POMPE DISEASE: A Clinical Spectrum

1
POMPE DISEASE A Clinical Spectrum
2
POMPE DISEASE INTRODUCTION
OVERVIEW

• Rare, progressive, and often fatal
• Irreversible pathology caused by deficiency of
  lysosomal acid alpha-glucosidase (GAA)
• Autosomal recessive genetic mutations
• Spectrum of disease with a range of signs and
  symptoms
• Classified in three disease families
• Also considered a cardiac disorder due to
  prominent cardiomyopathy/cardiomegaly in infants

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420. Raben N, et al. Curr Mol Med.
20022145-166.
3
POMPE DISEASE HISTORY
OVERVIEW
Cori GT. Harvey Lect. 19548145-171. Engel AG.
Brain. 197093599-616. Hers HG. Biochem J.
19638611-16. Hirschhorn R, et al. In The
Metabolic and Molecular Bases of Inherited
Disease. 20013389-3420. Hudgson P, et al.
Brain. 196891435-462. Pompe JC. Ned Tijdschr
Geneeskd. 193276304-312. Reuser AJJ, et al.
Eur J Pediatr. 2002161S106-S111. Stoeckle H,
et al. Am J Cardiol. 19618675-681.
4
POMPE DISEASE NEED FOR COMMON NOMENCLATURE
OVERVIEW

• Synonyms
• Glycogen storage disease type II (GSD-II)
• Acid maltase deficiency (AMD)
• Glycogenosis, type II
• Disease Families
• Lysosomal storage disease
• Glycogen storage disease
• Neuromuscular disease/metabolic muscle disease

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
5
POMPE DISEASE A CONTINUUM OF CLINICAL PHENOTYPES
OVERVIEW
6
POMPE DISEASE PATHOGENESIS
PATHOLOGY

• GAA essential for degradation of lysosomal
  glycogen
• Deficit causes accumulation and distention

Raben N, et al. Curr Mol Med. 20022145-166..
7
POMPE DISEASE TISSUE DESTRUCTION
PATHOLOGY

• Myofibrils replaced by glycogen with eventual
  muscle tissue destruction

Data on file, Genzyme Corporation.
Raben N, et al. Curr Mol Med. 20022145-166..
8
POMPE DISEASE KEY ORGAN SYSTEMS IMPACTED
PATHOLOGY

• Glycogen storage primarily affects muscle tissue
• Major muscle groups
• Cardiac muscle (infantile)
• Proximal skeletal muscle (esp. in trunk and lower
  limbs)
• Respiratory muscles

Glycogen accumulation in cardiac muscle
Data on file, Genzyme Corporation.
Data on file, Genzyme Corporation.
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
9
POMPE DISEASE EXTENT OF ENZYME ACTIVITY
PATHOLOGY

• Residual GAA activity is generally inversely
  correlated with disease severity
• Infantile-onset Late-onset lt1 of
  normal lt40 of normal

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
10
POMPE DISEASEEPIDEMIOLOGY
INHERITANCE
Varies by ethnic group highest among
African-Americans and Chinese.
Ausems MGEM, et al. Community Genet.
1999291-96. Hirschhorn R, et al. In The
Metabolic and Molecular Bases of Inherited
Disease. 20013389-3420.
11
POMPE DISEASE INHERITANCE PATTERN
INHERITANCE
Adapted from Hirschhorn R, et al. In The
Metabolic and Molecular Bases of Inherited
Disease. 20013389-3420.
12
POMPE DISEASE GENETICS
INHERITANCE

• GAA gene located on chromosome 17
• Around 150 mutations in GAA gene identified to
  date
• Defects include missense and nonsense base pair
  changes, splicing defects, and small and large
  deletions and insertions
• Some mutations are common in general populations
  or certain ethnic groups, but most are private
  mutations identified in individual patients
• Updated list of mutations
• www2.eur.nl/fgg/ch1/pompe/mutations.html

Raben N, et al. Curr Mol Med. 20022145-166.
Mutations in GSD II. http//www2.eur.nl/fgg/ch1/p
ompe/mutations.html.
13
POMPE DISEASE COMMON MUTATIONS
INHERITANCE
Chinese patients from Taiwan
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
14

POMPE DISEASE OVERVIEW OF CLINICAL FEATURES
CLINICAL PRESENTATION
Infantile-onset
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
15

POMPE DISEASE OVERVIEW OF CLINICAL FEATURES
CLINICAL PRESENTATION
Late-onset
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
16
POMPE DISEASE PHYSICAL DISABILITY
CLINICAL PRESENTATION
Severe Functional Deficit Relative To Patient Age

• Pompe PEDI (Pediatric Evaluation of Disability
  Inventory) used to assess functional status of 30
  children and adolescents

