Overview of the “International Guidelines
for the Management and Treatment of
Morquio A Syndrome”
Guidelines establish the standard of care for Morquio A1
International guidelines for the evaluation, treatment, and symptom-based
management of Morquio A have recently been published1
• Guidelines were developed over 2 expert meetings
of an international panel of specialists with extensive
experience in managing Morquio A1
• Specialties represented included1
• Pediatrics
• Genetics
• Orthopedics
• Pulmonology
• Cardiology
• Anesthesiology
• The Guidelines were developed to provide a comprehensive standard of care to aid clinicians
as they manage and treat this complex multisystemic disease1
Bronchodilator
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15.
doi:10.1002/ajmg.a.36833.
2
The underlying cause of Morquio A is an enzyme deficiency that
leads to multisystemic consequences1-3
• Also referred to as MPS IVA, mucopolysaccharidosis IVA4
• Serious, progressive, life-threatening disease5
• Autosomal recessive lysosomal storage disorder (LSD) 4
• Caused by deficient activity of N-acetylgalactosamine-6 sulfatase (GALNS),
an enzyme that catalyzes the breakdown of 2 glycosaminoglycans (GAGs),
keratan sulfate (KS) and chondroitin-6-sulfate (C6S) 5,6
• Accumulation of these GAGs in lysosomes leads to cell engorgement and
disruption of normal cell function2,3,7
• Wide genotypic and phenotypic heterogeneity associated
with Morquio A results in variable clinical presentation5
Cell with GAG accumulation
in lysosomes (Bank 2009)
• Multisystemic manifestations contribute to loss of endurance5
• Varied spectrum of manifestations, organ involvement, and rate of
disease progression necessitate an individualized management
plan for each patient1,8
References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15.
doi:10.1002/ajmg.a.36833. 2. Northover H, Cowie RA, Wraith JE. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis. 1996;19(3):357-365. 3. Tomatsu S,
Montaño AM, Oikawa H, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol. 2011;12(6):931-945.
doi:1389-2010/11. 4. Tomatsu S, Montaño AM, Nishioka T, et al. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum Mutat.
2005;26(6):500-512. 5. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in
Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021. 6. Bank RA, Groener JEM, van Gemund JJ, et al. Deficiency in N-acetylgalactosamine-6-sulfate
sulfatase results in collagen perturbations in cartilage of Morquio syndrome A patients. Mol Genet Metab. 2009;97(3):196-201. doi:10.1016/j.ymgme.2009.03.008. 7. Montaño AM, Tomatsu S,
Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007;30(2):165-174. doi:10.1007/s10545007-0529-7. 8. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.
Bronchodilator
3
Morquio A leads to progressive organ damage and complex
multisystemic manifestations1,2
AUDIOLOGICAL
Conductive and neurosensory hearing loss3,4
NEUROLOGICAL
Odontoid dysplasia, cervical myelopathy,
cervical spine instability, tetraplegia2,3
ABDOMINAL
Mild hepatosplenomegaly, hernias, loose
stools, diarrhea, constipation, abdominal pain3-5
MUSCULOSKELETAL
Bone deformity, short stature,
abnormal gait, joint laxity, contractures
and subluxation, dysostosis multiplex2,3
OPHTHALMOLOGICAL
Diffuse corneal clouding, cataracts, reduction in visual acuity3,6,7
DENTAL
Dentinogenesis imperfecta, hypodontia, pointed
cusps, spade-shaped incisors, thin enamel, abnormal
buccal surfaces3,8
CARDIOVASCULAR
Mitral and aortic valve stenosis and regurgitation, tricuspid
regurgitation, hypertrophy3,9-11
RESPIRATORY
Obstructive sleep apnea, respiratory infections, respiratory
failure2,3,9
References: 1. Northover H, Cowie RA, Wraith JE. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis. 1996;19(3):357-365. 2. Tomatsu S, Montaño AM,
Oikawa H, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol. 2011;12(6):931-945. doi:1389-2010/11. 3.
Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
4. Hendriksz CJ, Al-Jawad M, Berger KI, et al. Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36(2):309-322.
doi:10.1007/s10545-012-9459-0. 5. Shunji Tomatsu; International Morquio Organization. Mucopolysaccharidosis type IVA: Morquio A syndrome. http://www.arianascure.com/edcd.pdf. Published
2005. Accessed November 12, 2014. 6. Danes BS. Corneal clouding in the genetic mucopolysaccharidoses: a cell culture study. Clin Genet. 1973;4(1):1-7. 7. Leslie T, Siddiqui MAR, Aitken DA,
Kirkness CM, Lee WR, Fern AI. Morquio syndrome: electron microscopic findings. Br J Ophthalmol. 2005;89:917-929. 8. Kinirons MJ, Nelson J. Dental findings in mucopolysaccharidosis type IV A
(Morquio’s disease type A). Oral Surg Oral Med Oral Pathol. 1990;70(2):176-179. 9. Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating
progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021. 10. Ireland MA, Rowlands DB.
