Adult-onset

download report

Transcript Adult-onset

LSD Part 3B
Some examples of treatable
pediatric and adult onset
lysosomal disorders
Serge Melançon MD, FRCPC, FCCMG
Director, Biochemical Genetics Services
February 2010
Gaucher cell 1882
Ernest GAUCHER (1854-1919)
Type 1 Gaucher Disease:
acid β – glucosidase deficiency
The clinical manifestations result from glucosylceramide
engorged macrophages causing:
 enlargement and dysfunction of the liver and spleen,
 displacement of normal bone marrow by storage cells,
and
 damage to bone leading to infarctions and to fractures
 rare adult-onset patients have presented early
symptoms of Parkinson disease.
Type 1 Gaucher Disease:
acid β – glucosidase deficiency
 Some patients with severe visceral (liver and spleen)
enlargement have minimal skeletal involvement,
 Some with severe bone disease have minimal visceral
disease.
 In others, visceral involvement and skeletal involvement
are approximately equal in severity.
 The type of mutation seems to have less influence on
the sites of disease involvement, than on overall
visceral disease severity.
Type 1 Gaucher Disease
• Patients may be diagnosed as late as the eighth or ninth
decade of life.
• Asymptomatic "patients" are ascertained only in the
course of family studies or population surveys.
• Mildly affected individuals are almost invariably found to
have the 1226G/1226G (N370S/N370S) genotype.
• Median age of appearance of the first clinical symptoms
of patients with this genotype is about 30 years.
Emergent concepts in GD
• Neurological: Parkingsonism
• Skeletal: avascular necrosis, lytic lesions, chronic
osteomyelitis (after splenectomy) osteoporotic vertebral
crush fractures, osteonecrosis of pelvis
• Pulmonary: Fibrosis, emphysema
• Neoplastic: hematopoietic malignancies
• Immune: polyarthropathy, coeliac and liver diseases
• Vitamin B12 deficiency
• Co-morbidities: viral or alcoholic hepatitis
Diagnosis of Gaucher Disease
• Assay of acid β-glucosylceramidase enzyme
activity in WBC or skin fibroblasts (unreliable for
carrier detection)
• Bone marrow examination
The changes are nonspecific, and bone marrow
examination is not a reliable diagnostic test.
• Molecular Genetic Testing
sensitivity
11 targeted mutation analysis
98%
Gene sequence analysis
99%
FD case report
• Two males of Italian descent who were identified at ages 38 and
42 years during evaluations for hypercholesterolemia and
rheumatoid arthritis, respectively.
• The finding of proteinuria in each led to renal biopsies that
revealed
accumulation of lamellated crystalline
structures in the cytoplasm of endothelial cells
With podocytes diffusely distended by
numerous intracytoplasmic vacuoles
Fabry disease
• Low levels of α-galactosidase A activity
confirmed their diagnoses.
• Neither had acroparesthesias, angiokeratoma,
anhidrosis, or corneal whorling.
Angiokeratomas
Cornea verticillata
α - Galactosidase A Deficiency: Fabry Disease
•
•
•
X-linked recessive
Systemic deposition of glycosphingolipids
with terminal α-galactosyl moieties (GL3) in
body fluids and in the lysosomes of
endothelial, perithelial, and smooth-muscle
cells of blood vessels.
Deposition also occurs in ganglion cells,
and in many cell types in the heart,
kidneys, eyes, and most other tissues.
α - Galactosidase A Deficiency: Fabry Disease
• Progression is organ-specific in severity and pace,
and does not clearly follow a typical pattern or
sequence in individual patients or cohorts of patients
• Multi-organ assessment and monitoring are required
to determine disease severity
• Early involvement leads to early symptoms involving
the peripheral and autonomic nervous system
• Late complications involve the heart, kidneys, and
cerebrovascular system
α - Galactosidase A Deficiency: Fabry Disease
• Among adults, the age at diagnosis and age at initiation of
ERT were reported to occur 10 and 8 years later in females
than males, respectively.
• Women develop renal, cardiac, and cerebrovascular
manifestations of Fabry disease and a greater effort must
be made to diagnose and monitor these patients.
• Nearly half of the 138 Fabry Registry patients who reported
strokes, experienced them prior to being diagnosed with
Fabry disease.
