Fabry disease

Deficiency of the lysosomal enzyme α-Galactosidase A (αGal A, EC 3.2.1.22), caused by mutations in the α-galactosidase (GLA) gene, results in storage of mainly globotriaosylceramide (Gb3) and to a lesser extent galabiosylceramide (CDH). The disorder has an X-linked (semi-dominant) pattern of inheritance.

Fabry disease (OMIM 301500) is the most common lysosomal storage disorder. An accurate estimation of the prevalence of Fabry disease is difficult to make due to great phenotypic heterogeneity. The estimated birth prevalence reported for The Netherlands is 0,42 per 100,000 male births (or 0,21 for total birth). The actual total prevalence of Fabry disease may be higher, because of under diagnosis of female patients and atypical disease manifestations.

Phenotypes and determinants of disease severity

Fabry disease can be divided into a severe classical phenotype and a generally milder nonclassical phenotype. Male patients with classic Fabry disease often have no or very low residual enzyme activity. Patients with classical disease present with characteristic symptoms such as neuropathic pain, cornea verticillata and angiokeratoma. Long term disease manifestations include progressive renal failure, hypertrophic cardiomyopathy, cardiac rhythm disturbances and stroke.

Nonclassical Fabry disease (late-onset Fabry disease or atypical Fabry disease) has a more variable disease course. Patients are generally less severely affected. Furthermore, disease manifestations may be limited to a single organ.

Fabry disease has an X-linked inheritance pattern, yet women often have disease manifestations. They are generally less severely affected than men, but the phenotype in women is highly variable, even within the same family. This may be the result of skewed X inactivation.

Gb3 is the main storage product in Fabry disease. In addition, lysoGb3 (or globotriaosylsphingosine), a deacylated form of Gb3 has been identified as a secondary storage product. Plasma lysoGb3 level is a sensitive biomarker for Fabry disease and can be used to distinguish Fabry disease patients from non-patients and classical from non-classical Fabry disease patients.

Manifestations in male patients with classical Fabry disease

Although considerable variation exists among males, the clinical manifestation of Fabry disease usually includes a number of symptoms. The first presenting signs are periodic pains in hands and feet (acroparesthesias), skin abnormalities (angiokeratomas), decreased or absent sweating (hypo- or anhidrosis) and characteristic corneal deposits, known as cornea verticillata. The acroparesthesias are induced by heat (often at temperatures above 25°C), fever and exercise or occur spontaneously. A large percentage of patients suffers from cochlear and auditory abnormalities causing sensory hearing loss, vertigo and tinnitus.

As the diseases progresses, several other organ manifestations become apparent. Renal disease first shows itself in the form of albuminuria, progressing over time to kidney function loss and ultimately renal failure. The heart becomes hypertrophic and as the disease advances, progressive fibrosis of the heart, ultimately causing loss of cardiac function, occurs. Throughout the course, cardiac disease rhythm abnormalities (bradycardia, atrial fibrillation, (non-sustained) ventricular tachycardia) may occur and in a significant number of patients the aortic root is dilated. In the brain white matter lesions become apparent (these may be asymptomatic) and in the majority of patients cerebrovascular events take place in the course of the disease.

Manifestations in female patients with classical Fabry disease

All symptoms mentioned above have also been observed in female patients, though they develop at a later age, are often less severe and progression to overt kidney failure is seldom observed in female patients. Not all female patients develop symptoms of Fabry disease. On the other hand, cardiac disease, with widespread fibrosis, rhythm disturbances and heart failure does occur in female patients.

Manifestations in non-classical Fabry disease

In both female and male non-classical patients the heterogeneity is even larger compared to the classical patients. Often organ involvement is limited and the disease may for example only cause cardiac hypertrophy. On average, the age at which the symptoms occur is later compared to the patients with classic Fabry disease and a significant proportion of the female patients remains asymptomatic throughout life.

Treatment

Supportive treatment

Pain management

The chronic and acute pain-episodes in Fabry disease require different approaches. Acute pain is usually due to a febrile illness, exercise or heat. Treatment consists of a strong analgesic (e.g. morphine analogues) in combination with paracetamol to reduce fever and treatment of the underlying infection if present. First line treatment of chronic neuropathic pain is carbamazepin, but phenytoin and gabapentin are also used. To diagnose small fiber neuropathy, temperature discrimination tests (QST test) and a skin biopsy, looking at the intraepidermal nerve fiber density, can be performed.  