Mucopolysaccharidosis type IV as a cause of mitral stenosis in an adult. Br Heart J. 1981;46(1):113-115. 11. John RM, Hunter D, Swanton RH. Echocardiographic abnormalities in type IV
mucopolysaccharidosis. Arch Dis Child. 1990;65(7):746-749.
4
Management of the multisystemic consequences
of Morquio A requires a multidisciplinary approach1
To address both the underlying cause and multisystemic complications, the Guidelines
call for a coordinated approach consisting of a team of specialists anchored by
a geneticist or metabolic physician1
Pulmonologist
Ophthalmologist
Dentist
Gastroenterologist
Cardiologist
Geneticist/metabolic
specialist
Audiologist
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the
management and treatment of Morquio A syndrome. Am J Med Genet Part A.
2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Neurosurgeon
Orthopedic specialist
5
Recommended management starts with diagnosis and continues
with care throughout the patient’s lifetime1
DIAGNOSIS
At diagnosis, a team of specialists should be assembled by the patient’s geneticist or
metabolic specialist to perform comprehensive assessments and to begin long-term
management1
• Diagnosis should be confirmed with an enzyme assay2,3
• The Guidelines recommend the immediate initiation of enzyme replacement therapy
(ERT) to mitigate disease progression and improve overall patient outcomes1
ONGOING ASSESSMENTS AND INTERVENTIONS
The Guidelines outline essential ongoing assessments that allow for early intervention to
address clinical manifestations and help the patient avoid permanent damage1
• A coordinated healthcare team led by a geneticist or metabolic specialist is essential to
ensure comprehensive care1
TRANSITION TO ADULT CARE
Continued coordination is important as new specialists join the patient’s healthcare team1
References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part A.
2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Clarke LA, Winchester B, Giugliani R, Tylki-Szymańska A, Amartino H. Biomarkers for the mucopolysaccharidoses:
discovery and clinical utility. Mol Genet Metab. 2012;106(4):396-402. doi:10.1016/j.ymgme.2012.05.003. 3. Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage
disorders: a review. Biochem Res Int. 2012;2012:471325. doi:10.1155/2012/471325.
6
Prompt diagnosis and comprehensive multisystemic evaluation is a
critical first step toward establishing an individualized management
plan1
ASSESSMENTS RECOMMENDED AT DIAGNOSIS 1,a
MUSCULOSKELETAL
Physical examination, standardized upper/lower extremity
function test, radiographs
AUDIOLOGICAL
Multimodal hearing assessment
RESPIRATORY
Forced vital capacity (FVC), maximum voluntary ventilation
(MVV), respiratory rate, oxygen saturation, overnight sleep study
ABDOMINAL
Assessments of gastrointestinal problems
NEUROLOGICAL
Neurological exam, plain radiograph, magnetic resonance
imaging (MRI) scan
DENTAL
Evaluation of oral health
CARDIOVASCULAR
Electrocardiogram, echocardiogram, heart rate
ENDURANCE
6-minute walk test (6MWT)
OPHTHALMOLOGICAL
Slit-lamp biomicroscopy of cornea, intraocular pressure,
refractive error, examination of posterior segment
QoL
QUALITY OF LIFE (QoL)
Reproducible, age-appropriate QoL questionnaires
(eg, EQ-5D-5L)
• Multidisciplinary collaboration and referrals are recommended for optimal treatment, starting
with comprehensive baseline assessments performed by the appropriate specialists1
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
a For
a comprehensive list of assessments, consult the Guidelines.
7
ERT should be initiated upon diagnosis to replace deficient GALNS1
•
The goal of ERT in Morquio A is to reduce GAG accumulation in order to restore cellular
function1,2
•
VIMIZIM® (elosulfase alfa) is the only ERT indicated for patients with Morquio A1
At a cellular level,
GAGs accumulate
in the lysosomes and
occupy an increasingly
greater area of the
cytoplasm, which disrupts
normal cell function.3,4
VIMIZIM is an exogenous
recombinant human
enzyme that replaces
deficient GALNS in the
lysosome.1
References: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014. 2. Wood TC, Harvey K,
Beck M, et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis. 2013;36(2):293-307. doi:10.1007/s10545013-9587-1. 3. Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int.
