Mucopolysaccharidosis I (MPS I) (α-

669

Mucopolysaccharidosis I (MPS I) ( α- ^L -Iduronidase Deficiency):

Hurler (MPS I-H), Hurler-Scheie (MPS I-H/S), and Scheie (MPS I-S) Syndromes

Mucopolysaccharidosis I consists of three clinical entities with varying degree of clinical manifestations, all due to the same lysosomal enzyme deficiency, α-

-iduronidase. Hurler (MPS I-H) and Scheie (MPS I-S) syndromes represent pheno- types at the two ends of the clinical spectrum; the Hurler- Scheie syndrome (MPS I-H/S) represents a phenotype of inter- mediate clinical severity. In most instances, the subtype of MPS I can only be assigned on the basis of clinical criteria, includ- ing the rate of progression of symptoms. The incidences for MPS I-H, MPS I-H/S, and MPS I-S are estimated to be 1/76,000–1/144,000, 1/280,000, and 1/840,000–1/1,300,000 live births, respectively.

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal recessive 2. The IDUA gene

a. Localized to chromosome 4p16.3, close to the Huntington disease gene

b. Spans 19 kb including 14 exons

3. Caused by mutations in the α-

-iduronidase (IDUA) gene a. Two major alleles (W402X and Q70X) and a minor allele (P533R) accounting for over half the MPS I alleles in the Caucasian population

b. No functional enzymes produced by above mentioned alleles, giving rise to the severe form of α-

- iduronidase deficiency (MPS I-H)

c. Limited mutations expected to cause the attenuated clinical phenotypes of MPS I-S or MPS I-H/S d. One of a mutation resulting in Scheie syndrome is a

base substitution in intron 7 that creates a new splice site and produces a frameshift. Since the old splice site is not obliterated, some normal enzyme still can be made to overcome the worst features of MPS I e. Most other alleles that lead to MPS I-S or MPS I-H/S

carry missense mutations

f. In the Japanese population studied, MPS I-H/S results from compound heterozygosity of two mutations (704ins5 and R89Q), which, in homozygous form, would give rise to MPS I-H and MPS I-S, respectively 4. Genotype–phenotype correlations

a. General principle

i. Any combination of two severe alleles leads to severe MPSI. A severe allele is one that produces the severe phenotype in either the homozygous state or compound heterozygous state

ii. Intermediate and mild MPSI: usually associated with one severe allele and another allele that per- mits production of some residual enzyme activity

b. Alleles associated with severe phenotype

i. Two common severe mutations (W402X and Q70X) always confer a severe phenotype whether present in a homozygous state or in a compound heterozygous state

ii. Additional mutations (474-2a-g, A327P, P533R, A75T, L218P)

c. Alleles associated with mild phenotype i. 678-7a-g

ii. R89Q 5. Pathophysiology

a. Underlying molecular defect leads to a loss or marked reduction in α-

-iduronidase, a lysosomal enzyme involved in the degradation of glycosaminoglycans heparan sulfate and dermatan sulfate

b. Because of the enzyme deficiency, excessive accumu- lation of acid mucopolysaccharides (glycosaminogly- cans) in the tissue occurs, leading to wide effect on various systems and remarkable changes in the mor- phogenesis

CLINICAL FEATURES

1. Hurler syndrome (MPS I-H) a. General clinical characteristics

i. The prototype of MPS representing the severe end of clinical spectrum

ii. A progressive disorder with multiple organ and tissue involvement, leading to death in childhood iii. Normal phenotype at birth and in early infancy

but deteriorates progressively afterward

iv. Diagnosis usually made between 4–18 months of age

v. Short stature (linear growth stops at 2–3 years of age)

vi. Developmental delay by age 12–24 months, with a maximum functional age at the level of 2–4 years, followed by progressive mental dete- rioration

