Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia

Alyssa B. Becker, Jiang Qian, Benjamin Gelman, Michele Yang, Peter Bauer, Arnulf H. Koeppen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)665-675
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume76
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Friedreich Ataxia
Adenine
Nervous System
Pathology
Guanine
Cerebellar Nuclei
Cardiomyopathies
Diabetes Mellitus
Spinal Nerve Roots
Ataxia
Trinucleotide Repeat Expansion
Chorea
Mutation
Sequence Deletion
Spinal Ganglia
Point Mutation
Cardiac Myocytes
Fathers
Hypertrophy
Atrophy

Keywords

  • Cardiomyopathy
  • Compound heterozygosity
  • Dentate nucleus
  • Dorsal root ganglion
  • Frataxin
  • Friedreich ataxia

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia. / Becker, Alyssa B.; Qian, Jiang; Gelman, Benjamin; Yang, Michele; Bauer, Peter; Koeppen, Arnulf H.

In: Journal of Neuropathology and Experimental Neurology, Vol. 76, No. 8, 01.08.2017, p. 665-675.

Research output: Contribution to journalArticle

Becker, Alyssa B. ; Qian, Jiang ; Gelman, Benjamin ; Yang, Michele ; Bauer, Peter ; Koeppen, Arnulf H. / Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia. In: Journal of Neuropathology and Experimental Neurology. 2017 ; Vol. 76, No. 8. pp. 665-675.
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