Summary
Clinical characteristics.
Most individuals with Canavan disease have the neonatal/infantile form. Although such infants appear normal early in life, by age three to five months, hypotonia, head lag, macrocephaly, and developmental delays become apparent. With age, children with neonatal/infantile-onset Canavan disease often become irritable and experience sleep disturbance, seizures, and feeding difficulties. Swallowing deteriorates, and some children require nasogastric feeding or permanent feeding gastrostomies. Joint stiffness increases, so that these children resemble individuals with cerebral palsy. Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life without regression. In spite of developmental delay most of these children can be educated in typical classroom settings and may benefit from speech therapy or tutoring as needed. Most children with mild forms of Canavan disease have normal head size, although macrocephaly, retinitis pigmentosa, and seizures have been reported in a few individuals.
Diagnosis/testing.
The diagnosis of Canavan disease is established in a proband with typical clinical findings and elevated N-acetylaspartic acid (NAA) in urine and/or with biallelic pathogenic variants in ASPA identified by molecular genetic testing.
Management.
Treatment of manifestations:
Neonatal/infantile Canavan disease. Treatment is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway. Hospice care is a resource used by the families of the individuals affected by the disease. Physical therapy minimizes contractures and maximizes motor abilities and seating posture; special education programs enhance communication skills. Seizures are treated with antiepileptic drugs. Gastrostomy may be needed to maintain adequate food intake and hydration when swallowing difficulties exist.
Mild/juvenile Canavan disease. May require speech therapy or tutoring but no special medical care.
Surveillance:
Neonatal/infantile Canavan disease. Follow up every six months to evaluate developmental status and evidence of any new problems.
Mild/juvenile Canavan disease. Annual routine follow up by a pediatric neurologist or a developmental pediatrician is indicated.
Genetic counseling.
Canavan disease is inherited in an autosomal recessive manner. Each pregnancy of a couple in which both partners are heterozygous for a pathogenic variant in ASPA has a 25% chance of resulting in a child with Canavan disease, a 50% chance of resulting in a child who is an asymptomatic carrier, and a 25% chance of resulting in a child who is unaffected and not a carrier. Carrier testing is available on a population basis for individuals of Ashkenazi Jewish heritage. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible when the pathogenic variants in the family are known.
Diagnosis
Suggestive Findings
Canavan disease should be suspected in individuals with
The triad of hypotonia, head lag, and macrocephaly after age three to five months
Poor visual following and difficulties with suck and swallow
Developmental delays (with regression in infantile form and without regression in mild/juvenile form)
Leukodystrophy on neuroimaging (generalized in infantile form and localized to basal ganglia in mild/juvenile form)
Elevated N-acetylaspartic acid (NAA) in urine using gas chromatography-mass spectrometry (GC-MS)
Establishing the Diagnosis
The diagnosis of Canavan disease is established in a proband with typical clinical findings and elevated N-acetylaspartic acid (NAA) in urine using gas chromatography-mass spectrometry (see Note) and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing (see Table 1).
Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with neonatal/infantile (severe) Canavan disease, elevated concentration of NAA in urine is sufficient for diagnosis of affected individuals [Michals & Matalon 2011]. (2) Canavan disease is associated with decreased aspartoacylase enzyme activity; individuals with severe Canavan disease may have unmeasurable enzyme activity, and carriers (heterozygotes) may have enzyme activity ~50% of normal. Aspartoacylase enzyme activity may not be reliable in the diagnosis of Canavan disease because enzyme activity fluctuates with culture conditions; therefore, measurement of the urinary concentration of NAA is the preferred diagnostic method [Matalon et al 1993].
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Canavan disease is broad, infants with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a mild/juvenile Canavan disease phenotype indistinguishable from many other inherited disorders with developmental delay are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Canavan disease, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing. Sequence analysis of ASPA detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Targeted analysis for the pathogenic variants p.Glu285Ala, p.Tyr231Ter, and p.Ala305Glu can be performed first in individuals of Ashkenazi Jewish ancestry.
Targeted analysis for the pathogenic variant p.Ala305Glu can be performed first in individuals of non-Ashkenazi Jewish ancestry.