2012;2012:471325. doi:10.1155/2012/471325. 4. Hendriksz CJ, Al-Jawad M, Berger KI, et al. Clinical overview and
treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis.
2013;36(2):309-322. doi:10.1007/s10545-012-9459-0.
Within the lysosome,
VIMIZIM increases
catabolism of GAGs
(KS and C6S)—restoring
cell function. 1,2
Please see Important Safety Information,
including boxed warning, on slide 38.
8
VIMIZIM® (elosulfase alfa) significantly improves endurance
as measured by the 6MWT1,2
Guidelines confirm the 6MWT as a validated measure of endurance3
• Compared with placebo, VIMIZIM®
(elosulfase alfa) 2 mg/kg/week demonstrated
a statistically significant improvement of 22.5
meters (14.9%) in 6MWT distance in only 24
weeks (P=0.0174)1,2
• Patients who continued receiving VIMIZIM
through the extension trial stabilized walking
ability after 72 weeks in extension study1,2
Initiating ERT with VIMIZIM at diagnosis is considered an essential first step
toward creating an effective management plan for patients with Morquio A.3
References: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014. 2. Hendriksz
CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the
pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012. 3.
Hendriksz CJ, Al-Jawad M, Berger KI, et al. Clinical overview and treatment options for non-skeletal
manifestations of mucopolysaccharidosis type IVA. J Inherit Metab Dis. 2013;36(2):309-322.
doi:10.1007/s10545-012-9459-0.
Please see Important Safety Information,
including boxed warning, on slide 38.
9
VIMIZIM® (elosulfase alfa) demonstrated a favorable trend
in most additional trial end points1
Summary of VIMIZIM® (elosulfase alfa) clinical trial Week 24 efficacy end points1
16 years old
Reference: 1. Hendriksz CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in Morquio A
syndrome in the pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012.
Please see Important Safety Information,
including boxed warning, on slide 38.
10
VIMIZIM® (elosulfase alfa) has also shown a positive trend related to
activities of daily living (ADL)1
ADL measured using MPS health assessment questionnaire (HAQ)1
• Of the 52 HAQ questions, responses to 34 questions favored weekly treatment,
12 favored placebo, and 6 showed no difference1
16 years old
Reference: 1. Hendriksz CJ, Giugliani R, Harmatz P, et al. Multi-domain impact of elosulfase alfa in
Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2013;36(2):309-322.
doi:10.1016/j.ymgme.2014.08.012.
Please see Important Safety Information,
including boxed warning, on slide 38.
11
VIMIZIM® (elosulfase alfa) safety and tolerability
• 176 patients ages 5 to 57 were
enrolled in the 24-week, phase
3 pivotal study1
28
• The most common adverse reactions
that occurred were pyrexia, vomiting,
headache, nausea, abdominal pain,
chills, and fatigue1
• Acute reactions requiring intervention
were managed by
• Temporarily interrupting or
discontinuing the infusion1
• Administering additional
antihistamines, antipyretics,
or corticosteroids1
Reference: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc;
2014.
aSafety
and effectiveness in pediatric patients <5 years of age has not been
established and is currently being evaluated.17
Please see Important Safety Information,
including boxed warning, on slide 38.
12
Guidelines emphasize need for ongoing multisystemic assessments1
ASSESSMENTS1,a
QoL
FREQUENCY1,a
MUSCULOSKELETAL
Standardized upper extremity function test, radiographs
• At diagnosis/baseline, annually
RESPIRATORY
FVC, MVV, respiratory rate, oxygen saturation, overnight sleep study
• At diagnosis/baseline, annually
NEUROLOGICAL
Neurological exam
plain radiograph
MRI scan
CT scan
•
•
•
•
CARDIOVASCULAR
Electrocardiogram
echocardiogram
heart rate
• At diagnosis, every 1 to 3 years, as clinically indicated
• At diagnosis, every 2 to 3 years, as clinically indicated
• At diagnosis, annually
OPHTHALMOLOGICAL
Refractive error and intraocular pressure
• At diagnosis, as clinically indicated
AUDIOLOGICAL
Multimodal hearing assessment
• At diagnosis, annually
ABDOMINAL
Assessments of gastrointestinal problems
• As clinically indicated
DENTAL
Evaluation of oral health
• At diagnosis, annually
ENDURANCE
6MWT
• At diagnosis, annually, before and regularly after initiation of ERT
QUALITY OF LIFE (QoL)
Reproducible, age-appropriate QoL
questionnaires (eg, EQ-5D-5L)
At diagnosis/baseline, every visit (minimum, every 6 months)
At diagnosis, every 1 to 3 years
At diagnosis, annually
As clinically indicated
• At diagnosis, annually
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
a Note:
For additional detail, please consult the Guidelines.
