Morquio syndrome

Morquio's disease refers to an extremely rare, inherited metabolic disorder is selected from the group of mucopolysaccharidoses.

Historical

1929, the rare disease was first described by the Uruguayan pediatrician Luis Morquio - described (1867, 1935, Montevideo ), and later named after him. At the same time also described the British radiologist James Brailsford Frederik (1888 - 1961 from Birmingham), the disease, also naming as Morquio - Brailsford syndrome is common. Mostly, however, the name is Mucopolysaccharidosis type IV (MPS type IV ) is used.

Several clay figures from the Tumaco -La were found Tolita culture that existed in the border area between Colombia and Ecuador, some 2,500 years ago. These figures showed dwarfism, a narrow rib cage with stand shoulder high, a short nose, a short neck and more typical facial changes, which were interpreted by researchers as representations of Morquio's disease

Molding

This is caused by a defective protein substance ( enzyme). It differs depending on the enzyme defect between:

• Morquio's disease type A. This is a common form sulfatase deficiency ( N -acetyl- galactosamine -6- sulfate sulfatase deficiency) based on gene 16q24.3 (No. 253000 in the " Online Mendelian Inheritance in Man / OMIM " - index)
• Morquio's disease type B. The rarer form is a beta- galactosidase deficiency based on gene 3p21.33 (No. 253010 in the " Online Mendelian Inheritance in Man / OMIM " index )

Appearance and clinical

The severity of the disease is very different, the sufferers of type B are usually less affected. It is quite possible that the disease is diagnosed because of lack of symptoms until adulthood, other patients have already marked as infants physical signs. Typical is a short stature with a short neck and typical face shape, and a corneal opacity and X - legs, there is no mental retardation, and no enlargement of the spleen or liver. In detail, can be found:

• Dwarfism: The final size is rarely more than 120 cm. The dwarfism is dysproportioniert by the shortening of the long bones with emphasis on the hull. This often falls only on four years of age.
• External appearance: Typical are a pigeon chest ( pectus carinatus, a rare funnel chest ), a joint laxity ( hypermobility ) and knock knees (Genoa valga ). The neck is usually short. The face shows typical changes that are reminiscent of gargoyle figures ( Gargoyles ) at Gothic churches and are therefore often referred to as gargoylism: The chin is enlarged and above, the coarsened face with prominent cheek with a large head ( macrocephaly ).
• Spine: The bone changes in the spine ( spondyläre dysplasia) are so typical that an x-ray often leads to the diagnosis. The vertebral bodies are flat ( platyspondyly ), especially the vertebrae at the junction between thoracic and lumbar spine are often wedge-shaped, with consequent formation of a hump. Further, there is a bony system disorder with a too small and not sufficiently fixed dens ( the alveolar process of the second cervical vertebra ), whereby there is a risk ( atlantoaxial ) instability. This can lead to spinal stenosis up to paraplegia. One danger is especially for endotracheal intubation under general anesthesia. Spinal cord compression can, however, both the neck - head junction ( atlantooccipital ) and at the transition between the thoracic and lumbar spine gradually develop ( throrakolumbal ) with increasing fatigability and reduced walking distance. At the pool there is a hypoplasia of the lower portion of the ilium, and usually a epiphyseal dysplasia of the femoral head ( femoral head epiphysis ), which is often reminiscent of a Perthes disease in the radiograph. There is usually a coxa valga. The metacarpals metatarsals are pointed to the body, shortening all long bones.
• Eyes: corneal opacities that are often only visible with the slit lamp.
• Teeth: most defects in the enamel, the teeth va of the upper jaw are often smaller with a clear gap formation.
• Belly: the connective tissue are umbilical and inguinal hernias extremely common, which often need to be surgically

Genetics

The inheritance is autosomal recessive. In type A Matalon 1974 described a defect in a 6- sulfatase, DiFerrante showed in 1978 that it is the N -acetyl- galactosamine -6- sulfate sulfatase ( GALNS ), at the proposal of Neufeld (1987 ) also briefly as galactose -6- sulfatase is designated. 1987 Gibson succeeded in the purification and biochemical description of the enzyme, which was then cloned and sequenced in 1991 by Japanese research group led by Tomatsu. In this case, a sequence of 552 amino acids showed a prepeptide of which an N-terminal 26 amino acid signal peptide is cleaved complete, so that the active form is a 496 amino acid peptide with two asparaginase Glykolysierungsstellen. There is a high homology to other sulfatases. The working group localized the protein on chromosome 16q24.3. The local GALNS gene was analyzed in more detail by Nakashima 1994. It is about 50,000 nucleotide bases (50 kb ) long and consists of 14 exons. Analyzes of mutations showed an enormous variability, Tomatsu summed 2005 a total of 148 known mutations on the GALNS gene. This large genetic heterogeneity is responsible for the pronounced clinical variability. Nelson proposed in 1988 for Type A subdivision in the clinical manifestations hard - classical, intermediate and slightly protruding.

By the defect of an enzyme in the degradation of endogenous glycosaminoglycans, which were formerly called mucopolysaccharides and represent mainly scaffolding proteins, fall excessively fission products, which can not be further processed. These are therefore initially stored in lysosomes and therefore counted the mucopolysaccharidoses to the lysosomal storage diseases. Partial intermediates are also excreted increased, this is the Morquio's disease type A, the keratan sulfate in the urine, in type B chondroitin -6- sulfate. In particular, the fission products are however stored in characteristic organs - mostly skeletal system, connective tissue, parts of the eye, liver and spleen - and then lead to malfunction. Unlike the other mucopolysaccharidoses in Morquio's disease is the storage only in connective tissue cells (v, a fibroblast ) instead of, and not in the central nervous system or in the liver or spleen. Therefore, the affected have normal intelligence and no enlargement of the liver or spleen. The treatment was previously symptomatic, but there are some defects of enzyme supplements, but not yet for the Morquio's disease.

A prenatal diagnosis by chorionic villus sampling or amniocentesis is possible.