b. Coarse facial features (one of the earliest signs) i. Ocular hypertelorism

ii. Prominent eyes iii. Bushy eyebrows

iv. Depressed nasal bridge v. Wide nostrils

vi. Large and thickened lips vii. Large tongue

viii. Hypertrophy of the gum and the bony alveolar

ridge

c. Other craniofacial features

i. A large scaphocephalic head with frontal bossing ii. Communicating hydrocephalus common after age 2–3 years. Shunting procedures may be ben- eficial for relieving increased intracranial pres- sure for some children

iii. Noisy breathing with persistent nasal discharge (chronic rhinorrhea)

iv. Upper respiratory and ear infections d. Ophthalmologic features

i. Progressive clouding of the cornea (the hallmark of the syndrome) beginning at the first year of life, leading to impaired vision

ii. Open-angle glaucoma

iii. Retinal degeneration resulting in decreased peripheral vision

iv. Night blindness e. Auditory features

i. Frequent sensorineural or mixed deafness ii. Contributing factors:

a) Frequent middle ear infection from Eustachian tube dysfunction, caused by stor- age of glycosaminoglycans within the oro- pharynx

b) Dysostosis of the ossicles of the middle ear c) Scarring of the tympanic membrane d) Damage to the eighth nerve f. Cardiovascular features

i. Cardiac valvular disease resulting from storage of mucopolysaccharide in the mitral, aortic, tri- cuspid, or pulmonary valves, leading to conges- tive heart failure

ii. Thickened coronary artery valves, leading to angina pectoris and myocardial infarction iii. Possible fatal cardiomyopathy as a presenting

feature for some MPS I infants less than 1 year old. Endocardial fibroelastosis has been noted postmortem in these patients

g. Gastrointestinal features i. Protuberant abdomen

ii. Progressive hepatosplenomegaly h. Skeletal abnormalities: dysostosis multiplex

i. Short neck

ii. Characteristic kyphoscoliosis when on attempt to sit

iii. Ultimate frank gibbus deformity iv. Stiff joints with limited mobility

v. Claw hands (flexed stubby fingers and broad hands)

i. Connective tissue abnormalities

i. Inguinal and umbilical hernias: common find- ings and usually present at birth

ii. Thick skin j. Prognosis

i. Bedridden before the end of the juvenile period ii. Early demise prior to 10 years of age

iii. Usual causes of death

a) Obstructive airway disease b) Respiratory infection c) Cardiac complications

2. Scheie syndrome (MPS I-S) a. The mildest form of MPS I b. Normal stature

c. Normal intelligence

d. Onset of significant signs usually after 5 years e. Diagnosis commonly made between 10 and 20 years

of age

f. Coarse facial features g. Deafness in some patients h. Joint stiffness

i. Claw hands ii. Stiff painful foot i. Carpal-tunnel syndrome j. Pes cavus

k. Genu valgum

l. Ocular manifestations i. Corneal clouding ii. Glaucoma

iii. Retinal degeneration

m. Aortic valvular disease (stenosis and regurgitation due to mucopolysaccharide deposits in the valves and chordae tendineae)

n. Obstructive airway disease with sleep apnea in some patients

o. Mild hepatosplenomegaly p. Mild dysostosis multiplex

q. Less common pachymeningitis cervicalis (compres- sion of the cervical cord by thickened dura) than MPS I-H/S

r. Potential normal life span

3. Hurler-Scheie compound (MPS I-H/S)

a. Clinical phenotype intermediate between Hurler and Scheie syndromes

b. Progressive somatic involvement, including dysos- tosis multiplex, with little or no intellectual dys- function

c. Age of onset: usually between 3 and 8 years d. Survival to adulthood common

e. Deafness

f. Craniofacial features

i. Coarse facial features less obvious ii. Micrognathia in some patients iii. Broad mouth

