursuits were jerky with no nystagmus. There was
mild incoordination in the upper limbs. Reflexes were
symmetrically normal and there was no focal deficit in power.
Gait was unsteady with a broad base. The typical rash
(angiokeratoma corporis diffusum) was present periumbilically, although this was not noted at initial examination. Formal neuropsychological assessment found deterioration in
general intellectual and memory functions. Language and
frontal lobe executive functions were well preserved.
Late onset cerebellar syndrome was diagnosed and a variety
of investigations were instituted. Full blood count, urea and
electrolytes, and random blood glucose results were within
normal limits. The serum creatinine was initially normal but
had risen to 158 µmol/l by the time of diagnosis. γ Glutamyl
transferase and alkaline phosphatase concentrations were
modestly increased but other liver function tests were normal.
Random blood alcohol was undetectable. Cerebrospinal fluid
(CSF) protein concentration was increased at 0.81 g/l but
there were no cells in the CSF and immunofixation did not
show oligoclonal bands.

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Figure 1 T2 weighted magnetic resonance images in a patient
with Fabry’s disease.

The following tests were normal or negative: autoantibodies
(anticardiolipin antibodies, antinuclear antibody, extractable
nuclear antibody, antinuclear cytoplasm antibody), lupus
anticoagulant, CSF lactate, Whipple’s polymerase chain
reaction, mitochondrial DNA mutations (mitochondrial
myopathy, encephalopathy, lactacidosis, and stroke-like episodes; myoclonus epilepsy with ragged red fibres; and a
syndrome of neuropathy with ataxia and retinitis pigmentosa), serum gliadin antibody, and aminoaciduria screen.
Cranial magnetic resonance imaging showed generalised
atrophy with multiple areas of high signal intensity on proton
density and T2 weighted axial sections involving the white
matter of both cerebellar and cerebral hemispheres (fig 1).
These were thought to be areas of ischaemia or demyelination.
Nerve conduction studies showed bilateral carpal tunnel
syndrome and evidence of a mild sensory motor neuropathy
with reduced motor and sensory amplitudes in both lower
limbs. Visual evoked responses were normal on the right and
delayed on the left. An electrocardiogram showed left bundle
branch block but a transthoracic echocardiogram showed no
significant valve heart disease. Carotid Doppler echocardiography showed only minimal atheroma.
DNA testing for cerebral autosomal dominant arteriopathy
with subcortical infarcts and leucencephalopathy (CADASIL)
was negative. Skin biopsy showed abnormal small dermal
blood vessels on light microscopy but no changes consistent
with CADASIL. Electron microscopy of the skin showed membrane bound collections of electron dense bodies in the
endothelial cells, fibroblasts, and pericytes (fig 2). The changes
.............................................................
Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy
with subcortical infarcts and leucencephalopathy; CSF, cerebrospinal
fluid

Fabry’s disease

Figure 2 Electron microscopy of skin biopsy of a patient with
Fabry’s disease. The accumulated sphingolipids appear as
intracellular striated structures. Original magnification (top) ×6400,
(bottom) ×23 200.

were thought to result from a lysosomal storage disorder. A
white cell enzyme assay was carried out and this showed
greatly reduced α galactosidase activity, confirming the
diagnosis of Fabry’s disease.

DISCUSSION
Fabry’s disease is a lysosomal storage disorder inherited as an
X linked recessive trait and caused by deficient activity of the
lysosomal enzyme α galactosidase A. It has a prevalence of
1/40 000 and can produce various neurological complications.
Although Fabry’s disease usually appears in childhood or adolescence with typical skin lesions and painful “crises”, atypical