Management of albuminuria and renal failure

The appearance of protein in the urine of Fabry patients is an early sign of renal involvement and an independent predictor of renal function loss. Independent of treatment with enzyme replacement therapy, which is discussed below, measures should be taken to reduce protein excretion to normal or as low a level as can be reached without inducing orthostatic hypotension. First line treatment consist of long angiotensin converting enzyme (ACE) inhibitors and lowering of salt intake. If side effects, such as persistent cough, occur the ACE inhibitor should be replaced by an angiotensin receptor blocker. In case of persistent proteinuria despite these measures, addition of a diuretic such as hydrochlorothiazide can be attempted, with adequate monitoring of blood pressure and potassium levels .

Renal replacement therapy is to be initiated when end-stage renal failure is present. Used treatment modalities (hemodialysis, peritoneal dialysis and renal transplantation) do not differ from those used in patients with other causes of renal failure, though limited cardiac function should often be taken into consideration in Fabry patients. Obviously, in the case of a female relative acting as kidney-donor, it should be excluded that this donor carries the Fabry mutation.

Enzyme replacement therapy

Enzyme replacement therapy is currently the only form of treatment for Fabry disease available in the Netherlands. Two different forms of enzyme replacement therapy are available; agalsidase-alfa (Replagal, Shire), produced in human fibroblasts and registered at a dose of 0.2 mg/kg biweekly , and agalsidase-beta (Fabrazyme, Genzyme), produced in Chinese hamster ovary cells and registered at a dose of 1.0 mg/kg biweekly. Initially, reports on efficacy of both recombinant enzyme preparations were positive,  showing clearance of storage material in heart and kidney biopsies and indicated potential protection of kidney and cardiac function.

Recent data show that new clinical events (such as development of end stage renal failure, myocardial infarction, ventricular fibrillation or cerebrovascular events) do occur during treatment with enzyme replacement therapy. Male sex, classical phenotype and increasing age at treatment initation are risk factors for progression of disease while on ERT. Other risk factors are reduced renal function, proteinuria, cardiac hypertrophy and fibrosis, hypertension and occurrence of events before start of ERT. Earlier start of ERT, especially in male patients with classic Fabry disease, may improve treatment outcome.

Not all patients diagnosed with Fabry disease need treatment with ERT, since not all patients with non-classical Fabry disease and not all female patients with classical disease will develop symptoms. Therefore, careful monitoring of signs of organ involvement in these patients is very important to evaluate if treatment is warranted. In addition, if progression of disease occurs despite ERT, it may be prudent to stop treatment when no further benefit is to be expected. To make a balanced decision regarding starting or stopping ERT in Fabry patients in our clinic, we have a bimonthly indication committee meeting with a multidisciplinary team including a cardiologist, a nephrologist,  neurologist, a clinical geneticist and two metabolic specialist to reach a balanced descicion.

Antibodies against recombinant α galactosidase A are formed almost exclusively in male patients, since the residual endogenous enzyme, present in female patients, protects against an immune response. Approximately  40 to 70% of all treated male Fabry patients develop antibodies against the recombinant enzyme. The number of antibody positive Fabry patients is higher in those treated with αGAL β versus those treated with αGAL α, most likely due to the difference in dose. Available data point towards a significant negative effect of  antibody formation on ERT effectiveness in Fabry disease. LysoGb3 clearance from plasma and urine is less effective in antibody positive versus antibody negative male Fabry patients and high titers of anti-αGAL IgG are associated with reduced clearance of Gb3 from the dermal capillary endothelial cells.

Other

An alternative treatment is migalastat, an oral chaperone treatment that received marketing authorization in the EU in 2016 , but is not reimbursed in the Netherlands. This treatment may only be effective in a small subset of patients. Substrate reduction therapies, also oral, are under development, as are newer enzyme therapies.

Amsterdam UMC

SPHINX is officially acknowledged as center of expertise for Fabry disease. All Dutch patients with Fabry disease will be referred to us once the diagnosis of Fabry disease is likely or certain for treatment and participation in research.

The Amsterdam UMC participates in several research projects. More information on this can be found in the research section.