Alpha-mannosidosis

The α - mannosidosis is a rare autosomal recessive lysosomal storage disease.

Prevalence

The α - mannosidosis is a prevalence of about 1: an extremely rare disease in 500,000 live births.

Symptoms

The α - mannosidosis is characterized in affected patients with immunodeficiency, abnormalities of the face, changes in the skeleton, deafness and intellectual deficits. The first symptoms may be visible at birth. With age, the disease progresses, however, and the condition of the person concerned continues to deteriorate. In addition to the symptoms already mentioned, some may be born with clubfoot or in the first twelve months of hydrocephalus ( water on the brain ) develop.

The immune -related, especially in the first few decades recurrent infections. Among the skeletal abnormalities are found mild to moderate dysostosis multiplex, among other things, scoliosis ( lateral deviation of the spine) and deformation of the sternum. The anomalies of the face are an enlarged skull, a prominent forehead, rounded eyebrows, saddle nose, macroglossia ( enlarged tongue ), widely spaced teeth, and prognathism (a form of malocclusion ). Slight strabismus is also a common symptom.

The hearing loss is characterized by a moderate to severe disturbance of the sound sensation. The motor function of the patients is also affected by muscle weakness, joint abnormalities and ataxia.

From patient to patient, the symptoms may differ materially.

Genetics and pathogenesis

The α - mannosidosis is based on an autosomal recessive mode of inheritance. Mutations in MAN2B1 gene is located on chromosome 19 locus p13.2 - q12, are the cause of the disease. MAN2B1 the gene encodes α -mannosidase for the enzyme. Mutations in this gene can result in a decreased activity of α -mannosidase, which accumulate mannose glycoconjugates in tissues of affected patients.

Diagnosis

The diagnosis can be made by determining the activity of α -mannosidase into leukocytes or other nucleated cells. A DNA analysis ( genetic testing ) may be performed to confirm the results. The excretion of increased amounts of high-mannose oligosaccharides in the urine is an indication of the disease, but there is no specific proof. Prenatal diagnosis is both biochemical and molecular genetic methods possible.

Therapy

There has been no established curative therapy. A promising therapeutic approach is enzyme replacement therapy ( ERT), which could be but so far only tested in preclinical studies. In animal models, guinea pigs so that the accumulation of oligosaccharides could be reduced in the tissue. An exception while the brain, since the applied enzyme caused, it can not reach the brain through the blood- brain barrier. Similar experiments with knockout mice - here the Man2b1 gene of the mice was switched off - also surprisingly led to a reduction of the oligosaccharides in the brain of experimental animals. The ERT for patients with α - mannosidosis is the goal of the European project Hue -Man.

In some patients, an allogeneic stem cell transplantation was performed. The results were sometimes quite promising. The therapeutic benefits but weigh exactly when the significant risks of allogeneic stem cell transplantation. Allogeneic stem cell transplantation is especially in young patients in the first decade of life, with less advanced disease, a treatment option.

The administration of zinc sulfate ( zinc substitution ) showed in vitro a significant increase in the activity of αMannosidase why this was initially a common therapeutic approach. In long-term studies, however, showed no significant effect in patients with α - mannosidosis.

The usual treatment is symptomatic. It is ideally a proactive treatment, such as physiotherapy, the possible future complications prevents applied. The immunodeficiency caused by the infections often need to be treated.

Forecast

The patient's condition worsens with age. The function of the skeletal muscle and motor function can be increasingly demanding, so the majority of those affected is wheelchair-bound. No patient is completely socially independent. Many patients are older than 50 years. As the progression of the disease, all patients are hard of hearing and need a hearing aid.

First description

The doctor Per- Arne Öckerman (* 1933) from the University of Lund in Sweden, described in 1967 as first in a boy a new form of lysosomal storage disease with similar symptoms such as Hurler syndrome, but no mucopolysaccharides accumulate.

Veterinary Medicine

In cattle, particularly in the race, Aberdeen Angus ' the α - mannosidosis is a relatively common disease spread.