1. Overview of the “International Guidelines for the Management and Treatment of Morquio A Syndrome”
REFERENCES:
None required

2. 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
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: /ajmg.a
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 2/col 2/para 2
[SUBHEAD]: Hendriksz 2014 p 2/col 2/para 2
[BULLETS 1-3]: Hendriksz 2014/p 2/col 2/para 2
[SUB-BULLETS]: Hendriksz 2014/p 2/col 2/para 2
Bronchodilator

3. 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
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: doi: /ajmg.a Northover H, Cowie RA, Wraith JE. Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review. J Inherit Metab Dis. 1996;19(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): doi: / Tomatsu S, Montaño AM, Nishioka T, et al. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum Mutat ;26(6): 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): doi: /j.ymgme 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): doi: /j.ymgme 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): doi: /s Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2): doi: /s
Cell with GAG accumulation in lysosomes
(Bank 2009)
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 2/col 1/para1-2;
Northover 1996/p 357/para 1;
Tomatsu 2011/p 931/col 1/para 1/col 2/para 1/p 934/col 1/para 1
[BULLET 1]: Tomatsu 2005/p 500/col 1/para 1
[BULLET 2]: Harmatz 2013/p 2/col 1/para 2
[BULLET 3]: Tomatsu 2005/p 501/col 1/para 4
[BULLET 4]: Harmatz 2013/p 1/col 2/para 1/p 2/col 1/para 1;
Bank 2009/p 1/col 1/para 1/col 2/para 1
[BULLET 5]: Northover 1996/p 357/para 1/p 358/para 3;
Tomatsu 2011/p 931/col 2/para 1;
Montano 2007/p. 166/col 1/para 4/col 2/para 1
[BULLET 6]: Harmatz 2013/p 2/col 1/para 2-3
[BULLET 7]: Harmatz 2013/p 4/col 1/para 2/col 2/para 1
[BULLET 8]: Walker 2013/p 211/col 2/para 2/p 213/fig 1;
Hendriksz 2014/p 12/col 2/para 2
[PHOTO]: Bank 2009/p 3
Bronchodilator

