MUCOPOLYSACCHARIDOSES

Dr Mariam Abdul Rashid

 Mucopolysaccharidoses group of metabolic
disorders caused by the absence or
malfunctioning of lysosomal enzymes needed
to break down molecules called
glycosaminoglycans (GAG).

Cause deficiency in the activity of

lysosomal enzyme required for GAG
degradation.
 This accumulation results progressive
cellular damage, organ failure, cognitive
impairment and reduced life expectancy.

Prominent feature skeletal and joint

abnormalities, skeletal dysplasia, decreased
joint mobility, short stature and CTS (carpal
tunnel).
 The MPS disorders inherited in an
autosomal recessive pattern affect both
males and females equally.

MPS II X-linked recessive disorder

generally affects only males.
MPS I (Hurler, Hurler-Scheie, Scheie
Syndromes)
 Hurler and Scheie syndromes were both determined to be due to a
deficiency of -L-iduronidase .

Mutation of the -L-iduronidase gene would produce Hurler

syndrome, while a different mutation was responsible for Scheie
syndrome.

An intermediate MPS I phenotype, which was termed Hurler

Scheie syndrome, was speculated to occur when an individual was
heterozygous for both a Hurler and a Scheie mutation.

Thus MPS I is classified into three separate diseases on the basis of

clinical presentation; that is, Hurler syndrome (severe), Hurler
Scheie syndrome (intermediate) and Scheie syndrome (mild).
 The skeletal abnormalities seen in these patients are
collectively referred to as dysostosis multiplex.

These skeletal changes result in :

a. profound loss of joint range of motion
b. restricted mobility
c. growth slowing or arrest in childhood and short
stature
d. hand and wrist involvement (common), decreased
wrist range of motion, stiffening of the IP joint and
curved finger, hands take on a claw-like appearance.
 Other signs and symptoms

a. coarse facial features

b. vision loss,
c. hearing loss,
d. decreased pulmonary function and obstructive sleep apnoea,
e. frequent and recurrent respiratory infections,
f. cardiac disease,
g. hepatomegaly and splenomegaly,
h. umbilical and inguinal hernias,
i. chronic diarrhoea,
j. communicating hydrocephalus
k. spinal cord compression.
Skin lesions (pebbling) in a patient with MPS II.

Unique among the MPS disorders, MPS II patients may have a

distinctive skin lesion (pebbling), which is described as ivory-
white papules that are 210 mm in diameter, often coalescing
to form ridges.
 Diagnosis
The measurement of urinary GAG levels.
(increased urinary excretion of dermatan- and
heparan sulphate).
A positive result is very suggestive of an MPS, but
false-negative results are very common.
False-negative results occurlack of sufficient
sensitivity in the various assays and because of
samples that are too dilute.
Thus a negative urinary GAG analysis does not
rule out MPS.
 Gold standard enzyme activity assays
measurement of -iduronidase activity in
leukocytes or cultured fibroblasts.

Prenatal diagnosis measurement of enzyme

activity in cultivated chorionic villus or
amniocytes.
 Gene sequencing identify the mutation
present.

By identifying the gene mutation in the MPS

patient, at-risk family members can be offered
genetic counselling and genetic carrier testing.
 Treatment

Currently, hematopoietic stem cell transplantation (HSCT ) with bone marrow or

umbilical cord blood stem cells has been shown to prevent many of the clinical
features of the severe phenotypes of MPS I, VI and VII.

If performed before developmental deterioration begins in MPS I, successful HSCT

can significantly preserve intellectual development in most children.

Yet, even when full engraftment does occur, there are certain abnormalities that
remain resistant to HSCT treatment and will require intervention, particularly
corneal clouding, cardiac valvular deformities and skeletal abnormalities.

In addition, HSCT does not appear to reverse any cognitive or intellectual

deterioration after it has already occurred.

Although it has been attempted, HSCT has not shown promise for the treatment of
MPS II, III or IV.
 HSCT carries significant risk of morbidity and
death.

The clinical success of HSCT depends on the age

of the child at transplantation, the degree of
clinical involvement, the childs cardiopulmonary
status and neurological development, the type of
donor and the ability to achieve stable
engraftment without the development of graft-
vs-host disease.
 Over the last 8 years, enzyme-replacement therapy (ERT)
with recombinant human enzyme for MPS I, II and VI has
been approved in the USA, Europe and many other
countries worldwide.

As with HSCT, the earlier that ERT is initiated, the better the
potential outcome.

The benefits of ERT for certain of the MPS disorders may

include improvements in joint mobility, walking ability, and
pulmonary and respiratory function; reduction in liver and
spleen volume; and significant reduction in urinary GAG
excretion.
 Ocular features in patients with MPS
The widespread GAG accumulation also affects
the eyes of patients with MPS.

