Aspartoacylase deficiency (Canavan disease)

INTRODUCTION AND BACKGROUND — Aspartoacylase deficiency (Canavan disease; MIM #271900) is an autosomal recessive spongiform leukodystrophy that is prevalent in, but not restricted to, Ashkenazi Jewish individuals. The disease typically begins in infancy and is marked by relentless progression.

Canavan disease was first described in the early 20th century as spongy degeneration of central nervous system myelin in infancy. The discovery of N-acetylaspartic aciduria due to aspartoacylase deficiency in a leukodystrophy was made in 1987 [1]. The realization that this leukodystrophy was actually Canavan disease with abnormal N-acetylaspartic acid (NAA) metabolism was not made until 1988 [2]. Elevated urinary NAA excretion and aspartoacylase deficiency had been reported two years previously, but without a direct association to spongy degeneration of myelin in infancy [1]. The aspartoacylase gene was cloned in 1993, and numerous pathogenic variants have been identified since then [3-6].

Although the Canavan disease eponym is widely used, aspartoacylase deficiency is preferable. Of interest, Canavan's own report was linked to Schilder disease or Krabbe disease (galactocerebrosidase deficiency) and not spongy degeneration.

ETIOLOGY — Aspartoacylase deficiency is caused by pathogenic variants in the ASPA gene that encodes the enzyme aspartoacylase. The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in the brain and to oligodendrocyte dysfunction, spongiform changes, and absence of myelin. However, the precise mechanisms causing spongiform degeneration are uncertain.

Genetics — Aspartoacylase deficiency is transmitted in an autosomal recessive fashion. The ASPA gene encoding aspartoacylase is located on chromosome 17pter-p13 [4]. Several pathogenic variants have been defined in ASPA, but just four of them account for >99 percent of aspartoacylase deficiency cases in Ashkenazi Jews [3,5,7-10].

In non-Ashkenazi individuals, a broad range of distinctly different pathogenic variants, including large deletions, have been identified [8-15]. Unique ASPA pathogenic variants were found in the Japanese and Scandinavian populations [16,17], as well as in Northern and Southern Indian populations [18,19]. A novel homozygous pathogenic variant, associated with a milder juvenile-onset form of aspartoacylase deficiency, was reported in the Telugu Devanga Chettiar community from southern India [20].

Biochemistry — NAA, formed from acetyl-CoA and aspartic acid, is the second most prevalent free amino acid in the brain. It is localized to neurons, where it is synthesized within mitochondria and transferred to oligodendrocytes via axoglial contact zones between the innermost oligodendrocyte plasma membrane and the axonal membrane [21]. In neurons, NAA is converted to N-acetylaspartylglutamate (NAAG) and is taken up by astrocytes, where it is hydrolyzed to NAA and glutamate. The NAA is then taken up by oligodendrocytes, the primary location of aspartoacylase [22-24].

The synthesis of NAA in neuronal mitochondria is mediated by aspartate N-acetyltransferase (ANAT), which is encoded by NAT8L. The export of NAA from neurons may occur via anion channels and transporters along the very high intracellular-extracellular gradient. The high-affinity sodium-dependent dicarboxylate cotransporter 3, or NaDC3, which is encoded by SLC13A3, has been proposed to be involved in the uptake of NAA into astrocytes and oligodendrocytes. Astrocyte-oligodendrocyte gap junctions may also be involved in NAA transport [25].

Aspartoacylase catalyzes the conversion of NAA to aspartate (aspartic acid) and acetate. By mechanisms that are largely unknown, deficiency of aspartoacylase leads to oligodendrocyte dysfunction, the prominent spongiform changes, and absence of myelin [26,27]. Levels of NAA are markedly increased in plasma, urine, and cerebrospinal fluid [28,29].

Loss-of-function mutations of the ASPA gene lead to structural changes, including decreased thermal or conformational stability, which result in diminished or nearly absent enzymatic activity [30,31].

Pathogenesis — Abnormal myelination, with associated prominence of swollen, vacuolated astrocytes, is a fundamental hallmark of aspartoacylase deficiency. However, the specific role of NAA in the pathogenesis of this disease is unknown [32-34]. Multiple hypotheses for the pathogenic mechanisms underlying these findings have been proposed:

●One suggestion is that a reduction in aspartic acid as a result of aspartoacylase deficiency adversely affects the recycling of aspartate for NAA synthesis and the availability of aspartate for intercellular signaling [35].