iv. Square jaw v. Short neck

g. Ophthalmologic features

i. Corneal clouding in all patients ii. Glaucoma

iii. Retinal degeneration iv. Optic atrophy

h. Valvular heart disease (mitral valve insufficiency) developing by the early to mid-teens

i. Skeletal features i. Short stature ii. Small thorax

iii. Severe joint involvement (stiffness) iv. Kyphoscoliosis

v. Back pain

vi. Characteristic claw hand deformity

vii. Carpal tunnel syndrome

j. Gastrointestinal features

i. Varying degree of hepatomegaly ii. Hernias

k. Pachymeningitis cervicalis (compression of the cervi- cal cord due to mucopolysaccharide accumulation in the dura)

l. Communicating hydrocephalus uncommon in patients who have normal intelligence

m. Spondylolisthesis of the lower spine, leading to spinal cord compression

n. Causes of death (around teens and 20s) i. Upper airway obstruction

ii. Cardiac involvement

DIAGNOSTIC INVESTIGATIONS

1. Developmental assessment 2. Ophthalmologic examination

3. ECG and echocardiography for cardiac status 4. Cranial ultrasound for hydrocephalus 5. Skeletal survey

a. Dysostosis multiplex b. Skull

i. Large, thickened calvarium

ii. Premature closure of lambdoidal and sagittal sutures iii. Shallow orbits

iv. Enlarged J-shaped sella

v. Abnormally spaced teeth with dentigerous cysts c. Ribs

i. Oar-shaped, narrowed at the vertebral ends ii. Flat/broad at the sternal ends

d. Vertebra

i. Beaked anteriorly (anterior hypoplasia) of lum- bar vertebrae with kyphosis (an early sign) ii. Scalloped posteriorly

iii. Thoracolumbar gibbus, resulting from anterior wedging of the vertebrae

iv. Hypoplasia of the odontoid, leading to atlantoax- ial subluxation

e. Pelvis

i. Poorly formed pelvis ii. Small femoral heads iii. Coxa valga

f. Long bones

i. Widened diaphysis of the long bones ii. Lack of normal modeling and tabulation iii. Irregular metaphysis

iv. Poorly developed epiphyseal centers

v. Distal ends of the radius and ulna angulate toward each other

vi. Claw hands

vii. Thickened and bullet-shaped phalanges

viii. Coarsening of the trabeculae of the phalanges and metacarpals

ix. Proximal narrowing of the metacarpals

x. Marked irregularity and retarded ossification of the carpal bones

g. Other bones

i. Short, thickened, and irregular clavicles

ii. Shortened and trapezoid-shaped phalanges with widened diaphyses

6. Biochemical/molecular studies for MPS I-H, MPS I-HS, and MPS I-S

a. Excessive urinary excretion of glycosaminoglycans (dermatan and heparan sulfates): a useful preliminary test

b. Metachromatic staining of fibroblasts and leukocyte inclusions (nonspecific lab findings)

c. Enzyme assay: deficient α-

-iduronidase in WBC, serum, cultured fibroblast, and CSF

d. Accumulation of glycosaminoglycans in cultured fibroblasts correctable by uptake of α-

-iduronidase e. Mutation analysis or sequence analysis of IUDA

gene: possible to identify both IDUA mutations in 95% of patients with MPS I

f. Characterization of gene mutation: worthwhile for phenotype prediction and genetic counseling

7. Carrier testing

a. Measurement of α-

-iduronidase enzyme activity: not a reliable method, requiring testing of obligatory car- riers within the family first to determine if their levels of IDUA enzyme activity can be distinguishable from the normal

b. Molecular genetic testing of IUDA to identify carriers among at-risk family members when both mutation alleles have been identified in an affected family member

