Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia

In a small percentage of patients with Friedreich ataxia (FA), the pathogenic mutation is compound heterozygous, consisting of a guanine-adenine-adenine (GAA) trinucleotide repeat expansion in one allele, and a deletion, point mutation, or insertion in the other. In 2 cases of compound heterozygous...

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Bibliographic Details
Published in:Journal of neuropathology and experimental neurology 2017-08, Vol.76 (8), p.665-675
Main Authors: Becker, Alyssa B, Qian, Jiang, Gelman, Benjamin B, Yang, Michele, Bauer, Peter, Koeppen, Arnulf H
Format: Article
Language:English
Subjects:
Adult
Child
Enzyme-Linked Immunosorbent Assay
Frataxin
Friedreich Ataxia - genetics
Friedreich Ataxia - pathology
Heterozygote
Humans
Iron-Binding Proteins - genetics
Iron-Binding Proteins - metabolism
Male
Myocardium - pathology
Nervous System - metabolism
Nervous System - pathology
Original
Trinucleotide Repeat Expansion - genetics
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Summary:In a small percentage of patients with Friedreich ataxia (FA), the pathogenic mutation is compound heterozygous, consisting of a guanine-adenine-adenine (GAA) trinucleotide repeat expansion in one allele, and a deletion, point mutation, or insertion in the other. In 2 cases of compound heterozygous FA, the GAA expansion was inherited from the mother, and deletions from the father. Compound heterozygous FA patient 1, an 11-year-old boy (GAA, 896/c.11_12TCdel), had ataxia, chorea, cardiomyopathy, and diabetes mellitus. Compound heterozygous FA patient 2, a 28-year-old man (GAA, 744/exon 5 del), had ataxia, cardiomyopathy, and diabetes mellitus. Microscopy showed cardiomyocyte hypertrophy, iron-positive inclusions, and disrupted intercalated discs. The cardiac lesions were similar to those in age-matched homozygous FA patients with cardiomyopathy and diabetes mellitus (boy, 10, GAA 1016/1016; woman, 25, GAA 800/1100). The neuropathology was also similar and included hypoplasia of spinal cord and dorsal root ganglia, loss of large axons in dorsal roots, and atrophy of the dentate nucleus (DN). Frataxin levels in heart and DN of all 4 FA cases were at or below the detection limits of the enzyme-linked immunosorbent assay (≤10 ng/g wet weight) (normal DN: 126 ± 43 ng/g; normal heart: 266 ± 92 ng/g). The pathologic phenotype in homozygous and compound heterozygous FA is determined by residual frataxin levels rather than unique mutations.
ISSN:0022-3069
1554-6578
DOI:10.1093/jnen/nlx047