Mucopolysaccharides Medical Genetics Dr Derakhshandeh, PhD

2 Definition  A gel-like substance found in:  body cells  mucous secretions  synovial fluids

3Mucopolysaccharidoses  Genetic disorders  Deficiency of enzymes necessary to breakdown mucopolysaccharides (MPS)  Excessive accumulation of mucopolysaccharides in body tissues

4 Mucopolysaccharidoses Results: –many serious physical disorders –Various genetic deformities such as: skeletal deformities (especially of the face) mental retardation decreased life expectancy

5 Examples Hunter syndrome Hurler syndrome Scheie syndrome Sanfilippo syndrome Morquio disease Maroteaux-Lamy syndrome

6

7 Hurler syndrome type I ( Alpha-L-iduronate deficiency )

8 Hurler syndrome type I Definition An inherited disease (AR) Storage of abnormal quantities of this material (mucopolysaccharide) in different body tissues is responsible for the symptoms and appearance of the disease

9 Hurler syndrome (type I)

10 Hurler syndrome type I

11 Key Symptom Images Claw hand Coarse facial features Corneal clouding Hernia Mucopolysaccharidosis I (MPS I) Disease (Hurler, Hurler-Scheie, Scheie Syndromes)

12 Causes of the Hurler syndrome Inherited as an autosomal recessive trait Metabolic defect: inability –The body's to make an enzyme: lysosomal alpha-L-iduronase lysosomal alpha-L-iduronase

13 incidence & and risk factors Approximately 1 in 150,000 infants are affected Newborn infants with this defect appear normal at birth By the end of the first year, signs of impending problems begin to develop

14 MPS (Type I) The children slowly develop Coarse, thick, facial features Prominent dark eyebrows Progressive stiffness Mental retardation

15Prevention Genetic counseling: important for parents with a family history of Hurler syndrome Prenatal diagnosis: An amniocentesis in the amniotic fluid are then cultured and the a-L-iduronidase activity in the cells is determined.

16Symptoms Short stature Severe mental retardation Thick, coarse facial features with low nasal bridge Full lips with a thick, large tongue Increased body hair (hirsutism)

17 Symptoms Umbilical hernia Deafness Stiffness (in joints) Shortness of breath Abnormal bones of spine and claw hand

18 MPS: Signs HepatomegalySplenomegaly Enlarged tongue Retinal pigmentation Hip dislocation Kyphosis Heart murmurs Heart valve damage from thickening

19 Tests that may indicate the syndrome Increased excretion of dermatan sulfate and heparan sulfate in the urine Absence of lysosomal alpha-L- iduronidase (in cultured fibroblasts) Culture of cells from amniotic fluid obtained by amniocentesis for enzyme testing (prenatal testing)

20 Tests that may indicate the syndrome Abnormal histological staining of white blood cells called metachromasia X-ray of the skeleten X-ray of the spine X-ray of the chest ECG

21 Hunter syndrome type II (Sulpho-idoronide sulphatase deficiency )

22 Hunter syndrome type II

23 Hunter syndrome type II

24 Hunter syndrome type II (Sulpho-idoronide sulphatase deficiency ) X-linked Coarse, thick, facial features Progressive stiffness decreased mental development Hepatomegaly (liver enlargement) Splenomegaly (spleen enlargement) Abnormal bone x-rays

25 Sanfilippo syndrome type III

26 Sanfilippo syndrome type III

27 Sanfilippo syndrome type III

28 Sanfilippo syndrome type III Definition Sanfilippo syndrome is one of the hereditary mucopolysaccharide storage diseases it is characterized by the absence of one of several enzymes These enzymes help the body get rid of a substance normally found outside of our cells called a mucopolysaccharide This substance is called heparan sulfate, and in Sanfilippo syndrome, large amounts of it are excreted in the urine

29 Alternative Names Mucopolysaccharidosis type III subtypes A - B – C - D Type IIIA: heparan sulfate sulfatase deficiency Type IIIB: N- acety-glucos-aminidase- deficiency Type IIID: N-acetyl-glucos- amine-6-sulfate sulfatase deficiency

30 Sanfilippo syndrome Causes an autosomal recessive trait It is possibly the most common of the mucopolysaccharide storage diseases It has a relatively late onset rather than during the first year of life It has a relatively late onset rather than during the first year of life

31Causes Coarse, thick, facial features Prominent dark eyebrows Progressive stiffness gait disturbances speech disturbances decreased mental development that progresses to severe mental retardation

32Prevention Genetic counseling: important for prospective parents with a family history of Sanfilippo syndrome Prenatal diagnosis: An amniocentesis in the amniotic fluid are then cultured and the enzyme activity in the cells is determined.

33 Symptoms Family history of Sanfilippo syndrome May have normal growth during first few years, but final height is below average Delayed development followed by deteriorating mental status Deterioration of gait Coarse facial features Full lips Heavy eyebrows that meet in the middle of the face above the nose Diarrhea Stiff joints that may not extend fully

34 Sanfilippo syndrome Signs and tests Hepatomegaly (liver enlargement) Splenomegaly (spleen enlargement) Corneas clear Echocardiogram may show thickened heart Abnormal bone x-rays such as thickened skull and oval vertebrae

35 Sanfilippo syndrome Signs and tests Seizures mental retardation Activities of one of the enzymes may be low in fibroblast skin cells Urine may have increased heparan sulfate Abnormal pathological staining character of white blood cells called metachromasia

36 Features and Characteristics children with Sanfilippo syndrome Occasional enlarged head Coarse facial features Coarse hair Excessive hair growth Joint stiffness

37 Sanfilippo syndrome Severe diarrhea or constipation Severe hearing loss Hyperactivity Aggressive and destructive behavior Poor attention Physical aggression Speech and language delay Sleep disturbance Severe intellectual impairment most often before 6 years of age Mild growth retardation Vision impairment

38 Morquio syndrome Type IV

39 Morquio syndrome Type IV Skeletal abnormality - hand

40 Skeletal abnormality: flattened vertebrae

41

42 Morquio syndrome Type IV subtypes A & B Type IVA: Galactose-6- sulfatase deficiency Type IVB:  Galactosidase deficiency

43 Features and Characteristics children with Morquio syndrome Joint stiffness Mild growth retardation Stiff joints that may not extend fully Without mental retardation ! Abnormal bone x-rays –X-ray of the skeleten –X-ray of the spine –X-ray of the chest

44 Prevention Genetic counseling: important for prospective parents with a family history of Morquio syndrome Prenatal diagnosis: An amniocentesis in the amniotic fluid are then cultured and the enzyme activity in the cells is determined.

45 Maroteaux-Lamy syndrome Type V (N-Acetyl-galactose-amin-4- sulfatase (Arylsulfatase B)

46 Maroteaux-Lamy syndrome TypeV

47 Maroteaux-Lamy syndrome TypeV

48 Features and Characteristics Maroteaux-Lamy syndrome Coarse facial features

49Treatment At the present time, there is no cure for MPS disorders. Enzyme replacement therapy and gene therapy are the two treatments that researchers have been focusing on to eventually cure MPS diseases. There are a number of research institutions around the world working on finding a cure for the MPS diseases including facilities in the United States, Canada, England, and Australia.