Abnormalities of the brain and spinal cord that cause ataxia.

The brain and spinal cord constitute the central nervous system (CNS), and the cranial nerves, spinal roots and peripheral nerves (such as the well-known sciatic nerve) are the components of the peripheral nervous system (PNS). Ataxia is caused by disorders of the CNS and the PNS. However, most of us will think of the cerebellum in the dominant ataxias (spinocerebellar ataxias, or SCA) and of the spinal cord in recessive ataxia, such as Friedreich's ataxia (FRDA). However, brain and spinal cord are very complex organs, and a disease in a single location does not explain the variable symptoms and signs of SCA or FRDA. It may help to look at the anatomy of the brain and spinal cord as shown in the drawings (fig. 1-4 on next page).

[FIGURES 1-4 OMITTED]

Looking at the base of the brain (fig. 1), three structures are of concern in ataxia. They are the cerebellum (1 in fig. 1), the pons (2 in fig. 1), and the inferior olive (3 in fig. 1). The cerebellum, literally the "little brain," has a corrugated surface due to leaflet-like foldings, the folia. The pons, literally the "bridge," is a protuberance that crosses the brain stem. The olive is named after its olive-like shape. Cerebellum and pons can also be seen after a brain is cut in the midline (fig. 2). In this illustration, the term "medulla oblongata" is used (3 in fig. 2). Literally the "extended marrow," it means a continuation of the spinal cord. It is the location of the inferior olive. A frontal section of the brain (fig. 3) shows another important structure in ataxia research, the dentate nucleus (4 in fig. 3). Literally "teethed" nucleus, it was named after its multiple delicate back-and-forth turns. The spinal cord (fig. 4) can also be divided into gray and white matter, similar to the brain. The structures of importance in ataxia research are the anterior horns (1 in fig. 4), the dorsal horns (2 in fig. 4), the dorsal column (3 in fig. 4), the dorsal nuclei of Clarke (4 in fig. 4), and the spinocerebellar tracts (5 in fig. 4). Just inside the spino-cerebellar tracts lie the corticospinal tracts.

The brain is a very large organ. Normally, it weighs 1,350 grams (nearly three pounds) and in weight is second only to the liver. The main structures of importance in ataxia research are the cerebellum and the brain stem. Together, they weigh only 180 grams (less than one-half pound). However, most of the control circuits for coordinated movements reside here. The dentate nucleus in the depth of the cerebellum (4 in fig. 3) is the main way-station for the output from the cerebellum. All impulses from the cerebellar cortex must go through the dentate nucleus where they are further processed. The spinal cord provides information to the cerebellum through the small gray matter collections called the dorsal nuclei of Clarke (4 in fig. 4) and the spinocerebellar tracts (5 in fig. 4). The dorsal columns (3 in fig. 4) provide signals on the position of arms, fingers, legs and toes (proprioception). Loss of these fibers adds to the severity of ataxia. In some forms of hereditary ataxia, muscle atrophy occurs due to disease of the anterior horns, eight shown as 1 in fig. 4, and neuropathy affects the dorsal horns (2) in fig. 4. Immediately inside the spinocerebellar tracts lie the corticospinal tracts (5a in fig. 4). They convey motor function that is also of concern in ataxia.

Under the microscope, the most impressive of all nerve cells in the cerebellum are Purkinje cells (fig. 5). It resembles the twigs of the North American cedar (fig. 6). The purpose of such a enormous branching is enlargement of the surface. In the case of the Purkinje cell, the main function is to make a wide receptive field for many nerve impulses from other locations in the nervous system. The delicate twigs of the cedar provide a large surface for the exchange of carbon dioxide and oxygen during the short warm season in North America.

[FIGURES 5-6 OMITTED]

Figures 7-12 show the abnormalities in three types of ataxia: FRDA (fig. 7), spinocerebellar ataxia type 2 (SCA-2) (figs. 8 and 9); and SCA-3/Machado-Joseph disease (MJD) (figs. 10-12).

[FIGURES 7-12 OMITTED]

In FRDA (fig. 7), the disease of the spinal cord affects the long fiber tracts labeled 3 and 5, and the dorsal nuclei of Clarke, labeled 4. The loss of the spinocerebellar fibers (5) causes incorrect input to the cerebellum which reacts with "ataxia." The loss of the dorsal columns (3 in fig. 7) adds to the ataxia because the patient cannot sense the correct position of his or her extremities. In FRDA, the disease process also affects the corticospinal (or pyramidal) tracts (5a in fig. 7), and patients also have superimposed weakness of their unsteady limbs.

The young man whose brain is shown in fig. 8 had olivopontocerebellar atrophy (OPCA) due to SCA-2. His father was similarly affected. However, due to the serious expansion of his cytosine-adenine-guanine (CAG) repeats, the son had a short and severe course. The destruction of Purkinje cells is illustrated in fig. 9. In SCA-2, atrophy of the pons is often very severe (2 in fig. 8).

In SCA-3/MJD (fig. 10), the cerebellar cortex escapes (fig. 11) but the dentate nucleus shows an unusual proliferation of nerve tissue called "grumose degeneration" (fig. 12).

Friedreich's ataxia is an autosomal recessive disorder, and both parents must be carriers of expanded guanine-adenine-adenine (GAA) repeats. Parents are not clinically affected. In contrast, SCA-2 and SCA-3/MJD are autosomal dominant diseases, and only one parent carries the CAG expansion (and is also affected). As the science of molecular genetics has progressed, the classification of the ataxias has been greatly modified. The old term "OPCA" is now rarely used to describe SCA-1, SCA-2 or SCA-7 but it remains useful in the description of the pathology of ataxia. It has become apparent that the most common form of OPCA is due to a non-hereditary disease of the brain called multiple system atrophy.

The tissue donation program of the National Ataxia Foundation is coming of age. It has been a most valuable experience. Among donated tissues, SCA-2 was the most common form of dominant ataxia, followed by SCA-3. SCA-1 and SCA-6 were uncommon. The most frequent recessive ataxia was FRDA. Research in the hereditary ataxias may also provide answers for the sporadic forms, especially multiple system atrophy. The study of hereditary Parkinson's disease has improved our understanding of the much more common sporadic form of this disorder. Similarly, we may expect that detailed analysis of hereditary ataxia will benefit patient with sporadic ataxia.

The National Ataxia Foundation will continue to offer tissue donation to all patients with hereditary or sporadic ataxia.

Editors Note: NAF would like to thank Dr. Koeppen for editing the presentation he gave at the 2003 Annual Meeting in Atlanta for this very informative article. Additionally, his excellent photos help all of us understand ataxia better. For information on tissue donation please note contact information on page 16 of this issue of Generations.

Dr. Koeppen received his M.D. from the University of Geottingen Medical School in Germany, his post-graduate education in neurology at the Somerset Hospital in Somerville, NJ, the Montifiore Hospital and Medical Center in New York, and Northwestern University in Chicago. He is currently Chief of Neurology Services at the VA Medical Center in Albany, New York, and Professor of Neurology at the Albany Medical Center. Dr. Koeppen is also a member of the National Ataxia Foundation Medical and Research Advisory Board and coordinates tissue donation for ataxia research.

Arnulf H. Koeppen, MD

Albany, NY