AFD is an X linked disorder caused by mutations in the GLA gene which encodes for the lysosomal enzyme -galactosidase A. Reduction in -galactosidase A activity leads to accumulation of neutral glycosphingolipids, primarily globotriaosylceramide, in a variety of tissues leading to a multisystem disease with protean manifestations. After an asymptomatic phase, clinical manifestations develop in childhood and become exacerbated during adulthood. The survival of untreated males is 20 years less than males from the general population. Death occurs in middle age and beyond from cardiac, renal and neurological complications. In general, females have less severe disease but are not immune to life-threatening complications which generally occur later on in life.2 3
The classic cardiac manifestation is concentric LVH, but infrequently hypertrophy can be asymmetric, mimicking hypertrophic cardiomyopathy caused by sarcomeric gene mutations. Diastolic dysfunction dominates the early stages of the disease, and can progress to restriction and/or systolic impairment. As AFD is an X linked disease, hypertrophy is commoner and more severe in males, and also occurs at a younger age than females.2 4
Electrocardiography typically shows LVH by voltage criteria, and one in five patients has a short PR interval. Atrial fibrillation and VT are encountered in 17% and 8% of patients, respectively. Conduction tissue infiltration causes sinus and atrio-ventricular node dysfunction, with a large minority requiring antibradycardia pacing. These arrhythmias may cause syncope, as well as sudden cardiac death.5
Proteinuria is an early manifestation of renal involvement, and aggressive treatment with angiotensin-converting enzyme inhibitors is recommended in an attempt to prevent progression to end-stage renal failure which afflicts males in their third decade of life.6
Ischaemic strokes and transient ischaemic attacks occur in up to one-quarter of patients, frequently in association with cardiac and renal disease. The vertebrobasilar and posterior circulations are most commonly affected. The aetiology of these events is probably related to small vessel disease caused by the deposition of globotriaosylceramide in vascular endothelium.7
In addition to the life-threatening complications described above, AFD patients often have a myriad of other symptoms from multiple organ involvement. The earliest complaint is a ‘burning’ pain affecting the extremities (acroparesthesia) caused by small fibre neuropathy. Gastrointestinal symptoms are also common and include postprandial nausea, vomiting, abdominal pain, distention and irregular bowel habit. Vascular skin lesions (angiokeratomas) are often seen around the umbilicus, groin and trunk in a swimsuit distribution. Impaired sweating (hypohydrosis) and lymphoedema are caused by the accumulation of globotriaosylceramide in sweat glands and lymphatics, respectively. Patients frequently complain of sensorineural hearing loss, dizziness from vestibular dysfunction and tinnitus from inner ear involvement.3 8
Apart from proteinuria, our patient did not have any other extracardiac manifestations. Predominant cardiac involvement is unusual and may relate to a number of specific GLA mutations, including N215S, where residual enzyme activity limits the development of AFD-related complications.9
Administration of recombinant -galactosidase A is the cornerstone of treatment. Randomised controlled trials are limited, but the data so far suggest that it may have a beneficial effect on conduction system disease and LVH, as well as stabilisation of renal function.2 3
There is some evidence to suggest that early treatment with enzyme replacement therapy, prior to the development of irreversible fibrosis secondary to globotriaosylceramide deposition is more effective. This may explain why our patient developed complications despite enzyme replacement therapy.10
Even though AFD is a rare disease with an estimated incidence of up to 1/40 000 live male births, this case illustrates the value of screening for AFD in patients with unexplained LVH, especially if the hypertrophy is concentric because the prevalence in this group can be up to 4%.2 3
AFD should also be considered in young patients with unexplained cerebrovascular accidents or renal disease.3
Associated symptoms such as acroparesthesia may provide clues to the diagnosis but are not invariably present as illustrated by our patient. Identifying patients with AFD is important because effective treatment has now become available and family screening for AFD enables the detection and treatment of preclinical disease, for example, proteinuria to prevent long-term complications in affected relatives.
- AFD is responsible for unexplained LVH in up to 4% of cases.
- AFD is commonly associated with multiple symptoms from an early age.
- Males have more severe disease than females.
- Cardiac, renal and cerebrovascular complications are responsible for early mortality.
- Recombinant enzyme replacement therapy is the cornerstone of treatment.