Transcript pps lecture - Statistics

‫بسم هللا الرحمن الرحیم‬
Alexander
&
canavan
Leukodystrophies
Dr Bita Shalbafan
Neurologist
Labafi nejad Hospital
Alexander disease
Definition
Alexander disease is a rare genetic
disorder that predominantly affects
infants and children and is
associated with cerebral white
matter disease.
Pathophysiology
Sporadic mutations in the GFAP
gene are the cause of most cases
of Alexander disease.
Pathology
Intracytoplasmic astrocytic
inclusions known as
Rosenthal fibers are the
hallmark of Alexander GFAP
is the intermediate filament
peculiar to the astrocytes,
where it contributes to
cytoskeletal formation and
maintenance, cell
communication, and may
affect functioning of the
blood–brain barrier.
disease.
The diagnosis
The diagnosis of Alexander disease can be
established based upon clinical and radiographic
(MRI) features.
The diagnosis is usually confirmed by
demonstrating a GFAP gene mutation.
Although genetic testing is not necessarily required
for the diagnosis, genetic confirmation should
always be attempted due to the heterogeneity of
the disease and its presentation.
Differential diagnosis
The differential diagnosis of Alexander disease
involves consideration of other disorders that
present with macrocephaly and/or cerebral
white matter changes.
subtypes of Alexander disease
Four subtypes of Alexander disease —
neonatal, infantile, juvenile, and adult — are
traditionally recognized
But
a revised classification of Alexander disease
proposes two subtypes – types I and II – based
upon statistical analyses:
Prevalence
Prevalence of various forms of AxD was
determined as
27.3% (infantile),
24.2% (juvenile),
and 48.5% (adult).
type I
The main characteristics of
infantile and juvenile AxD
include
delayed psychomotor
development
or mental retardation,
convulsions,
macrocephaly,
and predominant cerebral white
matter abnormalities in the
frontal lobe on brain MRI.
Type II
Type II onset may occur across the lifespan,
The main characteristics of adult AxD include
bulbar signs,
muscle weakness with hyperreflexia,
autonomic dysfunction,
eye movement abnormalities,
bulbar symptoms,
and atypical neuroimaging signal abnormalities
(and/or atrophy of medulla oblongata and
cervical spinal cord on MRI features)
why in some patients GFAP mutations lead to late onset ?
In particular, it is not clear why in some patients GFAP
mutations lead to late onset and prevalent localization of
pathological, neuroradiological and clinical changes in
the lower brainstem, while in other patients AD onset
occurs early and supratentorial abnormalities dominate
the picture. The explanation for these different
phenotypes may reside in the affected mutation sites
and their effects on the GFAP protein, as confirmed for a
few mutations observed in adults, which displayed an
effect milder than severe mutations associated with . In
addition, other genetic or still unknown environmental
factors have been hypothesized to influence the
phenotype These modifiers might explain the variable
disease expressivity and the reduced penetrance of
some variants, which may also be detected in healthy
parents infantile AD
Typical MRI features of Alexander
disease
1-Extensive cerebral white
matter changes with
frontal predominance,
2-Periventricular rim of high
T1 signal and low T2 signal,
Subependymal cysts
3-Basal ganglia and thalamic
abnormalities,
4-Contrast enhancement of
selected gray and white
matter structures
5-Brainstem abnormalities
The clinical picture is not specific, but
AOAD must be considered in
patients of any age with lower
brainstem signs. When present,
palatal myoclonus is strongly
suggestive of AOAD. Pyramidal
involvement, cerebellar ataxia,
urinary disturbances and sleep
disorders are common.
Infrequent findings include scoliosis
and dysautonomia. Fluctuations
may occur. The course is variable,
usually slowly progressive and less
severe than the AD forms with
earlier onset.
Less common MRI features
1-Multifocal brainstem
lesions resembling
multiple tumors,
2-Medullary and cervical
spinal cord signal
abnormalities or
3-atrophy
4-Ventricular garlands
Prevalence of AxD in Japan was estimated to •
be approximately 1 case per 2.7 million
individuals
Treatment
Treatment of
Alexander
disease
remains
supportive.