13
Assessments can reveal the need for specialized interventions to
optimize patient outcomes1
MANIFESTATION ASSESSED1,a
MUSCULOSKELETAL
RESPIRATORY
QoL
INTERVENTIONS1,a
• Upon diagnosis, refer to MPS-experienced orthopedic surgeon
• Pursue supportive therapies
– Influenza and pneumococcus vaccinations
– Bronchodilators
– Prompt treatment of upper respiratory infections
NEUROLOGICAL
• Spinal decompression
• Spinal fusion
CARDIOVASCULAR
• Avoid beta-blockers to treat tachycardia
OPHTHALMOLOGICAL
• Refractive correction/low vision aids
• Corneal transplantation
AUDIOLOGICAL
• Ventilation tubes
• Postaural hearing aids
ABDOMINAL
• Surgical repair of recurrent hernias
DENTAL
• Preventative measures against formation of caries
• Fissure sealing of dentition
ENDURANCE
• ERT provides a systemic treatment approach
QUALITY OF LIFE (QoL)
• Efforts should be made to keep patients independently mobile as
long as possible as QoL drops dramatically when patients become
wheelchair dependent
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of
Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
a Note:
For additional detail, please consult the Guidelines.
14
Focus on: musculoskeletal involvement
Specialty area: Orthopedics
Skeletal and joint abnormalities are the most apparent and prevalent disease manifestations
of Morquio A1
• Common manifestations include short stature, abnormalities in the spine, upper extremities, thorax,
hips, and/or lower extremities, and joint and gait abnormalities1
- Unlike most other MPS disorders, patients with Morquio A have joint hypermobility throughout the
body which can lead to spinal cord complications1 (see neurological involvement, slide 19)
Dysostosis multiplex changes
in the pelvis and hips
Knee valgus
(Left: Image courtesy of Christina Lampe, MD and
Ralph Lachman, MD)
(Right: Atinga 2008)
More than 70% of patients with Morquio A have had at least 1
surgical procedure.2
References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of
Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Harmatz P, Mengel KE,
Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic
clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021.
Note: For additional detail, please consult the Guidelines.
15
Focus on: musculoskeletal involvement
Specialty area: Orthopedics
Guideline-recommended assessments
ASSESSMENTS1
FREQUENCY1
Standardized upper extremity function test, radiographs
• At diagnosis, annually
Guideline-recommended interventions
• Immediately refer patients to a geneticist to begin ERT with VIMIZIM® (elosulfase alfa)1
• Refer to an orthopedic surgeon with experience treating MPS diseases1
Note: For additional detail, please consult the Guidelines.
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Please see Important Safety Information,
including boxed warning, on slide 38.
16
Focus on: respiratory involvement
Specialty area: Pulmonology
Respiratory impairment is the leading cause of morbidity and mortality in patients
with Morquio A1
• Respiratory impairment can be due to obstructive or restrictive disease1
• Narrowed and tortuous airways can be caused by a combination of GAG deposits in airway walls,
abnormalities in the skull and spine, tracheal distortion, tracheobronchomalacia, and thickened secretions1
• Respiratory complications can contribute to reduced endurance in patients with Morquio A1
• Patients with Morquio A have a significant increase in surgical risks as a result of respiratory
manifestations of the condition1
• Sleep-disordered breathing can be an early sign of respiratory impairment1
GAG deposits
Narrow, tortuous
trachea
(Left: Berger 2013)
Narrow trachea
(Right: Image FPO)
GAG deposits within the upper airway causing narrowing
of the pharynx and larynx
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
17
Focus on: respiratory involvement
Specialty area: Pulmonology
Guideline-recommended assessments
ASSESSMENTS1
FREQUENCY1
FVC, MVV, respiratory rate, oxygen saturation, overnight
sleep study
• At diagnosis, annually
Guideline-recommended interventions
• Patients may benefit from supportive therapies such as regular influenza and pneumococcus
vaccinations, bronchodilators, and aggressive, timely treatment of upper respiratory infections1
Respiratory complications pose an increased surgical risk. 1
See Surgical intervention section, slide 33.