• This highlights the need for earlier diagnosis, so patients
can be monitored for risk factors associated with stroke.
α - Galactosidase A Deficiency: Fabry Disease
• Children were reported to be diagnosed at a
median age of 9 years for both genders.
• They experienced substantial symptoms, and few
were treated with ERT or received pain
management.
• Children with Fabry disease should be monitored
for signs/symptoms and their neuropathic pain
should be treated appropriately.
Diagnosis of Fabry Disease
Fabry disease should be considered in males and
females with the following signs:
1. Periodic crises of severe pain in the extremities
(acroparesthesias)
2. Vascular cutaneous lesions (angiokeratomas)
3. Hypohidrosis
4. Characteristic corneal and lenticular opacities
5. Stroke
6. Left ventricular hypertrophy
7. Renal insufficiency of unknown etiology
Diagnosis of Fabry Disease
• Alpha-galactosidase A (α-Gal A) enzyme activity
(Unreliable for carrier detection)
• Molecular Genetic Testing
sensitivity
• Sequence analysis/mutation scanning ~ 100%
in males, unknown in females
• Determination of urinary GL3 appears to be a
reliable screening test in affected individuals
(Auray-Blais C et al. Molecular Genetics and Metabolism 93 (2008) 331–340)
PD case report
• 32 years-old female with
back pain
• Progressive proximal
muscle weakness
• Exercise-induced urinary
incontinence
• Disproportionate atrophy
of the paraspinal
muscles seen on CT
scanning
PD case report
• No signs of cardiomyopathy on heart US
• Somnolence, morning headache, orthopnea, and
exertional dyspnea
• Obstructive sleep apnea
• Pulmonary function revealed diminished vital capacity
Pompe is a familial, pan-ethnic Disease
 Estimated prevalence <10,000 patients
worldwide
 Higher frequency in individuals of following
descent:
-African American
-Dutch
-Chinese
Clinical Manifestations
Pompe disease is a metabolic myopathy (cardiac, skeletal and
smooth muscle) with a continuum of clinical manifestations
 From early onset + rapid progression to death
 To later onset + slower progression
(longer survival with marked morbidity)
• Clinical spectrum determined by:
 GAA mutations: fully deleterious  partially deleterious
 GAA activity: total deficiency  partial deficiency
 Glycogen accumulation and muscle damage: rapid  slower
A spectrum of GAA Gene Mutations
Exists In Pompe Disease
GAA mutations
Genzyme data;
Clinicals
n=340
alleles
(Genzyme
n=340
alleles)
c.-32-13T>G
(22%)
c.525delT
(6%)
Del Ex18
(6%)
R854X
5%
R854X
(5%)
As of November 2005, 230 cases genotyped at Genzyme; 59 novel mutations
Patients with Pompe Disease Share a
Common Pathophysiology
GAA Mutations
GAA Deficiency
Muscle Pathology
Total deficiency
OR
Rapid glycogen accumulation
Age at symptoms: <1 year
Partial deficiency
Less rapid glycogen accumulation
Age at symptoms: adulthood
Pompe Disease: Progression
Rate of Clinical Deterioration
Rapid
Slower
[Early symptom onset]
[Later symptom onset]
PLUS
From Nyhan and Ozand
Atlas of Metab Dis
Disease Duration
Short
(death in 1st year of life)
Picture from IPA website
Longer
(with significant morbidity)
Pompe Disease: Onset in Infancy
Quadriceps
Myopathy
Baseline, age 8 mos.
Heart
Cardiomyopathy
Courtesy Dr. B. Byrne
Pompe Disease: Late Onset
Loss of ambulation
Respiratory Failure
Pictures from the IPA Website
Progressive Muscle Weakness Leads to Loss of Independent
Ambulation and Respiratory Failure
(IPA Dutch Cohort; n=54)
1st symptoms
Progressive muscle
weakness
Use of ambulatory devices (48%)
Use of ventilator support (37%)
Hagemans et al. Brain 2005
Diagnosis of Pompe Disease
Specific tests
Acid alpha-glucosidase (GAA) enzyme activity.
In cultured fibroblasts (6 weeks) or in peripheral blood (blood spots)
 Complete deficiency (activity <1% of normal controls) of GAA
enzyme activity in classic infantile-onset PD.
