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Mucopolysaccharidosis(Hunter, Hurler, also discussion of Fragile X)

The findings of coarse facies, macrocephaly, and hepatosplenomegaly, asdescribed for the child in the vignette, are suggestive of a lysosomal storage

disease. This class of disorders typically results from deficient enzyme activity andthe consequent lysosomal accumulation of its substrate. The disorders includethe lipidoses (eg, Tay-Sachs disease), glycoproteinoses, mucolipidoses,

and mucopolysaccharidoses.

Because the substrates for the lysosomal storage disorders are large molecules thatdo not diffuse readily through the body, the affected sites can be predicted basedon the usual tissues in which the substrate is used. For example, a defect in the

storage of mucopolysaccharides, which are major constituents of connective tissue,

results in a combination of coarse facies, corneal clouding, organomegaly, joint

stiffness, dysostosis multiplex, hernias, short stature, and in some disorders, mentalretardation.The phenotype of each disorder is determined by the specific enzyme

deficiency and the resultant pattern of degradation products that accumulate.

The diagnosis of the mucopolysaccharidoses (MPSs), such as would be suspectedfor the child in the vignette, can be confirmed by measuring the urinary excretion

of mucopolysaccharides.However, the definitive diagnosis is made bydetermination of the specific enzymatic activity in isolated leukocytes or culturedskin fibroblasts. Prenatal diagnosis of each of the MPSs by the measurement of

specific enzyme activity in fetal cells or by the incorporation of labeled substrates

into cultured amniotic cells is available. Carrier status can be identified inindividuals who have a positive family history by determination of the appropriate

enzyme activity in isolated leukocytes or serum. In addition, the molecular bases ofsome of the MPSs are known, allowing for more specific molecular identification

of carriers after the mutant alleles in the family have been characterized.

MPS type IH (Hurler disease) is one of the more severe MPSs that results from the

deficiency of alpha-L-iduronidase activity. It is characterized byprogressive organ

involvement and mental retardationthat lead to death, usually in the first

decade.Patients appear normal at birth and have accelerated growth in the firstyear followed by deceleration and short stature. The diagnosis usually is made by 2years of age when organomegaly, corneal clouding, coarse features, enlarged

tongue, and joint stiffness all are apparent. Developmental delay appears between

12 and 28 monthsof age and is followed by subsequent regression. Othercomplications include hearing loss, chronic respiratory infections, cardiac

insufficiency due to valvular disease, and increased intracranial pressure.

Hurler (crouched down, hurlinga L-id, but can't seewhere it lands and can't

hearwhen it lands)

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autosomal recessive absence of lysosomal alpha-L-iduronidase

short stature with deceleration of growth between 6 and 18 months slow regression of developmental milestones

coarse facies, full lips stiff joints enlarged tongue

hepatosplenomegaly cloudy corneas, hearing loss kyphosis with gibbus deformity thickening of coronary vessels or valves

Hunter (also croucheddown, but not as much since Heis a Hunter, who grabs a

spear with a clawhand and can see and hearhis prey.

X-linked recessive deficiency of iduronate sulfatase

short stature with deceleration of growth between 2-4 years of age severe mental deficiency with aggressive hyperactive behavior; also a form

without impairment coarsening of facial features, full lips stiff joints

clawhand hepatosplenomegaly

clear corneas gibbus deformity (less severe than Hurler)

MPS type IS (Scheie disease) and MPS type IH/S (Hurler-Scheie disease) aremilder disorders that also result from allelic mutations in the alpha-L-

iduronidase gene, but they are characterized by a less severe clinical course,

presumably due to the presence of a higher level of residual enzymatic

activity. MPS type II (Hunter syndrome), which is inherited in an X-linked

recessive pattern, is notable for the absence of corneal clouding and the presence ofsevere and mild forms with and without mental impairment. MPS types

IIIA, IIIB, IIIC, and IIID (the Sanfilipposyndromes) result from one of fourenzyme deficiencies and are characterized bybehavioral problems, seizures, andless severe somatic manifestations, with survival reported into the third

decade. Children who have MPS type IV (Morquio syndrome) have normalintelligence and severe skeletal findings that sometimes are confused with thespondyloepiphyseal dysplasias. Themost clinically significant complication of this

disorder is upper cervical spinal cord compression due to atlantoaxial

instability.Patients who have MPS type VI (Maroteaux-Lamy disease) have a

somatic phenotype similar to Hurler disease, but they have normal intelligence.

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- MPS 1H (Hurler): organomegaly, coarse features, joint stiffness, developmental

regression, death in 1st decade

- MPS 1S (Scheie) 1H/S (Sheie-Hurler):milder disease- MPS 2 (Hunter): X-linked, no corneal clouding, severe/mild, +/- MR

- MPS 3 (Sanfilippo): less severe somatic stuff, but behavior problems/seizures,survival into 20s- MPS 4 (Morquio): severe skeletal findings, normal intelligence

- MPS 5 ?- MPS 6 (Maroteaux-Lamy): like Hurler, but nl intelligence

Hurler is badness, Hunter in boys only, Sanfillipo seizes, Morquio morphs hisskeleton

Fragile X mental retardation can present with global developmental delay, and

some patients may be macrocephalic, but it is not associated with organomegaly.Chromosomal abnormalities typically result in a combination of growth retardation,

mental retardation, and congenital defects. Hypothyroidism can share somecharacteristics with the mucopolysaccharidoses, including coarse features and

retardation, but organomegaly is not typical. Infants who have congenitalinfections that lead to retardation and organomegaly usually present in the first

year of life, and coarse facies are not characteristic.

References:

Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR,

Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases ofInherited Disease. 7th ed. New York, NY: McGraw-Hill, Inc;

1995:2465-2494Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991; 60:257-280