341

affected men can present in adulthood. Most late presentations of Fabry’s disease are precipitated by cardiac or renal
complications; neurological presentation in adulthood remains rare. Interestingly, when our patient was questioned
directly after the diagnosis, it emerged that he had been
referred to a hospital clinic at the age of six with (hitherto
unexplained) distal limb pains.
While the clinical signs are important, showing reduced or
absent α galactosidase deficiency in leucocytes is essential for
the diagnosis of Fabry’s disease.1 The enzymatic defect leads to
the systemic accumulation of neutral glycospingolipids in
plasma and tissues. The lipid is stored as a myelin figure-like
whorl of membranes in endothelial and smooth muscle cells,
myocardium, fibroblasts, and epithelial cells of the glomerulus
seen on electron microscopy.2 Most female carriers are asymptomatic but they may experience isolated acroparaesthesiae,
cardiac symptoms, or a characteristic benign corneal dystrophy. Clinical manifestations in affected male patients result
from a progressive disease of small vessels and may initially
involve the typical rash (angiokeratoma corporis diffusum),
autonomic dysfunction, and debilitating pain. Renal disease
and vasculopathy of heart and brain may lead to early death in
adulthood. In our patient the typical childhood presentation
had been unrecognised and the rise in serum creatinine was, in
retrospect, a clue to the multisystemic nature of the condition.
Progressive accumulation of ceramidetrihexoside in the
intima and media of cerebral blood vessels causes ischaemic
lesions in the majority of affected patients. The appearance of
the lesions on magnetic resonance imaging is typical of small
vessel disease.3 There is a prothrombotic tendency in patients
with Fabry’s disease; increased incidences of thrombophlebitis
and central retinal artery occlusion have been described.4 The
risk of cerebrovascular disease is increased as a result of the
combination of small vessel disease and a prothrombotic tendency. Ascertaining carrier status in young women of
childbearing age has obvious genetic implications.
Fabry’s disease has been considered untreatable until
recently but new advances in enzyme replacement therapy
have raised the possibility of halting or reversing much of the
multisystem damage that occurs in these patients. Treatment
strategies such as gene therapy, substrate deprivation, and
administration of α galactosidase enzyme are being evaluated.
Administration of α galactosidase A has been shown to be safe
and effective in reducing the accumulation of ceramidetrihexoside and in improving both creatinine clearance and cardiac conduction in a recently concluded randomised controlled trial.5
We suspect that the true incidence of Fabry’s disease is
higher than previously thought and some degree of galactosidase deficiency may underlie some cases of otherwise
unexplained cerebrovascular disease. While the association of
Fabry’s disease with cerebrovascular disease and vascular
dementia has been described in other literature,6 such a
neurological presentation in midlife has not been described
before. Fabry’s disease should be considered in the differential
diagnosis of cerebrovascular disease where other risk factors
are not present.

.....................

Authors’ affiliations
R Mohanraj, Research Fellow, Epilepsy Unit Western Infirmary, Glasgow
G11 6NT, UK
J P Leach, J C Broome, D F Smith, Walton Centre for Neurology and
Neurosurgery, Liverpool L9 7LJ, UK
Correspondence to: Dr J P Leach, Department of Neurology, Walton
Centre for Neurology and Neurosurgery, Lower Lane, Liverpool L9 7LJ,
UK; j.leach@liv.ac.uk
Received 1 February 2002
Accepted 27 February 2002

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Mohanraj, Leach, Broome, et al

REFERENCES
1 Peters FPJ, Sommer A, Vermeulen EC, et al. Fabry’s disease: a
multidisciplinary disorder. Postgrad Med J 1997;73:710–2.
2 Schatzki PF, Kipreos B, Payne J. Fabry’s disease: primary diagnosis by
electron microscopy. Am J Surg Pathol 1979;3:211–9.
3 Crutchfield KE, Patronas NJ, Dambrosia JM, et al. Quantitative analysis
of cerebral vasculopathy in patients with Fabry disease. Neurology
1998;50:1746–9.

4 Utsumi K, Yamamoto N, Kase R, et al. High incidence of thrombosis in
Fabry’s disease. Intern Med 1997;36:327–9.
5 Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement
therapy in Fabry’s disease: a randomised control trial. JAMA
2001;285:2743–9.
6 Mendez MF, Stanley TM, Medel NM, et al. The vascular dementia of
Fabry’s disease. Dement Geriatr Cogn Disord 1997;8:252–7.

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