Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia
J Neuropathol Exp Neurol
Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia
Arnulf H. Koeppen 0
Alyssa B. Becker 0
Jiang Qian 0
Paul J. Feustel 0
0 From the Research Service, Veterans Affairs Medical Center , Albany, NY (AHK , ABB); Department of Pathology, Albany Medical College , Albany, NY (AHK , JQ); and Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY (PJF) Veterans Affairs Medical Center , 113 Holland Ave., Albany, NY 12208 , USA
After Friedreich's description in 1877, depletion of myelinated fibers in the dorsal columns, dorsal spinocerebellar and lateral corticospinal tracts, and neuronal loss in the dorsal nuclei of Clarke columns were considered unique and essential neuropathological features of Friedreich ataxia (FA). Lack of large neurons in dorsal root ganglia (DRG), thinning of dorsal roots (DR), and poor myelination in sensory nerves are now recognized as key components of FA. Here, we measured cross-sectional areas of the mid-thoracic spinal cord (SC) and neuronal sizes in lumbosacral DRG of 24 genetically confirmed FA cases. Mean thoracic SC areas in FA (24.17 mm2) were significantly smaller than those in 12 normal controls (37.5 mm2); DRG neuron perikarya in FA (1362 mm2) were also significantly smaller than normal (2004 mm2). DRG neuron sizes were not correlated with SC areas. The FA patients included a wide range of disease onset and duration suggesting that the SC undergoes growth arrest early and remains abnormally small throughout life. Immunohistochemistry for phosphorylated neurofilament protein, peripheral myelin protein 22, and myelin proteolipid protein confirmed chaotic transition of axons into the SC in DR entry zones. We conclude that smaller SC areas and lack of large DRG neurons indicate hypoplasia rather than atrophy in FA.
Atrophy; Dorsal roots; Dorsal root ganglion; Friedreich ataxia; Hypoplasia; Spinal cord
INTRODUCTION
Since Friedreich’s illustration in 1877 of dorsal column
degeneration in the disease that now bears his name (
1
), many
generations of medical trainees have accepted that the most
important abnormalities reside in the spinal cord. Beyond the
dorsal columns, the disease also affects the dorsal
spinocerebellar and lateral corticospinal tracts, and the dorsal nuclei of
Clarke columns. While Friedreich was aware of thinning of
the dorsal spinal roots, he wrote that dorsal root ganglia
(DRG) were normal (
1
). Remarkably, he observed that the
nerve fibers in the dorsal roots (DR) were more abundant than
normal and rather thin, displaying only rare thicker fibers
similar to those in the intact ventral roots. Over the ensuing years,
it became clear that DRG are a critical target of the disease,
and that fiber loss in the dorsal columns and neuronal atrophy
of the dorsal nuclei could be secondary. The
neuropathological phenotype also includes hypoplasia or atrophy of Betz
cells of the motor cortex that matches the invariable
degeneration of the lateral corticospinal tracts. Although the normal
dentate nucleus (DN) receives sparse collaterals from mossy
fibers of spinal origin, the severe lesion of the DN in
Friedreich ataxia (FA) is not obviously related to the damaged
spinal cord.
Irrespective of disease onset, the spinal cord in FA is
thinner than normal (
2
), and the bony spinal canal in FA
patients is abnormally narrow on plain radiographs (
3
). In
retrospect, this old observation gains significance because of more
recent measurements of magnetic resonance images (
4–6
).
The narrow spinal canal on plain X-ray films in FA (
3
) must
be interpreted as the result of incomplete anteroposterior and
transverse enlargement of the spinal cord during growth.
Therefore, thinning of the spinal cord in FA may be more
appropriately termed hypoplasia, although it is likely that
inflammation and invasion of DRG neurons continue to damage
afferent fibers in DR (
7
). It is of interest that Friedreich had
already proposed in 1877 that smallness of the clavae (gracile
and cuneate nuclei) was developmental (
1
).
The neurons of DRG, satellite cells, and Schwann cells
of DR and peripheral nerves derive from the neural crest (
8
),
although boundary cap cells may also contribute to the
constituents of DRG and proximal and distal processes (
9
). Axons
deriving from DRG neurons grow into the periphery where
they become sensory nerves, into the gray matter of the spinal
cord, and, over remarkably long distances, into the nuclei of
the dorsal columns. Histoautoradiography and
immunohistochemistry have clarified the developmental steps in the
complex specification of DRG neurons (
10–13
), but it is unknown
how frataxin deficiency impacts this elaborately tooled
process. Total absence of frataxin in genetically engineered mice
is lethal to the embryo (14), but it must still be determined
2017 American Association of Neuropathologists, Inc.
This work is written by US Government employees (...truncated)