Transcript Pompe Disease Overview and Treatment with (ALGLUCOSIDASE

Dr.Zahra Alian
Pediatric Endocrinologist
Pompe Disease
A Progressive, debilitating, life-threatening, but
under-recognized
Contents
• Introduction
• Clinical Presentation
• Diagnosis
• Management
• Enzyme Replacement Therapy(ERT)
Pompe Disease Introduction
INTRODUCTION
Pompe Disease
• Progressive, multisystemic, debilitating, often fatal
neuromuscular disease
• First described in 1932 by Dutch pathologist J.C. Pompe
• Also known as acid maltase deficiency (AMD), glycogen storage
disease type II (GSD-II), or glycogenosis type II
• Characterised by progressive degeneration of skeletal,
respiratory and, primarily in infants, cardiac muscle
• Encompasses a single disease continuum with variable rates of
disease progression
Pompe J-C.Ned Tijdschr Geneeskd 1932; 1932:304.
INTRODUCTION
Pompe Disease
• Characterised by the deficiency of
a lysosomal enzyme, acid alpha-glucosidase
(GAA)
• Results in progressive intracellular
accumulation of glycogen, primarily in
muscle cells
• Signs and symptoms begin anywhere from
early infancy through adulthood
• Recognising Pompe disease is challenging
since signs and symptoms may be shared
with other disorders
• With disease-specific treatment now
available, early recognition and diagnosis is
even more urgent
Kishnani PS, Hwu W-L, Mandel H, Nicolino M, Yong F, Corzo D. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 2006; 148:671-676.
Winkel LP, Hagemans ML, van Doorn PA, et al. The natural course of non-classic Pompe's disease; a review of 225 published cases. J Neurol 2005; 252:875-84.
INTRODUCTION
Disease Classification
• Pompe patients often classified by clinical presentation
– Rapidly progressive and often fatal by 1 year of age
• Historically referred to as infantile-onset or early onset
• Symptoms begin in early infancy
– Relentlessly progressive and often fatal
• Historically referred to as juvenile-onset or late onset
• Symptoms begin anywhere from early childhood up to adulthood
• Single-disease with one enzyme deficiency
– Despite this wide range of phenotypes, a deficiency of the same
lysosomal enzyme underlies all forms of Pompe disease
Hesselink RP, Wagenmakers AJ, Drost MR, Van der Vusse GJ. Lysosomal dysfunction in muscle with special reference to glycogen storage disease type II. Biochim Biophys Acta 2003; 1637:164-70.
Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med 2006; 8:267-288.
INTRODUCTION
Disease Nomenclature
• Categorised in several disease families
–
–
–
–
Lysosomal storage disease
Glycogen storage disease
Neuromuscular disease/metabolic muscle disease
Cardiac disorder (due to cardiomyopathy/cardiomegaly in infants)
• Synonyms
– Glycogen storage disease type II (GSD-II)
– Acid maltase deficiency (AMD)
– Glycogenosis type II
Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med 2006; 8:267-288.
INTRODUCTION
Genetics and Incidence
• Autosomal recessive
inheritance
• GAA gene located on
chromosome 17q25
• Over 200 mutations in GAA gene
identified to date
– See www.pompecenter.nl for complete list of
mutations
• Poor genotype-phenotype
correlations have been documented
• 1:40,000 combined incidence
Kuo WL, et al. Hum Genet 1996; 97:404-6. www.pompe center.nl/index.html. Accessed December 15, 2006.
Kroos MA, et al. Neurol 2007;68:110-5. Ausems MG, et al. Eur J Hum Genet 1999; 7:713-6.
INTRODUCTION
Pathogenesis of Pompe Disease
Illustration based on Raben et al. Curr Mol Med. 2002;2:145-166.
•
GAA enzyme
essential for
degradation of
lysosomal
glycogen
•
Inherited enzyme
deficiency results
in glycogen
accumulation and
lysosomal
distention
INTRODUCTION
Glycogen Accumulation Leads to Tissue Destruction
Glycogen accumulation
in cardiac muscle
• Glycogen storage primarily affects
muscle tissue
• Major muscle groups
– Cardiac muscle (infant)
– Proximal skeletal muscle (esp. in trunk and
lower limbs)
Glycogen accumulation
in skeletal muscle
– Respiratory muscles
Illustration based on Thurberg et al. Lab Investigations. 2006;86:1208-1220.