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
18
Focus on: neurological involvement
Specialty area: Neurology
Cervical spine instability, spinal cord compression and resulting surgical risks drive the critical
need to identify and treat instability in the spine1
• Identify spinal cord compression early
and correlate findings with imaging studies
of the spine to avoid long-term consequences1
• Signs of severe spinal cord compression1
• sensory anomalies
• upper and lower extremity weakness
• lower back pain
• urinary dysfunction
• unsteady gait
T2 hyperintensity and focal atrophy
• radiating leg pain
paralysis
16• years
old
(Solanki 2013)
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
19
Focus on: neurological involvement
Specialty area: Neurology
Guideline-recommended assessments
ASSESSMENTS1
FREQUENCY1
Neurological exam
• At diagnosis/baseline, every visit (minimum, every 6 months)
Plain radiograph
• At diagnosis, every 1 to 3 years
MRI scan
• At diagnosis, annually
CT scan
• As clinically indicated
Guideline-recommended interventions
• When warranted, interventions can include spinal decompression, fusion, or a combination of both1
Pre-surgical assessments are required to minimize the risks associated
with spinal cord compression.1 See surgical intervention, slide 33.
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
20
Focus on: cardiovascular involvement
Specialty area: Cardiology
High heart rate in patients with Morquio A compensates for small cardiac stroke volume1
• Cardiac valve abnormalities can include valve thickening, regurgitation, and/or stenosis1
• Patients with Morquio A may also experience myocardial hypertrophy and/or cardiomegaly1,2
• Impaired cardiac function contributes to reduced endurance in patients with Morquio A1,2
Autopsy specimen of patient with Morquio A shows thickening
of mitral valve cusps, tricuspid valve cusps, and chordae
16 years old
(Ireland 1981)
References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio
A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2. Harmatz P, Mengel KE, Giugliani R, et al.
The Morquio A clinical assessment program: baseline results illustrating progressive, multisystemic clinical impairments in
Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61. doi:10.1016/j.ymgme.2013.01.021.
Note: For additional detail, please consult the Guidelines.
21
Focus on: cardiovascular involvement
Specialty area: Cardiology
Guideline-recommended assessments
ASSESSMENTS1
FREQUENCY1
Electrocardiogram
• At diagnosis, every 1 to 3 years, as clinically indicated
Echocardiogram
• At diagnosis, every 2 to 3 years, as clinically indicated
Heart rate
• At diagnosis, annually
Guideline-recommended interventions
• Treatment of tachycardia with beta-blockers should be avoided1
• Valve replacement may be considered for patients with severe aortic or mitral valve disease1
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
22
Focus on: ophthalmological involvement
Specialty area: Ophthalmology
Ongoing assessments of ophthalmological conditions related to Morquio A help identify
the need for corrective interventions1
• Diffuse corneal clouding and refractive error problems (eg, astigmatism, myopia, and hyperopia)
are typical for patients with Morquio A1
Corneal clouding
(Image courtesy of C Gail Summers)
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
23
Focus on: ophthalmological involvement
Specialty area: Ophthalmology
Guideline-recommended assessments
ASSESSMENTS1
FREQUENCY1
Slit-lamp biomicroscopy of cornea
• At diagnosis, as clinically indicated
Intraocular pressure
• At diagnosis, as clinically indicated
Refractive error
• At diagnosis, as clinically indicated
Examination of posterior segment
• At diagnosis, as clinically indicated
Scotopic and photopic electroretinogram
• As clinically indicated
Guideline-recommended interventions
• Corneal clouding can be managed surgically by corneal transplant; note that concomitant retinopathy,
glaucoma, or optic nerve atrophy can reduce efficacy of corneal transplant1
• Impaired vision may be improved by refractive correction or low-vision aids1
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
24
Focus on: audiological involvement
Specialty area: Audiology
Hearing loss is underestimated in patients
with Morquio A despite the onset of auditory
impairment in the first decade of life1
• Patients with Morquio A typically develop
neurosensory or mixed conductive and
neurosensory hearing loss1
• Common causes of hearing loss can include
recurrent respiratory tract infections or otitis
media, deformity of the ossicles, and/or
abnormalities of the inner ear1
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
25
Focus on: audiological involvement
Specialty area: Audiology
Guideline-recommended assessment
ASSESSMENT1
FREQUENCY1
Multimodal hearing assessment
• At diagnosis, annually
Guideline-recommended interventions
• Ventilation tubes treat conductive hearing loss from middle ear fluid1
• Postaural hearing aids may be most appropriate if a progressive neurosensory element
to hearing loss is present1
T-tubes should be used the first time fluid is retained in the middle ear
due to the anesthetic risks and risk of reoccurrence.1
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
26
Focus on: abdominal involvement
Specialty area: Gastroenterology
Although the prevalence of abdominal conditions is lower in patients with Morquio A
than in other MPS disorders, regular assessment is recommended1
• Routine clinical evaluations may reveal umbilical, inguinal, or bilateral diaphragmatic hernias,
hepatomegaly, splenomegaly, and other gastrointestinal disorders (eg, chronic constipation, diarrhea)1
Guideline-recommended interventions
• Hernias can be surgically repaired by herniorrhaphy and frequently recur1
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
27
Focus on: dental involvement
Specialty area: Dentistry
Physiological abnormalities in dentition results in caries formation susceptibility1
• Small, widely spaced teeth, often with thin, structurally
weak enamel and small pointed cusps, spade-shaped
incisors, pitted buccal surfaces, and other abnormalities
of dentition are characteristic of Morquio A1
• Regular dental visits are recommended1
Guideline-recommended interventions
• Caries prevention can include fluoride supplementation
and/or fissure sealing as appropriate1
16 years old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Pediatric (top) and adult (bottom)
teeth with typical features: widely
spaced teeth, pointed cusps, and
spade-shaped incisors (Hendriksz 2014)
Note: For additional detail, please consult the Guidelines.
