127: Fabry Disease Flashcards
1
Q
What is the incidence of Fabry disease in different populations?
A
The incidence of Fabry disease is estimated to be between 1:40,000 and 1:170,000 across all ethnic groups. Specific incidences include 1:3200 in Italy and 1:7000 in Japan.
2
Q
What are the primary causes of Fabry disease?
A
Fabry disease is caused by a partial or complete deficiency of the lysosomal enzyme α-galactosidase A.
3
Q
What is the significance of globotriaosylsphingosine levels in Fabry disease?
A
Elevated levels of globotriaosylsphingosine correlate with the severity of Fabry disease and inhibit the activity of α-galactosidase A.
4
Q
How does the expression of Fabry disease vary in females?
A
In females, the expression of Fabry disease can be variable due to the Lyon hypothesis, which states that one X chromosome is inactivated randomly.
5
Q
What are the characteristics of angiokeratomas in Fabry disease?
A
Angiokeratomas are a cutaneous hallmark of Fabry disease, present in 70% of males and 39% of females. They are pinpoint lesions, dark red to blue-black, that do not blanch on pressure.
6
Q
Where are angiokeratomas typically located in males with Fabry disease?
A
In males, angiokeratomas are typically found in the ‘bathing trunk’ area, including the genitals, buttocks, lower abdomen, umbilicus, groins, inner thighs, and sacrum.
7
Q
What is the incidence of Fabry disease in the general population?
A
1 in 40,000 to 1 in 170,000.
8
Q
What is the genetic basis of Fabry disease?
A
It is caused by a partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A.
9
Q
What is the cutaneous hallmark of Fabry disease?
A
Angiokeratoma.
10
Q
In which demographic is Fabry disease more prevalent?
A
It affects all ethnic groups, with a higher incidence in males.
11
Q
What is the typical age range for the appearance of angiokeratomas in males?
A
Between ages 5-15 years.
12
Q
What is the significance of globotriaosylsphingosine in Fabry disease?
A
Elevated levels correlate with disease severity and inhibit the activity of alpha-galactosidase A.
13
Q
What is the Lyon hypothesis in relation to Fabry disease?
A
It explains the variable expression in females due to random inactivation of one X chromosome.
14
Q
What are the common locations for angiokeratomas in males?
A
Typically in the bathing trunk area, including genitals, buttocks, and lower abdomen.
15
Q
What is the life expectancy for individuals with Fabry disease?
A
20 years in males and 15 years in females.
16
Q
What types of mutations are associated with the GLA gene in Fabry disease?
A
More than 600 mutations including missense, nonsense, and single amino acid deletions and insertions.
17
Q
What histopathological features are observed in Fabry disease?
A
- Dilated, ectatic capillaries in the papillary dermis
- Thinned epidermis with acanthosis at the edges
- Overlying focal compact orthokeratosis
- Cytoplasmic vacuoles in endothelial, perithelial, perineural, eccrine, and smooth muscle cells filled with glycosphingolipid
- Presence of zebra bodies on electron microscopy.
18
Q
How do cutaneous vascular lesions relate to disease severity in Fabry disease?
A
Presence of cutaneous vascular lesions is associated with higher disease severity scores and increased prevalence of major organ involvement.
19
Q
What facial features are associated with Fabry disease?
A
‘Pseudoacromegalic’ facial appearance includes periorbital fullness, prominent ear lobes, bushy eyebrows, recessed forehead, and pronounced nasal angle.
20
Q
What is the significance of lower-limb edema and lymphedema in Fabry disease?
A
Lower-limb edema and lymphedema are frequently observed and may indicate underlying changes related to glycosphingolipid accumulation.
21
Q
What are zebra bodies and their significance in Fabry disease?
A
Zebra bodies are characteristic electron-dense, lamellated, intracytoplasmic vacuolar inclusions seen on electron microscopy.
22
Q
What is the relationship between cutaneous vascular lesions and disease severity in Fabry disease?
A
The presence of telangiectases and/or angiokeratomas is associated with higher disease severity scores.
23
Q
What is the significance of lymphedema in Fabry disease?
A
Lymphedema is frequently observed and may indicate underlying changes related to glycosphingolipid accumulation.
24
Q
How do telangiectases present in patients with Fabry disease?
A
Telangiectases blanch on diascopic pressure, are more common in males, and often occur at sun-exposed sites.
25
What is the typical age of onset for telangiectases in Fabry disease?
The mean age of onset is 26 years in males and 42 years in females.
26
What factors contribute to the development of lymphedema in Fabry disease?
Glycosphingolipid accumulation, recurrent edema, and primary abnormalities of the lymphatics.