INTRODUCTION
Pompe Disease:
Natural Evolution and Clinical Manifestations
Mutation of
GAA gene
Early
mortality
GAA enzyme
deficiency
Loss of
ambulation and
cardio-respiratory
distress
Cellular
accumulation
of glycogen
Continuous
progressive decline
to organ failure
Pathological changes
in muscle fibres
Clinical
manifestations
and events
Clinical Presentation
CLINICAL
PRESENTATION
Variable Rates of Disease Progression
BASED ON van der Ploeg A et al. Lancet 2008; 372:1342-1353
CLINICAL
PRESENTATION
Pompe Disease in Infants
Cardiac
• Marked cardiomegaly/cardiomyopathy
• Progression to cardiac failure
Musculoskeletal
• Profound and rapidly progressive muscle
weakness (hypotonia, floppy baby, head lag)
• Delayed motor milestones
Respiratory
•
•
•
•
Frequent respiratory infections
Progression to respiratory insufficiency
Premature death due to cardiorespiratory failure
Sleep disordered breathing
Gastrointestinal
• Difficulty feeding/failure to thrive
• Organomegaly (hepatomegaly/macroglossia)
Kishnani PS, et al. Genet Med 2006;8:267-288. Gilbert-Barness E. Ann Clin Lab Sci 2004; 34:15-34. Roe CR, Ding J. New York, New York: McGraw-Hill; 2001.
CLINICAL
PRESENTATION
Pompe Disease in Infants
Normal Infant
With permission from M. Russell-Taylor, MD
Infant with Pompe Disease
With permission from B. Byrne, MD
• Cardiac involvement
– Develops in 92% of infants at a median age of 4 months
– Heart can be greatly enlarged
– Progression to cardiac failure
Kishnani et al. J Pediatr 2006; 148:671-676. Hirschhorn R, Reuser AJJ. New York: McGraw Hill, 2001:3389-3420.
CLINICAL
PRESENTATION
Pompe Disease in Infants
Electrocardiogram of an Infant
• ECG abnormalities
With permission from B. Byrne, MD
van den Hout HMP, et al. Pediatrics. 2003;112:332-340. Kishnani et al. J Pediatr 2006; 148:671-676.
–
Shortened PR
intervals
–
Tall QRS
complexes
CLINICAL
PRESENTATION
Pompe Disease in Infants
• Musculoskeletal
– Profound and rapidly
progressive muscle weakness
• Hypotonia
• Floppy baby
• Head lag
– Markedly elevated plasma
creatine kinase (CK)
– Elevated aspartate
aminotransferase (AST) and
alanine aminotransferase (ALT)
– Delayed motor milestones
van den Hout HMP, et al. Pediatrics. 2003;112:332-340. Kishnani et al. J Pediatr 2006; 148:671-676. Hirschhorn R, Reuser AJJ. New
York: McGraw Hill, 2001:3389-3420.
CLINICAL
PRESENTATION
Pompe Disease in Infants
• Respiratory muscle involvement
– Frequent infections
– Respiratory insufficiency
– Sleep disordered breathing
• Nutrition/gastrointestinal
– Failure to thrive
– Poor weight gain
– Feeding problems, including difficulty sucking and swallowing
– Macroglossia
van den Hout HMP, et al. Pediatrics. 2003;112:332-340. Kishnani et al. J Pediatr 2006; 148:671-676. Hirschhorn R, Reuser AJJ. New
York: McGraw Hill, 2001:3389-3420.
CLINICAL PRESENTATION
Differential Diagnosis: Infants
1. Kishnani et al. Genet Med 2006; 8:267-88. 2. Gilbert-Barness E. Ann Clin Lab Sci 2004; 34:15-34. 3. Roe, et al. In: The Metabolic and Molecular
Bases of Inherited Disease. New York, New York: McGraw-Hill; 2001.
CLINICAL
PRESENTATION
Pompe Disease in Children & Adults
Musculoskeletal
•
•
•
•
•
•
Proximal muscle weakness
Gait abnormalities
Muscle pain
Difficulty climbing stairs
Frequent falls
Scapular winging
Respiratory
•
•
•
•
•
•
•
Respiratory failure/insufficiency
Orthopnea
Exertional dyspnea
Respiratory infections
Daytime somnolence
Morning headache
Nocturnal hypoventilation
Gastrointestinal
• Feeding and swallowing difficulties
• Poor weight gain/maintenance
• Difficulty chewing or jaw muscle fatigue
Kishnani PS, et al. Genet Med 2006;8:267-288. Gilbert-Barness E. Ann Clin Lab Sci 2004; 34:15-34. Roe CR, Ding J. New York, New York: McGraw-Hill; 2001.