Canavan disease
History
Canavan disease, also called
Canavan-Van Bogaert-Bertrand
disease,
aspartoacylase deficiency or
aminoacylase 2 deficiency,
degenerative disorder
that causes progressive damage
to nerve cells in the brain
Canavan disease has an autosomal
recessive pattern of inheritance
Pathophysiology
Aspartoacylase deficiency is
caused by mutations in the
ASPA gene that encodes the
enzyme aspartoacylase.
The resulting deficiency of
aspartoacylase leads to
accumulation of Nacetylaspartic acid (NAA)
Pathology
The resulting deficiency of
aspartoacylase leads to
accumulation of N-acetylaspartic
acid (NAA) in brain and to
oligodendrocyte dysfunction,
spongiform changes, and absence
of myelin. However, the precise
mechanisms causing to
spongiform degeneration are
uncertain.
Symptoms
Aspartoacylase deficiency typically presents at
about age three months with lethargy and
listlessness, weak cry and suck, poor head control,
and hypotonia with a paucity of extremity
movement.
Macrocephaly becomes prominent by three to
six months. Thereafter hypotonia progresses to
spasticity and tonic extensor spasms.
By age six months, neurologic abnormalities are
invariant. Little subsequent development is noted.
Blindness from optic atrophy occurs between 6
and 18 months.
Seizures are noted in about 50 percent of patients.
Pseudobulbar signs and decerebrate posturing
dominate the end stage.
Brain imaging
Brain imaging by CT and MRI reveals
diffuse and symmetrical white matter
involvement
pathologic findings
The gross pathologic findings are dominated
by spongy degeneration of
deep cortex,
subcortical white matter,
and cerebellum.
The spongiform changes reflect vacuolated
astrocytes in deeper cortical layers and in
adjacent subcortical white matter.
Diagnosis
the diagnosis of aspartoacylase
deficiency is supported by
1- elevated levels of urine Nacetylaspartic acid (NAA) and
2-deficient aspartoacylase
activity in cultured skin
fibroblasts.
3-Genetic testing may be
obtained for purposes of genetic
counseling.
Differential diagnosis
The differential diagnosis of
aspartoacylase deficiency includes
other progressive white matter
diseases
of infancy, particularly
-Krabbe disease,
-metachromatic leukodystrophy,
-early-onset adrenoleukodystrophy,
-Alexander disease,
-and demyelinating disorders.
Prevalence
Although Canavan disease may occur in any
ethnic group, it affects people of Eastern
European Jewish ancestry more frequently.
About 1 in 40 individuals of Eastern European
(Ashkenazi) Jewish ancestry are carriers.
Canavan disease is caused by a
defective ASPA gene which is
responsible for the
production of the enzyme
aspartoacylase. Decreased
aspartoacylase activity
prevents the normal
breakdown of N-acetyl
aspartate, wherein the
accumulation of Nacetylaspartate, or lack of its
further metabolism interferes
with growth of the myelin
sheath of the nerve fibers in
the brain.
Pathophysiology
Treatment
No effective treatment is available for
aspartoacylase deficiency.
Management is supportive and
aimed at maintaining nutrition and hydration,
protecting the airway,
preventing seizures,
minimizing contractures,
and treating infections.
1-Triacetin supplementation has
shown promise in a rat
model.(Triacetin, which can be
enzymatically cleaved to form
acetate, enters the brain more
readily than the negatively charged
acetate.)
The defective enzyme in Canavan
disease, aspartoacylase, converts
N-acetylaspartate into aspartate
and acetate. Mutations in the gene
for aspartoacylase prevent the
breakdown of N-acetylaspartate,
and reduce brain acetate
availability during brain
development. Acetate
supplementation using Triacetin is
meant to provide the missing
acetate so that brain development
can continue normally.
Current research
Current research
2-A team of researchers headed by Paola Leone are
currently at the University of Medicine and Dentistry of
New Jersey, in Stratford, New Jersey. The brain gene
therapy is conducted at Cooper University Hospital.
The procedure involves the insertion of six catheters
into the brain that deliver a solution containing 600
billion to 900 billion engineered virus particles. The
virus, a modified version of AAV, is designed to replace
the aspartoacylase enzyme.[7] Children treated with
this procedure to date have shown marked
improvements, including the growth of myelin with
decreased levels of the n-acetyl-aspartate toxin
Current research
3-AAV-MBP-GFP was
administered to the
striatum of ASPAdeficient mice at P10
and brains analysed
three weeks later to
determine spread
and selectivity of
transgene
expression.
Thank you
For
Your attention!