galactosialidosis
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Galactosialidosis, also known as
neuraminidase Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glyc ...
deficiency with
beta-galactosidase β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides. β- ...
deficiency, is a genetic
lysosomal storage disease Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
. It is caused by a mutation in the CTSA gene which leads to a deficiency of enzymes β-galactosidase and neuraminidase. This deficiency inhibits the
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...
s of cells from functioning properly, resulting in the accumulation of toxic matter within the cell. Hallmark symptoms include abnormal spinal structure, vision problems, coarse facial features, hearing impairment, and intellectual disability. Because galactosialidosis involves the lysosomes of all cells, it can affect various areas of the body, including the brain, eyes, bones, and muscles. Depending on the patient's age at the onset of symptoms, the disease consists of three subtypes: early infantile, late infantile, and juvenile/adult. This condition is considered rare, with most cases having been in the juvenile/adult group of patients.


Signs and symptoms

The signs and symptoms of galactosialidosis range from mild to severe, and can vary amongst patients depending on the age of the individual when symptoms begin as well as the specific subtype of disease each person has. Symptoms can also vary amongst individuals within the same subtype, but it is known that the earlier a person shows symptoms, the more severe the disease tends to progress over time. Individuals who are diagnosed with early infantile galactosialidosis have symptoms which present just before or after birth and tend to be most severe. The most common symptoms include abnormal fluid build up,
hepatosplenomegaly Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and his ...
, enlarged heart, abnormal bone development, kidney disease that progressively worsens, coarse facial features, and a cherry red spot on the back of the eye. Those who are diagnosed with late infantile subtype have symptoms which are similar to early infantile, except that they present around 6 months of age and tend to be less severe. Additional symptoms in this subtype can include growth problems, hearing or vision problems, and seizures. Juvenile/adult subtype symptoms include impaired balance or coordination, dark red spots on the skin or
angiokeratoma Angiokeratoma is a benign cutaneous lesion of capillaries, resulting in small marks of red to blue color and characterized by hyperkeratosis. ''Angiokeratoma corporis diffusum'' refers to Fabry's disease, but this is usually considered a distinct c ...
s, vision loss, seizures, and muscle jerks or
myoclonus Myoclonus is a brief, involuntary, irregular (lacking rhythm) twitching of a muscle or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus (myo "muscle", clonic "jerk") describes a medical sign and, generally, is ...
. The symptoms of this subtype tend to be less severe than the first two subtypes, and typically start in adolescence, with the average age being 16 years of age.


Causes


Molecular biology

Galactosialidosis is caused by a mutation in the CTSA gene. This gene encodes the enzyme
cathepsin A Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the ''CTSA'' gene. Function This gene encodes a glycoprotein that associates with lysosomal enzymes beta-galactosidase and ne ...
, which forms a protein complex with neuraminidase-1 and
beta-galactosidase β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides. β- ...
to break down fats, sugars, and proteins ingested by
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...
s. Cathepsin A is required in this process because within the complex, it prevents neuraminidase-1 and beta-galactosidase from breaking down prematurely, so that they may perform their functions properly. When the CTSA gene is mutated, the protein structure of cathepsin A is defected, making it incapable of binding to other proteins or form complexes. This leads to a deficiency of beta-galactosidase (GLB1) and neuraminidase-1 (NEU1). As a result, the lysosome is unable to break down toxic substances and waste builds up within the cell.


Genetic inheritance

All individuals diagnosed with galactosialidosis have inherited the condition in an '' autosomal recessive manner'', regardless of age or subtype. All genes consists of two copies, one received from each parent. When a disease is recessive , it means that two mutated copies of a gene are required for someone to inherit the trait or disorder. When each parent carries one mutated copy of the same gene, there is a 25% possibility that their offspring will inherit both copies of the gene and develop the disease. In galactosialidosis, both parents of the patient would have carried a mutated copy of the CTSA gene. The affected child inherits both copies, leading to the development of the disease. There are no known environmental or medical associations related to the cause of galactosialidosis.


Mechanism of disease

Galactosialidosis occurs when a patient inherits two copies of a mutated CTSA gene. Encoding of the mutated gene results in a defective form of the protein
cathepsin A Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the ''CTSA'' gene. Function This gene encodes a glycoprotein that associates with lysosomal enzymes beta-galactosidase and ne ...
. When the structure of cathepsin A is disrupted due to mutation, it becomes non-functional and cannot form a digestive complex with neuraminidase-1 and beta-galactosidase. As a result, toxic materials accumulate within the cells of the body due to the
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...
s' inability to perform its functions.