CLINICAL
PRESENTATION
Pompe Disease in Children & Adults
Musculoskeletal
• Progressive weakening of skeletal muscles
– Primarily limb-girdle muscles
– Difficulty walking, climbing stairs, rising from chair
and floor
– Difficulty reaching and throwing
– Frequent falls
• Muscle atrophy
– Scoliosis, kyphosis, lordosis
– Scapular winging
Elevated creatine kinase (CK)
Elevated aspartate aminotransferase (AST) & alanine
aminotransferase (ALT)
Gower manoeuvre
CLINICAL
PRESENTATION
Pompe Disease in Children & Adults
Respiratory
•
•
•
•
Respiratory insufficiency/distress
Diaphragm weakness
Sleep disordered breathing/nocturnal
hypoventilation
Exertional dyspnoea
•
Eventual need for mechanical ventilation
Gastrointestinal
•
•
Feeding and swallowing difficulties
Difficulty chewing, jaw muscle fatigue
•
•
Reflux
Poor weight gain
Kishnani PS, et al. Genet Med 2006;8:267-288. Gilbert-Barness E. Ann Clin Lab Sci 2004; 34:15-34. Roe CR, Ding J. New York, New York: McGraw-Hill; 2001.
CLINICAL
PRESENTATION
Disease impact on Quality of Life
* p<0.01
•
Diminished quality of life in adult patients with Pompe disease
– Comparison of SF-36 health survey scores in 51 Dutch patients with Pompe
disease and Dutch general population
Hagemans et al. Neurology. 2004;63:1688-1692.
CLINICAL
PRESENTATION
Pompe disease is a diagnostic challenge
The clinical presentation in children and
adults is heterogeneous, making diagnosis
particularly challenging.
The American Association of
Neuromuscular & Electrodiagnostic
Medicine (AANEM) Guidelines highlight a
broad range of neuromuscular and genetic
disorders in the differential diagnosis for
Pompe disease. An excerpt from the
AANEM Guidelines is provided.
Disorder Type
Diagnoses
Dystrophies
•
•
•
•
•
Limb-girdle muscular dystrophy
Duchenne/Becker muscular dystrophy
Myofibrilar myopathy
Myotonic dystrophy type 2
Danon disease
Inflammatory
myopathies
• Polymyositis
• Inclusion body myositis
Other metabolic
myopathies
• Mitochondrial myopathy
• McArdle disease
Motor neuron
disorders
• Spinal muscular atrophy
• Amyotrophic lateral sclerosis (ALS)
• Kennedy disease
NM junction
disorders
• Myasthenia gravis
• Congenital myasthenic syndromes
Pompe disease should be considered as part of the differential diagnosis
for all children and adults presenting with limb-girdle muscle weakness
and respiratory insufficiency.
American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). Diagnostic criteria for late-onset (childhood and adult) Pompe disease.
Muscle Nerve. 2009;40(1):149-160.
Diagnosis
DIAGNOSIS
Diagnostic Delays Are Common
Kishnani et al. J Pediatr 2006; 148:671-676. Winkel et al. J Neurol 2005; 252:875-84.
DIAGNOSIS
Confirming the Diagnosis
• Confirmatory diagnosis requires quantitative enzyme (GAA)
activity assay
• Historically, methods were invasive
– Skin biopsy
– Muscle biopsy
• Now, minimally invasive blood tests can accurately quantify
GAA activity
– Dried blood spots
– Mixed leukocytes
– Lymphocytes
• Mutation Analysis
– Especially for carrier testing (family/sibling)
– Potential for prognostic value
Kishnani PS, et al. Genet Med 2006;8:267-288. Gilbert-Barness E. Ann Clin Lab Sci 2004; 34:15-34. Roe CR, Ding J. New York, New York: McGraw-Hill; 2001.
Early diagnosis of IOPD allows prompt initiation of
alglucosidase alfa therapy
• Early diagnosis of IOPD allows early initiation of alglucosidase
alfa therapy while muscle dysfunction and damage remain
reversible.
