Neuraminidase Deficiency Health Article

Inheritance of neuraminidase deficiency

Neuraminidase deficiency is an autosomal recessive disorder that can be caused by any one of a number of different mutations in the NEU1 gene encoding the lysosomal neuraminidase. The disorder is autosomal because the NEU1 gene is located on chromosome 6, rather than on the X or Y sex chromosomes. The disorder is recessive because it only develops when both genes encoding neuraminidase, one inherited from each parent, are defective; however, the two defective NEU1 genes do not need to carry the same mutations. If the two mutations are identical, the individual is a homozygote. If the two mutations are different, the affected individual is called a compound heterozygote. Individuals with one defective gene and one normal gene encoding neuraminidase may have reduced levels of the active enzyme, but they do not have symptoms of neuraminidase deficiency.

All of the offspring of two parents with neuraminidase deficiency will inherit the disorder. All of the offspring of one parent with neuraminidase deficiency and one parent with a single defective NEU1 gene will inherit at least one defective NEU1 gene. They will have a 50% chance of inheriting two defective genes and, therefore, developing neuraminidase deficiency. The offspring of one parent with neuraminidase deficiency and one parent with normal NEU1 genes will inherit a defective gene from the affected parent, but will not develop neuraminidase deficiency. The offspring of parents who both carry one defective NEU1 gene have a 50% chance of inheriting one defective NEU1 gene and a 25% chance of inheriting two genes and developing neuraminidase deficiency. Finally, the children of one parent with a single defective NEU1 gene and one parent with normal NEU1 genes will have a 50% chance of inheriting the defective gene, but will not develop neuraminidase deficiency.

Mutations in the NEU1 gene

A number of different mutations that can cause neuraminidase deficiency have been identified in the NEU1 gene. The type of neuraminidase deficiency, sialidoses types I or II, as well as the severity of the symptoms, depends on the specific mutation(s) that are present. Some mutations change one amino acid out of the 415 amino acids that compose a single neuraminidase molecule. Other identified mutations result in a shortened enzyme. Many of the identified mutations are clustered in one region on the surface of the protein. These mutations result in a sharp reduction in the activity of the enzyme and lead to the rapid degradation of neuraminidase inside the lysosome.

Some mutations in the NEU1 gene lead to a complete absence of neuraminidase activity, with little or no neuraminidase enzyme present in the lysosomes. These mutations usually result in the severe, infantile-onset, type II sialidosis. Other mutations result in an inactive protein that is present in the lysosome. These mutations generally result in juvenile-onset, type II sialidosis, with symptoms of intermediate severity. Some mutations significantly reduce, but do not obliterate, neuraminidase activity in the lysosome. Individuals with at least one mutated gene of this type are not completely neuraminidase-deficient and have mild, type I sialidosis. Occasionally, individuals have multiple mutations in the NEU1 gene, leading to more severe forms of neuraminidase deficiency.

Demographics

Neuraminidase deficiency is an extremely rare disorder. Because of its similarities to many other disorders, it has been difficult to determine its frequency. In the United States, it is estimated to occur in one out of every 250,000 live births. In Australia, the estimate is one out of 4.2 million. Since neuraminidase deficiency is an autosomal rather than a sex-linked disorder, it occurs equally in males and females.

As an autosomal recessive disorder, neuraminidase deficiency requires two copies of the defective gene, one inherited from each parent. Thus, neuraminidase deficiency is much more common in the offspring of couples who are related to each other (consanguineous marriages), such as first or second cousins.

Sialidosis type I appears to be more common among Italians. Type 2 sialidosis seems to occur more frequently among Japanese.

Signs and symptoms

The clinical symptoms of neuraminidase deficiency are similar to the symptoms of the mucolipidoses, including I-cell disease (mucolipidosis II) and pseudo-Hurler polydystrophy (mucolipidosis III). Furthermore, the clinical distinctions between sialidoses types I and II may not be clearly defined.