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: 25% chance of being affected b. Patient’s offspring:

i. MPS I-S: not increased unless the spouse is a carrier

ii. MPS I-H and MPS I-H/S: not surviving to repro- ductive age

2. Prenatal diagnosis from samples of CVS, amniocentesis, and feta blood

a. Enzyme assays (deficient α-

-iduronidase) and increased level of

S-sulphate incorporation meas- ured in cultured cells obtained from amniocentesis or CVS for pregnancy at risk

b. Mutation analysis of the IDUA gene in fetal DNA extracted from cells obtained by CVS or amniocente- sis if both mutant IDUA alleles have been identified in a previously affected sib or in the parents of the at- risk fetus

3. Management

a. Early infant stimulation programs

b. Eye care: corneal transplantation successful but donor grafts eventually becoming cloudy

c. Range of motion exercises to preserve joint function d. Physical therapy

e. Orthopedic surgery

i. Surgical decompression of the median nerve for carpal tunnel syndrome resulting in various restoration of motor hand activity

ii. Trigger digits

iii. Genu valgum

iv. Kyphoscoliosis

v. Acetabular dysplasia

vi. Atlanto-occipital stabilization

f. Ventriculoperitoneal shunting for hydrocephalus i. Generally palliative

ii. May improve quality of life

g. Tracheotomy or high pressure continuous positive airway pressure with supplemental oxygen

h. Tonsillectomy and adenoidectomy to correct Eustachian tube dysfunction and to decrease upper air- way obstruction

i. Cardiovascular care

i. Bacterial endocarditis prophylaxis ii. Valve replacement surgery j. Surgical repair of inguinal hernias

k. Early surgical intervention to prevent severe complica- tions from progressive compression of the spinal cord l. Major anesthetic risks exhibited by patients with MPS I i. Avoid hyperextension of the neck since dysosto- sis multiplex can lead to instability of the spine including the atlantoaxial joint

ii. Difficulty in induction of anesthesia due to inability to maintain an adequate airway iii. Require fiberoptic laryngoscopy for intubation

iv. Slow recovery from anesthesia

v. Common postoperative airway obstruction m. Allogenic bone marrow transplantation from an unaf-

fected, HLA-compatible donor

i. Beneficial effect: replacement of deficient macrophages by marrow-derived donor macrophages to provide ongoing source of nor- mal enzyme capable of gaining access to the var- ious sites of storage

ii. Slows the course of congnitive decline if the therapy starts before the developmental delay is evident

iii. Improves survival, reducing facial coarseness, hepatosplenomegaly, hearing, and normal car- diac function

iv. Skeletal manifestations and corneal clouding continue to progress despite successful trans- plantation. Surgeries will be required for the per- sistent orthopedic problems

v. Significantly limited by the availability of donors.

The immunosuppressive therapy for the preven- tion of rejection carries significant toxicity vi. The procedure of the transplantation carries a

high risk of morbidity and mortality. Failure to achieve stable engraftment and development of graft-versus-host disease are significant barriers to successful bone marrow transplantation for many children

vii. Hematopoietic stem cell transplantation: the treatment of choice for a child with Hurler syn- drome who is younger than two years of age and has minimal or no central nervous system disease n. Cord-blood transplantation:

i. Use cord-blood transplants from partially HLA- matched, unrelated donors

ii. Donors readily available

iii. An excellent source of stem cells for transplantation

iv. Sustained engraftment can be achieved without total-body irradiation in young children

v. Low incidence for acute graft-versus-host dis- ease (GVHD)

vi. Absence of extensive chronic GVHD vii. As effective as bone marrow transplantation o. Enzyme replacement therapy

i. An etiology-specific treatment that seeks to address the underlying pathophysiology of MPSI by delivering sufficient IDUA activity to reverse and prevent glycosaminoglycans accumulation ii. Effectiveness depending on the ability of recom-

binant enzymes injected intravenously to enter cells and localize to the lysosome, the appropri- ate intracellular site

iii. Use of recombinant human α-

-iduronidase (Laronidase: Aldurazyme)

a) Significant reduction in liver size b) Increase in height and weight c) Decrease in joint restriction

d) Improvement in breathing (respiratory func- tion) and sleep apnea

e) Decreased glycosaminoglycan storage f) Recommended for patients with the milder

or attenuated forms of MPSI. Infusions of recombinant enzyme are a safer alternative for treating the somatic disease and improv- ing the quality of life of such patients.