Diagnosis

When the characteristic symptoms of galactosialidosis are suspected, patients can undergo specific testing to confirm their diagnosis. One common method includes
enzyme assay Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition. Enzyme units The quantity or concentration of an enzyme can be expressed in molar amounts, as with a ...
s which measure the activity of neuraminidase-1 and beta-galactosidase. Decreased levels in enzymatic activity indicate a deficiency in cathepsin A. A complete
urinalysis Urinalysis, a portmanteau of the words ''urine'' and ''analysis'', is a panel of medical tests that includes physical (macroscopic) examination of the urine, chemical evaluation using urine test strips, and microscopic examination. Macroscopic ...
can be performed to detect the presence of
oligosaccharide An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sug ...
s, which would pass through the urine as excess amounts accumulate within cells due to lysosomal dysfunction. A diagnosis can more specifically be confirmed through molecular genetic analysis, which is used to identify a mutation in the CTSA gene. Once a mutation is detected, the results are combined with a clinical exam and patient symptoms to fully diagnosis galactosialidosis. The age of the patient at the onset of symptoms is used to determine the specific disease subtype of the patient: early infantile patients are diagnosed between birth and 3 months of age, late infantile patients are diagnosed between 3-12 months of age, and juvenile/adult patients are normally diagnosed in adolescence when symptoms begin. A
prenatal Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
diagnosis was made by Kleijer et al. in 1979 by measuring
beta-galactosidase β-Galactosidase (EC 3.2.1.23, lactase, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase), is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides. β- ...
and
neuraminidase Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glyc ...
activities in cultured amniotic fluid cells.


Prevention

Because the disease is genetically inherited, the only prevention available for this condition is through genetic carrier screening that can detect the presence of a recessive, mutated CTSA gene in parents before they decide to have children. If both parents are found to be carriers of the mutated gene, there will be a 25% possibility of the child inheriting the disease; this cannot be prevented.


Treatment

Currently, there is no cure for galactosialidosis. However, there are treatments available that help to manage symptoms and provide supportive care. For example, a treatment plan may include medications to control seizures or muscle jerks. It is also common for patients to establish routine care with a
medical geneticist Medical genetics is the branch tics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the caus ...
,
neurologist Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
, and ophthalmologist depending on the symptoms they are experiencing and the frequency at which they occur.


Prognosis

The prognosis of individuals diagnosed with galactosialidosis vary between patients, depending on age and severity of symptoms. Therefore, there is no established average age at which patients die or have increased risk of death. There is no chance of full recovery in any form of the disease.


Early infantile

Patients diagnosed with early infantile subtype have more severe, threatening symptoms and a decreased chance of survival because this subtype develops more rapidly, however it is noted that most patients do live into late infancy.


Late infantile

Because patients with late infantile subtype develop symptoms within the first year of life, their condition is not as severe as early infantile subtype and the chance of survival is higher, however the quality of life for the patient will still be greatly affected due to the fact that the patient is so young when symptoms occur. The patient will still require a detailed care plan to manage symptoms.


Juvenile/adult

Patients diagnosed with juvenile/adult subtype have less severity of symptoms, but will have to manage progressive mental disability, spinal deformities, and seizures amongst other common symptoms. However, this subtype is typically associated with a normal life expectancy.


Epidemiology

Galactosialidosis is considered a very rare disease, though the prevalence of it is not exactly known. Less than 150 cases have been reported in literature; of that population, about 60% of cases were of the juvenile/adult subtype with symptoms beginning at or after 16 years of age. It is also documented that most cases occur in people of Japanese descent.


Research

There is a current need for future research that leads to a better understanding of galactosialidosis, advances in diagnoses, and more effective treatment. More recent research has been done to define the demographics and clinical characteristics of the patient population with galactosialidosis, with the ultimate goal of using this information toward a gene transfer treatment study. There are currently at least two ongoing clinical trials for galactosialidosis. One study involves research of the glycoproteinoses that constitute some of the rarest lysosomal diseases, including galactosialidosis,
aspartylglucosaminuria Aspartylglucosaminuria (AGU) is an inherited disease that is characterized by a decline in mental functioning, accompanied by an increase in skin, bone and joint issues. The disease is caused by a defect in an enzyme known as aspartylglucosaminid ...
,
fucosidosis Fucosidosis is a rare lysosomal storage disorder in which the FUCA1 gene experiences mutations that severely reduce or stop the activity of the alpha-L-fucosidase enzyme. The result is a buildup of complex sugars in parts of the body, which lead ...
,
Schindler disease Schindler disease, also known as Kanzaki disease and alpha-N-acetylgalactosaminidase deficiency is a rare disease found in humans. This lysosomal storage disorder is caused by a deficiency in the enzyme alpha-NAGA (alpha-N-acetylgalactosaminidas ...
, and
sialidosis Mucolipidosis type I (ML I) is an inherited lysosomal storage disease that results from a deficiency of the enzyme alpha-N -acetyl neuraminidase (sialidase). The lack of this enzyme results in an abnormal accumulation of complex carbohydrates know ...
amongst other diseases. It is a longitudinal study of 100 patients who are diagnosed with any one of nine glycoproteinoses. The purpose of the study is to better define how common the diseases are, identify clinical features that could contribute to early diagnoses, detail progression of the diseases, assess the supportive therapies currently being used, and identify possible treatments.


References


External links

* {{Glycoproteinoses Glycoprotein metabolism disorders Rare diseases Autosomal recessive disorders