FOUNDATION MODULE

FLIPPED CLASS –MUCOPOLYSACCHARIDOSIS (MPS)

PRE-READING MATERIAL

LEARNING OBJECTIVES

 Classify polysaccharides.
 Relate the structure of homopolysaccharides and heteropolysaccharides with their
biomedical importance with the help of clinical scenarios provided.
 Describe the biochemical basis of following lysosomal disorders:
 Hurler syndrome
 Hunter syndrome
 Sanfilippo syndrome
 Sly syndrome
 Correlate the metabolic abnormalities observed in the given lysosomal disorders with
their clinic-pathological presentation.
 Enumerate the available screening and laboratory diagnostic methods for the given
Lysosomal storage disorders

MUCOPOLYSACCHARIDOSIS (MPS):
Lysosomal storage diseases (LSDs) are inborn errors of metabolism i.e metabolic disorders
due to congenital enzyme deficiencies. These are characterized by the accumulation of
substrates. If these substrates are glycosaminoglycans, they are called
mucopolysaccharidosis and when these are sphingolipids, they are called sphingolipidosis
and both come under a common name of lysosomal storage diseases
Mucopolysaccharidosis refers to a group of inherited conditions in which the body is unable
to properly breakdown mucopolysaccharides (long chains of sugar molecules that are found
throughout the body). As a result, these sugars buildup in cells, blood and
connective tissue which can lead to a variety of health problems.
Worldwide, the prevalence of all types of MPS has been 1 case in 16,000-30,000 births.
Mucopolysaccharidosis (MPS) the lysosomal storage diseases resulting from deficiency of
lysosomal enzymes which degrades glycosaminoglycans. The incomplete degradation
process leads to the accumulation of glycosaminoglycans in lysosomes of various tissues,
which interferes with cell function. These congenital enzyme deficiencies result in
accumulation of products in various organs' cells during degradation of glycosphingolipids
and Glycosaminoglycans, due to the defective functioning of lysosomes.
Seven distinct forms and numerous subtypes of mucopolysaccharidosis have been
identified. Associated signs and symptoms and the severity of the condition vary
significantly by form. In general, most affected people appear healthy at birth and
experience a period of normal development, followed by a decline in physical and/or mental
function. As the condition progresses, it may affect appearance; physical abilities; organ and
system functioning; and, in most cases, cognitive development.
Although rare individually, their prevalence is significant when viewed collectively. These
single-gene disorders is caused by mutant genes on a particular chromosome locus which
transcribes a particular inactive enzyme. The underlying genetic cause varies by form. Most
cases are inherited in an autosomal recessive manner, although one specific form (Type II)
follows an X-linked pattern of inheritance.
Most LSDs have an autosomal recessive pattern of inheritance. Two have an X-linked
inheritance pattern: Hunter disease, Fabry disease. The last decade has observed
tremendous advances in understanding many of these conditions. Treatment is based on
the signs and symptoms present in each person
CLINICAL PRESENTATIONS:
Clinical presentations of these cases vary, depending on each type of enzyme defect. All the
patients appeared healthy at birth, and symptoms appear at around 1 or 2 years. Clinical
features, radiological findings, and especially enzyme assays have allowed us to establish a
definitive diagnosis in these cases. However, in low- and middle-income countries, it is
difficult to have a definitive diagnosis of one of the mucopolysaccharidoses due to lacking
enzyme assays. Enzyme testing is usually the initial diagnostic test, but genetic analysis of
the gene mutations adds precision.
SIGNS AND SYMPTOMS:
Patients with MPS have normal development initially, with abnormalities appearing in
infancy or later in childhood. Those with multiple organ system involvement may have the
following presentations:
 Central nervous system (CNS) disease – Hydrocephalus; cervical spine myelopathy
 Cardiovascular disease – Angina; valvular dysfunction; hypertension; congestive heart
failure
 Pulmonary disease – Airway obstruction, potentially leading to sleep apnea, severe
respiratory compromise, or cor pulmonale
 Ophthalmologic disease – Corneal clouding; glaucoma; chronic papilledema; retinal
degeneration
 Hearing impairment – Deafness
 Musculoskeletal disease – Short stature; joint stiffness; symptoms of peripheral nerve
entrapment
BIOCHEMICAL BASIS:
Lysosomes have luminal and structural proteins which includes amino acid and lipid
transporters, ion-channels like calcium channels, membrane catabolic enzymes, trafficking,
fusion machinery and lysosomal associated proteins.
Abnormalities in these can interfere with lysosomal functions and result in LSDs. Lysosomes
communicate with the endoplasmic reticulum, mitochondria, peroxisomes to exchange
content. The lysosomal enzymes and other proteins are synthesized in the ribosomes and
transported to the endoplasmic reticulum (ER), where they are folded and attain a three-
dimensional form.
Defective activity of the lysosomal enzymes blocks the degradation process of
mucopolysaccharides, leading to abnormal accumulation of heparan sulfate, dermatan
sulfate, and keratan sulfate. These degradation by-products are then secreted and detected
in the urine. MPS can be subclassified according to the type and amount of substance that
accumulates.