●Another plausible hypothesis is that of a cytotoxic mechanism involving NAA or its metabolic product, NAAG [36,37].

•It has been proposed that the extracellular concentration of NAA increases up to 1000-fold secondary to absent or markedly decreased aspartoacylase activity, resulting in disruption of the oligodendrocyte-axon interface and interruption of myelination [38-40]. However, NAA concentration in the brain of patients with aspartoacylase deficiency is less than twofold elevated [41]. In an animal model, deficient aspartoacylase expression resulted in altered oligodendrocyte maturation, markedly reduced myelination, and increased levels of GFAP protein, a marker of gliosis [42]. In addition, NAA is taken up by astrocytes, producing the prominent vacuolization within their cytoplasm, and leading to macrocephaly. In this model, NAA is cytotoxic for astrocytes and not oligodendrocytes. The turnover of NAA is regarded as highly dynamic [43]. As such, failure of NAA degradation could provide a profound osmotic force, resulting in the observed vacuolar changes in the brain [44,45]. Disrupted osmoregulation between neurons, astrocytes, and oligodendrocytes in the presence of elevated NAA may result in increased extracellular hydrostatic pressure within myelin lamellae, leading to intramyelinic splitting [25]. The disruption of mitochondria in astrocytes may be a secondary phenomenon, but a primary alteration in mitochondrial metabolism has been proposed as potentially related to the prominent cellular alterations. N-acetylaspartate synthase deficiency corrected the myelin and neuronal phenotype in a mouse model of Canavan disease [46,47]. These findings strongly support the notion that elevation of NAA is the major disease mechanism.

•A further potential pathogenetic mechanism involves NAAG as a trigger of glutamate excitotoxicity [48]. NAAG is synthesized from NAA and glutamate and is increased in patients with aspartoacylase deficiency. It has been proposed that glutamate excitotoxicity may arise both directly from elevated NAA and indirectly via the catabolism of NAAG to NAA and glutamate [25].

•The possibility of an acetate deficit secondary to low or absent aspartoacylase activity (NAA is hydrolyzed to acetate and L-aspartate) also has been suggested [49,50]. This hypothesis suggests that a deficiency in NAA-derived acetate within oligodendrocytes may affect postnatal myelin lipid synthesis and may impact histone acetylation and epigenetic gene regulation [25].

•Finally, oxidative stress may play a role in the pathogenesis of aspartoacylase deficiency, based upon evidence that NAA produces lipid peroxidation and protein oxidation and reduces antioxidants in rat brain [51,52]. NAA-derived acetyl groups may be a means by which oligodendrocytes preserve energetic resources during myelination by uncoupling fatty acid synthesis from oxidative metabolism [53]. Further support for this hypothesis was found in the salutary effect of anaplerotic therapy in a Canavan disease mouse model [54].

These hypotheses are not mutually exclusive, and multiple mechanisms are likely involved in the pathogenesis of aspartoacylase deficiency [25,55].

EPIDEMIOLOGY — Aspartoacylase deficiency is most prevalent among Ashkenazi Jewish individuals [29,32]. It has been described in other populations as well, including a large series from Saudi Arabia [56]. The carrier frequency among the Ashkenazi ranges from 1:37 to 1:57, yielding a range of approximate prevalence rates between 1:6000 and 1:14,000 [57,58]. The disorder is much less common in non-Ashkenazi populations [7-10]. However, sufficient data are not available to calculate a prevalence rate in groups other than Jewish people.

CLINICAL FEATURES

Neonatal/infantile (severe) form — The initial presentation of aspartoacylase deficiency, generally at approximately age three months, features lethargy and listlessness, weak cry and suck, poor head control, and hypotonia with a paucity of extremity movement [59]. However, poor feeding, irritability, and visual inattention have been described in neonates.

Macrocephaly becomes prominent by three to six months, and thereafter hypotonia progresses to spasticity, hyperreflexia, extensor plantar responses, and tonic extensor spasms. The extensor spasms may occur in response to noise, but infants with aspartoacylase deficiency do not exhibit the hyperacusis noted in Tay-Sachs disease.

By age six months, neurologic abnormalities are invariant in those with the typical form of aspartoacylase deficiency. Little subsequent development is noted, although visual fixation may be acquired later only to be lost.

Blindness in association with optic atrophy occurs between 6 and 18 months. Seizures, usually generalized tonic-clonic, are noted in approximately one-third of patients in the first year of life; the prevalence of seizures increases with age, such that nearly all patients age >10 years have seizures [60]. Unlike most leukodystrophies, the cerebrospinal fluid protein is usually normal. Fair complexion has been described, but this is of dubious significance.

