Fabry disease



OVERVIEW

Definition

Fabry disease is a rare lysosomal storage disease, an X-linked genetic disorder that can cause multi-organ and multi-system involvement, mainly including the skin, nerves, eyes, kidneys, heart and brain [1].

The X and Y chromosomes are the chromosomes that determine biological sex, with XY chromosome combinations in males and XX chromosome combinations in females.

Male patients with Fabry disease pass the abnormal X chromosome to all of their daughters, while the probability of a son getting the disease is zero; female patients have a 50% risk of passing the abnormal X chromosome to both sons and daughters.

Classification

Classification according to age of onset

Classic

Most common in males, with onset in childhood.

Onset is usually between 6 and 10.1 years of age in males and between 9 and 15 years of age in females.

Late-onset

Most common in females, with 40 to 70 years of age as the high incidence age group.

Clinical manifestations are mainly cardiac and renal involvement with cardiomyopathy and renal insufficiency [2].

Incidence

The exact prevalence of Fabry disease is not known, and the predicted prevalence in the general population is 1/100,000, i.e., about 1 in 100,000 people will develop the disease [2].

The prevalence of Fabry disease in newborns has been reported abroad to be approximately 1/1250 to 1/8882 [3].

Causes

Causes of the disease

Fabry disease is an X-linked lysosomal storage disease caused by a defect in the gene for the lysosomal hydrolase α-galactosidase A (α-GalA).

Normally, α-GalA hydrolyzes the α-galactose residues at the end of nerve sphingolipids [the vast majority of which are trihexylglucose ceramides (GL-3)].

In contrast, mutations in the GLA gene encoding α-GalA located on chromosome Xq22 in patients with Fabry disease result in partial or total loss of α-GalA enzyme function, leading to impaired catabolism of GL-3.

In turn, GL-3 accumulates in the lysosomes of tissue cells such as nerves and blood vessels in a variety of organs, including the heart, kidney, lungs, eyes, brain, and skin, causing corresponding ischemia, infarction, and dysfunction.

Since the deposition of GL-3, an alpha-GalA substrate, is a gradual process, the clinical manifestations of Fabry disease often involve different organs with age.

Symptoms

Main Symptoms

The clinical manifestations of Fabry disease are characterized by multi-organ and multi-system involvement, with the kidneys, heart, and brain being the main organs involved in the later stages of the disease, and the clinical manifestations tend to be heavier in male patients than in female patients.

Skin

Angiokeratomas, which occur in 2/3 of men and 1/3 of women with classic Fabry disease, are the earliest and most specific clinical feature.

They are mainly characterized by single or multiple red spots protruding from the skin surface; their number and size may increase with age and correlate with the severity of other systemic lesions.

They are located in the “sitting area” of the external genitalia, scrotum, buttocks and inner thighs.

It is common in patients younger than 10 years of age.

Facial

Characteristic facial features appear between the ages of 10 and 20 years, including protrusion of the supraorbital bones, forehead elevation, and thickening of the lips.

Eye

Ocular involvement is a common early symptom, characterized by corneal swirling clouding, tortuous blood vessels, dry eye, posterior capsular cataract or symptomatic conjunctival lymphadenopathy.

In severe cases, it can lead to reduced or even loss of vision.

It is commonly seen in patients under 10 years of age.

Nervous system

Patients may present with peripheral nerve pain, manifesting as chronic or intermittent intolerable burning sensations in the soles of the feet and palms of the hands that radiate to the proximal extremities, or even painful spasms.

Sweating disorders, mostly characterized by little or no sweating.

Patients may also experience hearing loss, dizziness, vertigo and other symptoms.

Brain

The main manifestations are stroke and transient ischemic attack, and a few manifestations are basilar artery dilatation and cognitive impairment.

It is common in patients aged 40 to 50 years.

Kidney

Early stage of the disease may show urinary concentration dysfunction, such as increased nocturia, polyuria and enuresis.

With the progression of the disease may gradually appear increased foam in the urine (proteinuria).

It is common in patients aged 10 to 20 years, and about 30% of patients progress to end-stage renal disease around 30 years of age.

Heart

Patients often have left ventricular hypertrophy, arrhythmias, coronary microvascular dysfunction (myocardial ischemia, myocardial infarction), valvular infiltrative lesions (mitral/aortic regurgitation), and heart failure, which is often manifested by chest tightness, shortness of breath, irritability, and angina.

It is mostly an advanced manifestation of the disease and a major cause of death.

It is common in patients aged 40 to 50 years.

Gastrointestinal tract

Mostly nausea, vomiting, abdominal distension, cramping abdominal pain, etc. after eating, and may also manifest as intermittent diarrhea or constipation [2,4-5].