Stepwise enzymatic reactions catalyze the degradation of these compounds. A deficient

enzyme or accessory protein will prevent the forward reaction and lead to substrate
accumulation. The accumulated compounds are excreted and form the basis for
measurement in the urine. In MPS, these compounds are GAG, linked to carbohydrates or,
when linked to amino acids proteoglycans (PTG). The tissue distribution varies with these
compounds. Keratan sulfate is present in the cornea, cartilage, intervertebral disks,
dermatan sulfate in the heart, blood vessels, and skin. Heparan sulfate is present in the
lungs, blood vessels, and on the surface of cells and explains the multiorgan involvement
and organ predilection.
 MUCOPOLYSACCHARIDES
Fig 14.4 Lippincott’s page 159, Chapter 14.
 MUCOPOLYSACCHARIDOSIS
Fig 14.12 Mucopolysaccharidosis Chapter 14 Lippincott’s
LAB DIAGNOSIS AND SCREENING:
Diagnosis
Antenatal screening studies that may be useful include the following:
 Chorionic villus sampling
 Amniocentesis
Postnatal diagnostic studies that may be helpful include the following:
 Urinalysis, focusing on glycosaminoglycans (eg, dermatan sulfate, heparin
sulfate, and keratin sulfate)
 Serum assays for lysosomal enzymes (alpha-L-iduronidase, iduronate sulfatase,
heparan N-sulfatase, N-acetylglucosaminidase, alpha-glucosamine- N-
acetyltransferase, N-acetyl alpha-glucosamine-6-sulfatase, N-
acetylgalactosamine-6-sulfatase, N-acetylgalactosamine-6-sulfatase, B-
galactosidase, N-acetylgalactosamine-4-sulfatase, and B-glucuronidase)
Imaging studies that may be warranted are as follows:
 Plain radiography (to detect dysostosis multiplex)
 Computed tomography (CT) of the cranium (to help diagnose hydrocephalus)
 Echocardiography (to monitor ventricular function and size in MPS patients
with cardiovascular disease)
 Magnetic resonance imaging (MRI; to evaluate spinal involvement)
Other tests to be considered are as follows:
 Electroretinography
 Audiologic assessment

MANAGEMENT:
Specific treatment or cure is limited for MPS. Management has been limited to supportive
care and experimental treatment modalities. Medical treatment modalities include the
following:
 Laronidase
 Idursulfase
 Elosulfase alfa
 Vestronidase alfa
Surgical care for specific conditions may include the following:
 Hydrocephalus – Ventriculoperitoneal shunting
 Corneal clouding – Corneal transplantation
 Cardiovascular disease – Valve replacement
 Obstructive airway disease – Tracheostomy
 Orthopedic conditions – Carpal tunnel release; soft tissue procedures to release
hip, knee, and ankle contractures; hip containment surgeries; corrective
osteotomy for progressive valgus deformity at the knee; posterior spinal fusion
Multispecialty care is mandatory for these patients and should include a pediatrician
(internist), a neurologist, a cardiologist, an ophthalmologist, an audiologist, an orthopedic
surgeon, and a physical and occupational therapist.
Enzyme replacement therapy for MPS III (A), San Filippo syndrome type A and for MPS IV
(Morquio syndrome) is currently under investigation. The FDA approved laronidase
(Aldurazyme) as a treatment for MPS I Specifically, this enzyme replacement therapy is
approved for treating patients with the Hurler and Hurler syndrome
PROGNOSIS:
The prognosis varies, depending on the type of MPS. Most of these patients have shortened
life spans, and some die in infancy. These disease processes have significant effects on the
growth and development of the musculoskeletal system, including joint stiffness or
hyperlaxity, deformities, and progressive loss of function. Multiple other organ systems are
involved. The type and extent of organ system involvement are variable, depending on the
subset of the disease.
Bone marrow transplantation has some positive effects systemically, such as reduction in
hepatosplenomegaly, airway obstruction, and cardiopulmonary disease. These effects have
resulted in improved life span, and many of these patients survive beyond the first decade
of life.

RESOURCES
1. Lippincott’s textbook of biochemistry
2. Harpers textbook of biochemistry
3. Internet resources
https://www.youtube.com/watch?v=1BcZkRxxc4Y&ab_channel=Dr.Mungli
https://rarediseases.org/rarediseases/mucopolysaccharidoses/#:~:text=A%20diagnosis%20of%20a
%20mucopolysaccharidosis,to%20detect%20excessive%20levels%20of