Note: This targeted testing is most appropriate when (1) biochemical testing indicates a diagnosis of Canavan disease or (2) the individual is of Ashkenazi Jewish ancestry.
A multigene panel that includes ASPA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Note: Follow-up urinary NAA or enzyme testing may help to interpret sequencing results if a variant of unknown significance is identified.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by developmental delay, comprehensive
genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is non-diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Canavan Disease
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|
| ASPA | Targeted
testing 3 | p.Glu285Ala, p.Tyr231Ter | Ashkenazi Jewish: 98% 4
Non-Ashkenazi Jewish: 3% 4 |
| p.Ala305Glu | Ashkenazi Jewish: 1% 5
Non-Ashkenazi Jewish: 30%-60% 5 |
| Sequence analysis 6 | ~99% 7 |
| Gene-targeted deletion/duplication analysis 8 | 9 reported 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Various molecular methods may be used to detect targeted variants.
- 4.
- 5.
Kaul et al [1994b], Elpeleg & Shaag [1999]
- 6.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 7.
Kaul et al [1994b], Elpeleg & Shaag [1999], Olsen et al [2002], Zeng et al [2002], Michals & Matalon [2011]
- 8.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 9.
Shaag et al [1995], Elpeleg & Shaag [1999], Zeng et al [2006], Caliebe et al [2010], Cozzolino et al [2011]
Clinical Characteristics
Clinical Description
Canavan disease is a neurodegenerative disorder associated with spongy degeneration of the white matter of the brain. Typical presentation is in the first several months of life, although a later presentation is also recognized.
Neonatal/Infantile (Severe) Canavan Disease
Presentation. Most individuals with Canavan disease have the neonatal/infantile form. Such infants appear normal early in life, but by age three to five months, hypotonia, head lag, macrocephaly, and developmental delays become apparent.
Hypotonia is an early finding associated with poor head control.
Inability to support the head is a constant feature of this disorder.
With age, hypotonia gives way to spasticity.
Macrocephaly. In early infancy the head circumference may be normal or in some cases remain at the upper limit of normal. However, in the majority of individuals, the head circumference increases after age six months and by the first year is above the 90th percentile.
Developmental delay becomes more obvious with increasing age:
Children are especially delayed in their motor skills and are not able to sit, stand, walk, or talk.
They learn to interact socially, laugh and smile, reach for objects, and raise their heads in the prone position.
Vision and hearing. Early in life there is a decreased ability to fix and follow. Optic atrophy usually develops in the second year of life. Hearing is usually not impaired.
Progression. With age, children with neonatal/infantile-onset Canavan disease often become irritable and experience sleep disturbance, seizures, and feeding difficulties. Swallowing deteriorates, and some of the children require nasogastric feeding or permanent feeding gastrostomies. Joint stiffness increases, so that these children resemble individuals with cerebral palsy.
Prognosis. Most individuals with Canavan disease die in the first decade of life. However, with improved medical and nursing care a larger number of children survive beyond the first decade.
Mild/Juvenile Canavan Disease
Presentation. Children with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life without regression. In spite of developmental delay most of these children can be educated in typical classroom settings and may benefit from speech therapy or tutoring as needed [Matalon & Michals Matalon 2015]. Most of the children with mild forms of Canavan disease have normal head size, although macrocephaly, retinitis pigmentosa, and seizures have been reported in a few individuals [Tacke et al 2005, Delaney et al 2015].
Neuroimaging
Neonatal/infantile (severe) Canavan disease. CT or MRI performed in infancy may be interpreted as normal [Matalon & Michals-Matalon 2000]. Diffuse, symmetric white matter changes are observed in the subcortical areas and in the cerebral cortex; involvement of the cerebellum and brain stem is less marked [Matalon et al 1995].
Magnetic resonance spectrometry (MRS) to detect N-acetylaspartic acid has been reported as the best method for the diagnosis of Canavan disease in infants, even with normal serum and urine N-acetylaspartic acid levels [Karimzadeh et al 2014].
Mild/juvenile Canavan disease. Brain MRI does not show general white matter changes, although increased signal intensities in the basal ganglia have been reported [Surendran et al 2003, Yalcinkaya et al 2005, Michals & Matalon 2011].