Intravenously administered enzyme is not expected to cross the blood-brain barrier and affect central nervous system disease

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Fig. 1. A child with Hurler syndrome showing a large head with frontal bossing, coarse facial features, ocular hypertelorism, cloudy (steamy) cornea, depressed nasal bridge, large tongue, short neck, protuberant abdomen, umbilical hernia, stiff joints, and claw hands.

Fig. 2. Claw hand. The radiographs show thick bullet-shaped pha- langes, proximal narrowing of the metacarpals, poorly ossified carpal bones, and angulating toward each other of the distal ends of the radius and the ulnar.

Fig. 3. Radiographs showing oar-shaped ribs with relatively narrow proximal portion, narrow iliac bodies and flaring wings, shallow acetabula, coxa valga, anterior wedging of the lumbar vertebrae, decreased AP diameter of the vertebral bodies with posterior scallop- ing, and the marked thoracolumbar gibbus.

Fig. 7. Metachromasia of the cultured fibroblasts.

Fig. 4. Radiograph of the upper extremities show the lack of normal modeling and tabulation of the diaphyses, leading to short tubular bones. The radial and ulnar articular surfaces are angulated toward each other. Marked irregularity and retarded ossification of the carpal bones are noted. The findings in the lower extremities are less marked.

Fig. 5. Skull radiograph showing a large scaphocephalic calvarium with early appearance of the J-shaped sella turcica.

Fig. 6. Post-mortem findings of the brain showing cloudy lep- tomeninges secondary to cloudy CSF.

Fig. 8. Positive MPS spot test.

Fig. 10. A 14-year-old boy with Hurler-Scheie compound showing, short stature, semi-crouching stance, joint stiffness (A), coarse facies (B) and claw hands (C). When he was 3 years old, he started to complain difficulty in raising his arms above his head and diffi- culty in moving his hands and fingers because of bent fingers and joint contractures. He was noted to have dwarfism, coarse thickened skin, hirsutism, a big head with frontal bossing, coarse facies with hypertelorism, cloudy cornea, large lips and large tongue, short neck, short trunk with a mild kyphosis, hepatomegaly, claw hands, anteri- orly converted shoulders, protuberant abdomen, flexion contractures of elbows, wrists, and knees , and crouching stance. The urine for mucopolysaccharide was positive and the blood for metachromasia was positive. Skin fibroblasts was deficient in α-^L-iduronidase.

Fig. 9. A 14-month-old boy with Hurler syndrome showing a large head, coarse facies, protuberant abdomen, umbilical hernia, a lumbar gibbus, and claw hands. The radiographs showed cardiomegaly, thick- ened ribs, and beaked vertebral body (L2). The α-iduronidase enzyme level was 0.0 (87.10–190.50 nmol/mg/hr).

Fig. 11. Radiographs. Skull (A) show macrocephaly, frontal bossing, small and airless mastoids, and anterior pocketing of the sella turcica (“shoe-shaped” or “J-shaped” sella). Clavicles (B) are short with widened medial aspects of both clavicles. Ribs are oar-shaped and wide in their lateral and anterior portions with moderate narrowing of the paravertebral portions of the lower ribs (C). Vertebral bodies have concaved anterior and posterior margins and decreased in sagittal diameters. The second lumbar vertebra was hypoplastic with anterior inferior beaking forming almost a hook-shaped deformity. Claw hands were present with tapering of both distal ends of radius and ulnar to form “V-shaped” (D). Carpal bones were small, irregular, and crowded together. Metacarpals and phalanges were wide and short with proximal pointing of metacarpals. Bone age was retarded. Pes cavus was present.