Corneal clouding, ocular hypertension/glaucoma,

retinal degeneration and optic nerve
swelling/atrophy are among the most typical
features in MPS patients.

Progressive pseudo-exophthalmos due to shallow

orbits , hypertelorism, strabismus, farsightedness
and astigmatism have also been reported.
Slit lamp photography using diffuse illumination shows moderate corneal clouding in a 12-
year-old female with MPS I (Hurler syndrome) (A).

The slit beam identifies opacities throughout all levels of the cornea

(B) Corneal clouding or haze can also be identified with a penlight held tangentially to the
cornea.
 External examination shows pseudoexophthalmos (due to shallow
orbits) and mild to moderate corneal clouding in an 8-year-old
female with MPS I (Hurler syndrome).

Also noticeable are typical coarse facial features with shallow nasal
bridge.
Corneal clouding and photosensitivity

Corneal clouding is a common feature in MPS.

Alroy et al demonstrated that corneas affected
by MPS I have an increased mean fibril
diameter and irregular fibril distribution
compared to normal corneas.
Corneal clouding resulted from the buildup of
GAGs, most likely heparan sulfate, in the
stromal keratocytes.
 In the early stages, corneal clouding may first be
asymptomatic or present as photophobia, glare and/or
tearing with exposure to bright light.

In more aggravated forms, corneal clouding can be identified

by a mild haze or a milky, ground glass appearance of the
cornea.

As corneal clouding runs a progressive course, visual acuity

becomes increasingly affected and ultimately, can lead to
blindness.
 Progressive corneal clouding is especially prominent in
patients with MPS I, MPS VI and, to a lesser extent, in MPS VII.

Severe corneal clouding seems more common in patients with

MPS VI than in those with MPS I .
 Ocular hypertension/glaucoma
Elevated intraocular pressure and subsequent optic nerve damage
can occur secondary to GAG-mediated narrowing of the anterior
chamber angle (in angle-closure glaucoma) or obstruction outflow
through the trabecular meshwork (open-angle glaucoma).

Glaucoma has mostly been detected in patients with MPS I and

MPS VI and may be asymptomatic or present acutely with red eye,
increased corneal clouding, headaches and nausea.

Clinical signs of glaucoma include enlargement of the optic cup,

ocular hypertension and visual field defects and, if undetected,
progresses to irreversible blindness.
 Retinal degeneration
GAG deposition within retinal pigment epithelial cells and in the photoreceptor
matrix leads to progressive photoreceptor loss, retinal degeneration and
dysfunction of the remaining photoreceptors.

Optic nerve atrophy may also occur with advanced retinal degeneration.

Initially, retinal degeneration may clinically appear as sensitivity to light and night
blindness. Later, patients may develop peripheral vision constriction, which
presents clinically as gradual tunnel vision and can be associated with clumsiness.
Ultimately, patients experience central visual field loss.

Retinal degeneration generally progresses very slowly, with the time of onset
depending on the severity of the phenotype.

Predominantly, patients with MPS I, MPS II, MPS III and MPS IV are reported to
have retinal degeneration.
 Optic disc swelling and optic nerve
atrophy
GAG-mediated thickening of the dura and sclera and thickening of the
subarachnoid space can lead to optic nerve compression, resulting in optic
disc swelling and subsequent optic nerve atrophy if the swelling is
prolonged .

Increased intraocular pressure and subsequent optic disc cupping/atrophy

can be another cause of optic nerve atrophy.

Optic nerve atrophy causes reduced contrast sensitivity and may affect the
visual field, ultimately leading to vision loss.

Optic disc/nerve pathologies have mostly been reported in patients with

MPS I and MPS VI.

Thickening of the optic nerve sheath has been demonstrated ultrasonically

in patients with MPS I, II and VI.
Optic nerve abnormalities in a patient with
MPS I with elevated intracranial pressure.

(A) The optic nerve is swollen (margin is

obscured) and the vessels are
congested (papilloedema).

(B) When optic nerve oedema persists over

time, the patient develops optic atrophy;
also visible in this photograph is arteriolar
attenuation (arrows), suggesting the
presence of retinal degeneration, which
can contribute to the finding of optic
atrophy.
 Reduced vision
Ocular features in MPS very often lead to visual impairment .

While for most patients, irreversible vision loss occurs gradually, some
patients experience rapid loss of vision due to acute glaucoma or optic
nerve swelling followed by atrophy.

Other common conditions that affect vision in patients with MPS include
amblyopia, strabismus (mostly exotropia with outward deviation of the
eyes) and hypermetropia or astigmatism.

Reduced visual acuity, amblyopia, ocular motility disorders and refractive

errors, resulting in the need for spectacle wear for the majority of
patients, have been especially reported in patients with MPS I and MPS VI.

A more rigid and flattened cornea and shortened axial length have been
postulated as potential GAG-mediated causes of farsightedness.
 Thank you..