Other symptoms

Respiratory system: chronic bronchitis, dyspnea, bronchial asthma and other obstructive pulmonary dysfunction, as well as sleep apnea, are often seen.

Skeletal system: osteoporosis is more common, mostly in the lumbar spine and femoral neck, and is prone to fractures.

Psychosomatic and cognitive function: anxiety and depression may be present, and some patients may develop cognitive decline or dementia, which is most common in the age of 30 to 40.

Consultation

Department of Medicine

Internal medicine

If symptoms of multi-organ damage such as red spots protruding from the surface of the skin, little or no sweating, unexplained limb pain, or gastrointestinal symptoms occur, it is recommended that prompt medical attention be sought.

Pediatric Internal Medicine

Children with symptoms such as angiokeratoma, decreased vision, increased nocturia, dizziness, vertigo, nausea, vomiting, etc. may visit the pediatrics department

Emergency Department

If symptoms such as bilateral lower extremity edema, dyspnea, chest tightness, angina, etc. occur, it is recommended to go to the Emergency Department immediately or call 120 emergency.

Preparation for medical treatment

Preparing for your visit: registering, preparing your documents, FAQs

Tips for seeking medical treatment

Parents should record the age, duration and severity of symptoms for the doctor’s reference.

Wear clothes that are easy to put on and take off to facilitate relevant examinations.

Preparation Checklist

Symptom Checklist

Particular attention needs to be paid to the time of symptom onset, special manifestations, etc.

When did the red spots on the skin appear? Are they more frequent than before?

Have you recently felt a decrease in vision?

Are there any symptoms of limb pain?

Are there any symptoms of hearing loss, dizziness, vertigo, less sweating, vomiting, diarrhea, etc.?

Medical History Checklist

Are there any relatives in the family with Fabry disease?

Checklist

Test results from the last 6 months to bring to the doctor’s office

Laboratory tests: blood alpha-GlaA enzyme activity assay, blood and urine GL3 and Lyso-GL-3 assays

Other tests: histopathologic examination, genetic examination

Diagnosis

Diagnosis is based on

Medical history

Family history of Fabry disease.

Clinical manifestations

Patients often present with unexplained pain in the extremities, little or no sweating, angiokeratomas in the skin, and unexplained gastrointestinal discomfort.

In adulthood, chest tightness, wheezing, edema, dizziness, and other cardiac, cerebral, and renal symptoms occur.

Laboratory Tests

Blood α-GlaA enzyme activity assay

Samples are mostly peripheral blood leukocytes, plasma, etc. In male patients, α⁃GalA activity is severely decreased or absent, which may indicate Fabry disease.

More than 30% of female patients have α⁃GalA activity within the reference range. Therefore, female patients cannot rely on this test alone to confirm or exclude the diagnosis [6].

Plasma GL⁃3 levels

A commonly used biochemical indicator for the diagnosis of Fabry disease.

Plasma GL⁃3 levels are significantly higher in male patients than in the healthy population, and are generally lower in female patients and mostly within the reference range, thus of limited diagnostic significance in women.

Plasma Lyso⁃GL⁃3 levels

It is more sensitive than GL⁃3 and correlates well with the clinical phenotype. Significantly elevated plasma Lyso⁃GL⁃3 levels can help to differentiate between classic and late-onset disease.

In male patients, it can monitor disease severity and progression, and is more sensitive than α⁃GalA activity for diagnosis in women, but has a high false positive rate.

In addition, it can be used to assess the therapeutic efficacy of enzyme replacement therapy.

Genetic testing

An important test for diagnosis, DNA is often extracted from peripheral blood, dried blood smear samples, or tissues such as hair follicles, but it is expensive.

In addition to making a definitive diagnosis, genetic testing can identify the type of mutation to assist in determining the clinical phenotype and guide family screening.

Histopathologic biopsy

This is a diagnostic aid and can be performed on kidney, heart, skin, or nerve tissue.

Light microscopy reveals vacuolated changes in the corresponding tissue cells.

Electron microscopy shows the corresponding tissue cells, such as glomerular epithelial cells, tubular epithelial cells, vascular endothelial cells, cardiomyocytes, and sweat glands of the skin.

The cytoplasm is filled with osmiophilic “myeloid vesicles”, which are round or ovoid in shape, and the inner part of the vesicles is laminated, similar to the structure of onion skin or myelin sheath, which is a typical pathological feature of lysosomal glycolipid aggregation.

Cardiac ultrasonography

Cardiac ultrasonography may suggest hypertrophic cardiomyopathy, which is mainly characterized by left ventricular hypertrophy, and needs to be combined with laboratory and pathological examinations.

Differential diagnosis

Systemic lupus erythematosus

Similarities: Both may present with multiple organ disease such as skin, kidney and heart.

