Morquio's disease

Classification according to ICD-10
E76.2	Other mucopolysaccharidoses - Morquio's disease
ICD-10 online (WHO version 2019)

Morquio's disease (Morquio's disease) is an extremely rare, congenital metabolic disorder belonging to the group of mucopolysaccharidoses .

Historical

In 1929, the rare disease was first described by the Uruguayan pediatrician Luis Morquió (1867–1935, from Montevideo ), and later named after him. At the same time, the British radiologist James Frederik Brailsford (1888–1961, from Birmingham) also described the disease, and it is also known as Morquio-Brailsford syndrome. Usually, however, the term mucopolysaccharidosis type IV (MPS type IV) is used.

Several clay figurines from the Tumaco-La Tolita culture, which existed around 2,500 years ago in the border area between Colombia and Ecuador , have been found. These figures showed short stature, a narrow chest with raised shoulders, a short nose, a short neck and other typical facial changes that were interpreted by researchers as depictions of Morquio's disease.

to form

The reason for this is a defective protein , or more precisely an enzyme . Depending on the enzyme defect, a distinction is made between:

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

Morquio's disease Mucopolysaccharidosis IV Rö-standing view of the legs with typical changes near the joints

Appearance and Clinic

The severity of the disease varies widely, and type B patients are usually less affected. It is quite possible that the disease will not be diagnosed until adulthood due to the lack of symptoms; other patients have clear physical signs even as small children. Typical is a short stature with a short neck and typical face shape, as well as corneal opacity and knock knees, there is no intellectual disability and no enlargement of the spleen or liver. In detail there are:

• Short stature: The final size is rarely more than 120 cm. The short stature is disproportionate due to the shortening of the long tubular bones with emphasis on the trunk. This is often only noticeable from the age of four.
• External appearance: Typical are a keel breast (pectus carinatus; rarely a funnel chest ), a joint laxity ( hypermobility ) and X-legs (Genoa valga). The neck is usually short. The face shows typical changes that are reminiscent of gargoyles (gargoyles) in Gothic churches and are therefore often referred to as gargoylism : the chin is enlarged and protruding, the face is coarser with pronounced cheeks and a large head ( macrocephaly ).
• Spine: The bone changes in the spine (spondylar dysplasia) are so typical that an X-ray often leads to the diagnosis. The vertebral bodies are flatter ( platyspondyly ), especially the vertebrae at the transition between thoracic and lumbar spine are often wedge-shaped with the resulting formation of a gibbus . There is also a bony attachment disorder with a dens axis that is too small and insufficiently fixed (the tooth process of the second cervical vertebra), which creates the risk of (atlantoaxial) instability. This can lead to spinal canal stenosis up to cross-sectional symptoms. There is a particular danger with endotracheal intubation under general anesthesia . A spinal cord compression can develop slowly at the neck-head junction (atlantooccipital) as well as at the junction between thoracic and lumbar spine (throracolumbar) with increasing fatigue and reduced walking distance. In the pelvis, there is hypoplasia of the lower part of the ilium and mostly epiphyseal dysplasia of the femoral head (femoral head epiphysis), which on x-rays often resembles Perthes' disease . There is usually a coxa valga . The metatarsal bones (ossa metatarsalia) are pointed close to the body, all long tubular bones are shortened.
• Eyes: corneal opacities that are often only visible with a slit lamp .
• Teeth: mostly defects in the enamel , the teeth v. a. of the upper jaw are often smaller with clear gaps.
• Belly: due to the weak connective tissue, umbilical and inguinal hernias are very common and often require surgical treatment

genetics

The inheritance is autosomal - recessive . In 1974 Matalon described a defect in a 6-sulfatase in type A, DiFerrante was able to show in 1978 that it is N-acetyl-galactosamine-6-sulfate sulfatase (GALNS), which Neufeld (1987) suggested for short as Galactose-6-sulfatase is called. In 1987 Gibson succeeded in the purification and biochemical description of the enzyme , which was then cloned and sequenced in 1991 by the Japanese group led by Tomatsu. A sequence of 552 amino acids was shown as prepeptide, from which an N-terminal signal peptide comprising 26 amino acids is cleaved off, so that the active form is a peptide comprising 496 amino acids with two asparaginase glycolysis sites. There is a high degree of homology to other sulfatases. The working group localized the protein on chromosome 16q24.3 . The GALNS gene there was analyzed in more detail by Nakashima in 1994. It is around 50,000 nucleotide bases (50 kb) long and comprises 14 exons . Analyzes of the mutations showed an enormous variability, in 2005 Tomatsu totaled a total of 148 known mutations on the GALNS gene. This great genetic heterogeneity is responsible for the pronounced clinical variability. In 1988 Nelson proposed a subdivision of type A into the clinical manifestations difficult-classic, intermediate and light.

Due to the defect of an enzyme in the breakdown of the body's own glycosaminoglycans, which were formerly known as mucopolysaccharides and which are predominantly structural proteins, there are excessive breakdown products that cannot be processed further. These are therefore initially stored in lysosomes and therefore mucopolysaccharidoses are counted among the lysosomal storage diseases. In some cases, intermediate products are also increasingly excreted, this is keratan sulfate in the urine in Morquio's disease type A, and chondroitin-6 sulfate in type B. Above all, the fission products are stored in characteristic organs - mostly the skeletal system, connective tissue, eye segments, liver and spleen - and then lead to functional disorders there. In contrast to the other mucopolysaccharidoses, the storage of Morquio's disease takes place exclusively in connective tissue cells (especially fibroblasts ) and neither in the central nervous system nor in the liver or spleen. Therefore, people have normal intelligence and no enlargement of the liver or spleen. Specific enzyme replacement therapy for Morquio A's disease with elosufase alfa has been possible since 2014. The first clinical studies are promising.

A prenatal diagnosis using a chorionic villus sampling or amniocentesis is possible.

literature

• Press service of the Johannes Gutenberg University, Mainz Clinic
• Society for MukoPolySaccharidoses
• Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University: [1]
• UN Riede, HE Schaefer: General and special pathology. 3. Edition. Georg-Thieme-Verlag, Stuttgart 1993, ISBN 3-13-683303-1 .
• B. Leiber: The clinical syndromes . Urban and Schwarzenberg, Munich 1996, ISBN 3-541-01718-X .

Web links

• mps-ev.de (German mucopolysaccharidosis self-help group)

Individual evidence

1. ^ JE Bernal, I. Briceno: Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador. In: Clin. Genet. 2006; 70, pp. 188-191.
2. ^ Monthly Pediatric Medicine, Volume 155, Number 7, M.Beck: Lysosomal storage disorders.
3. ^ 1. Sanford M, Lo JH. Elosulfase alfa: first global approval. Drugs. April 2014; 74 (6): 713-82. Jones SA, Bialer M, Parini R, Martin K, Wang H, Yang K, u. a. Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 years. Pediatr Res. September 2, 2015.

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