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Jaume Campistol and Sankar Surendran
302
tetrahydrobiopterin (BH4); a prospective multi-center cohort study.
Mol. Genet. Metab., 2013, 110, S49–S56.
[69] Feldmann, R; Wolfgart, E; Weglage, J; Rutsch, F. Sapropterin
treatment does not enhance the health-related quality of life of
patients with phenylketonuria and their parents. Acta. Paediatr.,
2017, 106, 953–958.
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In: Neurochemistry of Metabolic Diseases ISBN: 978-1-53618-339-9
Editor: Sankar Surendran © 2020 Nova Science Publishers, Inc.
Chapter 10
CURRENT TRENDS IN CANAVAN DISEASE
RESEARCH AND THERAPEUTIC EFFECT
Sankar Surendran
1,
and Vykuntaraju K. Gowda
2,3
1
School of medicine, Louisiana State University Health
Sciences Center, New Orleans, LA, US
2
Department of Pediatric Neurology,
Indira Gandhi Institute of Child Health, Bangalore, India
3
Child Neurology and Rehabilitation Center, Bangalore, India
ABSTRACT
Canavan disease (CD) is an autosomal recessive neurodegenerative
disorder with degeneration in the white matter and gray matter
degeneration of the brain leading to early death. Aspartoacylase (ASPA)
deficiency, elevated levels of N-acetyl aspartic acid (NAA), N-
acetylaspartylglutamate, and L-aspartate N-acetyltransferase activity
defect have been observed in patients with CD. The brain regions affected
in CD include caudate putamen, globus pallidus, corpus callosum,
Corresponding Author’s Email: sankar_surendran@yahoo.com.
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Sankar Surendran and Vykuntaraju K. Gowda
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periaqueductal gray matter, pons and thalamus. Although, macrocephaly
was considered as one of the main features in CD, a recent study showing
a CD patient with ASPA gene mutation developed microcephaly.
Therefore, macrocephaly cannot be a common feature in CD. More than
ninety-five mutations in the ASPA gene have been reported in CD.
However, ASPA gene therapy alone could not improve all the
pathophysiological abnormalities seen in CD. N-acetyl aspartic acid
inducing oxidative stress contribute to the disease pathophysiology.
Therefore, current studies have been focused to normalize the NAA level
by regulating its upstream pathway. Inhibition of NAA synthesizing
enzyme, L-aspartate N-acetyltransferase in a dose dependent manner may
improve pathophysiology seen in CD.
1. INTRODUCTION
Canavan disease (CD) (OMIM 271900) is a rare inherited
neurodegenerative disease found in multiethnic population. Although until
past decade studies had been describing the presence of CD mainly on
Ashkenazi Jewish population, recent studies from around the globe
suggests that the disease is prevalent from east coast to west coast. The
presence of patients with CD have been reported from several countries
including United States of America, Saudi Arabia, Turkey, Egypt, Yemen,
Kuwait, Tunisia, Canada, India and Pakistan. The disease was first
reported as spongiform degeneration of the brain by Myrtelle M. Canavan
in 1931 [1] and subsequently by van Bogaert and Bertrand in 1949 [2].
Patients with CD have reduced levels of aspartoacylase/aminoacylase 2/N-
acetylaspartate acid amidohydrolase (ASPA/ACY2, EC# 3.5.1.15) activity
in fibroblasts and elevated levels of N-acetylaspartic acid (NAA/NA-Asp)
in urine [3-5]. The enzyme deficiency is found in various organs including
brain, kidney and liver [6]. Elevated levels of NAA was also observed in
the cerebrospinal fluid, plasma [3] and brain of patients with CD.
