Galactosialidosis, also known as neuraminidase deficiency with beta-galactosidase deficiency, is a genetic lysosomal storage disease. 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 lysosomes 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 that present just before or after birth and tend to be most severe. The most common symptoms include abnormal fluid build-up, hepatosplenomegaly, 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 that are similar to early infantile, except that they present around six 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 angiokeratomas, vision loss, seizures, and muscle jerks or myoclonus. 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, which forms a protein complex with neuraminidase-1 and beta-galactosidase to break down fats, sugars, and proteins ingested by lysosomes. 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 defective, making it incapable of binding to other proteins or forming 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 consist 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.
Pathophysiology 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. 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 lysosomes' inability to perform their functions.
Diagnosis When the characteristic symptoms of galactosialidosis are suspected, patients can undergo specific testing to confirm their diagnosis. One common method includes enzyme assays which measure the activity of neuraminidase-1 and beta-galactosidase. Decreased levels in enzymatic activity indicate a deficiency in cathepsin A. A complete urinalysis can be performed to detect the presence of oligosaccharides, 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 diagnose 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 diagnosis was made by Kleijer et al. in 1979 by measuring beta-galactosidase and neuraminidase 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.
… excerpt ends here. Continue reading the full article.