28
Focus on: endurance involvement
Specialty area: Genetics
Multisystemic factors may reduce the endurance of patients with Morquio A and warrant
a systemic treatment approach1,2
• Impaired cardiac, respiratory, musculoskeletal,
and/or neurological function can contribute to
reduced endurance and a resulting impact
on functional status/mobility and quality of life1,2
• VIMIZIM® (elosulfase alfa) has been approved
for Morquio A syndrome and improves
endurance as measured by 6MWT3
16 years old
References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2.
Harmatz P, Mengel KE, Giugliani R, et al. The Morquio A clinical assessment program: baseline results illustrating
progressive, multisystemic clinical impairments in Morquio A subjects. Mol Genet Metab. 2013;109(1):54-61.
doi:10.1016/j.ymgme.2013.01.021. 3. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014.
Note: For additional detail, please consult the Guidelines.
Please see Important Safety Information,
including boxed warning, on slide 38.
29
Focus on: endurance involvement
Specialty area: Genetics
Guideline-recommended assessment
ASSESSMENT1
FREQUENCY1
6MWT
• At diagnosis, annually, before and regularly
after initiation of ERT
Guideline-recommended interventions
• The guidelines highlight the importance of initiating ERT as soon as possible upon diagnosis
to address the progressive decline in endurance caused by Morquio A1
The initiation of ERT with VIMIZIM® (elosulfase alfa) at diagnosis is critical
to help maximize patient outcomes and improve overall care.1
16 years old
Note: For additional detail, please consult the Guidelines.
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Please see Important Safety Information,
including boxed warning, on slide 38.
30
Focus on: disease burden
QoL Specialty area: Primary care
Pain, loss of mobility, frequent surgical interventions, and other factors significantly impact
the QoL of patients with Morquio A1
• Pain is a major but underreported symptom of Morquio A that is often related to musculoskeletal
problems and may occur throughout the body1
• Loss of independent mobility considerably contributes to diminution of QoL1
Guideline-recommended assessments
ASSESSMENTS1
FREQUENCY1
Pain assessment
• At diagnosis, every 6 months, pre-ERT
QoL questionnaire
• At diagnosis, annually, pre-ERT
Functional test/ADL questionnaire
• At diagnosis, annually, pre-ERT
Guideline-recommended interventions
• Simple interventions may considerably improve the functional capacity and QoL of patients
with Morquio A1
• 16
Efforts
be made to keep patients independently mobile as long as possible1
yearsshould
old
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
Note: For additional detail, please consult the Guidelines.
31
Patients with Morquio A face high surgical risk1-3
Compromised
respiratory function
Cervical instability
Cardiac problems
High
anesthesia
risk
Inability
to ventilate/
intubate
Need for
reintubation
Airway
obstruction
Surgical complications result in an 11% mortality rate in the Morquio A population.4
References: 1. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.
2. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit
Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2. 3. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A
syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 4. Lavery C, Hendriksz C. Mortality in patients with Morquio syndrome A. J Inherit Metab Dis Rep. 2015;15:5966. doi:10.1007/8904_2014_298.
