Friedreich Ataxia: Neuropathology Revised

Abstract

Friedreich ataxia is an autosomal recessive disorder that affects children and young adults. The mutation consists of a homozygous guanine-adenine-adenine trinucleotide repeat expansion that causes deficiency of frataxin, a small nuclear genome–encoded mitochondrial protein. Low frataxin levels lead to insufficient biosynthesis of iron-sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase, and iron dysmetabolism of the entire cell. This review of the neuropathology of Friedreich ataxia stresses the critical role of hypoplasia and superimposed atrophy of dorsal root ganglia. Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal columns, transsynaptic atrophy of nerve cells in Clarke column and dorsal spinocerebellar fibers, atrophy of gracile and cuneate nuclei, and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain γ-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second intrinsic CNS lesion. In light of the selective vulnerability of organs and tissues to systemic frataxin deficiency, many questions about the pathogenesis of Friedreich ataxia remain.

MRI Texture Analysis Reveals Bulbar Abnormalities in Friedreich Ataxia

“…In addition, corticospinal tracts are also damaged at this point. 14 The lack of correlation between texture parameters and clinical data was somewhat unexpected but might be related to our segmentation strategy. We opted to use large ROIs that included the whole medulla oblongata, and neurodegeneration in FA is not homogeneous in this region (posterior structures are more severely damaged).…”

“…11 The net results of the mutation are marked and progressive neuronal loss in the dorsal root ganglia, pyramidal tracts, and dentate nuclei of the cerebellum. 14 Brain MR imaging of patients with FA does not present clearly visible changes. However, some previous studies have already shown alterations by using advanced techniques.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Frataxin-deficient flies are hypersensitive to increased dietary iron uptake, but their mitochondrial function can be restored by inhibiting the mitochondrial iron uptake via mitoferrin [93]. The most severely affected organs are heart, cerebellum, and spinal cord, especially dorsal root ganglia [94]. Abnormal iron granules were detected in cardiomyocytes in FRDA while the total iron concentration was not different from that of control cases [95].…”

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

“…Adult haemoglobin is composed of two alpha and two beta globin chains, each containing an iron molecule embedded in a protoporphyrin ring, which is responsible for the transport of oxygen to all cells of the body [1] . Frataxin is a mitochondrial matrix protein which functions in iron-sulfur cluster containing enzymes within the chain assembly responsible for respiration and energy transduction [3,4] . While frataxin is encoded by the gene of chromosome 9, the beta globin chains of haemoglobin are encoded by a single gene on chromosome 11 and the alpha globin chains of haemoglobin are encoded by two genes which are closely linked on chromosome 16 [1,3,4] .…”

“…Although the two diseases are genetically different they are both related to abnormalities in proteins of iron metabolism namely frataxin in FA and haemoglobin in TM [1][2][3][4][5] . Adult haemoglobin is composed of two alpha and two beta globin chains, each containing an iron molecule embedded in a protoporphyrin ring, which is responsible for the transport of oxygen to all cells of the body [1] .…”