Introduction:
Canavan disease is an inherited, rare disorder that damages the capability of neurons (nerve cells) to transmit (send or receive) messages. This disease is a part of a genetic group of disorders called leukodystrophies. Leukodystrophies are a group of rare metabolic, genetic disorders that affect the brain, spinal cord, and nerves outside the central nervous system, interfering with the growth and maintenance of the myelin sheath. Myelin sheath is an insulating layer formed around the nerves, including the brain and spinal cord, that help transmit nerve impulses. Most people affected by Canavan disease have the neonatal or infantile Canavan form.
What Is Neonatal Canavan Disease?
Neonatal Canavan disease is also known as infantile Canavan disease. In this condition, the infected infants appear normal during the initial few months. Still, they develop noticeable features like developmental delays in motor skills and speech between the third and fifth months of life. Canavan disease can be a severe form. The severe form of Canavan disease is more commonly seen than the mild one. Infants with neonatal Canavan disease usually develop life-threatening complications by the age of 10 years.
How Does Neonatal Canavan Disease Occur?
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Canavan disease is an autosomal recessive disorder linked with gene loci (the physical location of a specific gene in a chromosome) on chromosome 17.
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It is mainly caused by a mutation in the ASPA gene, which encodes the enzyme aspartoacylase.
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Aspartoacylase hydrolyses N-acetylaspartic acid to acetate and aspartate.
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This mutation affects the metabolism of the N-acetylaspartic acid and ultimately results in the accumulation of N-acetylaspartic acid (NAA) in the brain area and an aspartoacylase deficiency.
Where Is Neonatal Canavan Disease Commonly Seen?
Neonatal Canavan disease affects all ethnic groups but is reported frequently in the Ashkenazi Jewish population. The carrier frequency is reported to be one in 40 to 58 people in this population.
What Are the Commonly Seen Features of Neonatal Canavan Disease?
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Infants do not develop motor skills like controlling head movements, sitting without support, and turning over.
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Hypotonia (weak muscle tone) and the inability to support the head are typical features of this disorder. It can progress to hyperreflexia (hyperactive stretch reflexes of the muscle) and spasticity (abnormal increase in muscle tone or muscle stiffness).
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Stiffness in the joint increases leading to some infants resembling individuals with cerebral palsy.
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Macrocephaly (unusually large head) becomes prominent from around three to six months.
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Retinitis pigmentosa (an eye disease that affects the retina, making cells in the retina break down over time, causing vision loss) occurs.
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Optic atrophy (a condition that affects the eye's optic nerve) causes decreased visual responsiveness.
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Blindness due to optic atrophy can occur around six to 18 months.
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Seizures, mainly generalized tonic-clonic seizures, are noted in about 50 of the patients.
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Sleep disturbances and irritability.
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Swallowing and feeding difficulties.
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As the ability to swallow declines, some infants may require permanent feeding gastrostomies (a surgical opening is done from the skin of the abdomen into the stomach area, and a feeding device is inserted in this opening) or nasogastric feeding (a tube is inserted into the nose down the throat and esophagus into the stomach and is used to give liquids, drugs, and liquid foods).
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Decerebrate posturing (abnormal body posture due to severe damage in the brain) and pseudo-bulbar signs (involuntary and uncontrollable outbursts of emotions not connected with the emotional state) dominate the end stages of Canavan disease.
How Is Neonatal Canavan Disease Diagnosed?
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Clinical Features - Neonatal Canavan Disease is diagnosed with specific clinical features like poor head control, macrocephaly, and hypotonia. Diagnosis is usually confirmed with detailed patient history, clinical evaluation, and specialized tests.
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Urine Test - An aspartoacylase deficiency can be detected by elevated levels of N-acetylaspartic acid (NAA) in the urine. Urine levels of NAA increase up to 200 times than in the reference range.
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Culture - A culture of connective tissue cells from the skin called the skin fibroblasts is done to detect deficient aspartoacylase activity.
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Prenatal Diagnosis - Prenatal diagnosis measures the level of NAA in the fluid surrounding the developing fetus (amniotic fluid) at around 16 to 18 weeks of gestation. If parents are known to have ASPA gene mutations, the prenatal diagnosis is made using chorionic villus sampling (CVS). Chorionic villi sampling is a procedure done to analyze any mutation. Here, the sample of placental cells is removed at 10 to 12 weeks of gestation.
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Genetic Testing - Genetic testing is usually done for genetic counseling. Biallelic pathogenic variants in ASPA are identified with molecular genetic testing.
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Neuroimaging - CT scans (computed tomography) show characteristic low attenuation of white matter in contrast to the unaffected gray matter. This difference is mainly due to the edema of white matter and spongiform degeneration. MRI (magnetic resonance imaging) features include megalocephaly. So, MRI scans show diffuse bilateral involvement of the white matter. Brain scans, CT, or MRI show leukodystrophy (a genetic disease that affects the white matter of the central nervous system) progressing with age and diffuse white matter degeneration.
How Can Neonatal Canavan Disease Be Managed?
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An appropriate assessment of the patient's developmental status and nutrition is needed to guide the treatment options.
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Supportive treatment is provided to maintain adequate nutrition and hydration, manage and cure infectious diseases and protect airways.
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In the case of mild juvenile canavan disease, medical care is not essential, but speech therapy may be required.
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Physical therapy and position changes to reduce contractures and increase motor abilities and seating posture.
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To increase communication skills, special education programs are needed.
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Seizures are managed with antiseizure medications.
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Botulinum toxin injections can help to treat spasticity.
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In case of difficulties in swallowing, a feeding gastrostomy tube is required to maintain food intake and hydration. Since the patient lacks sound reflexes, a feeding tube helps decrease the risks of aspiration.
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Ideally, no curable treatment options are present for severe cases of Canavan disease.
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For neonatal Canavan disease, a follow-up is essential every six months to evaluate the developmental status and to detect any new problems.
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For mild or juvenile Canavan disease, an annual follow-up by the specialist is required.
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Despite the developmental delay, most children can be educated in classroom settings and benefit from speech therapy or tutoring.
What Is the Outcome for an Infant With Neonatal Canavan Disease?
Morbidity is severe, and the prognosis is very poor for an infant with neonatal Canavan disease. Patients with neonatal Canavan disease depend on their caretaker for daily activities. Their life expectancy is about one decade, but with advanced medical care, some patients survive into their young adulthood or adolescence.
Conclusion:
A neonatal Canavan disease is a rare genetic condition in infants. The infected infants appear normal during their initial few years but start showing symptoms by the third or fifth months of life. The survival rate is very low for infants affected by this condition. Supportive treatments and physical therapy can help ease some of its conditions, but there are no curable treatment options available for this condition at present.
