Transcript History of the LSDs - Department of Medical Genetics

The Lysosome and lysosomal
storage disorders (LSD)
Part 3A
Clinical profile of the LSDs
Serge Melançon, MD
February 2010
PREVALENCE
The lysosomal diseases are a group
of more than 50 inherited metabolic
disorders with a total incidence
of 3-4 cases per 10,000 newborns.
Lysosomal Storage Disorders
Sandoff 2%
Gaucher
14%
Gm1 Gangliosidosis 2%
Mucolipidosis II/III 2%
Niemann Pick A/B 3%
MPS I H/S
9%
Maroteaux-Lamy 3%
Niemann Pick C
4%
Sanfilippo B
4%
Metachromatic
Leukodystrophy
8%
Tay-Sachs
4%
Cystinosis
4%
Sanfilippo A
7%
Morquio
5%
Pompe
5%
(For Australia1980-1996; Meikle et al., JAMA 281;249-254
Krabbe
5%
Hunter
6%
Fabry
7%
MPS
34%
PRESENTATION AND PROGRESSION
 While early onset pediatric forms of LSD present with
classical and rapidly progressive clinical courses,
 Heterogeneous and unusual clinical presentations
are the hallmark of common adult forms of LSD
PRESENTATION AND PROGRESSION
• Heterogeneous presentation across the
LSD categories and often even within a
single disease
• Wide clinical variability according to
different types of substrate stored and
locations of storage
• Clinical manifestations tend to be
progressive, as more waste substrate
accumulates over time.
PRESENTATION AND PROGRESSION
• As a group, LSDs affect nearly every organ
and system
• Symptoms vary in severity from relatively
mild to severe somatic and rapidly
progressive neurological manifestations
CLINICAL SPECTRUM
"Red Flag"
Symptoms
"Red Flag" Symptoms
• While none is an LSD hallmark, several
present across enough of the disorders to
raise a physician's suspicion and prompt
further investigation.
• LSD symptoms often present in clusters,
so the appearance of more than one of
these is even more suggestive
"Red Flag" Symptoms
1. Coarse facial features (sometimes with macroglossia)
2. Corneal clouding or related ocular abnormalities
3. Angiokeratoma
4. Umbilical / inguinal hernias
5. Short stature
6. Developmental delays
7. Joint or skeletal deformities
8. Visceromegaly (especially liver and spleen)
9. Muscle weakness or lack of control (ataxia, seizures, etc.)
10. Neurologic failure/decline or loss of gained development
Coarse facial features
Corneal clouding
Umbilical hernia
Skeletal
Abnormalities
Gaucher
MPS I
Angiokeratoma
Visceromegaly
Joint deformities
"Red Flag" Symptoms
Particularly noteworthy are the following signs:
1. Loss of motor skills,
2. Increasing dementia or behavioural abnormalities,
3. Muscular or neurological deterioration,
That suggest a progressive / degenerative disorder.
Cystine crystal deposits
Kyphosis
Aspartylglycosaminuria
Lymphadenopathy
Farber
Cystinosis
Ataxia
Krabbe
Hypertonia
Disease
Strabismus
Retinitis pigmentosa
Cherry red spot
Infantile Sialic acid SD
Small jaw
Neuronal ceroid lipofuscinosis
GM2 Gangliosidosis
Cardiomegaly
Macroglossia
Picnodysostosis
Pompe
Muscle waisting
Hypotonia
PROGRESSION AND
OUTCOME
PROGRESSION AND OUTCOME
• Predicting LSD progression and outcome
is challenging, especially in later-onset
patients
• LSDs with neurological involvement are
often the most severe with rapid decline
and high mortality rates
PRESENTATION AND PROGRESSION
• One disease is often associated with several
different gene mutations, which may account
in part for the disease's clinical heterogeneity.