Pseudobulbar signs and decerebrate posturing dominate the end stage of aspartoacylase deficiency. Feeding is a major issue with prominent swallowing dysfunction and gastroesophageal reflux. Death may occur in childhood, although survival into the teens is common [60], as the result of enhanced medical management, particularly alternative feeding strategies.

Juvenile (mild) form — The presence of a potential juvenile-onset form, beginning after age five and characterized by spasticity, cerebellar dysfunction, and blindness, was first described prior to the availability of biochemical and molecular diagnosis [61]. At that time, the diagnosis was based upon the characteristic clinical features and demonstration of spongiform degeneration of the brain. However, this is a nonspecific pathology shared by a number of other unrelated conditions [62], and it was unclear whether this represented a true case of aspartoacylase deficiency.

The disease typically begins in infancy but progresses at a highly variable rate, with no correlation of genotype or residual enzyme activity to clinical presentation [63], further expanding the conversation regarding juvenile-onset forms of the condition.

●One study reported 22 Ashkenazi infants with Canavan disease and typical onset in infancy [62]. There were 14 patients younger than age 6 who were clinically stable. Two patients died before the age of 5. Survival beyond age 5 was noted in six patients, with ages at death ranging from 6 to 17 years.

●Another series of 60 children, mainly Ashkenazi, with onset prior to 10 months of life demonstrated high variability in survival, including significantly different longevity in two siblings from two families [59].

The advent of readily available molecular testing for aspartoacylase deficiency has helped to clarify this question. In subsequent reports, milder disease expression has been associated with specific ASPA gene mutations that may produce a relatively benign phenotype with variable features, including mild developmental delay without regression, hypotonia, normocephaly, tremor, and mild coordination difficulties [20,64-69].

Neuroimaging — In patients with aspartoacylase deficiency, cranial imaging by computed tomography (CT) and magnetic resonance imaging (MRI) typically shows diffuse and symmetrical white matter involvement. CT shows marked reduction of white matter [70-74]. MRI demonstrates white matter that is hypointense on T1 and hyperintense on T2 (image 1 and image 2) [71-75]. The white matter may show multiple round or oval cystic changes with a honeycomb or cribriform appearance that may represent dilatation of Virchow-Robin spaces related to spongiform degeneration [75,76]. On diffusion-weighted MRI sequences, restricted diffusion in deep white matter and brainstem corresponding to cytotoxic brain edema is frequently present early in Canavan disease [77]. In individuals with delayed onset and slower progression, brain MRI may show less prominent white matter changes and increased signal intensity in basal ganglia [63,78,79]. In a case report of a girl with incidentally discovered Canavan disease who had a benign clinical course, there were atypical MRI findings of diffuse T2 and fluid-attenuated inversion recovery (FLAIR) signal hyperintensity and restricted diffusion involving the cortex and sparing the white matter [67].

Magnetic resonance spectroscopy (MRS) typically shows markedly increased levels of N-acetylaspartic acid (NAA) (image 3) [73,74,80,81], regardless of echo time utilized [82]. MRI without any white matter abnormalities but with elevated NAA peak on MRS was reported in a five-year-old child with the insidious onset of mild motor and speech delay [83].

MRS is also being studied to track the natural progression of metabolite changes and could serve as a measure for monitoring therapeutic interventions [84]. In some instances, NAA levels are normal, but other metabolites are reduced, yielding elevated ratios of NAA/choline and NAA/creatine [85].

Neuropathology — Brain weight is increased significantly in aspartoacylase deficiency, reflecting the prominent macrocephaly noted in early infancy [61]. However, by age 30 months, brain weight may be normal, reflecting the progressive white matter loss [61].

The gross pathologic findings are dominated by spongy degeneration of deep cortex, subcortical white matter, and cerebellum. The spongiform changes reflect vacuolated astrocytes in deeper cortical layers and in adjacent subcortical white matter. Grossly enlarged Alzheimer type II astrocytes are seen in gray matter.

Ultrastructural studies reveal disruption of mitochondria in astrocytes. Myelin is markedly reduced and may be virtually absent in some areas. Myelin lamellae within subcortical white matter are separated by vacuoles. With prolonged survival, white matter is depleted and vacuolization is present throughout the cortex.

Unlike galactosylceramide lipidosis (Krabbe disease) and sulfatide lipidosis (metachromatic leukodystrophy), peripheral nerves are generally uninvolved in aspartoacylase deficiency [61].