Patients with CD show various symptoms including hypotonia, mental
retardation, ataxia, brisk reflexes, convergent strabismus, hypotonia, motor
delay and difficulty to stand or walk. Macrocephaly was considered as one
of the major phenotypes in CD. However, a recent study showed CD
patient with ASPA gene mutation developed microcephaly [7]. Therefore,
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Current Trends in Canavan Disease Research …
305
macrocephaly may not be considered as an important feature during
diagnosis. Magnetic resonance imaging of the patient brain showed
increased intensity in both white matter and gray matter of the brain
including thalami, putamen, caudate nucleus, gray-white matter junctions
and pons.
Over ninety-five mutations have been identified in the ASPA gene of
patients with CD.
Aspartoacylase is a zinc containing carboxypeptidase metalloprotease
family [8]. Although ASPA deficiency is seen in CD, ASPA gene transfer
alone could improve some abnormalities seen in CD, however, it could not
improve all the pathophysiological abnormalities seen in CD. Patients with
CD have elevated levels of NAA. Altered levels of NAA resulting
oxidative stress contribute to the disease pathophysiology. Therefore,
recent studies have been focused to normalize NAA levels seen in CD by
inhibiting NAA regulating pathways.
2. ASPARTOACYLASE GENE MUTATIONS IN PATIENTS
WITH CANAVAN DISEASE
The human ASPA gene contains 5 introns and 6 exons with 313 amino
acids. The mouse ASPA contains 312 amino acids and rat ASPA contains
312 amino acids (GI: 50926810) to 314 amino acids (GI: 5689082). The
human ASPA protein has a molecular weight approximately 37 kDa. More
than ninety-five mutations in the ASPA gene with CD have been identified
from multiethnic population and these mutations are shown in Figure 1. A
13-year-old male patient from Canada had ASPA gene mutations Y288C
and a deletion -2A, -3C at the acceptor site of exon 3 [6, 9]. Two CD
patients from Saudi Arabia had a deletion of 3346 bp in the ASPA gene that
started at intron 2 (chr17: 3,332,550 position) and ended at intron 3 (chr17:
3,335,897 position) [10]. A 10-month-old Turkish patient with CD had
homozygous mutation (C432+1G>A) in the ASPA gene without
macrocephaly [11]. Aspartoacylase gene mutations G274R and 527del108
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Sankar Surendran and Vykuntaraju K. Gowda
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have been identified in Turkish patients, and a C218X mutation was found
in Gypsy patients [12].
Recent studies on patients with CD from around the globe showed
deletion of several exons and introns. Some patients with CD had deletion
of all six exons of the ASPA gene [10, 12]. A patient with compound
heterozygosity had a deletion in all exons except exon 1 of the ASPA gene.
Another patient with compound heterozygosity had 12.13 kb deletion
which was involved by the deletion of the ASPA gene from intron 3 to
intron 5 including exons 4 and 5 [12]. A child of consanguineous Turkish
parents with CD showed deletion of complete ASPA gene. A 13-year old
boy had p. Gly274Arg (c.820A>G) missense mutation [13]. These studies
suggest that ASPA gene mutations contribute to CD by a single base pair
change or deletion of several introns and exons in the ASPA gene. Two
Egyptian patients were diagnosed with CD, the first patient had five
missense mutations (c.427 A > G; p. I143V, c.502C > T; p. R168C, c.530
T > C; p. I177T, c.557 T > C; p. V186D c.548C > T; p. P183L) and a silent
mutation (c.693 C > T; p. Y231Y). The second patient was homozygous
for two missense mutations (c.427 A > G; p. I143V and c.557 T > A; p.
V186D) [14]. An Iranian patient had homozygous C.202G>A mutation in
the exon 1 of the ASPA gene [15].
A 2-year-old Egyptian child with CD had a novel homozygous
missense variant c.91G > T, p.V31F in the ASPA gene [16]. A patient had
p.A305E and p. A7Vdel8_69 mutations in the ASPA gene [17]. Two
Egyptian patients had a novel missense mutation Ile177Thr in the exon 4
of the ASPA gene [18]. Two patients from India had ASPA gene mutations
c.162 C > A (p. Asn54Lys) and c.859 G > A (p. Ala287Thr). Third patient
had compound heterozygous for two novel mutations c.728 T > G, p.