27
What diagnostic tools are useful when other tests are inconclusive in Fabry disease?
Electron microscopy and immunoelectron microscopy using anti-Gb3 antibodies.
28
What systemic complications should be monitored in a male patient with Fabry disease?
Systemic complications to monitor include cerebrovascular, cardiac, and renal involvement.
29
What is the likely mechanism behind lymphedema and elevated serum VEGF-A levels in Fabry disease?
The lymphedema is likely due to glycosphingolipid accumulation, recurrent edema, or a primary abnormality of the lymphatics.
30
What dermatologic assessments are predictive of systemic morbidity in Fabry disease?
The presence of cutaneous vascular lesions is associated with higher disease severity scores.
31
What histopathologic features are characteristic of angiokeratomas?
Histopathologic features of angiokeratomas include dilated, ectatic capillaries in the papillary dermis and variable degrees of overlying focal compact orthohyperkeratosis.
32
What systemic complications are associated with widespread angiokeratomas?
The presence of widespread angiokeratomas is associated with higher disease severity scores and a higher prevalence of major organ involvement.
33
What are the common abnormalities of sweating associated with Fabry disease?
Reduced sweating is a classical feature of Fabry disease, affecting 53% of males and 28% of females.
34
What ocular findings are associated with sensory organ abnormalities in Fabry disease?
Cornea verticillate is characterized by lines radiating from the center of the cornea, occurring in >90% of males and 70% of females.
35
What gastrointestinal changes are commonly observed in patients with Fabry disease?
Common symptoms include cramping abdominal pain, nausea, diarrhea, and occasionally constipation.
36
What are the renal manifestations of Fabry disease?
Renal manifestations are seen in >90% of males, including microalbuminuria and hyperfiltration as early features.
37
What are the cardiac manifestations associated with Fabry disease?
Cardiac manifestations are increasingly recognized as a major cause of death in Fabry disease.
38
What is hypohidrosis and its prevalence in males and females with Fabry disease?
Hypohidrosis occurs in 53% of males and 28% of females.
39
What symptoms are associated with heat intolerance in Fabry disease?
Heat intolerance can result in reduced exercise tolerance, nausea, and light-headedness.
40
What is the Raynaud phenomenon in the context of Fabry disease?
Cold intolerance and the development of pain in the extremities in cold environments is a frequent complaint.
41
What ocular finding is most common in Fabry disease?
Cornea verticillate, characterized by opacities in the cornea, occurs in >90% of males and 70% of females.
42
What auditory findings are common in patients with Fabry disease?
Tinnitus and high-frequency sensorineural hearing loss are common, occurring in more than 50% of patients.
43
What gastrointestinal symptoms are often presenting in Fabry disease?
Cramping abdominal pain, nausea, diarrhea, and occasionally constipation are often the presenting symptoms.
44
What renal manifestations are seen in males with Fabry disease?
Renal manifestations are seen in >90% of males, including microalbuminuria and hyperfiltration.
45
What is a common cardiac manifestation in Fabry disease?
Left ventricular hypertrophy is a common presentation.
46
What triggers acroparesthesias in individuals with Fabry disease?
Triggers include increased body temperature, exercise, and stress.
47
What is the pathophysiology behind acroparesthesias in Fabry disease?
Acroparesthesias are caused by damage to nerve fibers due to inflammation and substrate accumulation.
48
What is the likely cause of sudden hearing loss and dizziness in a patient with Fabry disease?
The likely cause is high-frequency sensorineural hearing loss and vestibular dysfunction.
49
What is the significance of cornea verticillata in Fabry disease?
Cornea verticillata is the most common ocular finding, occurring in >90% of males and 70% of females.
50
What are the characteristics of the renal variant of Fabry disease?
The renal variant is characterized by decreased but not absent alpha-galactosidase A activity.
51
What is the underlying cause of heat intolerance in Fabry disease?
Heat intolerance is due to hypohidrosis or anhidrosis.
52
What is the significance of left ventricular hypertrophy in Fabry disease?
Left ventricular hypertrophy is a common cardiac manifestation caused by substrate deposition.
53
What other ocular findings are common in Fabry disease?
Other ocular findings include cataracts and lenticular changes.
54
What are the early renal manifestations of Fabry disease?
Early renal manifestations include microalbuminuria and hyperfiltration.
55
What other ocular findings are common in Fabry disease?
Other ocular findings in Fabry disease include cornea verticillata, cataracts, and lenticular changes.
56
What are the early renal manifestations of Fabry disease?
Early renal manifestations of Fabry disease include microalbuminuria and hyperfiltration.