Pregnancy — As affected individuals are unlikely to reproduce, no information is available regarding pregnancy in patients with aspartoacylase deficiency.

Findings from the knockout mouse model suggest reduced reproductive health in the homozygous affected females and heightened fetal lethality (50 percent fewer pups/litter) [86].

DIAGNOSIS — The clinical diagnosis of aspartoacylase deficiency is relatively straightforward. In symptomatic infants with compatible clinical features (eg, hypotonia, poor head control, macrocephaly) and neuroimaging findings, the diagnosis is supported by elevated levels of urine N-acetylaspartic acid (NAA) and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing [29].

Laboratory studies — In patients with clinical features and cranial imaging findings suggesting aspartoacylase deficiency, one should request measurement of NAA in urine using gas chromatography/mass spectrometry [87].

Urine levels of NAA are increased up to 200 times normal in aspartoacylase deficiency [28]. This measurement is determined by gas chromatography/mass spectrometry. Occasional patients with aspartoacylase deficiency have lower levels of urine NAA excretion, but the levels are still approximately five- to ten-fold higher than normal [88].

In affected infants, levels of NAA are also increased in plasma and in cerebrospinal fluid, but elevated urine NAA is sufficient to support the diagnosis [29].

Canavan disease may be suspected when the NAA peak is elevated in MR spectroscopy [80,81,83-85]. (See 'Neuroimaging' above.)

Aspartoacylase activity can be measured reliably in cultured skin fibroblasts [2,89,90]. This test is used to confirm the chemical diagnosis and to rule out false positives, particularly for patients who have an elevation of urine NAA that is lower than usual for aspartoacylase deficiency.

Molecular genetic testing — For patients diagnosed with aspartoacylase deficiency by elevated urine NAA levels, targeted molecular genetic testing of the patient and family members can be useful for purposes of genetic counseling, particularly in Ashkenazi children where the number of possible mutations is small, or in families with a previously affected sibling whose mutation is known. In non-Ashkenazi families with their first affected child and no previously identified mutation, complete molecular testing may be required to provide genetic counseling, especially when the family may wish to consider a future pregnancy. Genetic testing is also useful for molecular confirmation of aspartoacylase deficiency, which may be needed for participation in treatment trials.

Targeted mutation analysis can identify specific alleles that cause most cases of aspartoacylase deficiency [29]:

●In Ashkenazi Jewish cases, two pathogenic variants, p.Glu285Ala and p.Tyr231X, are found in approximately 98 percent of disease-causing alleles [12]. Two other pathogenic variants, p.Ala305Glu and c.433-2A>G, each account for approximately one percent of alleles [8].

●In non-Jewish patients of European origin, the p.Ala305Glu pathogenic variant accounts for 40 to 60 percent of disease-causing alleles [8,10].

Sequence analysis of the ASPA coding region can be performed first for individuals of non-Ashkenazi Jewish ancestry [29]. Complete or partial deletions of the entire ASPA gene in aspartoacylase deficiency are rare [14,91].

Prenatal diagnosis — Prenatal diagnosis is possible once pathogenic variants of ASPA have been identified in an affected member of the family [29].

For pregnancies at 25 percent risk (ie, the parents are each carriers of a pathogenic variant in the ASPA gene, or the pathogenic variant is known from a previously affected offspring), mutation analysis can be performed from cells obtained using chorionic villous sampling at approximately 10 to 12 weeks gestation or amniocentesis at approximately 15 to 38 weeks gestation [92,93]. Analysis of cell-free DNA in the mother's circulation is likely to become more available in the coming years [94].

Preimplantation diagnosis using single cell molecular methodologies has been accomplished successfully in one of two families evaluated [95].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of aspartoacylase deficiency includes other progressive white matter diseases of infancy, particularly the following:

●Krabbe disease (galactosylceramide lipidosis) (see "Krabbe disease")

●Metachromatic leukodystrophy (sulfatide lipidosis) (see "Metachromatic leukodystrophy")

●Vanishing white matter disease (see "Vanishing white matter disease")

●Alexander disease which, like Canavan disease, is associated with macrocephaly (see "Alexander disease")

Spongiform degeneration of the brain is a nonspecific pathology shared by several other unrelated conditions [62]. These include certain mitochondrial disorders (eg, Leigh syndrome), metabolic diseases (eg, glycine encephalopathy), and viral infections [29].

The subsequent clinical course, cranial imaging abnormalities, and biochemical studies should differentiate aspartoacylase deficiency from the others.