Differences: The typical skin manifestation of SLE is butterfly-shaped erythema on the face, and other skin manifestations are different from angiokeratomas, but a series of vasculitis manifestations, and there is usually no oligohydropenia, anhidrosis, and peripheral neuropathy, which can be differentiated by immune immunological antibody tests.

Nephrotic syndrome

Similarity: Both may present with renal lesions.

Differences: Nephrotic syndrome is characterized by massive proteinuria, high degree of edema, hyperlipidemia and hypoproteinemia, and is usually not accompanied by skin, nervous system and other organs, and can be differentiated by blood biochemistry and examination.

Anaphylactic purpura

Similarity: Both may present with skin lesions.

Differences: purpura is usually characterized by symmetrical purple spots, and is not accompanied by lesions in other organs, and can be distinguished by routine blood tests.

Treatment

Aim of treatment: to slow down the progress of the disease, improve the quality of life and prolong the life of patients.

Treatment principle: mainly adopt multidisciplinary joint diagnosis and treatment, formulate appropriate individualized treatment plan, and regularly monitor and adjust the treatment plan.

Enzyme Replacement Therapy

Enzyme Replacement Therapy (ERT) is currently the only specific clinical treatment for Fabry disease.

Commonly used ERT drugs include agalsidase α and agalsidase β, both administered intravenously.

The main adverse drug reaction is infusion reaction, which manifests as rash, headache, abdominal pain and fever, and even anaphylaxis, which can usually be effectively relieved by symptomatic treatment.

Currently, it is advocated to start ERT as early as possible to avoid irreversible damage to tissues and organs [7-8].

Symptomatic supportive treatment

Neuropathic pain: first-line therapeutic agents are anticonvulsants (e.g., carbamazepine, gabapentin, pregabalin, etc.), tricyclic antidepressants (e.g., amitriptyline), and 5-hydroxytryptamine/norepinephrine reuptake inhibitor (SNRI)-based medications (e.g., duloxetine, venlafaxine).

Chronic kidney disease management should include attention to statin use and the prevention and management of abnormalities of mineral and bone metabolism in chronic kidney disease.

Dialysis or renal transplantation may be considered in patients with renal failure.

If there is bradycardia or significant atrioventricular block, a pacemaker may be considered.

Antiplatelet agents (e.g., aspirin, clopidogrel) may be applied to prevent stroke if necessary.

Skin angiokeratomas: generally require no special management; laser treatment may be considered if requested by the patient.

Prognosis

Cure

Fabry disease lacks specific symptoms and is easily missed and misdiagnosed. The average time between the onset of symptoms and a definitive diagnosis in patients is 14.8 years, and can be up to several decades. The average time between the onset of symptoms and definitive diagnosis is 14.8 years, and can be up to several decades. Most patients develop symptoms in adolescence, and the prognosis is poor as the disease progresses and gets worse gradually.

Life expectancy is reduced by about 15 to 20 years for male patients and 6 to 10 years for female patients.

Hazards

Fabry disease can lead to multiple organ involvement such as nerves, kidneys, heart, skin, gastrointestinal tract, eyes, etc., which seriously affects patients’ normal life, work and study.

The heart, kidneys, and brain are affected by the disease, which can lead to more serious symptoms and even life-threatening.

Daily

Daily Management

Dietary management

Patients with Fabry disease are prone to various gastrointestinal symptoms, so they need to pay attention to their diet to ensure balanced nutrition, and it is recommended to eat small and frequent meals.

Avoid spicy and irritating foods, and eat foods high in fiber.

Life management

Ensure adequate sleep, appropriate exercise and avoid overwork.

Pay attention to moisturizing, avoid extreme temperature, etc. to avoid triggering or aggravating pain symptoms.

Maintain normal bowel movements and seek medical attention if you have not had a bowel movement for many days.

Keep skin clean and avoid picking and scratching angiokeratoma.

Psychological care

As the disease is progressive, patients with Fabry disease need to recognize the disease correctly and have regular follow-ups to understand their own disease conditions.

Family members need to do a good job of psychological care, so that they can maintain a calm mood, can selectively listen to music, watch movies to regulate mood, and more communication with relatives and friends.

Prevention

Since Fabry disease is an X-chromosome-linked disorder, genetic counseling and prenatal diagnosis are essential to prevent the disease from occurring in the next generation.

Patients with a confirmed diagnosis of Fabry disease are required to undergo a detailed family history, and all patients are recommended to undergo appropriate genetic counseling.

Routine prenatal diagnosis is usually performed by taking fetal chorionic villi at around 11 weeks of gestation or amniotic fluid at around 18 weeks of gestation for amniocyte GLA gene testing or α-GalA enzyme activity testing [9-10].