ASPA – Canavan disease

Canavan disease is a rare autosomal recessive leukodystrophy caused by loss-of-function mutations in the aspartoacylase gene (ASPA). ASPA encodes a zinc-dependent enzyme that hydrolyzes N-acetyl-l-aspartate (NAA) to acetate and aspartate, a key step in myelin lipid synthesis. Deficiency of ASPA leads to accumulation of NAA, spongiform degeneration of cerebral white matter, macrocephaly, hypotonia, and early neurodevelopmental arrest ([PMID:1288858]).

Extensive genetic studies have defined a broad spectrum of ASPA mutations. Sixty-four probands were screened revealing three predominant mutations—c.693C>A (p.Tyr231Ter), c.854A>C (p.Glu285Ala), and c.914C>A (p.Ala305Glu)—with the latter two accounting for 98.8% of Ashkenazi Jewish and 60% of non-Jewish European mutant alleles, respectively ([PMID:8023850]). Eighteen Ashkenazi Jewish patients were homozygous for c.854A>C (p.Glu285Ala) with a carrier rate of 1:59 in healthy individuals ([PMID:8037206]), and 24 different mutations were identified in 22 non-Jewish patients, including splice-site and indel variants ([PMID:8659549]). Over 200 unrelated cases now confirm ASPA as the definitive disease gene for Canavan disease.

Segregation analyses in multiple affected families, including a consanguineous Pakistani pedigree with homozygous c.820G>C (p.Gly274Arg) in siblings, demonstrate perfect co-segregation of biallelic ASPA variants with the phenotype in at least 2 additional relatives beyond probands ([PMID:22219087]).

Functional assays corroborate the pathogenicity of ASPA variants: expression of p.Tyr231Ter and p.Ala305Glu in vitro yields complete loss of enzyme activity ([PMID:8023850]). Aspa−/− mice recapitulate human pathology, exhibiting elevated brain NAA, demyelination, and motor deficits ([PMID:14567959]). High-resolution structural studies of mutants p.E285A, p.Y231C, and p.F295S reveal active-site disruption or destabilization of the catalytic core, explaining impaired substrate binding and catalysis ([PMID:25003821]).

Gene therapy in Aspa−/− mice using rAAV-mediated ASPA delivery improved survival and motor function but unveiled peripheral immune responses to NAA accumulation, suggesting that both central and systemic targeting may be required for optimal outcomes ([PMID:27039844]).

Key Take-home: Biochemical NAA quantification together with targeted ASPA gene sequencing provides a definitive diagnostic approach for Canavan disease, informs carrier screening in at-risk populations, and underpins development of gene therapy strategies.

References

• Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery • 1992 • Biochemical diagnosis of Canavan disease. PMID:1288858
• American journal of human genetics • 1994 • Canavan disease: mutations among Jewish and non-Jewish patients. PMID:8023850
• American journal of human genetics • 1994 • The frequency of the C854 mutation in the aspartoacylase gene in Ashkenazi Jews in Israel. PMID:8037206
• American journal of human genetics • 1996 • Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. PMID:8659549
• Molecular genetics and metabolism • 2003 • Canavan disease: a monogenic trait with complex genomic interaction. PMID:14567959
• Molecular biology reports • 2012 • A missense mutation (p.Gly274Arg) in gene ASPA causes Canavan disease in a Pakistani family. PMID:22219087
• Biochemistry • 2014 • Aspartoacylase catalytic deficiency as the cause of Canavan disease: a structural perspective. PMID:25003821
• Molecular therapy : the journal of the American Society of Gene Therapy • 2016 • rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System. PMID:27039844

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