• Early initiation of alglucosidase alfa therapy for IOPD
– Reverses cardiomyopathy1-5
– Prolongs overall and ventilator-free survival1,3,4
– Enables patients to reach motor milestones1,3,6
1.
2.
3.
4.
5.
6.
Nicolino et al. Genet Med 2009;11:210-9.
Levine et al. Pedatr Cardiol 2008;29:1033-42.
Kishnani et al Neurology 2007;68:99-109.
Kishnani et al. J Pediatr 2006;149:89-97.
Chen et al. J Pediatr 2009;155:271-5.
Kishnani et al. Pediatr Res. 2009;66:329-35.
The First and Only Disease Specific Therapy
for Pompe Disease
Disease-specific Treatment for Pompe Disease
• Alglucosidase alfa is the only disease-specific treatment for Pompe
disease.
• First approved by the EMEA and FDA in 2006, with >1200 patients
worldwide now treated
• Clinical trials in infants demonstrated prolonged survival and improved
cardiac and motor function
• Clinical trials in children and adults showed improved walking distance
and stabilized pulmonary function
• Increasing treatment experience indicates that alglucosidase alfa
changes the natural course of the disease
Kishnani et al. Neurology 2007;68;99-109. Nicolino et al. Genet Med 2009;11:2109. Kishnani et al. Pediatr Res 2009;66;329-55. van der Ploeg et al. Neurology
2008;71:155.
TREATMENT BASICS
Effect of Alglucosidase Alfa on Glycogen Storage
Pre-treatment
4 months post-treatment
glycogen
Electron micrographs of quadriceps muscle stained with Toluidine blue X198
Amalfitano et al. Genet Med 2001;3:132-8
CLINICAL DATA
Disease Management
DISEASE
MANAGEMENT
Disease Management
American College of
Medical Genetics (ACMG)
Guidelines call for a
multidisciplinary approach
to multisystemic disorder
Kishnani et al. Genet Med 2006; 8:267-288.
DISEASE
MANAGEMENT
Disease Management
Optimal treatment of Pompe disease requires a combination of
disease-specific and supportive therapies.
• Myozyme™ enzyme replacement therapy to treat the underlying
enzyme deficiency
• Cardiac management
– Regular chest x-rays and ECGs to monitor for arrhythmias
• Pulmonary and sleep study assessments
– Routine evaluation of pulmonary and sleep respiratory function
– Specific evaluation of diaphragmatic weakness by measurement of supine
vital capacity
• Management of respiratory insufficiency
– Potential use of supplemental oxygen or mechanical ventilation
– Aggressive management of pulmonary infections
• Physical therapy
Kishnani et al. Genet Med 2006; 8:267-288.
DISEASE
MANAGEMENT
Supportive Care
Supportive care may also include:
•
GI and nutritional assessment/management
of feeding problems (very important for infants and young children)
– Monitor growth parameters
– Provide adequate nutrition
• Feeding tubes
– Swallowing assessment
•
General medical management
– High infection risk/manage infections aggressively and and prevention of recurrent
infections
– Routine immunizations
•
Surgical management
– Anesthesia risk due to underlying cardiomyopathy
•
Psychosocial support
Kishnani et al. Genet Med 2006; 8:267-88. Ing R, et al. Paediatr Anaesth 2004; 14:514-9.
Clinical Benefit of Alglucosidase Alfa Reported in
Pompe patients
Improvements have been observed in
survival, invasive ventilator-free survival,
cardiac function, motor function, and growth
Treatment is associated with
improved walking distance and
stabilization of pulmonary function
Cardiac
Respiratory
Gastrointestinal
Musculoskeletal
Hirschhorn. The Metabolic and Molecular Basis of Inherited Diseases. 2001
CLINICAL DATA
Summary
Treatment of Pompe Disease
•
Pompe disease is a progressive, debilitating and often
fatal neuromuscular disease
•
Encompasses a single-disease continuum with variable
age of onset and rate of disease progression
•
Alglucosidase alfa is the first and only specific
treatment for Pompe disease
•
Prolonged survival and markedly improved
cardiomyopathy in infants treated with alglucosidase
alfa
•
Improvements in motor function and stabilization of
pulmonary function in children and adults treated with
alglucosidase alfa
•
Early diagnosis and treatment may be critical to
optimizing outcomes
SUMMARY