32
Surgical interventions require strong planning and coordination1,2
Creating a surgical plan should involve a multidisciplinary team of specialists
who are also experienced in treating patients with Morquio A3
• Specialties represented may include anesthesiology, pulmonology, neurosurgery, cardiology,
ENT, and radiology3
• In addition to the management guidelines, specialists should consult orthopedic and surgical
guidelines (listed on slide 37)
Key components of surgical planning include anesthetic care, continuous monitoring,
and postoperative care1-4
Bronchodilator
References: 1. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219. doi:10.1007/s10545-012-9563-1.
2. Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907.
doi:10.1111/j.1460-9592.2012.03904.x. 3. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment of Morquio A syndrome. Am J Med Genet Part
A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 4. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome):
presentation, diagnosis and management. J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2.
33
Make transitioning to adult care part of the individual management plan
• As patients get older they need to begin managing their own healthcare1
• Patients need you to help guide their transitions to ensure adult services are
knowledgeable
in managing Morquio A and to ensure that they aren’t lost to follow-up1
• It is important to have a formal, site-specific transition strategy1
• This should include joint visits with the pediatrician
and physician (eg, coordinating the adult patient
care for a few years and adding patient information
to a registry accessible to the adult team)1
• Encourage patients and their families to be
involved in this process1
Reference: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
34
Highlights from the management and treatment guidelines
• Morquio A syndrome is associated with profound skeletal and joint abnormalities and significant
nonskeletal manifestations1
• The multisystemic complications caused by Morquio A require coordinated multidisciplinary care
across a wide range of specialists with a geneticist at the center of care1
• Early diagnosis and baseline testing establish the basis for a comprehensive management plan1
• The initiation of ERT with VIMIZIM® (elosulfase alfa) at diagnosis is critical to help maximize outcomes
and mitigate disease progression, improving overall care1-3
• Ongoing assessments throughout the lifetime of each patient with Morquio A allow for interventions
to help those individuals avoid permanent damage1
• Surgical risks associated with Morquio A require thorough peri- and postoperative planning and care4-6
For additional resources related to the optimal care of patients with Morquio A,
please refer to slide 37.
References: 1. Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and
treatment of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833. 2.
VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014. 3. Hendriksz CJ, Giugliani R, Harmatz
P, et al. Multi-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet
Metab. 2013;36(2):309-322. doi:10.1016/j.ymgme.2014.08.012. 4. Walker R, Belani KG, Braunlin EA, et al.
Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2):211-219.
doi:10.1007/s10545-012-9563-1. 5. Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and
perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907.
doi:10.1111/j.1460-9592.2012.03904.x. 6. Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in
mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and
management. J Inherit Metab Dis. 2013;36(2):339-355. doi:10.1007/s10545-013-9586-2.
Please see Important Safety Information,
including boxed warning, on slide 38.
35
Morquio A Registry Study (MARS)
• Morquio A Registry Study (MARS) is a multicenter, multinational, observational Registry
of subjects diagnosed with Morquio A
• MARS is designed to gain better understanding of the variability and progression of the
disease in the population as a whole, and to monitor and evaluate long-term treatment
effects of VIMIZIM® (elosulfase alfa)
• All subjects with a confirmed diagnosis of Morquio A disease may be eligible to participate
in this Registry
• It is not required that subjects receive VIMIZIM to be eligible to participate
• The Registry started enrollment and is currently open in the EU and USA
• For information on participation please contact the BioMarin MARS Team
at MARS@bmrn.com
Please see Important Safety Information,
including boxed warning, on slide 38.
36
Key Morquio A treatment and management publications
For a more in-depth look at how to specifically manage and treat patients with Morquio A, experts
recommend the following resources:
• Hendriksz CJ, Berger KI, Giugliani R, et al. International guidelines for the management and treatment
of Morquio A syndrome. Am J Med Genet Part A. 2014;9999A:1-15. doi:10.1002/ajmg.a.36833.
• Solanki GA, Martin KW, Theroux MC, et al. Spinal involvement in mucopolysaccharidosis IVA (MorquioBrailsford or Morquio A syndrome): presentation, diagnosis and management. J Inherit Metab Dis.
2013;36(2):339-355. doi: 10.1007/s10545-013-9586-2.
• Berger KI, Fagondes SC, Giugliani R, et al. Respiratory and sleep disorders in mucopolysaccharidosis.
J Inherit Metab Dis. 2013;36(2):201-210. doi:10.1007/s10545-012-9555-1.
• Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children
with Morquio syndrome. Paediatr Anaesth. 2012;22(9):901-907. doi:10.1111/j.1460-9592.2012.03904.x.
• American Thoracic Society Committee on Proficiency Standards for Clinical Pulmonary Function
Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med.
2002;166(1):111-117. doi:10.1164/rccm.166/1/111.