4. Morquio A leads to progressive organ damage and complex multisystemic manifestations1,2
Audiological
Conductive and neurosensory hearing loss3,4
OPHTHALMOLOGICAL
Diffuse corneal clouding, cataracts, reduction in visual acuity3,6,7
NeurologiCal
Odontoid dysplasia, cervical myelopathy, cervical spine instability, tetraplegia2,3
Dental
Dentinogenesis imperfecta, hypodontia, pointed cusps, spade-shaped incisors, thin enamel, abnormal buccal surfaces3,8
Abdominal
Mild hepatosplenomegaly, hernias, loose stools, diarrhea, constipation, abdominal pain3-5
CARDIovascular
Mitral and aortic valve stenosis and regurgitation, tricuspid regurgitation, hypertrophy3,9-11
Musculoskeletal
Bone deformity, short stature, abnormal gait, joint laxity, contractures and subluxation, dysostosis multiplex2,3
REFERENCES:
[HEADLINE]: Northover 1996 p. 357/para 1/p. 358/ para 3;
Tomatsu 2011 p. 931/col 1/para 1/col 2/para 1/p. 932/col 1/para 1/col 2/para 1/p. 934/col 1/para 1;
[AUDIOLOGICAL]: Hendriksz 2014/p 10/col 1/para 4;
Hendriksz 2013/p 3/col 1/para 3/col 2/para 1-3
[NEUROLOGICAL]: Hendriksz 2014/p 9/col 2/para 1/p 3/table 1;
Tomatsu 2011/p. 936/col 1/para 2/col 2/para1-2
[ABDOMINAL]: Hendriksz 2014/p 10/col 1/para 7/col 2/para 1;
Tomatsu 2003/p. 66;
Hendriksz 2013/p. 4/col 1/para 2
[MUSCULOSKELETAL]: Hendriksz 2014/p 5/col 2/para 1-2/p. 3/table 1;
Tomatsu 2011/p. 934/table 2/col 2/para 2/p. 935/fig 3/p. 936/col 1/para 2
[OPHTHAL.]: Hendriksz 2014/p 9/col 2/para 4;
Danes 1973/p. 3/table 1;
Leslie 2005/p. 925/col 2/para 1-2/col 3/para 1
[DENTAL]: Hendriksz 2014/p 10/col 2/para 4;
Kinions 1990/p. 1/col 1/para 2/p. 2/col 2/Table 1
[CARDIO]: Hendriksz 2014/p 9/col 1/para 2;
Harmatz 2013/p. 6/col 2/para 2; Ireland 1981/p. 114/fig 1-2/col 1/para 3-4;
John 1990/p. 747/table
[RESPIRATORY]: Hendriksz 2014/p 8/col 2/para 1;
Harmatz 2013/p. 6/col 1/para 2/col 2/para 1;
Tomatsu 2011/p. 939/col 1/para 3/col 2/para 1
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): 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): doi: / 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: /ajmg.a 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): doi: /s Shunji Tomatsu; International Morquio Organization. Mucopolysaccharidosis type IVA: Morquio A syndrome. Published Accessed November 12, Danes BS. Corneal clouding in the genetic mucopolysaccharidoses: a cell culture study. Clin Genet. 1973;4(1): Leslie T, Siddiqui MAR, Aitken DA, Kirkness CM, Lee WR, Fern AI. Morquio syndrome: electron microscopic findings. Br J Ophthalmol. 2005;89: 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): 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): doi: /j.ymgme Ireland MA, Rowlands DB. Mucopolysaccharidosis type IV as a cause of mitral stenosis in an adult. Br Heart J. 1981;46(1): John RM, Hunter D, Swanton RH. Echocardiographic abnormalities in type IV mucopolysaccharidosis. Arch Dis Child. 1990;65(7):

5. Geneticist/metabolic specialist Orthopedic specialist
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
Dentist
Ophthalmologist
Gastroenterologist
Cardiologist
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 5/col 1/para 2
[SUBHEAD]: Hendriksz 2014/p 5/col 1/para 2/p 6/table 2
Geneticist/metabolic specialist
Audiologist
Neurosurgeon
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: /ajmg.a
Orthopedic specialist 5

6. Recommended management starts with diagnosis and continues with care throughout the patient’s lifetime1
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
DIAGNOSIS
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
ONGOING ASSESSMENTS AND INTERVENTIONS
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 3/col 1/para 1/p 5/col 1/para 2/p 12/col 2/para 1
[DIAGNOSIS BOX]: Hendriksz 2014/p 3/col 1/para 2/p 4/Fig. 2/col 1/para 2/col 2/para 2/p 5/col 1/para 2/p 6/Table II;
Clarke 2011/p v13/col 1/para 1/col 2/para 1;
Coutinho 2011/p 3/col 1/para 2
[ONGOING ASSESSMENTS BOX]: Hendriksz 2014p 5/col 1/para 2-4/p 6/Table II
[TRANSITION BOX]: Hendriksz 2014/p 12/col 2/para 1
[CALL OUT]: Hendriksz 2014/p 5/col 1/para 2, 4/p 6/Table II
Continued coordination is important as new specialists join the patient’s healthcare team1
TRANSITION TO ADULT CARE
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: /ajmg.a 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): doi: /j.ymgme Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int. 2012;2012: doi: /2012/

7. 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
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 3/col 1/para 2/p 4/col 1/para 1
[SUBHEAD]: Hendriksz 2014/p 3/col 1/para 2/p 4/col 1/para 1
[BULLET]: Hendriksz 2014/p 5/col 1/para 2-4/p 6/Table II
[ASSESSMENT TABLE]: Hendriksz 2014/p 6/Table II/p 10/col 2/para 2
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: /ajmg.a
a For a comprehensive list of assessments, consult the Guidelines.