MANAGEMENT — No effective disease-modifying therapy is available for aspartoacylase deficiency.

Supportive care — Management of aspartoacylase deficiency is supportive and aimed at maintaining nutrition and hydration, protecting the airway, preventing seizures, minimizing contractures, and treating infections [29]. Assessment of nutritional and developmental status is recommended to guide management.

●A feeding gastrostomy tube is typically needed to maintain adequate nutrition and hydration in the presence of dysphagia. A gastrostomy tube can also reduce the risk of aspiration. (See "Poor weight gain in children younger than two years in resource-abundant settings: Management", section on 'Estimation of energy requirements'.)

●Seizures are treated with standard antiseizure medications. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)

●Exercise (physical therapy) and position changes are helpful to reduce the risk of contractures and decubitus ulcers, and to improve sitting posture.

●Special education programs and interventions to enhance communication skills may be helpful, particularly for those with a less severe clinical course.

●Botulinum toxin injections can be used to treat spasticity.

Investigational therapies — Gene transfer, enzyme replacement therapy, antisense oligonucleotide therapy, aspartate N-acetyltransferase (ANAT) inhibition, modification of SLC13A3, acetate supplementation, anaplerotic therapy, and lithium are being studied as possible treatments for aspartoacylase deficiency.

●Several preliminary studies have evaluated gene transfer:

•The combined delivery of liposome enclosed enzyme and viral vector-mediated gene transduction was employed in two children [96,97]. While successful delivery could be demonstrated, the results did not demonstrate substantial efficacy.

•Adeno-associated viral vector (AAV) mediated gene transfer of ASPA was studied in 10 children with aspartoacylase deficiency [98,99]. No significant adverse immune response was noted, and no statement on efficacy was available.

•A knock-out mouse model has been developed, paving the way for additional gene therapy studies [86,100-105], and a spontaneously arising rat model with aspartoacylase deficiency also has been developed [106]. Effective gene transfer using an adeno-associated viral vector has been demonstrated in each model [107-109].

•A novel AAV variant, AAV/Olig001, engineered with preferential tropism for the oligodendrocyte cell surface, demonstrated widespread oligodendrocyte transduction in adult Canavan mice (except for the cerebellum) after intracerebroventricular administration to the CSF. This treatment resulted in an improvement in aspartoacylase activity, motor function, and vacuolation [110].

•Dual function AAV gene therapy utilizing an AAV vector designed to deliver ASPA and to inhibit ANAT activity was injected bilaterally directly into the striatum, thalamus, and cerebellum of adult Canavan mice, resulting in improvement in clinical parameters and reversal of pathologic findings [111].

•AAV-ASPA gene therapy was performed in a two-year-old boy with Canavan disease using simultaneous intravenous and intracerebroventricular administration and preventive immunomodulation. This treatment resulted in increased brain myelination, improved vision, and improved motor function at more than two years posttreatment [112].

•Neural progenitor cells have been transplanted successfully in the mouse knockout model and have differentiated into myelin-forming oligodendrocytes [113]. Cell-based therapy utilizing human-induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs) may provide an alternative to AAV-mediated gene therapy [114,115].

●Modified aspartoacylase has been shown to reach the central nervous system following intraperitoneal injection, resulting in a reduction of N-acetylaspartic acid (NAA) levels [116]. This finding suggests that enzyme replacement approaches may be examined in this model.

●Intracisternal administration of locked nucleic acid antisense oligonucleotide (LNA ASO) to knock down the expression of neuronal NAA synthesizing ANAT in adult Canavan mice resulted in a transient decrease in NAA and improvement in ataxia, but these effects were not sustained, suggesting that repeated doses may be necessary [117].

●Decreasing NAA by lowering its synthesis may be a useful approach [46,47]. Bisubstrate analog inhibitors of ANAT have been developed [118], and drug discovery screening techniques have identified potential ANAT inhibitors with drug-like chemical properties [119,120]. The use of ANAT inhibitors alone and in combination with other treatments may be complementary.

●In Canavan disease mice, knockout of the high-affinity sodium-dependent dicarboxylate cotransporter 3 (NaDC3), which is encoded by SLC13A3, resulted in decreased brain NAA accumulation, improved motor function, and decreased brain vacuolation [121]. However, SLC13A3 pathogenic variants have been linked to fever-induced acute reversible leukoencephalopathy with increased urinary excretion of alpha-ketoglutarate (OMIM#618384) in a small number of patients [122], which suggests that caution is indicated when considering the development of SLC13A3 inhibitors for clinical use.