Neuropathology
In neonatal/infantile Canavan disease subcortical spongy degeneration is observed. Electron microscopy (EM) reveals swollen astrocytes and distorted mitochondria.
Genotype-Phenotype Correlations
Neonatal/infantile (severe) Canavan disease is associated with complete loss of ASPA enzyme activity. The common p.Tyr231Ter, p.Glu285Ala, and p.Ala305Glu pathogenic variants in the homozygous or compound heterozygous (with each other) state are associated with neonatal/infantile disease [Matalon & Michals-Matalon 1998].
Mild/juvenile Canavan disease is associated with at least one "mild" pathogenic variant (p.Tyr288Cys, p.Arg71His, or p.Pro257Arg) with residual ASPA enzyme activity. Individuals are usually heterozygous with one mild variant and one severe variant [Surendran et al 2003, Yalcinkaya et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011].
Nomenclature
Other names for neonatal/infantile (severe) Canavan disease that are no longer in use:
Prevalence
While Canavan disease occurs in all ethnic groups, most reported individuals are of Ashkenazi Jewish origin.
Carrier frequency has varied from 1:40 to 1:82 in the Ashkenazi Jewish population depending on the source of samples [Kronn et al 1995, Matalon et al 1995, Fares et al 2008].
The carrier rate in non-Jews is not known; however, it is assumed to be much lower than the carrier rate in the Ashkenazi Jewish population.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Canavan Disease
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| Disorder | Gene(s) | MOI | Clinical Features of This Disorder |
|---|
| Overlapping w/Canavan disease | Distinguishing from Canavan disease |
|---|
| Alexander disease | GFAP | AD | | |
| Tay-Sachs disease | HEXA | AR | | |
| Metachromatic leukodystrophy | ARSA | AR | | Late-infantile onset (age <30 mos) after a period of apparently normal development |
| Glutaric acidemia type 1 | GCDH | AR | | Progressive movement disorder |
Leigh syndrome
(see also Mitochondrial Disorders Overview) | mtDNA | mt
AR | Spongy degeneration of the brain | Decompensation (often w/elevated lactate levels in blood &/or CSF) during an intercurrent illness is typically associated w/psychomotor retardation or regression. |
| Glycine encephalopathy (nonketotic hyperglycinemia) | AMT
GCSH
GLDC | AR | Spongy degeneration of the brain | Neonatal form manifests in 1st hrs/days of life w/progressive lethargy, hypotonia, & myoclonic jerks. Apnea Profound intellectual disability Intractable seizures
|
| Viral encephalitis | NA | NA | Spongy degeneration of the brain | History of viral infection in a previously typical individual |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; NA = not applicable; XL = X-linked
Mild/juvenile Canavan disease may be misdiagnosed as a mitochondrial disorder (see Mitochondrial Disorders Overview).
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with Canavan disease, the following evaluations are recommended if they have not already been completed.
Neonatal/infantile (severe) form
Juvenile/mild form
All Canavan disease. Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Neonatal/infantile Canavan disease
Treatment is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway.
Hospice care is a resource used by the families of the individuals affected by the disease.
Children benefit from:
Physical therapy to minimize contractures and optimize abilities and seating posture,
Other therapies to enhance communication skills (especially in those with a more gradual clinical course), and
Early intervention and special education programs.
Seizures may be treated with antiepileptic drugs.
A feeding gastrostomy may be required to maintain adequate intake and hydration in the presence of swallowing difficulties.
Botox® injections may be used to relieve spasticity.
Mild/juvenile Canavan disease. Individuals may require speech therapy or tutoring but require no special medical care.
Prevention of Secondary Complications
Neonatal/infantile Canavan disease
Contractures and decubiti need to be prevented by exercise and position changes.
Feeding difficulties and seizures increase the risk of aspiration, which can be reduced with use of a G-tube for feeding.
Surveillance
Neonatal/infantile Canavan disease. Follow up at six-month intervals by a pediatric neurologist to evaluate developmental status and evidence of any new problems is suggested.
Mild/juvenile Canavan disease. Annual routine follow up by a pediatric neurologist (or a developmental pediatrician) is indicated.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.