uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Infantile Cerebellar-Retinal Degeneration Associated with a Mutation in Mitochondrial Aconitase, ACO2
Show others and affiliations
2012 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 3, 518-523 p.Article in journal (Refereed) Published
Abstract [en]

Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.

Place, publisher, year, edition, pages
2012. Vol. 90, no 3, 518-523 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-173806DOI: 10.1016/j.ajhg.2012.01.009ISI: 000301762800018OAI: oai:DiVA.org:uu-173806DiVA: diva2:525826
Available from: 2012-05-09 Created: 2012-05-07 Last updated: 2012-06-14Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Halvardson, JonatanFeuk, Lars
By organisation
GenomicsScience for Life Laboratory, SciLifeLab
In the same journal
American Journal of Human Genetics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 226 hits
ReferencesLink to record
Permanent link

Direct link