57
What other auditory and vestibular findings are common in Fabry disease?
Other auditory and vestibular findings in Fabry disease include tinnitus, sudden deafness, and dizziness.
58
What gastrointestinal symptoms are common in Fabry disease?
Common gastrointestinal symptoms in Fabry disease include cramping abdominal pain, nausea, diarrhea, and occasionally constipation.
59
What is the likely underlying condition related to abnormal vasoreactivity of digital vessels in Fabry disease?
The likely condition is Raynaud phenomenon, which is related to autonomic dysfunction, abnormalities of nitric oxide synthetase, and increased oxidative stress in vascular endothelium and smooth muscle.
60
What other sensory organ abnormalities are associated with Fabry disease?
Other sensory organ abnormalities in Fabry disease include cornea verticillata, increased tortuosity of retinal vessels, optic atrophy, cataracts, lenticular changes, tinnitus, and high-frequency sensorineural hearing loss.
61
What are the common cardiac manifestations associated with Fabry disease?
Common cardiac manifestations include mitral valve prolapse, arrhythmia, and coronary artery disease.
62
What cerebrovascular manifestations are associated with Fabry disease?
Cerebrovascular manifestations of Fabry disease include ischemic or hemorrhagic strokes occurring early in life, Transient Ischemic Attacks (TIA), and strokes affecting the posterior circulation.
63
What are the global manifestations and other symptoms of Fabry disease?
Global manifestations and other symptoms of Fabry disease include lethargy, tiredness, failure to thrive in children, anemia, depression, sexual activity issues, autonomic dysfunction, endocrine abnormalities, obstructive airway pattern, and asthma.
64
What is the significance of diagnosing Fabry disease and how is it confirmed?
The diagnosis of Fabry disease is significant as it is often delayed. Confirmation requires demonstration of deficient α-galactosidase A activity, identification of the pathogenic mutation, biopsy of tissues, prenatal diagnosis, and measurement of globotriaosylsphingosine.
65
What are the common differential diagnoses for symptoms associated with Fabry disease?
Common differential diagnoses include pain associated with acroparesthesia, angiokeratomas mistaken for purpura, and widespread angiokeratomas in other lysosomal storage disorders.
66
What is the prognosis and clinical course for individuals with Fabry disease?
Earlier studies suggested that males die in the 4th-5th decade of life, while females live 15 years longer. Life expectancy is approximately 58.2 years for males and 75.4 years for females.
67
What is the recommended treatment approach for Fabry disease?
The treatment for Fabry disease is a multidisciplinary approach including various specialists such as physicians, dermatologists, cardiologists, nephrologists, neurologists, audiologists, and genetic counselors.
68
What is the role of MRI in Fabry disease?
MRI scanning is valuable in detecting early involvement and demonstrating scarring.
69
What are common global manifestations of Fabry disease?
Common global manifestations include lethargy, tiredness, failure to thrive in children, and anemia.
70
What percentage of Fabry disease patients experience depression?
Up to 50%.
71
What is essential for the definitive diagnosis of Fabry disease?
Demonstration of deficient alpha-galactosidase A activity in plasma, serum, or leukocytes and identification of the pathogenic mutation.
72
What is the average time between onset of symptoms and diagnosis of Fabry disease?
15 years.
73
What are the common causes of death in Fabry disease patients?
Cardiac disease and cerebrovascular disease.
74
What is the life expectancy for males and females with Fabry disease?
Males: 58.2 years, Females: 75.4 years.
75
What is the role of kidney transplant in end-stage renal failure for Fabry disease patients?
The role of ERT in this situation is to preserve the function of other organs.
76
What is the impact of chaperone-based enzyme enhancement therapy in Fabry disease treatment?
It consists of small molecules that rescue misfolded/mistrafficked enzymes from lysosomes and transport them to the endoplasmic reticulum.
77
What are the two formulations of Enzyme Replacement Therapy (ERT) for Fabry disease?
1. Agalsidase beta (Genzyme): 1mg/kg biweekly. 2. Agalsidase alpha (Replagal): 0.2mg/kg biweekly.
78
What is a common side effect of enzyme replacement therapy?
Infusion-related side effects such as fever and temperature changes.
79
What is the significance of genetic counseling for families with a member affected by Fabry disease?
It provides information on the inheritance patterns and risks of transmission of the disease.
80
What is the recommended treatment for patients with cold extremities related to Fabry disease?
Patients should stop smoking, avoid vasoconstricting medications, and maintain warm hands and feet with suitable clothing.
81
What is the purpose of prophylactic therapy with graduated compression hosiery in Fabry disease?