Mean chronological age 7.6 years Mean-age
mobility performance 1.5 years
Age (yr)
1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20 21
22 23 24 25 26 27 28 29 30
Patient Numbers
Haley SM, et al. Develop Med Child Neurol.
200345618-623.
17
INFANTILE-ONSET POMPE DISEASE SPECTRUM OF
DISEASE PROGRESSION
CLINICAL PRESENTATION
18

INFANTILE-ONSET POMPE DISEASEKEY CLINICAL
FEATURES
CLINICAL PRESENTATION

• Profound and rapidly progressive muscle weakness
  (hypotonia/floppy baby"/head lag)
• Delayed motor development
• Marked cardiomegaly/cardiomyopathy
• Progression to cardiac failure
• Frequent respiratory infections/aspiration
  pneumonia
• Progression to respiratory insufficiency
• Organomegaly (hepatomegaly, splenomegaly,
  macroglossia)
• Feeding difficulties, failure to thrive

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
19
INFANTILE-ONSET POMPE DISEASEMUSCULOSKELETAL
CLINICAL PRESENTATION

• Musculoskeletal
• Profound and rapidly progressive muscle weakness
• Cardiac
• Marked cardiomegaly/cardiomyopathy
• Respiratory
• Progression to respiratory insufficiency

Data on file, Genzyme Corporation.
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
20

INFANTILE-ONSET POMPE DISEASECARDIAC
CLINICAL PRESENTATION

• Cardiomegaly
• Chest x-ray
• Cardiomyopathy
• Echocardiogram
• Progression to cardiac failure
• EKG abnormalities
• Short PR intervals
• Tall QRS complexes

With permission from B. Byrne, MD
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
21
INFANTILE-ONSET POMPE DISEASEPULMONARY
CLINICAL PRESENTATION

• Respiratory distress/insufficiency
• Arterial blood gas
• Sleep studies
• Infections
• Ventilator support

Data on file, Genzyme Corporation.
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420. Raben N, et al. Curr Mol Med.
20022145-166.
22
INFANTILE-ONSET POMPE DISEASENATURAL HISTORY
CLINICAL PRESENTATION
van den Hout HMP, et al. Pediatrics.
2003112332-340. Data on file, Genzyme
Corporation.
23
INFANTILE-ONSET POMPE DISEASE SURVIVAL
CLINICAL PRESENTATION
van den Hout HMP, et al. Pediatrics.
2003112332-340. Data on file, Genzyme
Corporation.
24
INFANTILE-ONSET POMPE DISEASESURVIVAL
CLINICAL PRESENTATION
Based on n163 with available data.
Data on file, Genzyme Corporation.
25
INFANTILE-ONSET POMPE DISEASESYMPTOM FREQUENCY
AND ONSET
CLINICAL PRESENTATION














Data on file, Genzyme Corporation.
26
INFANTILE-ONSET POMPE DISEASEDIFFERENTIAL
DIAGNOSIS
CLINICAL PRESENTATION

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.Johns DR. In Harrisons
Principles of Internal Medicine. 15th ed.
2001404-407. Lotz BP. In Neuromuscular Function
and Disease Basic, Clinical, and
Electrodiagnostic Aspects. 20021443-1445.
27
INFANTILE-ONSET POMPE DISEASEDIFFERENTIAL
DIAGNOSIS (cont.)
CLINICAL PRESENTATION
Chen Y-T. In Harrisons Principles of Internal
Medicine. 15th ed. 20012281-2289. Johns DR. In
Harrisons Principles of Internal Medicine. 15th
ed. 2001404-407.
28
LATE-ONSET POMPE DISEASE SPECTRUM OF DISEASE
PROGRESSION
CLINICAL PRESENTATION
29
LATE-ONSET POMPE DISEASE KEY CLINICAL FEATURES
CLINICAL PRESENTATION

• Skeletal Muscles
• Progressive proximal muscle weakness, especially
  in trunk and lower limbs
• Gait abnormality
• Respiratory Muscles
• Respiratory symptoms
• Shortness of breath
• Fatigue on exertion
• Progression to respiratory failure
• Sleep-disordered breathing
• Others
• Scoliosis
• Scapular winging
• Muscle pain
• Frequent falls

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
30
LATE-ONSET POMPE DISEASE PROXIMAL WEAKNESS
CLINICAL PRESENTATION

• Weakness in the pelvic girdle muscles
  demonstrated by positive Gowers maneuver

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
31

LATE-ONSET POMPE DISEASESCAPULAR WINGING
CLINICAL PRESENTATION

• Atrophy of scapular and paraspinal muscles

Courtesy of Dr Herman F.M. Busch, Erasmus MC,
Rotterdam, The Netherlands.
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
32
LATE-ONSET POMPE DISEASENATURAL HISTORY
CLINICAL PRESENTATION
Mellies U, et al. Neurology. 2001571290-1295.
Data on file, Genzyme Corporation.
33
LATE-ONSET POMPE DISEASEQUALITY OF LIFE
CLINICAL PRESENTATION
Physical Health Measures
Mental Health Measures