8. 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
Within the lysosome, VIMIZIM increases catabolism of GAGs (KS and C6S)—restoring cell function. 1,2
REFERENCES:
[HEADLINE]: VIMIZIM PI p. 8, section 12.1, para 1
[SUBHEAD]: VIMIZIM PI p. 8, section 12.1, para 1;
Wood 2013 p. 2, col 1, para 2
[DESCRIPTION 1]: Coutinho 2012 p. 1, col 2, para 2;
Hendriksz 2013 p. 2, col 1, para 1
[DESCRIPTION 2]: VIMIZIM PI p 8, section 12.1, para 1
[DESCRIPTION 3]: VIMIZIM PI p 8, section 12.1, para 1;
References: 1. VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; Wood TC, Harvey K, Beck M, et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis. 2013;36(2): doi: /s Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int. 2012;2012: doi: /2012/ 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): doi: /s
Please see Important Safety Information, including boxed warning, on slide 38.

9. 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 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
REFERENCES:
[HEADLINE]: VIMIZIM PI/p. 9/sec. 14/para 3/p 10/sec. 14/para 1/Table 3;
Hendriksz 2014 (Multi-domain)/p. 2/col 2/para 1
[SUBHEAD]: Hendriksz 2014/p 11/col 1/para 2
[BULLET 1]: VIMIZIM PI/p. 9/sec. 14/para 3/p. 10/sec. 14/table 3;
[BULLET 2]: VIMIZIM PI/p. 10/section 14/table ;3
[CALL OUT]: Hendriksz 2014/p 3/col 1/para 1/p 4/col 1/para 2/col 2/para 2/p 5/col 1/para 2/p 12/col 2/para 1
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; 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): doi: /j.ymgme 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): doi: /s
Please see Important Safety Information, including boxed warning, on slide 38.

10. 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
REFERENCES:
[HEADLINE]: Hendriksz 2014 (Multi-domain)/p 2/col 2/para 1/p. 6/Fig. 2
[TABLE]: Hendriksz 2014 (Multi-domain)/p 2/col 2/para 1/p. 6/Fig. 2
16 years old
Please see Important Safety Information, including boxed warning, on slide 38.
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): doi: /j.ymgme

11. 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
REFERENCES
[HEADLINE]: Hendriksz 2014 (Multi-domain)/p 5/col 2/para 3,4/appendix 2
[SUBHEAD]: Hendriksz 2014 (Multi-domain)/p 5/col 2/para 3,4/appendix 2
[BULLET]: Hendriksz 2014 (Multi-domain)/p 4/col 2/para 3/p 5/col 2/para 3,4/appendix 2
[TABLE]: Hendriksz 2014 (Multi-domain)/p 5/col 2/para 3,4/appendix 2
16 years old
Please see Important Safety Information, including boxed warning, on slide 38.
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): doi: /j.ymgme

12. VIMIZIM® (elosulfase alfa) safety and tolerability
176 patients ages 5 to 57 were enrolled in the 24-week, phase 3 pivotal study1
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; 28
REFERENCES:
[FIRST BULLET]: VIMIZIM PI, p. 9, section 14, para 1
[SECOND BULLET]: VIMIZIM PI, p. 5, section 6.1, table 1
[THIRD BULLET]: VIMIZIM PI, p. 4, section 5.1, para 4
[TABLE]: VIMIZIM PI p. 5, section 6.1, table 1
[FOOTNOTE]: VIMIZIM PI p. 1, p. 7, section 8.4
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.

13. Guidelines emphasize need for ongoing multisystemic assessments1
Assessments1,a
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
At diagnosis/baseline, every visit (minimum, every 6 months)
At diagnosis, every 1 to 3 years
At diagnosis, annually
As clinically indicated
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
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 5/col 1/para 4/p 6/Table II
[TABLE]: Hendriksz 2014/p 6/Table II/p 10/col 2/para 2
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
QoL
QUALITY OF LIFE (QoL) Reproducible, age-appropriate QoL questionnaires (eg, EQ-5D-5L)
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: /ajmg.a
a Note: For additional detail, please consult the Guidelines.

