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Canavan Disease: a Neurometabolic Disease Caused by Aspartoacylase Deficiency

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Canavan Disease: a Neurometabolic Disease Caused by Aspartoacylase Deficiency Journal of Pediatric Sciences SPECIAL ISSUE Current opinion in pediatric metabolic disease Editor: Ertan MAYATEPEK Canavan Disease: A Neurometabolic Disease Caused By Aspartoacylase Deficiency Ute Lienhard and Jörn Oliver Sass Journal of Pediatric Sciences 2011;3(1):e71 How to cite this article: Lienhard U, Sass JO. Canavan disease: a neurometabolic disease caused by aspartoacylase deficiency. Journal of Pediatric Sciences. 2011;3(1):e71 JPS 2 REVIEW ARTICLE Canavan Disease: A Neurometabolic Disease Caused By Aspartoacylase Deficiency Ute Lienhard and Jörn Oliver Sass Abstract: Canavan disease is a genetic neurodegenerative disorder caused by mutations in the ASPA gene encoding aspartoacylase, also known as aminoacylase 2. Important clinical features comprise progressive psychomotor delay, macrocephaly, muscular hypotonia as well as spasticity and visual impairment. Cerebral imaging usually reveals leukodystrophy. While it is often expected that patients with Canavan disease will die in childhood, there is increasing evidence for heterogeneity of the clinical phenotype. Aspartoacylase catalyzes the hydrolysis of N- acetylaspartate (NAA) to aspartate and acetate. Its deficiency leads to accumulation of NAA in the brain, blood, cerebrospinal fluid and in the urine of the patients. High levels of NAA in urine are detectable via the assessment of organic acids by gas chromatography - mass spectrometry. Confirmation is available by enzyme activity tests and mutation analyses. Up to now, treatment of patients with Canavan disease is only symptomatic. Although it is a panethnic disorder, information on affected individuals in populations of other than Ashkenazi Jewish origin is rather limited. Ongoing research aims at a better understanding of Canavan disease (and of related inborn errors of metabolism such as aminoacylase 1 deficiency). Unraveling underlying mechanisms may provide a basis for future therapeutic approaches. Keywords: Canavan disease, aspartoacylase, aminoacylase, leukodystrophy, neurodegeneration, organic acids, N-acetylaspartate, ASPA, ACYI, NAT8L Received: 13/07/2010; Accepted: 14/07/2010 Introduction Canavan disease is a childhood leukodystrophy which often leads to death in childhood. Its name goes back to Myrtelle M. Canavan who published a case report Ute Lienhard, Jörn Oliver Sass on a child with a very enlarged head, neurological symptoms such as nystagmus, and psychomotor Labor für Klinische Biochemie & Stoffwechsel, retardation in 1931 [1]. In retrospect the first clinical Zentrum für Kinder- und Jugendmedizin description of the disorder was accredited to Globus Universitätsklinikum Freiburg Mathilden str. I and Strauss (1928) [2]. Bogaert and Bertrand defined it 79106 Freiburg, Germany as a clinical entity [3]. Corresponding Author: Jörn Oliver Sass Since the brain of patients with Canavan disease shows Labor für Klinische Biochemie & Stoffwechsel a spongy degeneration of the white matter [1,4] the Zentrum für Kinder- und Jugendmedizin disorder is also known as “spongy degeneration (van Universitätsklinikum Freiburg, Mathildenstr. 1 Bogaert and Bertrand type)” [5]. Canavan disease 79106 Freiburg, Germany follows an autosomal recessive trait of inheritance [6] Tel.: +49-761-270-4371 and is caused by mutations in the ASPA gene resulting Fax.: +49-761-270-4527 in deficiency in aspartoacylase (aminoacylase 2) [7], e-mail: [email protected] which catalyzes the hydrolysis of N-acetylaspartate (NAA) [8]. (Figure 1) 7 Journal of Pediatric Sciences 2011;3(1):e71 JPS 3 Figure 1: Aspartoacylase (ASPA; EC 3.5.1.15), also known as aminoacylase 2, catalyzes the hydrolysis of N-acetylaspartic acid. While Canavan disease is particularly frequent Later those features can change to spasticity [2,4,15]. among Ashkenazi Jews [3,5,9] it has been reported in The spasticity may resemble cerebral palsy. For this many populations [10-14]. reason some children with Canavan disease have been diagnosed with cerebral palsy [15]. Clinical features Children with Canavan disease are usually At the age of one or two years most Canavan patients considered symptom-free in the first three months of develop sleep disturbances and feeding problems. life, although mild retardation, hypotonia and Some children with Canavan disease suffer from inadequate visual tracking may be detectable in an seizures. In 38 of the 60 children included in the attentive examination [15]. Traeger and Rapin have survey by Traeger and Rapin, epilepsy was reported that about a fifth of the patients present at ascertained at various ages, from birth to 15 years birth with a poor suck, irritability and poor visual [16]. Others describe seizures