Ile243Ser; c.902 T > C, p. Leu301Pro [19]. A 9 months old Turkish girl
with Canavan Disease had a homozygous mutation c.79G>A in the
ASPA gene [20]. A child born to a consanguineous parent had a novel
mutation Y88X in the ASPA gene [21]. A patient with CD from Pakistan
had missense substitution 740A→G (p.G274R) in exon 6 of the ASPA
gene [22]. A female infant at age 6 months had the mutation c.432G>A in
exon 2 of the ASPA gene [23].
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Figure 1. Aspartoacylase gene mutations in patients with CD.
3. SYMPTOMS OF THE DISEASE
Patients with CD generally show clinical symptoms after four months
of age. The clinical symptoms in CD include megalencephaly/
macrocephaly or microcephaly, developmental delay, loss of muscle tone
(hypotonia) and psychomotor retardation (mental retardation) [2], poor
visual function or partial blindness, loss of fibers in the optic nerve (optic
atrophy) and axial hypotonia. Motor defect was severe in some patients
with spastic quadriplegia or spastic diplegia, difficult to sit, walk or talk
and also have feeding problem. Later stage, patients develop
convulsions/seizures and may die within ten-year old if the disease is
severe form of CD. Patients with mild form of CD show symptoms
including partial cortical blindness, nystagmus, retinitis pigmentosa, mild
developmental delay (reading skills delayed more than verbal skills) and
signal intensity in the basal ganglia. In mild form of CD, urine NAA level
is slightly elevated (99.90 ± 4.00 µg/mg creatinine) compared to normal
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subjects (< 83 µg/mg creatinine) [6, 9]. Some patients have poor sleep
spindles and absence of visual acuity.
Although macrocephaly has been used as one of the important features
to diagnose CD, recent study showed a child with ASPA gene mutation
c.859 G>A (p. Ala287Thr) in exon 6 developed microcephaly. At ten-
month old, the child showed developmental delay, visual difficulty and
difficulty in head control. At ten-months of age, head circumference was
41 cm, which is less than 3 SD [7]. At three-year old, the patient head
circumference was 43 cm, which is less than 3 SD (Figure 2). This study
suggests that CD phenotype can be either macrocephaly or microcephaly.
Parents of the child with microcephaly were normal suggesting parents
were carrier of the disease.
Figure 2. A four-year-old child with ASPA gene mutation showing microcephaly.
The symptoms seen in patients with CD reported from around the
globe vary among patients. Patients with CD develop phenotype including
mild ataxia, brisk reflexes, convergent strabismus [6, 9], hypotonia, motor
delay, difficulty to stand or walk, spasticity and intractable seizures [24],
spastic quadriparesis, oropharyngeal dysplasia, macrocephaly or
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microcephaly, mild seizures, oral phase dysphagia, severe upper
pharyngeal dysphagia and spasticity, progressive neuroregression,
difficulty in swallowing, spastic quadriparesis [10], axial hypotonia, lower
limb symmetric hypertonia accompanied by brisk deep tendon reflexes,
developmental delay without macrocephaly, mild defect in fine motor
skills, strabismus, intentional tremor, poor eye contact and impaired fixing,
sluggish response to sound, poor feeding and blindness.
Electroencephalographic study showed an active right temporal spike-
wave focus and epilepsy.
