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LSD Part 3BLSD Part 3BSome examples of treatable Some examples of treatable
pediatric and adultpediatric and adult onsetonsetlysosomal disorderslysosomal disorders
Serge Melançon MD, FRCPC, FCCMGDirector, Biochemical Genetics Services
February 2010February 2010
Ernest GAUCHER (1854-1919)
Gaucher cell 1882
Type 1 Gaucher Disease:acid β – glucosidase deficiency
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.
The clinical manifestations result from glucosylceramide engorged macrophages causing:
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.
• 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
Emergent concepts in GD
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 sensitivity11 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
With podocytes diffusely distended by numerous intracytoplasmic vacuoles
accumulation of lamellated crystalline structures in the cytoplasm of endothelial cells
Fabry disease• Low levels of α-galactosidase A activity
confirmed their diagnoses.• Neither had acroparesthesias, angiokeratoma,
anhidrosis, or corneal whorling.
Cornea verticillataAngiokeratomas
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.
• 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.
α - Galactosidase A Deficiency: Fabry Disease
Diagnosis of Fabry Disease
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
Fabry disease should be considered in males and females with the following signs:
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
R854X5%
GAA mutations Genzyme Clinicals n=340 alleles
As of November 2005, 230 cases genotyped at Genzyme; 59 novel mutations
c.-32-13T>G(22%)
c.525delT(6%)
Del Ex18(6%)
R854X(5%)
(Genzyme data; n=340 alleles)
Patients with Pompe Disease Share a Common Pathophysiology
Total deficiency
Partial deficiency
GAA Mutations GAA Deficiency Muscle Pathology
Less rapid glycogen accumulationAge at symptoms: adulthood
Rapid glycogen accumulationAge at symptoms: <1 year
OR
Pompe Disease: Progression
Rate of Clinical Deterioration
Rapid Slower
Disease Duration
[Early symptom onset] [Later symptom onset]
Longer(with significant morbidity)
Short(death in 1st year of life)
PLUS
Picture from IPA websiteFrom Nyhan and OzandAtlas of Metab Dis
Baseline, age 8 mos.
Myopathy
Cardiomyopathy
Quadriceps
Heart
Pompe Disease: Onset in Infancy
Courtesy Dr. B. Byrne
Pictures from the IPA Website
Loss of ambulation Respiratory Failure
Pompe Disease: Late Onset
1st symptoms
Progressive muscle weakness
Use of ambulatory devices (48%)
Use of ventilator support (37%)
Progressive Muscle Weakness Leads to Loss of Independent Ambulation and Respiratory Failure
(IPA Dutch Cohort; n=54)
Hagemans et al. Brain 2005
Diagnosis of Pompe Disease
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 muscle-specific changes
Specific tests
Diagnosis of Pompe Disease
• Sequence analysis/mutation scanning sensitivity
p.Arg854X ~ 50%-60% p.Asp645Glu ~ 40%-80% IVS1 -13T>G ~ 50%-85%
Other GAA sequence variants 83%-93%
Molecular Genetic Testing
Overall Survival at 18 Months of Age
Clinical Trial Patients
Untreated Historical Cohort
18/18 trial patients[100%]
1/61 untreated controls[2%; 95% CI: 0% - 6%]
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)
Upper Limit of NormalUpper Limit of Normal
All patients with data showed reduction in LV mass: 58% after 1 year of Myozyme, in averageM
eqn
LVM
Z-s
core
Baseline Week 26 Week 52
-1
0
1
2
3
4
5
6
7
8
9+7.1 Z-score
+3.2 Z-score
Challenges: Treat Early
0
10
20
30
40
50
60
% 70
47%
28%
Percent of Muscle Glycogen Increases with Age
< 6 months 6 months – 3 years
Functional Status Worsens with Longer Disease Duration
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 DiseaseMPS I Spectrum of Disease SeveritySeverity
HurlerHurler
LL-iduronidase deficiency-iduronidase deficiency
Less severeLess severeSevere Severe
Hurler-ScheieHurler-Scheie ScheieScheie
Disease Progression: Severe MPS IDisease Progression: Severe MPS I
10 months 12 months
22 months 34 months
39 months
Disease Progression: Moderate MPS I
6 years
Disease Progression: mild MPS I
3 years 4 years
6 years 8 years
11 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 THE END OF OF
LYSOSOMALLYSOSOMALDISORDERSDISORDERS