 Partial deficiency (activity that is 2%-40% of normal controls) of GAA
enzyme activity non-classic infantile-onset and late-onset forms
Muscle biopsy.
20%-30% of individuals with late-onset Pompe disease with
documented partial enzyme deficiency may not show any musclespecific changes
Diagnosis of Pompe Disease
Molecular Genetic Testing
• Sequence analysis/mutation scanning
sensitivity
p.Arg854X
p.Asp645Glu
IVS1 -13T>G
Other GAA sequence variants
~ 50%-60%
~ 40%-80%
~ 50%-85%
83%-93%
Overall Survival at 18 Months of Age
18/18 trial patients
[100%]
1/61 untreated controls
[2%; 95% CI: 0% - 6%]
Clinical Trial Patients
Untreated Historical Cohort
95% Confidence Intervals
Survival Free of Invasive Ventilation
at 18 Months of Age (Primary End Point)
15/18 trial patients
[83%; 95% CI: 66% - 100%]
1/61 untreated controls
[2%; 95% CI: 0% - 6%]
Clinical Trial Patients
Untreated Historical Cohort
95% Confidence Intervals
Changes in LV Mass (by cardiac echo)
All patients with data showed reduction in LV mass: 58% after 1 year of Myozyme, in average
+7.1 Z-score
9
8
Meqn LVM Z-score
7
6
+3.2 Z-score
5
4
3
2
Upper Limit of Normal
1
0
-1
Baseline
Week 26
Week 52
Challenges: Treat Early
Functional Status Worsens with Longer Disease Duration
Percent of Muscle Glycogen Increases with Age
% 70
60
50
47%
40
30
28%
20
10
0
< 6 months
6 months – 3 years
Late onset PD Trials
Forced Vital Capacity (FVC)
Study 2704, ‘LOTS’: Design
• 90 patients enrolled at 8 sites in US and EU
– 10 to 70 years (Mean = 44.5 years)
– 0 to 45.4 years symptoms duration (Mean = 15.7 years)
• Randomized, double-blind, placebo-controlled 12 month
study with 2:1 drug to placebo assignment
– US – 58 patients (2 pediatric, 56 adults)
– EU – 32 patients (2 pediatric, 30 adults)
• All patients were ambulatory and not invasively ventilated
• Pulmonary and muscle strength and function were
assessed every 12 weeks
– Primary Endpoints
• Distance walked in 6 minutes
• Forced Vital Capacity (FVC)
• Results
– Clinical benefits were seen for respiratory and motor function
Jessica, MPS I
MPS I
• Progressive, inherited
• Lysosomal storage disorder
– deficiency of -L- iduronidase enzyme
– progressive accumulation of
glycosaminoglycans (GAGs)
Multisystemic Manifestations
•
•
•
•
•
•
•
Brain
Ears, nose, throat
Lungs
Heart
Liver
Spleen
Bones and joints
MPS I Major Manifestations
Facial dysmorphism
Communicating
hydrocephalus
Developmental delay
Hearing loss
Corneal clouding
Skeletal abnormalities
Obstructive airway disease
Cardiac complications
Hepatomegaly
Joint stiffness
MPS I Spectrum of Disease Severity
Severe
Less severe
-L-iduronidase deficiency
Hurler
Hurler-Scheie
Scheie
Disease Progression: Severe MPS I
10 months
12 months
39 months
22 months
34 months
Disease Progression: Moderate MPS I
6 years
Disease Progression: mild MPS I
3 years
4 years
11 years
6 years
8 years
Diagnosis of MPS I
• Patients see several specialists before diagnosis
• Presumptive diagnosis
– observation of symptoms and laboratory findings
• coarse facial features
• hepatosplenomegaly
• skeletal, joint, or ocular findings characteristic of MPS I
• Family history/medical pedigree
• Analysis of urinary GAGs
Enzyme Assay: Definitive Diagnosis
• Assay for a-L-iduronidase activity
– measure in leukocytes, cultured skin fibroblasts,
serum, plasma
• Markedly deficient in affected patients
– less than 1% normal
• Enzyme activity does not correlate with
disease severity
THE END
OF
LYSOSOMAL
DISORDERS