• However, the very same mutations may result
in quite different outcomes in different
patients and genotype-phenotype correlations
are not always consistent
PRESENTATION AND PROGRESSION
Other factors can also influence outcome:
1. residual enzyme activity versus complete
deficiency,
2. age of diagnosis and of onset of treatment
or supportive care
3. environmental influences;
4. unknown genetic and epigenetic factors
PROGNOSIS
PROGNOSIS
• Early diagnosis is essential for more
diverse treatment options
• Early intervention is mandatory for the
most serious and debilitating symptoms,
particularly neurological and skeletal
• Once established these often will not
respond to even disease-specific
therapies
DISEASE MANAGEMENT
• Requires a multidisciplinary team
approach, with a lead physician
directing care and referring to other
specialists as necessary
• Treatment options vary across the LSDs
• Often various therapies and/or care will
be offered
The Treatment Team
Pediatrician
Ophthalmologist
Pulmonologist
Cardiologist
Surgeon
Otorhinolaryngologist
Interventional
Geneticist
Orthopedist
Neurologist
Dentist
Anesthesiologist
Gastroenterologist
Genetic Counselor
DISEASE MANAGEMENT
• For most LSDs, no disease-specific therapy is
currently available
• Clinical manifestations can only be addressed
through palliative measures such as physical
therapy, dialysis or surgery
• These methods can be effective in managing
symptoms, but they do not affect the
pathophysiology of the disease
DISEASE-SPECIFIC TREATMENT OPTIONS
DISEASE-SPECIFIC TREATMENT OPTIONS
• Hematopoietic stem cell transplant
(HSCT)
Healthy stem cells (from bone marrow or
cord blood) are transplanted i.v. to provide
normal enzyme producing cells to the
patient
• Enzyme replacement therapy (ERT)
A recombinant form of the deficient enzyme
is infused i.v. at definite intervals
DISEASE-SPECIFIC TREATMENT OPTIONS
• Enzyme enhancement therapy (EET)
Misfolded enzyme is stabilized during its
synthesis by the use of small chemical
chaperones
• Substrate reduction therapy (SRT)
The rate of production of the substrate is
slowed by drug therapy
Hematopoietic stem cell transplant
• First attempted in the 1980s and mostly used
for MPS I
• Positive results when performed early in a
disease's course, despite its challenges and
risks
 transplant failure or rejection
 toxicity of the conditioning regimen
 difficulty finding a good donor match
• Improved chance for success in newborns with
naturally suppressed immune systems
ENZYME REPLACEMENT THERAPY
ENZYME REPLACEMENT THERAPY
• R&D began in the mid-1960s
• Clinical trials by the 1980s
• Advances in recombinant DNA
manufacturing in the early 1990s
enabled enzyme production in
quantities large enough for
commercial development
ENZYME REPLACEMENT THERAPY
• The first ERT went on the market in
1991 for Gaucher type I
•
ERT is a treatment option for 6 LSDs
1. Gaucher Type I
2. Fabry
3. MPS I (Hurler/Scheie)
4. MPS II (Hunter)
5. Pompe (GSD type II)
6. MPS VI (Maroteaux-Lamy)
CURRENT COST OF ERT
SUBSTRATE REDUCTION THERAPY
• SRT was introduced in 2002 for Gaucher
Type I patients where ERT is not an option
• Further clinical studies are in progress for
 Fabry disease
 GM2-gangliosidoses (Tay-Sachs, Sandhoff,
GM2 activator disease)
 Niemann-Pick type C
Before SRT
After SRT
Glucosylceramide exceeds
capacity of residual
glucocerebrosidase activity.
Reduced level of glucosylceramide
helps relieve the burden on the
residual glucocerebrosidase.
RESEARCH EFFORTS FOR LSD
RESEARCH EFFORTS FOR LSD
TREATMENT OPTIONS
• Both HSCT and ERT have limited efficacy on
neurological symptoms, since the large
enzyme molecules cannot penetrate the
blood-brain barrier
• ERT development continues to face
challenges, such as difficulties targeting the
affected cell in remote tissues, such as joint,
bone and brain
RESEARCH EFFORTS FOR LSD
TREATMENT OPTIONS
• Small molecule drugs can generally be
administered orally and cross the blood-brain
barrier where they act as pharmacologic
"chaperones” to enable deficient proteins
• Enzyme enhancement therapy attempts to
stabilize misfolded protein and restore
enzyme activity
RESEARCH EFFORTS FOR LSD
TREATMENT OPTIONS
• Substrate synthesis inhibition therapy
 attempts to block a step in the production
of waste to minimize the accumulation
 may be most effective in patients with
some residual enzyme activity (rather than
total deficiency) and as an adjunct to other
treatments (such as ERT)
RESEARCH EFFORTS FOR LSD
TREATMENT OPTIONS
• Gene therapy
 involves replacing the patient's mutated
gene with a normal copy so proper enzyme
production can occur
 still only in preclinical (animal) studies, and
much research is needed, especially in
identifying appropriate vectors for gene
delivery
GENE THERAPY
ANY BURNING
QUESTION AT
THIS POINT?
How about an
exam question?
Biochemical and Cellular basis of lysosomal
storage disorders
1.
Most mutations result in the delivery of a defective
enzyme with a reduced catalytic activity to lysosomes
2.
Another (activator) protein required for optimal
hydrolase activity is defective or absent
3.
A mutation that causes misfolding results in defective
transport of a lysosomal hydrolase out of the
endoplasmic reticulum
4.
Alternatively, defective transport of a lysosomal
hydrolase out of the ER occurs because a multienzyme complex that is required for transport cannot
form (Cathepsin A / sialidase / -galactosidase )
Biochemical and Cellular basis of LSDs…
5
In the Golgi, defective glycosylation could result in
an enzyme with reduced catalytic activity
6
Alternatively, defective glycosylation with mannose6-phosphate in the Golgi could produce an enzyme
that cannot reach lysosomes
7
Defects in other transport steps from the Golgi
could also lead to an LSD
8
Defects in integral lysosomal membrane proteins
with transporter roles
9
Defects in proteins that are involved in other vital
regulatory events of lysosomal function (LAMP2,
lysosomal associated membrane protein 2)
Biochemical and Cellular basis of LSDs
1 catalytic activity
2 activator
3 misfolding
4 multienzyme complex
5 glycosylation
6 M-6-P targetting
7 other transport steps
8 membrane transporters
9 membrane regulators
Futerman AH & van Meer G (2004) 5:554-565