Canavan disease is a fatal, genetic neurological defect, characterized by progressive cerebral degeneration, especially of the white matter. This condition is one of the leukodystrophies, in which the myelin sheath undergoes degeneration, precipitating neurological defects. The most common form of presentation of the condition is the infantile form, in which affected infants appear quite normal till 3-5 months of age. Symptoms begin to appear after the age of 3-months, and include features such as hypotonia, microcephaly, abnormal posture, feeding difficulties, nasal regurgitation, and head lag. As the infant grows, mental retardation, failure to meet developmental milestones, poor motor skills, seizures, sleep disturbances, and blindness are noticed. Other rare forms of the disease are also noticed, which include the neonatal form, with onset at birth, and the relatively milder juvenile form, appearing after the age of five years.
The disease is frequent among the Ashkenazi Jewish population, where it occurs with an incidence of one affected patient in 6,400 to 13,500 of the population. Other populations which show a high frequency of affected children include those from Eastern Poland, Lithuania, Western Russia, and Saudi Arabia.
Diagnosis of Canavan disease can be done on the basis of increased levels of N-acetylaspartic acid in the urine, blood, or cerebrospinal fluid. In addition, head CT or MRI scans clearly show leukodystrophy. Genetic testing is also available to confirm the diagnosis of Canavan disease. Treatment however, is only of a symptomatic and supportive manner. At present, the prognosis for Canavan disease is poor, with most patients succumbing to the disease before the age of 4-years. Only rarely do children survive unto their teens.
Kaul et al. (1995) identified a novel missense mutation (c.454T>C; p.C152R) in the ASPA gene in an Arab patient with Canavan disease.
Masri and Hamamy (2006) reported the first cases of Canavan disease from Jordan. The proband was a one-month old infant, born to healthy consanguineous parents with an uneventful antenatal history. The infant was found to be irritable and had poor visual fixation, nystagmus, poor response to sound, axial and peripheral hypotonia, severe head lag, exaggerated deep tendon reflexes, and length at 25th, height at 10th, and head circumference at 75th percentile. A family study revealed that of the five elder siblings of the proband, three brothers, and one sister happened to be affected, with all of them showing developmental delay, poor visual fixation, poor response to sounds, spasticity, and poor head control. MRI scan of one of the brothers showed diffuse white matter disease. MRI of the proband, at the age of 3-months, however, did not show any abnormality. Electrophysiological tests and routine hematological and biochemical tests also returned normal results. However, the urine was found to have a high level of NAA (490 micromol/mmol of creatinine). Subsequently, the parents went on to have a pair of twins (of each gender), both of whom died in the first week of their lives, and a healthy daughter. Two of the proband's brothers died at the age of 10 and 5 years, while the proband himself succumbed to the condition at the age of 3-years. The two remaining affected children were alive at the ages of 13 and 9 years at the time of reporting.
Bin Nakhi et al. (2005) described a 3-month old Kuwaiti female who presented with macrocephaly, hypotonia, and global developmental delay. She was diagnosed with Canavan disease. Bin Nakhi et al. (2005) suggested performing molecular cytogenetic studies on Kuwaiti patients with Canavan disease and other neurometabolic disorders.
[Bin Nakhi HA, Ipe JA, Raimondo P. Canavan disease: a case report from Kuwait. New Egypt J Med. 2005; 34(6):300-2.
In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found five patients diagnosed with canavan disease. The median age of diagnosis was 9.5-months.
Ozand et al. (1990) studied a group of 12 patients, clinically diagnosed with Canavan disease. Cultured fibroblasts from these patients showed aspartoacylase activity 1% and 13% less as compared to a group of normal individuals, and a group of individuals with other leukodystrophies, respectively. Ozand et al. (1990) suggested that this group of 12 patients in Saudi Arabia diagnosed within a period of three years is an inordinately large population for a rare disease such as Canavan disease. In a retrospective study conducted in 1992, Ozand et al. indicated that infantile central nervous system spongy degeneration (Canavan disease) showed definite tribal occurrence.
Kaya et al. (2008) described six patients from Saudi Arabia with Canavan Disease. Only two of these patients were related; being twins. All patients presented with neuroregression, moderate to severe oral phase dysphagia, macrocepahy, central hypotonia, and highly elevated NAA in the urine. In all patients, except one of the twins, the diagnosis of Canavan Disease was confirmed by molecular testing, and mutations were found in the ASPA gene. At least one of the patients had consanguineous parents. Apart from the twins, two other patients had a family history of the condition.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organic acidopathies (OA) were diagnosed in 48 out of 248 cases (19%), which constitute the second largest group of IEM found in this cohort after lysosomal storage disease. Among OA, three cases from a single family were found to have Canavan disease. The estimated incidence of Canavan disease in this cohort was 2 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.