●Acetate supplementation has been proposed as potentially beneficial for myelin formation by oligodendrocytes based upon the presumption that aspartoacylase deficiency and resultant acetate deficiency in these cells could be responsible for abnormal myelination [49]. The acetate precursor glyceryl triacetate was evaluated in low doses (up to 25 mg/kg daily) in two children with aspartoacylase deficiency and in higher doses (up to 5.8 mg/kg daily) in an animal model [123]. No evidence of toxicity was noted with either dosing schedule. In addition, the two children demonstrated no further clinical deterioration, providing a rationale for evaluating a larger dose in affected children.

●Anaplerotic therapy using triheptanoin shows promise based upon a study in an animal model [54]. (See 'Pathogenesis' above.)

●Intraperitoneal lithium chloride injection produced reduction, albeit modest, of brain NAA levels in the spontaneous rat model of aspartoacylase deficiency [124]. In a study of six children with Canavan disease, lithium citrate administration was associated with a small but statistically significant decline in brain NAA detected by magnetic resonance spectroscopy [125].

SUMMARY

●Description – Aspartoacylase deficiency (Canavan disease; MIM #271900) is an autosomal recessive spongiform leukodystrophy that is prevalent in the Ashkenazi Jewish population. The disease typically begins in infancy and is marked by relentless progression. (See 'Introduction and background' above.)

●Etiology – Aspartoacylase deficiency is caused by pathogenic variants in the ASPA gene that encodes the enzyme aspartoacylase. The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in brain and to oligodendrocyte dysfunction, spongiform changes, and absence of myelin. However, the precise mechanisms causing spongiform degeneration are uncertain. (See 'Etiology' above.)

●Epidemiology – Aspartoacylase deficiency is highly prevalent among Ashkenazi Jewish individuals, but is much less common in other populations. (See 'Epidemiology' above.)

●Neonatal/infantile form – Aspartoacylase deficiency typically presents at approximately age three months with lethargy and listlessness, weak cry and suck, poor head control, and hypotonia with a paucity of extremity movement. Macrocephaly becomes prominent by three to six months. Thereafter hypotonia progresses to spasticity and tonic extensor spasms. By age six months, neurologic abnormalities are invariant. Little subsequent development is noted. Blindness from optic atrophy occurs between 6 and 18 months. Seizures are noted in approximately one-third of patients in the first year of life, and seizure prevalence increases with age. Pseudobulbar signs and decerebrate posturing dominate the end stage. (See 'Neonatal/infantile (severe) form' above.)

●Juvenile form – Juvenile forms of aspartoacylase deficiency are rare but may be underdiagnosed. Measurement of NAA in urine or by magnetic resonance spectroscopy (MRS) should be included as part of the evaluation of leukoencephalopathy at all ages. (See 'Juvenile (mild) form' above.)

●Imaging – Brain imaging by computed tomography (CT) and magnetic resonance imaging (MRI) reveals diffuse and symmetrical white matter involvement. MRS reveals markedly increased levels of NAA. (See 'Neuroimaging' above.)

●Pathology – The gross pathologic findings are dominated by spongy degeneration of deep cortex, subcortical white matter, and cerebellum. The spongiform changes reflect vacuolated astrocytes in deeper cortical layers and in adjacent subcortical white matter. (See 'Neuropathology' above.)

●Diagnosis – In symptomatic infants with compatible clinical features (eg, hypotonia, poor head control, macrocephaly) and neuroimaging findings, the diagnosis of aspartoacylase deficiency is supported by elevated levels of urine NAA and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of aspartoacylase deficiency includes other progressive white matter diseases of infancy, particularly Krabbe disease, metachromatic leukodystrophy, early-onset adrenoleukodystrophy, Alexander disease, and demyelinating disorders. (See 'Differential diagnosis' above.)

●Management – No effective disease-modifying therapy is available for aspartoacylase deficiency. Management is supportive and aimed at maintaining nutrition and hydration, protecting the airway, preventing seizures, minimizing contractures, and treating infections. Investigational therapies include gene transfer, enzyme replacement therapy, antisense oligonucleotide therapy, reduction in NAA synthesis by ANAT inhibition, modification of SLC13A3, acetate supplementation, anaplerotic therapy, and lithium. (See 'Management' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Alan K Percy, MD, and Raphael Schiffman, MD, MHSc, FAAN, who contributed to earlier versions of this topic review.