4. BRAIN REGIONS AFFECTED IN PATIENTS
WITH CANAVAN DISEASE
The brain regions affected in patients with CD reported from around
the globe include putamen, caudate nucleus, thalamus, U-fibers of the
occipital and temporal lobes, cerebellar white matter, pons, medulla [25],
subcortical white matter at the gray-white matter junctions bilaterally, the
tegmentum of the pons, white matter around the 4th ventricle [26],
posterior fossa, supratentorial CSF spaces of the brain, cerebral white
matter sparing the internal capsules, corpus callosum, globus pallidus,
posterior part of sub-cortical deep white matter, posterior limb of the
internal capsule, dentate nuclei of the cerebellum [27], lentiform nucleus,
posterior periventricular white matter, periaqueductal gray matter, anterior
limbs of internal capsules, external capsules, subcortical white matter,
cerebellar white matter, dentate nuclei, cerebellum [15], optic radiations,
substantia nigra [16] and brainstem. Magnetic resonance imaging of the
brain of a patient with microcephaly is shown in Figure 3.
Brain US showed alteration of echogenicity of both gray and white
matter with increasing of echogenicity of white matter, characterized by a
homogenous fine texture with high echogenicity of the pial demarcation of
the low echogenic cortex, mild ventricular dilatation and enlargement of
sinocortical space [28].
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Figure 3. Magnetic resonance imaging of the brain of a CD patient with microcephaly.
Thin arrow shows globus pallidus and thick arrow shows thalamus of the brain.
5. N-ACETYLASPARTYLGLUTAMATE AND
N-ACETYLASPARTIC ACID LEVELS
IN CANAVAN DISEASE
The neuropeptide, N-acetylaspartylglutamate (NAAG/NA-Asp-Glu) is
localized in neurons with high affinity for metabotropic glutamate
receptors, mGluR3, which is an antagonist at NMDA receptors. The
mGlu3 expression is high in neurons of the thalamic reticular nucleus.
While NAA and glutamate are ligases into NAAG by N-acetylaspartate-L-
glutamate ligase in neurons [29], NAAG is hydrolyzed by glutamate
carboxypeptidase II/ N-Acetylated-Alpha-Linked-Acidic-Dipeptidase
(GCPII/NAALADase, EC# 3.4.17.21) into NAA and glutamate [30-31]
(Figure 4). The GCPII is a zinc metalloenzyme expressed on astrocyte
membranes. N-acetylaspartylglutamate level is approximately 20-fold
higher in the urine of patients with CD [32-33].
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Figure 4. N-acetylaspartylglutamate is converted into N-Acetylaspartate and glutamate.
N-acetylaspartate (C
6
H
9
NO
5
) is synthesized from acetyl-coenzyme A
and aspartate by L-aspartate N-acetyltransferase [34]. N-acetylaspartic acid
has a molecular mass of 175 Da and has a negative charge at physiological
pH that enables transport across membranes. An up regulation by L-
aspartate N-acetyltransferase would result in an increased NAA level, one
of the possible ways of elevated NAA seen in CD. N-acetylaspartate is
deacetylated into aspartate and acetate by ASPA [35]. Urine NAA in
patients with severe form of CD is 1.18 mmol/mmol creatinine, while in
control subjects the level is 3.41 ± 1.99 µmol/mmol creatinine. The level of
NAA in CD patient serum is increased (18.0 µmol/L), while in normal
human serum the level was not detectable [36]. The levels of NAA in
control subjects are 6.6–35.4 µmol/mmol creatinine in urine; 0.17–0.81
µM in plasma; and 0.25–2.83 µM in cerebrospinal fluid. Prenatal diagnosis
showed amniotic fluid NAA level was 8.68 µM in one of the pregnancies
with CD, while control amniotic fluid levels were 0.30–2.55 µM [37]. The
level of urine NAA in patients with severe form of CD is elevated over 50-
80-fold. In brain interstitial space, the concentration of NAA is 80–100
mM [38]. The carrier transports at the prevalent interstitial NAA
concentration was 100 mmol/l or 10 pmol/mg of protein/min [39]. In
extracellular fluid, NAA level is elevated [40]. Elevated levels of NAA
alter expression of genes associated with inflammation, contractility, and
calcium channel. Contractility of circular smooth muscle cells was also
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