• Hendriksz CJ, Burton B, Fleming TR, et al. Efficacy and safety of enzyme replacement therapy with
BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised
placebo-controlled study [published online ahead of print May 9, 2014]. J Inherit Metab Dis.
doi:10.1007/s10545-014-9715-6.
37
Important Safety Information
INDICATION
VIMIZIM® (elosulfase alfa) is indicated for patients with Mucopolysaccharidosis type IVA (MPS IVA;
Morquio A syndrome).
IMPORTANT SAFETY INFORMATION
Life-threatening anaphylactic reactions have occurred in some patients during VIMIZIM®
(elosulfase alfa) infusions. Anaphylaxis, presenting as cough, erythema, throat tightness,
urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal
symptoms (eg, nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria,
have been reported to occur during VIMIZIM infusions, regardless of duration of the course of
treatment. Closely observe patients during and after VIMIZIM administration and be prepared to
manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them
seek immediate medical care should symptoms occur. Patients with acute respiratory illness
may be at risk of serious acute exacerbation of their respiratory compromise due to
hypersensitivity reactions, and require additional monitoring.
Due to the potential for anaphylaxis, appropriate medical support should be readily available when VIMIZIM
is administered and for an appropriate period of time following administration. In clinical trials, cases of
anaphylaxis occurred as early as 30 minutes from the start of infusion and up to three hours after infusion,
and as late into treatment as the 47th infusion.
38
Important Safety Information (cont’d)
In clinical trials, hypersensitivity reactions have been observed as early as 30 minutes from the start
of infusion but as late as six days after infusion. Frequent symptoms of hypersensitivity reactions (occurring
in more than 2 patients) included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea,
and flushing.
Because of the potential for hypersensitivity reactions, administer antihistamines with or without antipyretics
prior to infusion. Management of hypersensitivity reactions should be based on the severity of the reaction
and include slowing or temporary interruption of the infusion and/or administration of additional
antihistamines, antipyretics, and/or corticosteroids for mild reactions. However, if severe hypersensitivity
reactions occur, immediately stop the infusion of VIMIZIM and initiate appropriate treatment.
Consider the risks and benefits of re-administering VIMIZIM following a severe reaction.
Patients with acute febrile or respiratory illness at the time of VIMIZIM infusion may be at higher risk of
life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the
patient’s clinical status prior to administration of VIMIZIM and consider delaying the VIMIZIM infusion.
Sleep apnea is common in MPS IVA patients. Evaluation of airway patency should be considered prior
to initiation of treatment with VIMIZIM. Patients using supplemental oxygen or continuous positive airway
pressure (CPAP) during sleep should have these treatments readily available during infusion in the event
of an acute reaction, or extreme drowsiness/sleep induced by antihistamine use.
39
Important Safety Information (cont’d)
Spinal or cervical cord compression (SCC) is a known and serious complication of MPS IVA and may
occur as part of the natural history of the disease. In clinical trials, SCC was observed both in patients
receiving VIMIZIM and patients receiving placebo. Patients with MPS IVA should be monitored for signs
and symptoms of SCC (including back pain, paralysis of limbs below the level of compression, urinary
and fecal incontinence) and given appropriate clinical care.
All patients treated with VIMIZIM 2 mg/kg once per week in the placebo-controlled trial developed anti-drug
antibodies. The relationship between the presence of neutralizing antibodies and long-term therapeutic
response or occurrence of anaphylaxis or other hypersensitivity reactions could not be determined.
VIMIZIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known if VIMIZIM is present in human milk. Exercise caution when administering VIMIZIM to a
nursing mother. There is a Morquio A Registry that collects data on pregnant women and nursing mothers
with MPS IVA who are treated with VIMIZIM. Contact MARS@BMRN.com for information and enrollment.
Safety and effectiveness in pediatric patients below 5 years of age has not been established and is currently
being evaluated.
40
Important Safety Information (cont’d)
In clinical trials, the most common adverse reactions (≥10%) occurring during infusion included pyrexia,
vomiting, headache, nausea, abdominal pain, chills, and fatigue. The acute reactions requiring intervention
were managed by either temporarily interrupting or discontinuing infusion, and administering additional
antihistamine, antipyretics, or corticosteroids.
To report SUSPECTED ADVERSE REACTIONS contact BioMarin Pharmaceutical Inc.
at 1-866-906-6100, or FDA at 1-800-FDA-1088 or go to www.fda.gov/medwatch.
Please see accompanying full Prescribing Information, including boxed warning, or visit www.VIMIZIM.com.
41