Canavan disease is a rare inherited leukodystrophy caused by mutations in the ASPA gene. It results in a buildup of NAA in the brain, damaging myelin sheaths. There are two forms - neonatal/infantile onset within the first few months causes severe developmental delays, macrocephaly, hypotonia, and seizures. Mild/juvenile onset in childhood causes mild developmental delays. It is most common in Ashkenazi Jewish populations and diagnosis involves testing urine or amniotic fluid NAA levels or ASPA enzyme activity. Treatment is supportive and includes managing seizures, feeding difficulties, and spasticity.

1. CANVANS DISEASE
SUBMITTED BY,
DUSHYANTH B
14-PML-20

2. History…
 Canvans disease was first
discribed in 1931 by Myrtelle
Canvan.
 She is american
neuropathologist(1879-1953).

3. what is canvans disease?
 It is rare inherited disorder, that damages the ability of
nerve cells in the brain to send and receive messages.
 This is one of the a group of genetic disorder called
Leukodystrophies.

4. Structure of Neuron

5.  Canvans disease occurs in two forms.
 1) Neonatal / Infantile canvans disease
 2) Mild / Juvenile canvans disease.

6. Neonatal/Infantile canvans Disease
 Most common and most severe form.
 Affected infants appear normal for the first few
months of life, but by age 3-5 months, problems with
development become noticeable.
 These infants usually do not develop motor skills such
as…………
 turning over
 controlling head movement and
 sitting with out support.

7. Other common features….
 Weak muscle tone (hypotonia)
 An usually large head size (macrocephaly)
 Irritability
 Feeding and swallowing difficulties
 Seizures and
 Sleep disturbances may also develop.

8. Mild/Juvenile canvans disease
 It is less common.
 Mildly delayed development of speech and motor skills
starting in childhood.
 These delays may be so mild and non-specific that
they are never recognized as being caused by canvans
disease.

9. How common is canvan disease ?
 People of all ethnic backgrounds.
 It is most common in people of Ashkenazi (eastern
and central European) Jewish heritage.
 This disorder effects in 1 in 6,400 to 13,500 people in
the Ashkenazi Jewish population.

10. What genes are related to canvans
disease?
 Mutation of ASP A gene cause canvan disease.
 ASP A gene provides instructions for making an
enzyme called aspartoacylase
 Breaks down a compound called N-acetyl-L-aspartic
acid (NAA), which is predominantly found in neurons
in the brain.
 Function of NAA is unclear.
 Researcher had suspected that it played a role in
production of the myelin sheath.

11.  Enzyme may instead be involved in the transport of
water molecules out of neurons.
 Mutations in the ASA P gene reduce the function of
aspartoacylase, which prevents the normal breakdown
of NAA.
 Severely impair the enzyme’s activity, allowing NAA to
build up to high levels in the brain.
 Milder effect on the enzyme’s activity, leading to less
accumulation of NAA.

12. Excess amount of NAA in brain
leads to……
 If NAA is not broken down properly, the resulting
chemical imbalance interferes with the formation of
myelin sheath as the nervous system develops.
 Progressive destruction of existing myelin sheaths.
 Without this protective covering malfunction, which
disrupts normal brain development.

13. How do people inherit canvans
disease ?
 It is autosomal recessive pattern, which means both
copies of the genes in each cell have mutations.
 Mutation of gene is chromosome 17.
 The parent of an individual with an autosomal
recessive condition each carry one copy of the mutated
gene, but they typically don't show signs and
symptoms of the condition.

14. Inheritance pattern

15. Symptoms…..
 Intellectual disability
 Loss of previous acquired motor skills.
 Feeding difficulties.
 Abnormal muscle tone (floppiness or stiffiness).
 Poor head control.
 Megalocephaly.
 Paralysis.
 Blindness and,
 seizures may also occur.

16. Symptoms…

17. Diagnosis….
 The triad of hypotonia, macrocephaly, and head lag in
an infant after age three to five months raises suspicion
of neonatal/infantile (severe) Canavan disease.
Neuroimaging studies reveal leukodystrophy.
 In individuals with mild/juvenile Canavan disease,
neuroimaging may not be helpful.

18. Testing
 Urine: The concentration of NAA in the urine can be
measured using gas chromatography-mass
spectrometry (GC-MS)
 Control values in one series were 23.5±16.1 µmol/mmol
creatinine.
 In neonatal/infantile (severe) Canavan disease the mean
concentration of NAA was 1440.5±873.3 µmol/mmol
creatinine.

19.  In mild/juvenile Canavan disease, mild elevation of
NAA may be found, 106 µmol/mmol creatinine.
Amniotic fluid:
 The concentration of NAA can be measured in the
amniotic fluid by stable-isotope dilution and GC-MS
or by liquid chromatography tandem mass
spectrometry.
 NAA concentration in amniotic fluid was 0.30-2.55
µmol/L in controls and 8.68 µmol/L in
an affected pregnancy.

20. Aspartoacylase enzyme activity
Skin fibroblasts:
 Aspartoacylase enzyme activity can be assayed in
cultured skin fibroblasts, it may not be reliable
because the activity varies with culture conditions.
 Individuals with severe Canavan disease often have
immeasurable enzyme activity.
 Carriers of alleles associated with severe Canavan
disease have about one-half normal enzyme activity .

21. Amniocytes/CVS:
Aspartoacylase enzyme activity is extremely low
in normal amniocytes and chorionic villus
sampling (CVS). Enzyme activity cannot be
relied upon for prenatal testing

22. Treatment…..
Neonatal/infantile Canavan disease
 Treatment is supportive and directed to providing adequate
nutrition and hydration, managing infectious diseases, and
protecting the airway.
 Seizures may be treated with antiepileptic drugs (AEDs).
 A feeding gastrostomy may be required to maintain
adequate intake and hydration in the presence of
swallowing difficulties.
 Diamox® seems to reduce intracranial pressure.
 Botox® injections may be used to relieve spasticity.

23. Mild/juvenile Canavan disease:
 These individuals may require speech therapy or
tutoring but require no special medical care.

24. What other names do people use
for Canavan disease?
 ACY2 deficiency
 aminoacylase 2 deficiency
 ASP A deficiency
 aspartoacylase deficiency
 Canavan's disease.

25. References…..
 http://ghr.nlm.nih.gov/condition/canavan-disease
 http://www.ninds.nih.gov/disorders/canavan/canavan
.htm
 http://www.canavanfoundation.org/about_canavan_di
sease
 https://en.wikipedia.org/wiki/Canavan_disease
 http://radiopaedia.org/articles/canavan-disease