Myelin lesion in the aspartoacylase (Aspa) knockout rat, an animal model for Canavan disease.

Canavan disease (CD) is a fatal hereditary neurological disorder caused by a mutation in the aspartoacylase (ASPA) gene and characterized by neurological signs and vacuolation in the central nervous system (CNS). The mutation inhibits the hydrolysis of N-acetyl-aspartate (NAA) resulting in accumulation of NAA in the CNS. A new Aspa-knockout rat was generated by transcription activator-like effector nuclease (TALEN) technology. Herein we describe the pathological and morphometrical findings in the brain and spinal cords of Aspa-knockout rats. Although Aspa-knockout rats did not show any neurological signs, vacuolation with swollen axons, hypomyelination, and activated swollen astrocytes were observed mainly in the brainstem reticular formation, ascending and descending motor neuron pathway, and in the olfactory tract. Morphometrical analysis revealed no obvious change in the number of neurons. These changes in the CNS are similar to human CD, suggesting that this animal model would be useful for further study of treatment and understanding the pathophysiology of human CD.

Canavan's spongiform leukodystrophy (Aspartoacylase deficiency) with emphasis on sonographic features in infancy: description of a case report and review of the literature.

Canavan disease (CD; MIM 271,900) or spongy degeneration of the central nervous system (CNS) is a lethal, rare autosomal recessive leukodystrophy, first described in 1931 (Canavan in Arch Neurol Psychiatry 25: 299-308, 1931). The clinical presentation includes severe neurologic impairment and macrocephaly with onset of symptoms at the age of 3-5 months. Biochemical and genetic fundamentals of the disease are elucidated. Imaging diagnosis is principally based on MRI with important role of MR spectroscopy. We report the cerebral sonographic findings in a severely affected infant with CD: Diffuse hyperechogenicity and small multicystic changes of white matter as well as an inverted pattern of echogenicity between cortical gray and subcortical white matter. These findings are compared to to the few cases found in literature and to normal ultrasound examples. Finally, ultrasound and MRI imaging findings are correlated.

Canavan Disease: Clinical and Laboratory Profile from Southern Part of India.

BACKGROUND: Canavan disease (CD) is an autosomal recessively inherited leukodystrophy. It affects one in 6,400 to 13,500 people in the Jewish population. However, prevalence and presentation of the disease in India is largely unknown; hence, we are reporting this series. METHODS: This is a retrospective chart review in a tertiary care hospital from January 2015 to March 2020. CD was confirmed by elevated N- acetyl aspartate (NAA) levels in urinary gas chromatography and mass spectrometry (GCMS)/increased NAA peak in magnetic resonance spectroscopy (MRS) and/or detection of mutations. The data was extracted in a predesigned proforma and analyzed. RESULTS: We had 12 children with mean age at presentation being 6.8 months (range 3 months to 10 months.). Males were more commonly affected (83.3%, n = 10). Ten children (83.3%) were born out of consanguineous parentage. All of them had visual impairment and pyramidal signs. Seizures were noted in five (42%) children. Normal head size in three (25%) and microcephaly in two (16.66%) cases were noted. Magnetic resonance imaging (MRI) revealed signal changes with bilateral symmetric T2W white matter (WM) hyperintensities in subcortical U fibers in all cases. MRS was done in ten children, all of which showed increased NAA peak. Increased level of NAA in urinary GCMS was noted in six out of eight children. Six cases had homozygous pathogenic variants in ASPA gene. Antenatal diagnosis helped in prevention of recurrence in three families. CONCLUSION: Urinary NAA and MRS showing NAA peak are useful in diagnosis of CD. Macrocephaly is not a necessary finding to diagnose CD. Early diagnosis helps in genetic counseling and prevention of subsequent conceptions.

The natural history of Canavan disease: 23 new cases and comparison with patients from literature.

BACKGROUND: Canavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients). RESULTS: Onset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed. CONCLUSIONS: Early hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.

A Novel Mutation in Aspartoacylase Gene; Canavan Disease.

Objective Canavan disease (CD) is a type of vacuolating leukodystrophy with autosomal recessive inheritance. Aspartoacylase deficiency results in decrease of myelin biosynthesis, dysmyelination and brain edema. Although CD is a very common in Ashkenazi Jews patients, several cases have been reported from non-Jewish population. This report is based on a homozygous C.202G>A mutation in the ASPA gene identified from an Iranian patient. To our knowledge, this type of mutation has not been reported in non-Jewish population in the literature.

Brain ultrasound in Canavan disease.

Canavan disease (MIM 271900) is a rare autosomal recessive leukodystrophy due to mutations in the ASPA gene (MIM 608034) and characterized by a clinical onset at 3-5 months of life, macrocephaly and poor head control, weak cry and suck, development regression and hypotonia. Here, we report cranial ultrasound findings at birth and at 4 months of age in a patient affected with Canavan disease. The comparison of our sonographic data with few other cases in literature allows us to suggest a characteristic pattern in Canavan disease.