14. Assessments can reveal the need for specialized interventions to optimize patient outcomes1
Manifestation assessed1,a
INTERVENTIONS1,a
MUSCULOSKELETAL
Upon diagnosis, refer to MPS-experienced orthopedic surgeon
RESPIRATORY
Pursue supportive therapies
– Influenza and pneumococcus vaccinations
– Bronchodilators
– Prompt treatment of upper respiratory infections
Spinal decompression
Spinal fusion
NEUROLOGICAL
CARDIOVASCULAR
Avoid beta-blockers to treat tachycardia
Refractive correction/low vision aids
Corneal transplantation
OPHTHALMOLOGICAL
Ventilation tubes
Postaural hearing aids
AUDIOLOGICAL
REFERENCES:
[HEADLINE]: Hendriksz 2014/p 5/col 1/para 4
[MUSCULO.]: Hendriksz 2014/p 5/col 2/para 3
[RESPIRATORY]: Hendriksz 2014/p 8/col 2/para 6/p 9/col 1/para 1
[NEURO.]: Hendriksz 2014/p 9/col 2/para 3/p 7/col 2/para 2
[CARDIO.]: Hendriksz 2014/p 9/col 1/para 4
[OPHTHAL.]: Hendriksz 2014/p 10/col 1/para 3
[AUDIO.]: Hendriksz 2014/p 10/col 1/para 6
[ABDOMINAL]: Hendriksz 2014/p 10/col 2/para 3
[DENTAL]: Hendriksz 2014/p 10/col 2/para 6
[ENDURANCE]: Hendriksz 2014/p 4/col 1/para 2
[QOL]: Hendriksz 2014/p 8/col 2/para 2
ABDOMINAL
Surgical repair of recurrent hernias
Preventative measures against formation of caries
Fissure sealing of dentition
DENTAL
ENDURANCE
ERT provides a systemic treatment approach
QoL
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: /ajmg.a
a Note: For additional detail, please consult the Guidelines.

15. 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)
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 5/col 2/para 1
[BULLET]: Hendriksz 2014/p 5/col 2/para 1
[SUB-BULLET]: Hendriksz 2014/p 2/col 1/para 2/p 5/col 2/para 2
[PHOTOS]: Image courtesy of Christina Lampe, MD and Ralph Lachman, MD;
Atinga 2008/p 1632
[CALL OUT]: Harmatz 2013 MORCAP/p 3/col 1/para 2
(Left: Image courtesy of Christina Lampe, MD and Ralph Lachman, MD)
(Right: Atinga 2008)
Dysostosis multiplex changes
in the pelvis and hips
Knee valgus
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: /ajmg.a 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): doi: /j.ymgme
Note: For additional detail, please consult the Guidelines.

16. Note: For additional detail, please consult the Guidelines.
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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 6/Table II
[BULLETS]:Hendriksz 2014/p 4/col 2/para 2/p 5/col 2/para 3
Note: For additional detail, please consult the Guidelines.
Please see Important Safety Information, including boxed warning, on slide 38.
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: /ajmg.a

17. Narrow, tortuous trachea
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 trachea
Narrow, tortuous trachea
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 8/col 1/para 3
[BULLET 1]: Hendriksz 2014/p 8/col 1/para 3
[BULLET 2]: Hendriksz 2014/p 8/col 2/para 1
[BULLET 3]: Hendriksz 2014/p 8/col 2/para 3
[BULLET 4]: Hendriksz 2014/p 9/col 1/para 1
[BULLET 5]: Hendriksz 2014/p 8/col 2/para 1
[PHOTOS]: Berger 2013/p 205
(Left: Berger 2013)
(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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

