Table 304 Mucopolysaccharidoses And Mucolipidoses

Type

Name

Enzyme Defect

Storage Product

Genetics

Age at Onset

Primary Clinical Features

MUCOPOLYSACCHARIDOSES

1

Hurler's (MPS I)

Alpha L-iduronidase

Heparin sulfate (HS) and dermatan sulfate (DS)

Autosomal recessive

Birth or by 6 months

Abnormal facial appearance, hepatosplenomegaly, kyphoscoliosis, corneal clouding, mental retardation

2

Hurler-Schie MPS V/I

Alpha-L-iduronidase

Heparin sulfate (HS) and dermatan sulfate (DS)

Autosomal recessive

First year

Severe joint involvement, coarse facial features, hepatosplenomegaly, corneal clouding, but near-normal mentation

S

Scheie's (MPS V)

Alpha-L-iduronidase

Heparin sulfate (HS) and dermatan sulfate (DS)

Autosomal recessive

First year

Normal stature and less severe neurological deficits than in types l and 2

4

Hunter's (MPS II)

Iduronate 2-sulfatase

Heparin sulfate (HS) and dermatan sulfate (DS)

x-linked

First year

Similar to Hurler's but without corneal clouding

7, 8

Sanfilippo's A, B, C, D (MPS III)

A: Heparin sulfatase B: W-acetyl-alpha-D-glucosaminidase C:

W-acetyl-CoA-acetyl-alpha-D-glucosaminidase D: W-acetyl-alpha-D-glucosamine-6-sulfatase

A: Heparin sulfate B: Heparin sulfate C: Heparin sulfate D: Heparin sulfate

Autosomal recessive

First year

Hepatosplenomegaly and facial coarseness less than in Hunters and Hurler'.s. Mental and motor retardation, death by age 10. Among the subgroups, C is the most mild. In all subgroups, patients excrete heparin sulfate

9, 10

Morquio's A, B (MPS IV)

A: Acetyl galactosamine-6-sulfatase B: Beta-galactosidase

Keratan sulfate and chondroitin sulfate Keratin sulfate

Autosomal recessive

First year

Skeletal dysplasia with compressive neurological signs (severe in A, mild in B). No or little mental retardation. Corneal clouding 50 percent and organomegaly less prominent compared to other MPS. Survival to middle age

11

Maroteaux-Lamy(MPS VI)

Aryl sulfatase B

Dermatan sulfate

Autosomal recessive

First year

Growth retardation, coarse features, myelopathy

12

Sly's (MPS VII)

Beta-glucuronidase

Dermatan sulfate and heparin sulfate

Autosomal recessive

First year through childhood

Hepatosplenomegaly, psychomotor retardation, and coarse features

13

Multiple sulfatase (A, B, C)

Not known

Dermatan sulfate and heparin sulfate

Autosomal recessive

First year

Variable signs

MUCOLIPIDOSES

1

Sialidosis (ML, typel)

Neuraminidase

Oligosaccharide, glycolipids

Autosomal recessive

Adolescence

Cherry-red spot, myoclonic seizures, painful neuropathy, mildly coarse facial features

2

Lipomucosaccharidosis (ML 1, type 2)

Beta-galactosidase and sialidase

Oligosaccharide, glycolipids

Autosomal recessive

Infants

More severe than sialidosis. Facial and somatic dysmorphism, progressive mental retardation

S

I-cell disease (ML II)

Multiple lysosomal enzymes-- major marker is mannose-6-phospate transferase

Oligosaccharide, glycolipids

Autosomal recessive

Infants

Severe disease. Facial and somatic dysmorphism, progressive severe mental retardation, hepatosplenomegaly. Death often by age 10

4

Pseudo-Hurler's (ML III)

N-acetyl glueosamine-1-phosphotransferase

Oligosacchande, glycolipids

Autosomal reeessive

Childhood

Mild in comparison to l-cell. Corneal clouding. Survival to adulthood

5

Berman's mucolipidosis (ML IV)

Not yet characterized

Oligosaccharide, glycolipids

Autosomal recessive

Childhood

Most patients of Ashkenazi Jewish extraction

Although the infant with Hurler's disease may develop some sitting and walking skills as well as early language skills, these are soon lost. Severe mental retardation becomes apparent, and patients are usually bedridden before the end of the juvenile period.