To manage fully reversible edema.
82
What are some therapies directed at managing pain in Fabry disease?
Pain can be managed with diphenylhydantoin, carbamazepine, and gabapentin.
83
What should be monitored regularly in patients receiving enzyme replacement therapy?
Pain, quality of life, renal function, and cardiac function.
84
What is the role of enzyme replacement therapy (ERT) in treating Fabry disease?
ERT may induce clearance of GB3 from the skin but does not necessarily clear angiokeratomas.
85
What are the recommended skin-directed therapies for managing symptoms of Fabry disease?
Enzyme Replacement Therapy (ERT), Laser Treatments, Compression Therapy, Skin Care, and Hyperhidrosis Management.
86
What is the likely underlying phenomenon for cold intolerance and pain in extremities in Fabry disease?
The patient likely has Raynaud phenomenon, which can be managed with angiotensin II receptor antagonists and calcium channel blockers.
87
What therapeutic interventions should be considered for severe proteinuria and declining renal function in Fabry disease?
Therapeutic interventions include controlling hypertension, using ARBs, and enzyme replacement therapy (ERT).
88
What is the likely cause of cramping abdominal pain and diarrhea in a patient with Fabry disease?
The symptoms are likely due to neurologic abnormalities affecting the gastrointestinal system.
89
What treatment options are available for hyperhidrosis affecting palms and soles in Fabry disease?
Treatment options for hyperhidrosis include topical aluminum chloride hexahydrate and tap water iontophoresis.
90
What is a potential treatment for end-stage renal failure?
Kidney transplantation may be considered.
91
What symptoms is a patient with Fabry disease experiencing if they have cramping abdominal pain and diarrhea?
The symptoms are likely due to neurologic abnormalities affecting the gastrointestinal system. Management includes metoclopramide and pancrelipase to reduce GI symptoms.
92
What treatment options are available for hyperhidrosis in a patient with Fabry disease?
Treatment options include topical aluminum chloride hexahydrate, tap water iontophoresis, local botulinum toxin injections, oral glycopyrrolate sodium (up to 2mg TID), and chemical or endoscopic sympathectomy.
93
What improvements can be expected from enzyme replacement therapy (ERT) in Fabry disease?
ERT improves levels of Gb3 in plasma, urine, and tissue biopsy, as well as clinical parameters like renal function, pain, cardiac size and function, and quality of life. However, it cannot cross the blood-brain barrier and may induce antibody formation.
94
What lifestyle modifications are recommended for a patient with Fabry disease who has cold extremities?
The patient should stop smoking, avoid vasoconstricting medications (e.g., beta-blockers), and maintain warm hands and feet with suitable clothing.
95
What cardiac interventions might be necessary for a patient with Fabry disease diagnosed with mitral valve prolapse and arrhythmia?
Cardiac interventions may include antiarrhythmics, artificial pacemakers, and surgery such as septal ablation or cardiac transplant.
96
What is the mechanism of action of Migalastat in treating Fabry disease?
Migalastat is a chaperone-based enzyme enhancement therapy that rescues misfolded/mistrafficked enzymes from lysosomes and transports them to the endoplasmic reticulum.
97
What laser treatments are effective for angiokeratomas in Fabry disease?
Effective laser treatments include quasicontinuous wave and pulsed lasers, as well as newer lasers combining high-powered pulsed-dye and 1064-nm long-pulse Nd:YAG lasers.
98
What inheritance patterns and risks should be discussed during genetic counseling for Fabry disease?
Fabry disease is X-linked. Female patients have a 50% chance of transmitting the gene to both sons and daughters, while male patients will have no affected sons and 100% of daughters affected.
99
What is the rationale for prescribing ARBs in Fabry disease?
ARBs are used at the first sign of proteinuria and as an important adjunct to enzyme replacement therapy (ERT) to slow the decline of renal function.
100
What are some noncutaneous findings associated with Fabry disease?
Noncutaneous findings include chronic renal failure, hypertension, coronary vascular disease, left ventricle hypertrophy, valve disease, arrhythmias, acroparesthesias, cerebrovascular disease, dementia, depression, increased suicide ideation, cornea verticillata, conjunctival vessel aneurysms, increased tortuosity of retinal vessels, Fabry cataract, diarrhea, nausea, vomiting, postprandial flank pain, malabsorption, hearing loss, tinnitus, hypothyroidism, obstructive airway disease, osteopenia and osteoporosis, and anemia.
101
What are the recommended treatments for angiokeratomas in Fabry disease?