in about half of the fixation [16]. patients, mostly generalized tonic-clonic convulsions. As a reaction to a stimulus, tonic extensor spasms Usually, the disease manifests not later than at the often occur with an excessively ophistotonic posture age of six months [6]. Key clinical features are [4,6]. developmental delay, head lag and macrocephaly [3,15-17]. The head circumference exceeded the 90th Common understanding of Canavan disease is that percentile in 54 of 59 children with Canavan disease the life expectancy of children with Canavan disease reported by Traeger and Rapin [16]. is very short and that children with the classic course of the disease die mostly in the first three years of Observation of the three signs macrocephaly, their life [6]. However, there are more and more hypotonia and head lag should lead to suspicion of patients who achieve an age of more than ten years. Canavan disease, especially if there is evidence for Matalon and Michals-Matalon have contributed this white matter involvement [15]. Affected individuals to better medical and nursing care [15], although do not meet important developmental milestones. there is still no curative therapy. Increased awareness They do not acquire appropriate motor and verbal of the disease and improved diagnostic possibilities skills and do also lose abilities. Interaction is often deserve also consideration and may have led to more further impaired by ophthalmological symptoms [16]. frequent diagnosis of mild manifestations which may Optic atrophy, retinal degeneration and horizontal previously have escaped investigations and statistics. nystagmus are frequent findings in Canavan disease Notably, early reports on Canavan disease often [3,4,15,16]. referred to individuals of Ashkenazi Jewish origin [3,5,17] whereas more recent publications underline Early observed irritability usually increases with the the panethnic character of the disease [14,18–21]. progression of the disease [15]. Hypotonia and reduced motor activity are additional early Neuropathology recognizable features. Formerly, pathologic changes in the brain of Canavan 7 Journal of Pediatric Sciences 2011;3(1):e71 JPS 4 patients could only be detected at autopsy and Laboratory Investigations histopathological examination. In 1931, Myrtelle Canavan’s autopsy findings were spongy Metabolite Studies degeneration of the white matter and an expansion of Following the discovery that patients with Canavan cerebral ventricles and aqueduct. Cerebrum as well as disease present with N-acetylaspartic aciduria, the cerebellum were very soft and gelatinous [1]. In the determination of NAA levels in urine has become an histopathological examination of brains of affected important tool for the identification of individuals children Bogaert and Bertrand found a widespread with this inborn error of metabolism [28–30]. NAA is vacuolization change in both white and gray matter one of the parameters which are assessed by the [3]. Others reported a marked elevation of the analysis of urinary organic acids using gas number of protoplasmic astrocytes and a diffuse loss chromatography-mass spectrometry (Figure 2) [31]. of cortical neurons in Canavan disease [4]. Bal et al. have demonstrated that it is the L- enantiomer of NAA which accumulates in Canavan In electron microscopic studies, vacuoles have been disease [32]. Elevated concentrations of NAA have found within protoplasmic astrocytes. They are also been demonstrated in plasma and cerebrospinal considered the main cause for the vacuoulated fluid of affected individuals [33,34]. However, appearance of the white matter [5]. diagnostic investigations in urine are more easily accomplished. Radiology Nowadays the pathologic changes in the brains of Aspartoacylase Activity patients with Canavan disease can be visualized by Since Canavan disease is due to aspartoacylase cerebral imaging. Findings include leukodystrophic deficiency, enzyme assays have been developed signs, lack of myelin, brain atrophy and increasing which allow the confirmation of the diagnosis in ventriculomegaly [20,22,23]. Affection of the basal cultured skin fibroblasts [28,35,36]. Matalon et al. ganglia is revealed in some cases [22–24]. On CT reported that the aspartoacylase activity in cultured scans white matter changes can be demonstrated [23]. fibroblasts from heterozygous mutation carriers was Reversal of signal intensities in T1- and T2-weighted diminished to about half of the activity detected in MRI scans as well as elevated white matter T1 values normal fibroblasts [37]. are signs for pathologic changes in myelination [20,23,25]. Mutation Analysis The human ASPA gene encoding aspartoacylase was Brismar et al. 1990 considered CT and MRI results localized on the short arm of chromosome 17 (17p13- nonspecific for Canavan disease [26]. They found no ter) [38]. It comprises
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