Fabry disease is a rare genetic disease caused by GLA gene mutations that has two recognized forms. While the classic form typically is more severe and appears in childhood, late-onset Fabry generally manifests after age 30 and has milder symptoms.
The GLA gene provides the instructions for making the alpha-galactosidase A (Gal A) enzyme, which is responsible for breaking down a fatty substance called globotriaosylceramide (Gb3). In Fabry, mutations in GLA result in the absence or markedly deficient activity of this enzyme, leading to Gb3 accumulation and a range of symptoms.
Late-onset Fabry, which is threefold to tenfold more common than the classic type, is linked with some residual Gal A activity, which retains some ability to degrade Gb3. This means that patients will take much longer before the fatty molecule builds-up to toxic levels inside organs, leaving them with a normal childhood and adolescence.
Causes of late-onset Fabry
More than 965 mutations in the GLA gene have been reported to cause Fabry, either because they significantly reduce the amount of Gal A that is produced by cells, or because the stability and function of the enzyme is altered in the presence of such mutations, decreasing its activity.
The severity and type of symptoms varies depending on a patient’s specific GLA mutation. When patients preserve some level of enzyme activity — 3–15% of normal — and are able to break down some Gb3, the mutations lead to milder symptoms that emerge in adulthood.
In contrast, the classic form is associated with little to no Gal A activity — less than 3% of normal activity — causing more severe symptoms from a young age.
Late-onset Fabry in males, females
Fabry disease is inherited as an X-linked disorder, meaning that the GLA gene is located on the X chromosome. As males have only one X chromosome (inherited from the mother), those who have the mutated gene will develop the disease.
Late-onset Fabry is estimated to affect as many as one in 1,000 to one in 3,000 males, although the disease’s prevalence in males varies between regions and ethnicities.
In females — who have two X chromosomes, one from the mother and one from the father — the presence of a healthy gene copy can compensate for the mutated copy to a certain extent. So, even if a female has a mutation associated with late-onset Fabry, the gene copy in the other chromosome can make enough enzyme to prevent the disease from manifesting or to make symptoms milder.
The frequency of late-onset Fabry in females is estimated at around one in 6,000 to one in 40,000.
Unlike the classical form, late-onset Fabry disease patients normally do not show any symptoms during childhood or adolescence. Rather, they usually experience symptoms from ages 30 to 70.
As in classic Fabry, the progressive accumulation of Gb3 can lead to organ damage in people with the late-onset form, mostly in the heart, kidney, and brain. But the percentage of patients who experience severe problems in these organs is much lower.
Heart problems in such patients typically start with enlargement of heart muscles due to the extra effort needed to pump blood. This condition is seen in about 67% of late-onset Fabry males ages 40 or older, and in 32% of females in the same age range. It can progress to an abnormal heart rhythm and heart failure.
When Fabry affects the kidneys, patients progressively lose kidney function and eventually may experience kidney failure — when the kidneys no longer function as needed, requiring a transplant or dialysis. In males, kidney disease normally starts after age 40, but some patients may never progress to kidney failure. The frequency of kidney failure in females remains unknown.
Although cerebrovascular disease and stroke are more common in classic Fabry disease, late-onset patients also can experience blood vessel obstructions in several brain areas.
While not life-threatening, patients may experience dizziness and hearing loss due to the accumulation of Gb3 in the inner ear, which significantly affects quality of life. Patients also can have lung problems because the alveoli, the tiny air sacs where gas exchange takes place, become damaged.
The diagnosis of late-onset Fabry normally is made when patients present heart or kidney symptoms, but newborn screening can help identify additional patients with GLA mutations associated with late-onset Fabry disease.
Last updated: Nov. 9, 2021
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