18. 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
REFERENCES:
[HEADLINE]: No reference needed
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET]: Hendriksz 2014/p 8/col 2/para 6/p 9/col 1/para 1
[CALL OUT]: Hendriksz 2014/p 9/col 1/para 1
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

19. 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
radiating leg pain
paralysis
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 9/col 2/para 1-3
[BULLET 1]: Hendriksz 2014/p 6/table 2/p 9/col 2/para 2
[BULLET 2]: Hendriksz 2014/p 9/col 2/para 1
[PHOTO]: Solanki 2013/p 345/figure 5
T2 hyperintensity and focal atrophy
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

20. Focus on: neurological involvement
Specialty area: Neurology
Guideline-recommended assessments
Assessments1
FREQUENCY1
Neurological exam Plain radiograph MRI scan CT scan
At diagnosis/baseline, every visit (minimum, every 6 months)
At diagnosis, every 1 to 3 years
At diagnosis, annually
As clinically indicated
Guideline-recommended interventions
When warranted, interventions can include spinal decompression, fusion, or a combination of both1
REFERENCES:
[HEADLINE]: No reference needed
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET]: Hendriksz 2014/p 7/col 2/para 2
[CALL OUT]: Hendriksz 2014/p 7/col 2/para 2/p 8/col 1/para 1
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

21. 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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 9/col 1/para 2
[BULLET 1]: Hendriksz 2014/p 9/col 1/para 2
[BULLET 2]: Hendriksz 2014/p 9/col 1/para 2
Harmatz 2013 MORCAP/p 3/col 2/para 2
[BULLET 3]: Harmatz Morcap 2013/p 2/col 1/para 2-3/p 4/col 1/para 2/col 2/para 1/p 6/col 2/para 1;
Hendriksz 2014/p 11/col 1/para 1
[PHOTOS]: Ireland 1981/p 114/figs 1-2
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: /ajmg.a 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): doi: /j.ymgme
Note: For additional detail, please consult the Guidelines.

22. Focus on: cardiovascular involvement
Specialty area: Cardiology
Guideline-recommended assessments
Assessments1
FREQUENCY1
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
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
REFERENCES:
[HEADLINE]: No reference needed
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET 1]: Hendriksz 2014/p 9/col 1/para 4
[BULLET 2]: Hendriksz 2014/p 9/col 1/para 5
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

23. 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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 10/col 1/para 2,3
[BULLET]: Hendriksz 2014/p 9/col 2/para 4
[PHOTO]: Image courtesy of Gail Summers
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

24. Focus on: ophthalmological involvement
Specialty area: Ophthalmology
Guideline-recommended assessments
Assessments1
FREQUENCY1
Slit-lamp biomicroscopy of cornea Intraocular pressure Refractive error Examination of posterior segment Scotopic and photopic electroretinogram
At diagnosis, as clinically indicated
As clinically indicated
Guideline-recommended interventions
REFERENCES:
[HEADLINE]: No reference needed
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET 1]: Hendriksz 2014/p 10/col 1/para 3
[BULLET 2]: Hendriksz 2014/p 10/col 1/para 3
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

25. 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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 10/col 1/para 4-5
[BULLET 1]: Hendriksz 2014/p 10/col 1/para 4
[BULLET 2]: Hendriksz 2014/p 10/col 1/para 4
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

26. 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
REFERENCES:
[HEADLINE]: No reference needed
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET 1]: Hendriksz 2014/p 10/col 1/para 6
[BULLET 2]: Hendriksz 2014/p 10/col 1/para 6
[CALL OUT]: Hendriksz 2014/p 10/col 1/para 6
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

27. 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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 10/col 1/para 7/col 2/para 1-2
[BULLET 1]: Hendriksz 2014/p 10/col 1/para 7/col 2/para 1
[BULLET 2]: Hendriksz 2014/p 10/col 2/para 3
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