Patients with Hurler-Scheie disease (type 2) have severe joint involvement, short stature, small thoraces, hepatosplenomegaly, coarse facial features, and corneal clouding. They may have near-normal mental abilities. The small thorax and cardiac involvement in this disease often reflect mitral valve insufficiency.

Scheie's syndrome usually occurs in individuals of normal size, and their neurological deficits are less severe than those seen in patients with types 1 and 2 disease. These patients have only mild hepatosplenomegaly with marked coarseness of the facial features or severe mental retardation. Dysostosis multiplex or bony involvement is also mild, although a common feature is carpal tunnel symptomatology. It is rare for neurological problems to be severe enough to cause early complaints. Generally, ocular involvement, specifically corneal clouding or retinal abnormalities suggesting degeneration, lead to suspicions of an MPS disorder. In most instances, the diagnosis is not made before the age of 10 years, and frequently it is not recognized until age 20 or later.

Two types of Hunter's syndrome have been suggested, one with predominant mental retardation and one not associated with retardation. Children with Hunter's syndrome may have a facial appearance similar to that characteristic of Hurler's syndrome, but the cornea is not clouded in Hunter's disease. In fact, corneal findings are the most important features distinguishing Hunter's from Hurler's disease. Patients with Hunter's syndrome often have a macular skin rash over the arms, shoulders, and thighs that may change in character. Urinary excretion of heparin and dermatan sulfate is similar in Hunter's and Hurler's diseases.

Sanfilippo's syndrome (MPS III, types 5-8) is subgrouped into four types, each with milder dysostosis multiplex, facial abnormalities, and hepatosplenomegaly than the abnormalities seen in patients with Hunter's and Hurler's syndromes. As the child grows older, the liver and spleen may actually resume normal proportions. Hyperactivity, speech delay, and/or frank mental retardation are often the original presenting conditions. In early life, deterioration is slow, but by the end of the first decade, neurological deterioration becomes more rapid. These children are soon bedridden, and death usually occurs by the mid-teens. Sanfilippo's syndrome is a classic example of a neurodegenerative disease with a monophasic downhill course.

In 1929 Morquio'31] described a syndrome characterized by severe skeletal dysplasia; two types, severe (type A) and mild (type B), occur. In both forms, mental symptomatology is absent or only mildly present. Neurological symptoms may result from compression of the spinal cord or medulla. The skeletal changes include joint laxity, shortness of stature, pectus carinatum, shortened vertebrae, genu valgum, pes planus, and enlarged joints. The neck is short, and the odontoid process in the cervical region is often underdeveloped, accounting for the atlantoaxial subluxation seen. y Corneal clouding is present in 50 percent of cases, and hepatomegaly is less prominent than in other forms of mucopolysaccharidosis. Cardiac involvement may include aortic regurgitation. Patients usually survive until middle age.

These disorders are most easily confused with the muco- lipidoses and the GM 1 -gangliosidoses because of the associated facial and somatic progressive dysmorphisms. Full general and neurological assessments are necessary, and even with a full family history, these recessive diseases may not be fully expressed in an immediate family constellation. Important laboratory evaluations include identification of mucopolysaccharides in the urine and assays for enzyme defects in leukocytes and cultured fibroblasts (see Tabie 3.0.-4 ).

The mucopolysaccharidoses remain an essentially untreatable group of disease. Symptomatic palliative therapies are available, but these are slowly progressive diseases, and life expectancy is limited.

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