Recommended treatments include liquid nitrogen, electrocoagulation, surgical excision, and laser treatments: pulsed-dye 585 nm, neodymium YAG [Nd:YAG] 1064 nm, combined pulsed-dye and Nd:YAG, and intense pulsed light.
102
What are the differential diagnoses for angiokeratomas?
Differential diagnoses include angiokeratoma of Fordyce, vulva, Millbelli, solitary papular angiokeratoma, and circumscriptum.
103
What are some symptomatic treatments for Raynaud phenomenon in Fabry disease?
Symptomatic treatments include avoiding smoking, cold, and vasoconstrictor therapies, and medications such as losartan, diltiazem, fluoxetine, and sildenafil.
104
What are some treatments for pain management in Fabry disease?
Treatments include avoiding triggers, diphenylhydantoin, carbamazepine, and gabapentin.
105
What is a common approach to managing stroke risk in Fabry disease?
Using antiplatelet and anticoagulant medications.
106
What are some cardiovascular treatments for patients with Fabry disease?
Treatments include antihypertensive drugs, antiarrhythmia drugs, artificial pacemakers, implantable defibrillators, and coronary bypass.
107
What specific enzyme replacement therapies are available for Fabry disease?
Alpha-galactosidase B (Fabrazyme), alpha-galactosidase A (Replagal), and Migalastat for patients with amenable mutations.
108
What are the clinical findings associated with Fabry disease?
Clinical findings include acroparesthesia, angiokeratoma corporis diffusum, cardiac signs (heart and renal failure), stroke, and cornea verticillata.
109
What is the enzyme deficiency associated with Fabry disease?
α-Galactosidase A.
110
What are the clinical findings associated with GM1-gangliosidosis?
Clinical findings include facial dysmorphism, hematologic signs, mental retardation, and organomegaly.
111
What is the genetic deficiency associated with Aspartylglycosaminuria?
Aspartylglycosaminidase deficiency.
112
What are the electron microscopy findings for Fucosidosis?
Electron-lucent lysosomal dilation.
113
What are the clinical findings of Sialidosis?
Clinical findings include mental retardation, dystosis multiplex, vacuolated lymphocytes, and subtle coarse facial features.
114
What are the electron microscopy findings for Galactosialidosis?
Electron-lucent lysosomal dilation.
115
What are the clinical findings associated with Kanzaki Disease?
Clinical findings include mental retardation, coarse facial features, ocular signs, hearing loss, and neuropathy.
116
What is the genetic location of the enzyme deficiency for Aspartylglycosaminidase?
4q32.33.
117
What is a common dermatologic finding in patients with β-Mannosidosis?
Angiokeratoma corporis diffusum in bathing trunk area.
118
What is the enzyme deficiency in Sialidosis?
Neuraminidase.
119
What is the clinical significance of Angiokeratoma corporis diffusum?
It is a common dermatologic finding in several lysosomal storage disorders.
120
What are the clinical aspects and inheritance patterns of Fabry disease angio-keratomas?
Clinical aspects include multiple, clustered dark-red to blue-black macules and papules; larger lesions are warty (1-4 mm). Inheritance pattern is X-linked.
121
What are the key features of the Mibelli type of angio-keratoma?
Key features include grouped, warty, dark-red papules (1-5 mm), onset at 10-15 years, affecting both sexes (females > males), and primarily located on the lateral aspect and dorsum of fingers and toes.
122
What distinguishes the Fordyce type of angio-keratoma?
Clinical aspects include multiple warty, blue-black papules (1-4 mm), onset over 60 years, affecting males, primarily located on the genitals (mainly scrotum), with no inheritance pattern.
123
What are the characteristics of the Circumscriptum type of angio-keratoma?
Characteristics include unilateral plaque keratotic dark-red papules that may bleed, usually early onset or at birth, affecting both sexes, primarily located on lower legs or foot, with no inheritance pattern.
124
What is the typical age of onset for Fabry angio-keratoma?
5-12 years.
125
What body sites are affected by Fabry angio-keratoma?
Any part of the body, especially bathing trunk area, umbilicus, and lips.
126
What is a common association with Fabry angio-keratoma?
Acroparesthesias, heart and renal failure, stroke, cornea verticillata, deafness, etc.
127
What is the clinical aspect of the Fordyce angio-keratoma?
Multiple warty, blue-black papules (1-4 mm).
128
What is the typical age of onset for Fordyce angio-keratoma?
Over 60 years.
129
What body site is primarily affected by Fordyce angio-keratoma?
Genitals, mainly scrotum.
130
What is the clinical aspect of the Circumscriptum angio-keratoma?
Unilateral plaque keratotic dark-red papules, may bleed.
