Fabry Disease

Overview

Etiology

• X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy disorder
• Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in GLA on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics Xq21.3-q22
• Results in a deficiency of lysosomal alpha-Gal A

Classification

• Classic type (early onset)
  • Less common
  • More severe
  • Onset: childhood to teenage years
• Atypical type (late onset)
  • More common
  • Disease presentation based on particular organ system
  • Onset: age ≥ 30 years

Epidemiology

• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency:
  • Classic: 1 in 40,000 males
  • Atypical: 
    • 1 in 1,000–3,000 males
    • 1 in 6,000–40,000 females
• Ethnicity:
  • More common in Caucasians
  • Rare in Asians
  • Also seen in African Americans
• Men > women

Pathophysiology

• Deficiency in alpha-Gal A → accumulation of Gb3 (also known as ceramide trihexoside) in the lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles of various cells and tissues
• Gb3 derivatives are:
  • Cytotoxic Cytotoxic Parvovirus B19
  • Proinflammatory
  • Profibrotic
• Vascular endothelial accumulation leads to:
  • Vascular occlusion → ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage and infarction
  • Narrowing and occlusion of cerebral vessels → cerebral infarcts
• Accumulation in other tissues → organ dysfunction and clinical manifestations

Clinical Presentation

Time course

• Age of onset: 
  • Classic: childhood to teenage years 
  • Atypical: 30 years or older
• Progressive with advancing age
• Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids varies based on the severity of disease.
• Death commonly occurs between the 4th and 5th decade of life due to cardiac, renal, or cerebrovascular complications.

Signs and symptoms

The clinical presentation and severity vary, and men have more severe symptoms than women do.

Musculocutaneous:

• Limb pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways (acroparesthesia)
  • Major clinical symptom
  • Particularly affects hands and feet
  • Quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement:
    • Numbness
    • Tingling Tingling Posterior Cord Syndrome
    • Burning
  • Precipitated by:
    • Stress
    • Extremes in temperature
    • Physical exertion
• Angiokeratoma
  • Raised, red/purplish skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions
  • Painless
  • Bathing trunk distribution 
    • Abdomen
    • Genital
    • Proximal lower extremities
• Telangiectasias Telangiectasias Ataxia-telangiectasia

GI:

• Abdominal pain Abdominal Pain Acute Abdomen
• Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea

Ocular:

• Corneal verticillata
  • Corneal opacity Opacity Imaging of the Lungs and Pleura
  • Diffuse haziness or “whorls” on slit lamp Slit Lamp A microscope with a light source that can be projected into a linear beam. It allows cross-sectional viewing of the aqueous humor; conjuncteiva; cornea; eyelids; iris; and lens of the eye. Ophthalmic Exam exam
• “Fabry cataract Cataract Partial or complete opacity on or in the lens or capsule of one or both eyes, impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). Neurofibromatosis Type 2” (anterior and posterior subcapsular cataracts)
• Tortuosity and dilation of conjunctival and retinal vessels

Renal:

• Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
• Hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
• Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome

Neurologic:

• Transient ischemic attacks
• Ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke

Cardiac:

• Often extensive and progressive
• Myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
• Arrhythmias and conduction abnormalities
• Left ventricular hypertrophy Ventricular Hypertrophy Tetralogy of Fallot
• Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)
• Valvular abnormalities

Auricular:

• Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
• Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
• Tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies

Other:

• Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
• Body aches
• Pedal edema Pedal Edema Rocky Mountain Spotted Fever
• Exercise, heat Heat Inflammation or cold intolerance
• Decreased sweating (hypohidrosis) or the absence of sweating (anhidrosis)

Diagnosis and Management

Diagnosis

Clinical suspicion in children or adolescents will lead to testing and diagnosis. However, a late diagnosis is not uncommon given the varied clinical presentation.

• In males, diagnosis is made with alpha-Gal A enzyme assay.
  • < 3% of normal enzyme activity confirms the diagnosis.
  • Not accurate in females, where enzyme activity is normal
• In females, genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies for the GLA mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is used to make the diagnosis.
• A tissue biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma will show glycolipid deposits.
• Prenatal genetic screening Genetic Screening Physical Examination of the Newborn and newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care are also available.

Management

• There is no cure for FD.  
• Treatment is multidisciplinary and largely supportive, including:
  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways control
  • Medical management of cardiac, renal, and/or cerebrovascular complications
  • Slowing the build-up of fatty substances and progression of disease
    • Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) therapy with recombinant alpha-Gal A
    • Chaperone therapy repairs the faulty enzyme.

Differential Diagnosis

• Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease ( GD GD Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease): a lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside. Infantile GD GD Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease presents within 6 months of life with progressive neurodegeneration, loss of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology skills, hypotonia Hypotonia Duchenne Muscular Dystrophy, feeding difficulties, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, and death before age 3. Diagnosis is made with measurement of acid beta-glucosidase Beta-glucosidase An exocellulase with specificity for a variety of beta-d-glucoside substrates. It catalyzes the hydrolysis of terminal non-reducing residues in beta-d-glucosides with release of glucose. Gaucher Disease activity and confirmed with genetic analysis. Management is supportive.
• Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance lysosomal storage disorder caused by genetic mutations Genetic Mutations Carcinogenesis in the hexosaminidase A Hexosaminidase A A mammalian beta-hexosaminidase isoform that is a heteromeric protein comprised of both hexosaminidase alpha and hexosaminidase beta subunits. Deficiency of hexosaminidase A due to mutations in the gene encoding the hexosaminidase alpha subunit is a case of Tay-sachs disease. Deficiency of hexosaminidase A and hexosaminidase B due to mutations in the gene encoding the hexosaminidase beta subunit is a case of Sandhoff disease. Tay-Sachs Disease (HEXA) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, and a macular cherry-red spot upon physical examination. Diagnosis is made with measurement of enzyme activity. Management is supportive.
• Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease type A (NPD-A): a lysosomal storage disorder caused by an acid sphingomyelinase Acid sphingomyelinase Niemann-Pick Disease enzyme deficiency. The disease is characterized by progressive neurodegeneration starting within a few months of life and resulting in death by age 3. Clinical manifestations include macular cherry-red spot, difficulty feeding, loss of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology skills, hypotonia Hypotonia Duchenne Muscular Dystrophy, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management is supportive. 
• Sandhoff disease ( SD SD The standard deviation (SD) is a measure of how far each observed value is from the mean in a data set. Measures of Central Tendency and Dispersion): a lysosomal storage disorder caused by a deficiency in both HEXA and the hexosaminidase B (HEXB). Juvenile SD SD The standard deviation (SD) is a measure of how far each observed value is from the mean in a data set. Measures of Central Tendency and Dispersion is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include organomegaly, skeletal abnormalities, hyperacusis Hyperacusis An abnormally disproportionate increase in the sensation of loudness in response to auditory stimuli of normal volume. Cochlear disease, vestibulocochlear nerve diseases, facial nerve diseases, stapes surgery, and other disorders may be associated with this condition. Cranial Nerve Palsies, macular cherry-red spot, blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Diagnosis is made by measurement of HEXA and HEXB, as well as genetic analysis. Management is supportive.
• Pompe disease ( glycogen storage disease Glycogen storage disease A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. Benign Liver Tumors II): a lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency . There are 3 types with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onset and presentations. Clinical manifestations include failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, feeding difficulty, hypotonia Hypotonia Duchenne Muscular Dystrophy, progressive muscle weakness, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy, and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. Diagnosis is made with enzyme activity measurement and molecular gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics analysis. Management includes supportive measures and enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID).