Canavan disease, or Canavan-Van Bogaert-Bertrand disease, is a rare and fatal
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
degenerative disease that causes progressive damage to
nerve cell
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
s and loss of white matter in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
. It is one of the most common degenerative cerebral diseases of infancy. It is caused by a deficiency of the enzyme aminoacylase 2,
and is one of a group of genetic diseases referred to as
leukodystrophies
Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...
. It is characterized by degeneration of
myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
in the
phospholipid
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
layer insulating the
axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
of a
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
and is associated with a gene located on human
chromosome 17
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
.
Symptoms and signs
Symptoms of the most common (and most serious) form of Canavan disease typically appear in early
infancy
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
usually between the first three to six months of age.
Canavan disease then progresses rapidly from that stage, with typical cases involving
intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
, loss of previously acquired
motor skill
A motor skill is a function that involves specific movements of the body's muscles to perform a certain task. These tasks could include walking, running, or riding a bike. In order to perform this skill, the body's nervous system, muscles, and br ...
s, feeding difficulties, abnormal
muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
tone (i.e., initial floppiness -
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
- that may eventually translate into
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles.
...
), poor head control, and
megalocephaly
Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general populati ...
(abnormally enlarged head).
Paralysis
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
,
blindness
Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment ...
, or
seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s may also occur.
There exists a much less common variant of Canavan disease which is generally much less serious, and involves later onset of symptoms, which are often mild and nonspecific enough to go unrecognized as manifestations of Canavan's disease. This variant does not seem to have any effect on lifespan, and is typically limited to minor cases of speech and motor skill development delay.
Pathophysiology
Canavan disease is inherited in an autosomal recessive fashion. When both parents are carriers, the chance of having an affected child is 25%.
Genetic counseling
Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...
and
genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
are recommended for families with two parental carriers.
Canavan disease is caused by a defective ''
ASPA'' gene which is responsible for the production of the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
aspartoacylase
Aspartoacylase is a hydrolytic enzyme (, also called ''aminoacylase II'', ''ASPA'' and other names) that in humans is encoded by the ''ASPA'' gene. ASPA catalyzes the deacylation of ''N''-acetyl-l-aspartate (''N-acetylaspartate)'' into aspar ...
. Decreased aspartoacylase activity prevents the normal breakdown of
''N''-acetyl aspartate, wherein the accumulation of ''N''-acetylaspartate, or lack of its further metabolism interferes with growth of the
myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
sheath of the
nerve fibers of the brain. The myelin sheath is the
fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers spec ...
ty covering that surrounds
nerve
A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system.
A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the e ...
cells and acts as an
insulator, allowing for efficient transmission of nerve impulses.
Diagnosis
The diagnosis of neonatal/infantile Canavan disease relies on demonstration of very high concentration of N-acetylaspartic acid (NAA) in the urine. In mild/juvenile Canavan disease, NAA may only be slightly elevated; thus, the diagnosis relies on molecular genetic testing of ''ASPA'', the gene encoding the enzyme aspartoacylase.
Treatment
No cure for Canavan disease is known, nor is there a standard course of treatment. Treatment is symptomatic and supportive. Physical therapy may help improve motor skills, and educational programs may help improve communication skills. Seizures are treated with antiepileptic drugs and gastrostomy is used to help maintain adequate food intake and hydration when swallowing difficulties exist. Also, an experimental treatment uses
lithium citrate
Lithium citrate (Li3C6H5O7) is a chemical compound of lithium and citrate that is used as a mood stabilizer in psychiatric treatment of manic states and bipolar disorder. There is extensive pharmacology of lithium, the active component of this ...
. When a person has Canavan disease, his or her levels of ''N''-acetyl aspartate are chronically elevated. The lithium citrate has proven in a rat genetic model of Canavan disease to be able to significantly decrease levels of ''N-acetyl aspartate''. When tested on a human, the subject's condition reversed during a 2-week wash-out period after withdrawal of lithium.
The investigation revealed both decreased ''N''-acetyl aspartate levels in regions of the brain tested and magnetic resonance spectroscopic values that are more characteristic of normal development and myelination. This evidence suggests that a larger controlled trial of lithium may be warranted as supportive therapy for children with Canavan disease.
Experimental gene therapy trial results, published in 2002, used a healthy gene to take over for the defective one that causes Canavan disease.
In human trials, the results of which were published in 2012, this method appeared to improve the life of the patient without long-term adverse effects during a 5-year follow-up.
Prognosis
Canavan disease typically results in death or development of life-threatening conditions by the age of ten, though life expectancy is variable, and is highly dependent on specific circumstances. On the other hand, the milder variants of the disorder seem not to have any effect on lifespan.
Prevalence
Although Canavan disease may occur in any ethnic group, it mostly affects people of
Eastern Europe
Eastern Europe is a subregion of the Europe, European continent. As a largely ambiguous term, it has a wide range of geopolitical, geographical, ethnic, cultural, and socio-economic connotations. The vast majority of the region is covered by Russ ...
an
Jewish
Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""The ...
ancestry with about one in 40 (2.5%) individuals of
Eastern Europe
Eastern Europe is a subregion of the Europe, European continent. As a largely ambiguous term, it has a wide range of geopolitical, geographical, ethnic, cultural, and socio-economic connotations. The vast majority of the region is covered by Russ ...
an (
Ashkenazi
Ashkenazi Jews ( ; he, יְהוּדֵי אַשְׁכְּנַז, translit=Yehudei Ashkenaz, ; yi, אַשכּנזישע ייִדן, Ashkenazishe Yidn), also known as Ashkenazic Jews or ''Ashkenazim'',, Ashkenazi Hebrew pronunciation: , singu ...
)
Jew
Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""Th ...
ish ancestry being a carrier.
History
Canavan disease was first described in 1931 by
Myrtelle Canavan.
In 1931, she co-wrote a paper discussing the case of a child who had died at 16 months old and whose brain had a spongy white section. Canavan was the first to identify this degenerative disorder of the central nervous system, which was later named "Canavan disease".
Lawsuit
The discovery of the gene for Canavan disease, and subsequent events, generated considerable controversy. In 1987, the Greenbergs, a family with two children affected by Canavan disease, donated tissue samples to Reuben Matalon, a researcher at the University of Chicago, who was looking for the Canavan gene. He successfully identified the gene in 1993, and developed a test for it that would enable antenatal (before birth) counseling of couples at risk of having a child with the disease.
For a while, the Canavan Foundation offered free genetic testing using Matalon's test.
However, in 1997, after he relocated to Florida, Matalon's new employer,
Miami Children's Hospital, patented the gene and started claiming royalties on the genetic test, forcing the Canavan Foundation to withdraw their free testing. A subsequent lawsuit brought by the Canavan Foundation against Miami Children's Hospital was resolved with a sealed out-of-court settlement.
The case is sometimes cited in arguments about the appropriateness of patenting genes.
Research
Research involving
triacetin
Triacetin, is the organic compound with the formula . It is classified as a triglyceride, i.e., the triester of glycerol. It is a colorless, viscous, and odorless liquid with a high boiling point and a low melting point. It has a mild, sweet tast ...
supplementation has shown promise in a rat model.
Triacetin, which can be enzymatically cleaved to form
acetate
An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...
, 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 brain development can continue normally.
A team of researchers headed by
Paola Leone at the
University of Medicine and Dentistry of New Jersey
The University of Medicine and Dentistry of New Jersey (UMDNJ) was a state-run health sciences institution of New Jersey, United States.
It was founded as the Seton Hall College of Medicine and Dentistry in 1954, and by the 1980s was both a major ...
, has tried a procedure involving the insertion of six catheters into the brain that deliver a solution containing 600 to 900 billion engineered
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
particles. The virus, a modified version of
adeno-associated virus
Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus ''Dependoparvovirus'', which in turn belongs to the family ''Parvoviridae''. They are small (approximately 26 nm in di ...
, is designed to replace the aspartoacylase enzyme.
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.
A team of researchers of
University of Massachusetts Medical School
The University of Massachusetts Chan Medical School is a public medical school in Worcester, Massachusetts. It is part of the University of Massachusetts system. It is home to three schools: the T.H. Chan School of Medicine, the Morningside Grad ...
is working on developing rAAV-based and optimized gene replacement therapy, that would travel across the blood-brain-barrier.
Researchers discovered the first drug-like inhibitors of ''N''-acetyltransferase.
See also
*
The Myelin Project
The Myelin Project is 501(c)(3) nonprofit organization established in 1989 by Augusto Odone and his wife, Michaela. Their son, Lorenzo, suffered from adrenoleukodystrophy (ALD), the most common of the leukodystrophies. The story of the Odones' s ...
*
The Stennis Foundation The Stennis Foundation is a registered nonprofit organization based in the U.S. The foundation is primarily a fundraising organization, sending money to various research projects. Currently, the Stennis Foundation supports research at Duke, Kennedy ...
*
Fern Kupfer
Fern Lee Kupfer is an American author and retired professor of creative writing at Iowa State University. She has written several novels and as well as memoirs reflecting on her life experiences, the discovery that she is a carrier of the BRCA mut ...
References
External links
Information on the disorder from the National Institute of Neurological Disorder and Stroke GeneReviews/NCBI/UW/NIH entry on Canavan disease
{{DEFAULTSORT:Canavan Disease
Autosomal recessive disorders
Leukodystrophies
Lipid storage disorders
Ashkenazi Jews topics
Demyelinating diseases of CNS
Neurological disorders in children
Rare diseases
Disorders causing seizures