Canavan disease (CD) is a progressive neurological disorder that damages the white matter of the brain, classifying it as a leukodystrophy. It is caused by a deficiency of the enzyme aspartoacylase (ASPA), which is produced by the ASPA gene. ASPA normally breaks down N-acetylaspartic acid (NAA) within the brain. Without functional ASPA, NAA accumulates to toxic levels, leading to the progressive destruction and lack of formation of myelin, the protective covering around nerve fibers.
Recognizing the Need for Testing
Suspicion for Canavan disease typically arises in infants who fail to meet developmental milestones between three and six months of age. The most common form is the infantile type, which begins with non-specific neurological signs that prompt medical investigation. Physicians often observe a lack of head control and significant hypotonia, which is decreased muscle tone throughout the body.
A noticeable clinical sign is macrocephaly, an abnormally large head size that develops several months after birth. These infants also experience developmental delays, such as difficulty learning to roll over, sit up, or track objects. Feeding difficulties and increased irritability are common early indicators that the child’s nervous system is not developing correctly.
The combination of these signs—macrocephaly, low muscle tone, and developmental regression—suggests a severe neurological disorder, leading doctors to order the first round of diagnostic tests. Since these symptoms overlap with other conditions, initial testing is aimed at identifying the specific biochemical abnormality unique to Canavan disease.
Initial Diagnostic Screening
The first step in diagnosis focuses on measuring the concentration of N-acetylaspartic acid (NAA) in bodily fluids. NAA levels are assessed in samples of urine or blood plasma using specialized techniques like gas chromatography-mass spectrometry. In severe cases, NAA levels in the urine can be extremely high, sometimes exceeding 100 times the normal range.
Magnetic Resonance Spectroscopy (MRS) provides a highly suggestive screening tool by analyzing the chemical composition of the brain. This non-invasive imaging technique detects a markedly elevated NAA peak within the white matter. This distinctive biochemical signature on an MRS scan is considered pathognomonic, meaning it is highly characteristic of Canavan disease.
While extremely high NAA levels in body fluids and the brain strongly suggest a diagnosis, these findings alone are not considered definitive. The NAA accumulation confirms the biochemical consequence of the disease, not the underlying genetic cause. A definitive diagnosis requires confirmation at the molecular level.
Confirmatory Genetic Analysis
The gold standard for confirming Canavan disease is molecular genetic testing, which analyzes the ASPA gene. Since the disease is inherited in an autosomal recessive pattern, an individual must inherit two mutated copies of the ASPA gene—one from each parent—to be affected. The diagnostic test seeks to identify these two pathogenic variants.
Gene sequencing is typically performed on a blood sample to map the entire coding region of the ASPA gene. This process looks for specific errors in the DNA sequence that disrupt the production or function of the aspartoacylase enzyme. Identifying two such mutations confirms the clinical diagnosis.
Although Canavan disease occurs in all ethnic groups, testing often includes screening for specific, common mutations, particularly in individuals of Ashkenazi Jewish descent. For this population, two variants, E285A and A305E, account for the vast majority of cases. Comprehensive gene sequencing is performed to ensure all known or novel mutations are identified, especially in non-Ashkenazi patients.
Prenatal and Carrier Testing
For families with a known history of Canavan disease or who are planning a pregnancy, testing is available to determine carrier status or to diagnose the condition prenatally. Carrier screening is performed on prospective parents to determine if they carry a single copy of a pathogenic ASPA gene mutation. Since carriers do not exhibit symptoms, this blood test provides crucial information for family planning.
In the Ashkenazi Jewish population, the carrier frequency can be as high as 1 in 40, leading medical organizations to recommend screening for this group. If both parents are identified as carriers, their child has a one-in-four chance of inheriting two mutated copies and being affected by Canavan disease.
When both parents are known carriers, prenatal diagnosis can be offered through procedures like amniocentesis or chorionic villus sampling (CVS). The preferred method is to perform gene sequencing on the fetal cells obtained from these procedures to check for the two disease-causing ASPA mutations. Alternatively, if the specific parental mutations are unknown, the NAA level in the amniotic fluid can be measured, as highly elevated concentrations indicate an affected fetus.