Ablating the transporter NaDC3 prevents leukodystrophy in Canavan disease mice

2021 ◽  
Author(s):  
Yan Wang ◽  
Vanessa Hull ◽  
Sarah Sternbach ◽  
Brad Popovich ◽  
Travis Burns ◽  
...  
Keyword(s):  
Canavan Disease

Feline Spongy Encephalopathy With a Mutation in the ASPA Gene

2021 ◽  
pp. 030098582110021
Author(s):  
Yuta Takaichi ◽  
James K. Chambers ◽  
Moeko Shiroma-Kohyama ◽  
Makoto Haritani ◽  
Yumi Une ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Canavan Disease ◽  
Mass Spectrometry Analysis ◽  
Intensity Change ◽  
Gas Chromatography Mass Spectrometry ◽  
Clinical Genetic ◽  
Gene Encoding ◽  
Spongy Degeneration ◽  
Spectrometry Analysis ◽  
Dense Granules

Canavan disease is an autosomal recessive leukodystrophy caused by mutations in the gene encoding aspartoacylase (ASPA), which hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. A similar feline neurodegenerative disease associated with a mutation in the ASPA gene is reported herein. Comprehensive clinical, genetic, and pathological analyses were performed on 4 affected cats. Gait disturbance and head tremors initially appeared at 1 to 19 months of age. These cats eventually exhibited dysstasia and seizures and died at 7 to 53 months of age. Magnetic resonance imaging of the brain revealed diffuse symmetrical intensity change of the cerebral cortex, brainstem, and cerebellum. Gas chromatography–mass spectrometry analysis of urine showed significant excretion of NAA. Genetic analysis of the 4 affected cats identified a missense mutation (c.859G>C) in exon 6 of the ASPA gene, which was not detected in 4 neurologically intact cats examined as controls. Postmortem analysis revealed vacuolar changes predominantly distributed in the gray matter of the cerebrum and brain stem as well as in the cerebellar Purkinje cell layer. Immunohistochemically, these vacuoles were surrounded by neurofilaments and sometimes contained MBP- and Olig2-positive cells. Ultrastructurally, a large number of intracytoplasmic vacuoles containing mitochondria and electron-dense granules were detected in the cerebral cortex. All 4 cats were diagnosed as spongy encephalopathy with a mutation in the ASPA gene, a syndrome analogous to human Canavan disease. The histopathological findings suggest that feline ASPA deficiency induces intracytoplasmic edema in neurons and oligodendrocytes, resulting in spongy degeneration of the central nervous system.

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

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Annette Bley ◽  
Jonas Denecke ◽  
Alfried Kohlschütter ◽  
Gerhard Schön ◽  
Sandra Hischke ◽  
...  
Keyword(s):  
Severity Score ◽  
Canavan Disease ◽  
Psychomotor Development ◽  
Rank Test ◽  
First Year ◽  
Study Cohort ◽  
Pooled Data ◽  
Kaplan Meier ◽  
History Of ◽  
First Year Of Life

Abstract 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.

Radiological Clue to Diagnosis of Canavan Disease

2012 ◽  
Vol 80 (1) ◽  
pp. 75-77 ◽  
Author(s):  
Priya Sreenivasan ◽  
K. K. Purushothaman
Keyword(s):  
Canavan Disease

A missense mutation (p.G274R) in gene ASPA causes Canavan disease in a Pakistani family

2012 ◽  
Vol 39 (5) ◽  
pp. 6197-6201 ◽  
Author(s):  
Rashida Hussain ◽  
Shakeela Daud ◽  
Naseebullah Kakar ◽  
Adeel Ahmad ◽  
Abdul Hameed Baloch ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Canavan Disease ◽  
Pakistani Family

Juvenile Canavan Disease: A Leukodystrophy without White Matter Changes

2018 ◽  
Vol 49 (06) ◽  
pp. 420-421
Author(s):  
Prashant Jauhari ◽  
Lokesh Saini ◽  
Biswaroop Chakrabarty ◽  
Atin Kumar ◽  
Sheffali Gulati
Keyword(s):  
White Matter ◽  
Canavan Disease ◽  
White Matter Changes

Aspartoacylase deficiency and Canavan disease in Saudi Arabia

1990 ◽  
Vol 35 (2) ◽  
pp. 266-268 ◽  
Author(s):  
Pinar T. Ozand ◽  
Generoso G. Gascon ◽  
Mohammed Dhalla
Keyword(s):  
Saudi Arabia ◽  
Canavan Disease ◽  
Aspartoacylase Deficiency

scholarly journals Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease

2003 ◽  
Vol 7 (5) ◽  
pp. 580-587 ◽  
Author(s):  
Reuben Matalon ◽  
Sankar Surendran ◽  
Peter L Rady ◽  
Michael J Quast ◽  
Gerald A Campbell ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Knockout Mouse ◽  
Canavan Disease ◽  
Adeno Associated Virus ◽  
The Brain

scholarly journals Aspartoacylase Supports Oxidative Energy Metabolism during Myelination

2012 ◽  
Vol 32 (9) ◽  
pp. 1725-1736 ◽  
Author(s):  
Jeremy S Francis ◽  
Louise Strande ◽  
Vladamir Markov ◽  
Paola Leone
Keyword(s):  
Energy Metabolism ◽  
Postnatal Development ◽  
Strong Association ◽  
Canavan Disease ◽  
Lipid Synthesis ◽  
Systematic Analysis ◽  
Early Postnatal Development ◽  
Neuronal Viability ◽  
Oxidative Energy Metabolism ◽  
The Brain

The inherited leukodystrophy Canavan disease arises due to a loss of the ability to catabolize N-acetylaspartic acid (NAA) in the brain and constitutes a major point of focus for efforts to define NAA function. Accumulation of noncatabolized NAA is diagnostic for Canavan disease, but contrasts with the abnormally low NAA associated with compromised neuronal integrity in a broad spectrum of other clinical conditions. Experimental evidence for NAA function supports a role in white matter lipid synthesis, but does not explain how both elevated and lowered NAA can be associated with pathology in the brain. We have undertaken a systematic analysis of postnatal development in a mouse model of Canavan disease that delineates development and pathology by identifying markers of oxidative stress preceding oligodendrocyte loss and dysmyelination. These data suggest a role for NAA in the maintenance of metabolic integrity in oligodendrocytes that may be of relevance to the strong association between NAA and neuronal viability. N-acetylaspartic acid is proposed here to support lipid synthesis and energy metabolism via the provision of substrate for both cellular processes during early postnatal development.

Does ASPA Gene Mutation in Canavan Disease Alter Oligodendrocyte Development?

2006 ◽  
pp. 175-182 ◽  
Author(s):  
Shalini Kumar ◽  
Rasika Sowmyalakshmi ◽  
Sarah L. Daniels ◽  
Ruth Chang ◽  
Sankar Surendran ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Canavan Disease ◽  
Oligodendrocyte Development
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