28. 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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 10/col 2/para 4
[BULLET 1]: Hendriksz 2014/p 10/col 2/para 4
[BULLET 2]: Hendriksz 2014/p 6/Table II
[BULLET 3]: Hendriksz 2014/p 10/col 2/para 6
[PHOTO]: Hendriksz 2014/p 54
Pediatric (top) and adult (bottom) teeth with typical features: widely spaced teeth, pointed cusps, and spade-shaped incisors
16 years old
(Hendriksz 2014)
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

29. Note: For additional detail, please consult the Guidelines.
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
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 4/col 1/para 2/ col 2/para 2/p 11/col 1/para 1
Harmatz 2013/p 4/col 1/para 2/col 2/para 1
[BULLET 1]: Hendriksz 2014/p 11, col 1, para 1;
[BULLET 2]: VIMIZIM PI/p 2/section 1/p 8/section 12.1/p 9/section 14/para 3/p 10/table 3
16 years old
Note: For additional detail, please consult the Guidelines.
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: /ajmg.a 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): doi: /j.ymgme VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 2014.
Please see Important Safety Information, including boxed warning, on slide 38.

30. Note: For additional detail, please consult the Guidelines.
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
REFERENCES:
[HEADLINE]: No reference needed
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET 1]: Hendriksz 2014/p 4/col 1/para 2/col 2/para 2
[CALL OUT]: Hendriksz 2014/p 4/col 1/para 2/col 2/para 2/p 5/col 1/para 2
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.
Please see Important Safety Information, including boxed warning, on slide 38.
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: /ajmg.a

31. 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 QoL questionnaire Functional test/ADL questionnaire
At diagnosis, every 6 months, pre-ERT
At diagnosis, annually, pre-ERT
REFERENCES:
[HEADLINE]: No reference needed
[SUBHEAD]: Hendriksz 2014/p 11/col 2/para 4
[BULLET 1]: Hendriksz 2014/p 11/col 2/para 2
[BULLET 2]: Hendriksz 2014//p 11/col 2/para 2
[TABLE]: Hendriksz 2014/p 6/Table II
[BULLET 3]: Hendriksz 2014/p 11/col 2/para 5
[BULLET 4]: Hendriksz 2014/p 8/col 1/para 2
Guideline-recommended interventions
Simple interventions may considerably improve the functional capacity and QoL of patients with Morquio A1
Efforts should be made to keep patients independently mobile as long as possible1
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: /ajmg.a
Note: For additional detail, please consult the Guidelines.

32. Patients with Morquio A face high surgical risk1-3
Cervical instability
Compromised respiratory function
Cardiac problems
High anesthesia risk
Inability to ventilate/ intubate
Need for reintubation
Airway obstruction
REFERENCES:
[HEADLINE]: Walker 2013/p 213/Figure 1/p 214/col 2/para 5
[NAVY BLUE BOXES]: Solanki 2013/p 340/col 1/para 3/p 351/col 2/para 2;
Walker 2013/p 214/col 2/para 3/p 213/Figure 1
[GRAY CIRCLE]: Hendriksz 2014/p 8/col 1/para 1
[BLUE CIRCLES]: Solanki 2013/p351/col 2/para2/lines 9-11/p 352/col 2/para 1
[CALL OUT]: Lavery 2014/p 4/figure 1a
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): doi: /s 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): doi: /s 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: /ajmg.a Lavery C, Hendriksz C. Mortality in patients with Morquio syndrome A. J Inherit Metab Dis Rep. 2015;15: doi: /8904_2014_298.