• Significantly poorer quality of life vs general
  population (Plt0.001)
• On following scales physical functioning, role
  functioning-physical, general health, vitality,
  and social functioning

Hagemans MLC, et al. Neurology.
2004631688-1692.
34
LATE-ONSET POMPE DISEASE DIFFERENTIAL DIAGNOSIS
CLINICAL PRESENTATION
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
35

POMPE DISEASE DIAGNOSTIC TOOLS
DIAGNOSIS

• GAA enzyme activity (tested on glycogen or 4-MUG)
• Skin fibroblasts
• Muscle biopsy
• Leukocytes
• Dried blood spot (emerging technology)
• Mutation Analysis
• Especially for carrier testing (family/sibling)
• Prenatal diagnosis
• Amniocentesis
• Chorionic villi sampling
• Newborn screening (emerging technology)
• GAA activity in dried blood spot with analysis by
  fluorometry or mass spectrometry

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420. Umapathysivam K, et al. Clin
Chem. 2001471378-1383. Yijun L et al. Clin
Chem. 2004501785-1796, Chamoles N, et al. Clin
Chimica Acta. in press
36

POMPE DISEASE COMMON ASSESSMENT TOOLS
DIAGNOSIS

• Muscle
• Quantitative muscle testing (QMT)
• Manual muscle testing (MMT)
• Electromyography (EMG)
• Histopathology
• Motor function
• Pompe-Specific Pediatric Evaluation of Disability
  Inventory (Pompe PEDI)
• Evaluation for achievement of motor milestones
• Functional motor testing (timed tests, arm and
  leg functional testing)

Data on file, Genzyme Corporation.
Data on file, Genzyme Corporation.
Used in late-onset disease
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420.
37
POMPE DISEASE COMMON ASSESSMENT TOOLS (cont.)
DIAGNOSIS

• Cardiac
• Echocardiography
• Electrocardiography
• Chest x-ray
• MRI
• Pulmonary
• Pulmonary function tests (spirometry)
• Sleep studies
• Labs
• Creatine kinase (CK)
• Alanine and aspartate aminotransferase (ALT/AST)
• Urinary oligosaccharides (under investigation)

Data on file, Genzyme Corporation.
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420. An Y, et al. Mol Genet Metab.
200585247-254.
38

POMPE DISEASE DISEASE MANAGEMENT
PATIENT SUPPORT
Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420. Bodamer O, et al. Eur J Pediatr.
1997156S39-42. Treating Pompe.
http//www.pompe.com/healthcare/treating/pc_eng_hc
_treating.asp.
39
POMPE DISEASEPATIENT RESOURCES AND ASSOCIATIONS
PATIENT SUPPORT

• Pompe Community Website (Genzyme)www.pompe.com
• International Pompe Associationwww.worldpompe.or
  g
• Acid Maltase Deficiency Association
  (AMDA)www.amda-pompe.org
• United Pompe Foundationwww.unitedpompe.com
• Muscular Dystrophy Association (MDA)www.mdausa.o
  rg
• Association for Glycogen Storage
  Diseasewww.agsdus.org
• Association for Glycogen Storage Disease
  (UK)www.agsd.org.uk
• Australian Pompes Associationwww.pompedownunder
  .org
• National Organization for Rare Disorders, Inc.
  (NORD)www.rarediseases.org

These listings are provided by Genzyme as
additional information on Pompe disease.  The web
pages and their content are maintained by the
organizations listed.  With the exception of its
own websites, Genzyme does not endorse any
particular organization or the content contained
on their websites.
40
POMPE DISEASEEMERGING THERAPEUTIC STRATEGY
ENZYME REPLACEMENT THERAPY
TREATMENT OPTIONS

• Investigational ERT Phase II/III study in infants
  completed
• Other investigational ERT studies are ongoing

Hirschhorn R, et al. In The Metabolic and
Molecular Bases of Inherited Disease.
20013389-3420. Amalfitano A, et al. Genetics
Med. 20013132-138.
41
POMPE DISEASE INVESTIGATIONAL TREATMENT GENE
THERAPY
TREATMENT OPTIONS

• Goal to supply functional gene for enzyme needed
• Usually delivered via modified virus
• Serious safety concerns found with other diseases
• Pre-clinical testing ongoing
• Currently no approved gene therapies

Zaretsky JZ, et al. Hum Gene Ther.
199781555-1563. Pauly DF, et al. Gene Ther.
19985473-480.
42
POMPE DISEASE SUMMARY
CONCLUSIONS

• Continuum of clinical phenotypes from
  infantile-onset to late-onset disease
• Common pathophysiology GAA deficit leads to
  glycogen accumulation in tissues
• Autosomal recessive inheritance makes genetic
  counseling important with family history or
  affected child
• Early diagnosis is key to optimal management of
  symptoms
• Current management consists of multidisciplinary
  supportive measures
• Enzyme replacement therapy to address GAA deficit
  is currently being studied