Fabry disease: symptoms, life expectancy

The frequency of the disease is estimated at one person in 40,000 births. “This disease would therefore theoretically affect 1,500 patients in France. Currently, only 500 patients are diagnosed in France. It is therefore probable that this disease is under diagnosed“, indicates Dr. Thierry Baranger, nephrologist. As the defective gene responsible for this rare hereditary disease is carried by the X chromosome, the full manifestation of the disease affects boys almost exclusively. Since girls have two X chromosomes, those affected may have symptoms but do not fully develop Fabry disease.

What is Fabry disease?

“This is’a rare hereditary disease of genetic origincorresponding to a metabolic disordermore or less complete, glycosphingolipidsdisorder linked to an enzymatic deficiency of alpha-galactosidase A, a lysosomal enzyme, due to pathogenic variants of the GLA gene located on the X chromosomedetails it. This enzymatic deficiency leads to an accumulation of globotriaosylceramise (Gb3) and its deacylated derivative (lyso-Gb3) in the lysosomes, triggering a cascade of cellular events“.

Transmission of the disease is linked to the X chromosome (Xq21.3-q22). When a gene is X-linked, it is present on the X chromosome.”X-linked recessive diseases usually only develop in men, because they only have one X chromosome; therefore there is no paired gene to compensate for the effect of the abnormal gene.” Women have two X chromosomes, so they usually receive a normal gene or a compensation gene on the second X chromosome.”The normal or compensatory gene normally prevents development of the disease in women (unless the compensatory gene is inactivated or lost).

► When the father (affected by the disease) carries the abnormal gene on his X chromosome and when the mother has two normal genes, all their daughters will receive one abnormal gene and one normal gene, making them carriers and transmitters. None of their sons will receive the abnormal gene, because they will receive their father’s Y chromosome, not the affected X.

► When the mother is a carrier and the father has the normal gene, each son will have a probability of 50% of receiving the abnormal gene from their mother (and developing the disease). Each girl has a 50% probability of receiving one abnormal gene and one normal gene (therefore, to become a carrier) or a 50% probability of receiving two normal genes.

What are the symptoms of Fabry disease?

“The clinical picture is very variable, with a very mild form in heterozygous women (one gene residual alpha galactisade A enzymatic activity“, confirms the specialist. It is the classic form of the disease, developing from childhood, in the first decade, and which includes numerous multi-organ disorders:

• Recurrent pain in the hands and/or feet called acroparesthesias, exacerbated by physical exercise and febrile syndromes.
• Decrease or absence of sweatingthis results in difficulty adapting to sun exposure, heat and physical exercise.
• Angiokeratomas (red-purplish skin lesions like keratotic skin maculopapules) located preferentially on the flanks, lower back, and genital area.
• Gastrointestinal signs abdominal painfeeling of bloating, nausea, early satiety.
• Fatigue and exercise intolerance
• ENT damage : Sudden deafness, chronic deafness
• ¾ of patients have corneal abnormality called whorled cornea with swirling appearance of the cornea visible with a slit lamp examination (examination carried out by the ophthalmologist).

“As an adult, the picture becomes complete chronic kidney failurewith proteinuria, with risk of end-stage renal failure, cardiac complications (left ventricular hypertrophy, cardiac, atrial, ventricular rhythm disorders, atrioventricular conduction disorders), ENT damage (sudden deafness, chronic deafness) , osteoporosis and stroke, responsible for high morbidity and mortality.

What is the life expectancy in case of Fabry disease?

With age, progressive tissue deterioration can lead to failure of one or more target organs. “Compared to the general population, end-stage renal failure and certain cardiovascular or cerebrovascular complications, endangering life, reducing the life expectancy of untreated men and women“, observes our interlocutor. In the absence of treatmentt, the life expectancy of Fabry patients is therefore reduced. “En average, the figures found show a life expectancy of 50 to 65 years for men. Among women, it seems that we can add 10 to 15 years depending on the severity of the form“.

► In humansthe diagnosis is confirmed by the lowered or collapsed dosage of alpha galactosidase A on simple blood testunderlines Dr Baranger.

► In womentaking into account the inactivation of one of the two X chromosomes, the alpha galactosidase A dosage is normal in 40% of women suffer from Fabry disease. Consequently, it is necessary to resort to genetic analysis who will find the anomaly in the GLA gene coding for alpha galactosidase A.

What treatment to treat Fabry disease?

There is two main specific treatments. The choice and therapeutic care as a whole falls within the framework of the National Diagnostic and Care Protocol (PNDS) under the aegis of the HAS and is the responsibility of the reference center and all of the competence centers of the Fabry disease distributed throughout France. The two treatments are not cumulative.

► The first treatment is based on synthetic enzymes or enzymotherapy, to compensate for the lack of alpha galactosidase : there are two molecules: agalsidase alpha And agalsidase beta, explains the specialist. They are administered intravenously, every two weekss. Enzymotherapy, particularly if started early, provides stabilization or slowing down the worsening of renal function, left ventricular hypertrophy, digestive symptoms and the quality of life of patients.

► The second treatment is more recent (2021). “This is the chaperone molecule: migalastat. Therapeutic in capsule form, it helps in the correct molecular folding of enzymes that are still active but poorly conformed, thus allowing them to be active. This treatment only concerns around 35% of GLA gene mutations. In these cases, it appears more effective in reducing left ventricular mass index, and shows comparable renal effects.”.

In addition to the specific treatment, treatments linked to organic damage, treatments aimed at cardiac, renal, cerebrovascular (low dose aspirin), ENT, digestive or rheumatological, as well as neuropathic painkillers. If the therapeutic care and follow-up involves the doctor from the reference and/or competence center for Fabry disease in conjunction with the treating general practitioner, the necessary support is most of the time enriched by other specialists, and any healthcare professional participating in the patient’s medico-social care, from the school doctor to patient associations, without forgetting the MDPH, CAF and social security.

Thanks to Dr Thierry Baranger, nephrologist at the Polyclinique Bordeaux Nord Aquitaine and at the Polyclinique Bordeaux Rive Droite (GBNA health group)