33. 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
REFERENCES:
[HEADLINE]: Walker 2013/p 212/col 1/para 2-3;
Theroux 2012/p 4/col 1/para 4/col 2/para 1
[SUBHEAD 1]: Hendriksz 2014/p 5/col 1/para 3-4
[BULLET 1]: Hendriksz 2014/p 5/col 1/para 3-4/p 6/table 2
[BULLET 2]: No reference needed
[SUBHEAD 2]: Walker 2013/p 212/col 2/para 3/p 215/col 2/para 1/p 216/col 1/para 5;
Hendriksz 2014/p 12/col 1/para 3
[TABLE]: (Presurgical): Walker 2013/p 215/col 1/para 2
(Perioperative): Theroux 2012/p 6/col 2/para 2
(Anesthetic care): Solanki 2013/p 352/col 1/para 3
(Monitoring): Solanki 2013/p 352/col 1/para 3/p 353/col 1/para 1
(Postoperative care): Solanki 2013/p 352/col 1/para 4/col 2/para 1
Bronchodilator
References: 1. Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2): doi: /s Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9): doi: /j 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: /ajmg.a 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): doi: /s

34. 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
REFERENCES:
[HEADLINE]: No reference needed
[BULLET 1]: Hendriksz 2014/p 12/col 1/para 5/col 2/para 1
[BULLET 2]: Hendriksz 2014/p 12/col 2/para 1
[BULLET 3 (WITH SUB-BULLETS)]: Hendriksz 2014/p 12/col 2/para 1
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: /ajmg.a

35. 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
REFERENCES:
[BULLET 1]: Hendriksz 2014/p 3/Table 1/p 5/col 2/para 1
[BULLET 2]: Hendriksz 2014/p 5/col 1/para 2
[BULLET 3]: Hendriksz 2014/p 3/col 1/para 2/p 4/Fig. 2/p 5/col 1/para 2-4/p 6/Table II;
[BULLET 4]: VIMIZIM PI/p. 9/sec. 14/para 3/p 10/sec. 14/para 1/Table 3;
Hendriksz 2014 (Multi-domain)/p. 2/col 2/para 1;
Hendriksz 2014/p 3/col 1/para 2/p 4/Fig. 2/col 1/para 2/col 2/para 2/p 5/col 1/para 2-4/p 6/Table II;
[BULLET 5]: Hendriksz 2014/p 12/col 2/para 1/p 5/col 1/para 4/p 6/Table 2
[BULLET 6]: (Presurgical): Walker 2013/p 215/col 1/para 2
(Perioperative): Theroux 2012/p 6/col 2/para 2
(Anesthetic care): Solanki 2013/p 352/col 1/para 3
(Monitoring): Solanki 2013/p 352/col 1/para 3/p 353/col 1/para 1
(Postoperative care): Solanki 2013/p 352/col 1/para 4/col 2/para 1
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: /ajmg.a VIMIZIM [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; 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): doi: /j.ymgme Walker R, Belani KG, Braunlin EA, et al. Anaesthesia and airway management in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2): doi: /s Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9): doi: /j 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): doi: /s
Please see Important Safety Information, including boxed warning, on slide 38.

36. 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
NOTES:
Inform patients of the Morquio A Registry established in order to better understand the variability and progression of the disease in the population as a whole, and to monitor and evaluate long-term treatment effects of VIMIZIM. The Morquio A Registry will also monitor the effect of VIMIZIM on pregnant women, nursing mothers and their offspring, and determine if VIMIZIM is excreted in breast milk. Patients should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. For more information, contact
REFERENCES:
No references needed.
Please see Important Safety Information, including boxed warning, on slide 38.

37. 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: /ajmg.a
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 ;36(2): doi: /s
Berger KI, Fagondes SC, Giugliani R, et al. Respiratory and sleep disorders in mucopolysaccharidosis. J Inherit Metab Dis. 2013;36(2): doi: /s
Theroux MC, Nerker T, Ditro C, Mackenzie WG. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22(9): doi: /j 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 ;166(1): doi: /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: /s
REFERENCES:
No references required.

38. 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.
REFERENCES:
No references needed.
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.

39. 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.
   
REFERENCES:
No references needed.

40. 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 for information and enrollment.
Safety and effectiveness in pediatric patients below 5 years of age has not been established and is currently being evaluated.
REFERENCES:
No references needed.

41. 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 , or FDA at FDA-1088 or go to
Please see accompanying full Prescribing Information, including boxed warning, or visit
REFERENCES:
No references needed.