Mucopolysaccharidosis (Hunter, Hurler, also discussion of Fragile X)
The findings of coarse
facies,
macrocephaly,
and hepatosplenomegaly, as
described for the child in the vignette, are
suggestive of a
lysosomal
storage disease. This class of disorders typically results from deficient
enzyme activity and the consequent lysosomal accumulation of its substrate.
The disorders include the
lipidoses
(eg,
Tay-Sachs
disease), glycoproteinoses,
mucolipidoses,
and mucopolysaccharidoses.
Because the substrates for the
lysosomal
storage disorders are large molecules that do not diffuse readily through the
body, the affected sites can be predicted based on 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, mental retardation.
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 suspected
for the child in the vignette, can be confirmed by
measuring the urinary excretion of
mucopolysaccharides.
However, the definitive diagnosis
is made by determination of the specific enzymatic activity
in isolated leukocytes or cultured skin 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 in individuals who have a
positive family history by determination of the appropriate enzyme activity in
isolated leukocytes or serum. In addition, the molecular
bases of some 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 by progressive organ
involvement and mental retardation that lead
to death, usually in the first decade. Patients
appear normal at birth and have
accelerated growth in the first year followed by
deceleration and short stature. The diagnosis
usually is made by 2 years of age when
organomegaly,
corneal clouding, coarse features, enlarged tongue, and joint stiffness
all are apparent. Developmental delay appears between 12
and 28 months of age and is followed by subsequent regression. Other
complications include hearing loss,
chronic respiratory infections, cardiac insufficiency due to
valvular
disease, and increased intracranial pressure.
Hurler (crouched down, hurling a L-id, but can't see where it lands and can't hear when it lands)
Hunter (also crouched down, but not as much since He is a Hunter, who grabs a spear with a claw hand and can see and hear his prey.
MPS type IS (Scheie disease) and MPS type IH/S (Hurler-Scheie disease) are milder 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 of severe and mild forms with and without mental impairment. MPS types IIIA, IIIB, IIIC, and IIID (the Sanfilippo syndromes) result from one of four enzyme deficiencies and are characterized by behavioral problems, seizures, and less severe somatic manifestations, with survival reported into the third decade. Children who have MPS type IV (Morquio syndrome) have normal intelligence and severe skeletal findings that sometimes are confused with the spondyloepiphyseal dysplasias. The most 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.
- 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 his skeleton
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 some characteristics with the
mucopolysaccharidoses,
including coarse features and retardation, but
organomegaly
is not typical. Infants who have congenital infections 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 of
Inherited Disease. 7th ed. New York, NY: McGraw-Hill, Inc;
1995:2465-2494
Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991; 60:257-280