Galactosialidosis - Goldberg Syndrome

What is galactosialidosis ?

Galactosialidosis belongs to a family of disorders identified as lysosomal storage diseases. This disorder is characterized by the lysosomal accumulation of sialyloligosaccharides derived from glycoproteins and glycolipids due to the consequence of    combined defects in the lysosomal hydrolases, neuraminidase and β-galactosidase. It is also due to a defect in the  protective protein/cathepsin A (PPCA). 

Inheritance of galactosialodosis occurs as an autosomal recessive trait.


Background info about Galactosialidosis.

As explained before galactosialidosis is due to the defect in the lysosomal hydrolases, neurominidase , β-galactosidase and a defect in the protein (PPCA).


Neurominidase

The neuraminidase gene (NEU1) is a small gene located on chromosome 6p21.3 spanning only 3.5 kb comprising 6 exons encoding a 415 amino acid glycoprotein. Neuramindase has a dual function, it is involved in lysosomal degradation of sialylated glycoconjugates as well as in cellular immune responses.

  

Protective protein/cathepsin A (PPCA).  

The PPCA gene is located on chromosome 20q13.1 spanning 7.5 kb and comprising 15 exons that encode a 480 amino acid precursor glycoprotein of 54kDa. In the lysosomes the 54kDa PPCA precursor protein is proteolytically processed to two subunits of 32kDa and 20kDa held together by disulfide bonds. PPCA is released from thrombin-stimulated platelets and is found in granules of IL-2-activated natural killer (NK) cells.

Cathepsin A

Beta-galactosidase
composed of 16 exons encoding a 677 amino acid precursor protein that is processed to 654 amino acid glycoprotein that functions in a complex with PPCA and saposin B. Only 1%–2% of total β-galactosidase is found in the PPCA/neuramindase/β-galactosidase complex

β-galactosidase

The symptoms of Galactosialidosis

All patients with galactosialidosis exhibit general clinal manifestations like 

-coarse facial feature

-cherry-red spots in the eyes

-foam cells in the bone marrow

-vacuolated lymphocytes

*due to the range of phenotypic ariation of this disorder it has been divided into 3 subgroups.

1) Early infantile

2)Late infantile

3)Juvenile/Adult

Early infantile

Symptoms include 

-Hydrops (Also known as Hydrops Fetalis is a severe life-threatening problem of severe edema(swelling) in the fetus.

-Neonatal Edema ( neonatal is known as the period right after birth and neonatal edema is due to the obstruction to the lymphatic flow by defective development of lymph drainage system)

-Hepatosplenomegaly ( It is a medical condition in which bothe h liver and the spleen are enlarged)

-Skeletal dysplasia( coarse facial features. growth retardation and early death)

- Telangiectasias( A symptom seen only in the early infantile form and not in the other two,this is a condition in which there is the precense of small dilated vessels near the surface of the skin)

-Proteinuria(It refers to the presence if excess amount of serum proteins that are found int he urine,foamy urine is usually an indicator for this condition)

-Cardiomegaly(It is a medical condition in which the heart is enlarged)

-Septal thickening(A condition known to be septal hypertrophy is the thickening of the wall between the two chambers of the heart)

*Most patients die before 8 months if age to their cardiac/renal failure

Late infantile

*The observed symptoms are less severe than in early infantile patients although the symptoms would appear within the first few months after birth.

Symptoms include :

-Coarse facial features

-hepatosplenomegaly(as explained in early infantile)

-Dystosis multiplex(It is an hereditary disease (autosomal recessive) consisting of an error in the mucopolysaccaride metabolism and it is characterized by severe abnormalities in the development of skeletal cartilage and bone and mental retardation).

Juvenile/Adult

*The majority of galatosialidosis patients that fall into the juvenile/adult cases are usually from the japanese origins.

Symptoms include :

-Myoclonus(It is a condition of sudden twitching of muscles or parts of muscles without any rhythm or pattern that occurs in various brian disorders)

-Neurological detororation

-ataxia ( It is a neurological sign consisting of the lack of voluntary coordination of muscle movements)i

-angiokeratoma( It is a condition due to the benign cutaneous lesion of cappilaries, resulting in small marks of red to blue colour)

-eye anomalies (cherry-red spots)

-Mental retardation and seizures

*patients have long survival rate, the mean age in which the disorder presents itself is 16 years.

What causes Galactosialidosis ?

-Galactosialidosis are caused my mutations in the CTSA gene. The CTSA gene provides information for making a protein cathepsin A(as explained before). Cathepsin A are active in cellular compartments called lysosomes. These compartments contain enzymes that are able to degrade and recycle materials when they are no longer needed.

-Cathepsin A works together with 2 enzymes (neurominidase 1, and beta-galctosidase-as mentioned before) to form a protein complex. This complex breaks down sugar molecules(e.g.:oligosaccarides) attatched to certain proteins(glycoproteins) or fats(glycolipids).

-Cathepsin A is also found in the cell surface where it forms a complex with neurominidase 1 and a protein called elastin binding protein. The CTSA mutations would in turn interfere with the normal function of Cathepsin A. Most mutations would disrupt the protein structure of cathepsin A thereby impairing its ability to form complexes with neurominidase 1, beta-galactosidase and elastin binding protein.

-As a results these other enzymes are not functional or they either break down prematurely. Thereby due to all these deficiencies which in turn causes certain substances to accumulate in the lysosomes.

What are the treatment for Galactosialidosis ?

There is no CURE for galactosialodosis.

Treatment is usually symptomatic and supportive(For eg:taking medication to control the seizures)

Individuals are usually encouraged to routinely see ther genetic counsellors,neurological and ophthalmological and other specialists a their symptoms arises so as to keep them controlled

Bone marrow transplant is under investigation as a experimental therapy. No conclusive results are currently available on the long term benefits of the treatment.