- 1 case per 250,000 births in the United States
- 1 case per 100,000 births in Europe
- Both sexes are affected equally.
- Panethnic, but higher incidence noted in:
- European ancestry
- Druze community in Israel
- A lysosomal storage disorder
- Autosomal recessive inheritance
- 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 of the galactocerebrosidase gene (GALC) on chromosome 14q31
- Results in a deficiency of the enzyme GALC
- Many aspects of the pathophysiology remain unknown.
- Accumulation of galactocerebroside is toxic to:
- Oligodendrocytes in the CNS
- Schwann cells in the peripheral nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (PNS)
- Results in demyelination and neurologic manifestations
- Pathologic findings include:
- Globoid cells (hallmark): abnormal, multinucleated macrophages
- Generalized loss of myelin
- Absence of oligodendroglia
- Infantile (classic):
- Majority of cases
- Onset within 6 months
- Death by approximately 13 months
- Late-onset subtypes:
- Onset at ≥ 13 months of age and subdivided into:
- Late infantile
- Disease progression varies (usually faster in younger-onset subtypes).
- Onset at ≥ 13 months of age and subdivided into:
Signs and symptoms
The classic, infantile form progresses through the following stages:
- Stage 1:
- Irritability (most common initial symptom)
- Feeding difficulties
- Failure to thrive
- Gastroesophageal reflux
- Hypertonia, rigidity
- Hyperesthesia—auditory, tactile and visual
- Peripheral neuropathy
- Stage 2:
- Hyporeflexia or hyperreflexia
- Optic atrophy and blindness
- Opisthotonus (muscle spasm resulting in a backward arching of the head, neck, and spine)
- 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 (do not respond to anticonvulsants)
- Psychomotor deterioration (rapid and severe)
- Stage 3:
- Decerebrate posturing
- Severe spasticity
- Death is often due to infection or 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 and Management
- Prenatal screening is standard in certain locations.
- Diagnostic testing:
- Measurement of GALC activity:
- Often tested on blood leukocytes or 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. Structure and Function of the Skin fibroblasts
- Low or absent GALC confirms the diagnosis.
- Molecular genetic testing for the genetic mutation is also available.
- Measurement of GALC activity:
- Additional testing may show:
- ↑ CSF protein levels
- Evidence of demyelination on neuroimaging
- There is no cure for Krabbe disease.
- Management is supportive, focused on controlling symptoms.
- Stem cell transplantation is an option for infants who screen positive and have not yet developed symptoms.
- 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): lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside. Infantile GD presents within 6 months of life with progressive neurodegeneration, loss of motor skills, hypotonia, hepatosplenomegaly, feeding difficulties, and death before age 3 years. Diagnosis is made with measurement of acid beta-glucosidase activity and confirmed with genetic analysis. Management is supportive.
- Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. Fabry Disease: lysosomal storage disorder caused by alpha-galactosidase A (GLA) deficiency, resulting in glycophospholipid deposition in the vascular endothelium and smooth muscle cells. Clinical manifestations include acroparesthesias, 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. Structure and Function of the Skin lesions, decreased sweating, cerebrovascular and cardiovascular complications, and renal disease. Diagnosis is made with GLA enzyme activity. Management is supportive and can include enzyme replacement and chaperone therapies.
- 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): lysosomal storage disorder caused by acid sphingomyelinase 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 a macular cherry-red spot, difficulty feeding, loss of motor skills, hypotonia, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing. 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: 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 Inheritancelysosomal storage disorder caused by mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Clinical manifestations include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Diagnosis is made with enzyme activity testing and molecular genetic analysis. Management is supportive.
- Sandhoff disease (SD): lysosomal storage disorder caused by a deficiency in both HEXA and HEXB. Juvenile SD is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include organomegaly, skeletal abnormalities, hyperacusis, macular cherry-red spot, blindness, and seizures. Diagnosis is made by measurement of HEXA and HEXB, as well as genetic analysis. Management is supportive.
- Pompe disease (glycogen storage disease II): lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency. There are 3 types of Pompe disease, 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, 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. The diagnosis is made by measuring enzyme activity and molecular genetic analysis. Management includes supportive measures and enzyme replacement.
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