CHAPTER NINE
DEGENERATIVE DISEASES

ATAXIA AND CEREBELLAR DEGENERATION

Ataxia can be caused by lesions that interrupt the sensory input to the cerebellum (spinal or sensory ataxia), pathology of the cerebellar cortex resulting in incorrect execution of cortical signals (cerebellar ataxia), or by a combination of both (spinocerebellar ataxia). In terms of genetics, ataxias can be divided into 3 groups listed below.

Friedreich's ataxia (FRDA)-an autosomal recessive ataxia caused by GAA repeats on the frataxin gene

Spinocerebellar ataxias(SCA)-a group of autosomal dominant ataxias (25 entities at last count), caused by CAG repeats on multiple chromosomal loci

Cerebellar ataxias-a diverse group of sporadic diseases that cause cerebellar degeneration and degeneration of other anatomical systems

In addition to the inherited ataxias, cerebellar degeneration is caused by a variety of acquired conditions including prion disease, HIE, nutritional deficiency, and inherited metabolic diseases.

Friedreich's ataxia

Friedreich's ataxia (FRDA), the most frequent inherited ataxia, is an autosomal recessive spinal ataxia which begins usually before age 20 with ataxia of gait. Foot deformity (pes cavus), scoliosis, and cardiomyopathy are also common and there is an increased incidence of blindness, deafness, and diabetes. FRDA is primarily a sensory neuropathy. Loss of sensory ganglion cells and degeneration of their axons in peripheral nerves, dorsal roots, and posterior columns deprives the cerebellum of sensory input that is necessary to coordinate movement. There is also degeneration of the spinocerebellar tracts and, to a lesser extent, of the lateral corticospinal tracts, and loss of neurons in the dorsal nuclei (Clarke's columns). The cerebellar cortex is normal but there is loss of neurons inthe dentate nuclei, the main source of cerebellar output, and degeneration of the superior cerebellar peduncles. DNA analysis in FRDA shows GAA trinucleotide repeats of the FXN gene on chromosome 9q. FXN encodes a mitochondrial matrix protein, frataxin, which is involved in iron homeostasis. This suggests that FRDA is due to mitochondrial dysfunction and oxidative stress. FRDA may also result from mutations of one allele of the frataxin gene in association with GAA expansion of the other allele. Nutritional deficiency of the antioxidant vitamin E causes similar spinal cord lesions. A hereditary form of ataxia with vitamin E deficiency is caused by mutations of the alpha-tocopherol transfer protein.

Autosomal dominant spinocerebellar ataxias (ADSCAs). There is no other group of neurodegenerative diseases with the clinical and pathological diversity of the ADSCAs. This diversity is even more impressive considering that all these diseases have a common underlying molecular defect, namely CAG triplet expansion. If the expansion lies in a coding sequence, it is translated into a polyglutamine (polyQ) stretch of the affected protein.  Similar to Huntington’s disease (which is also caused by CAG repeats), the ADSCAs show the phenomenon of anticipation, i.e. lengthening of the CAG repeat with earlier onset and more severe disease in successive generations. The expansion occurs more often with paternal transmission.

In addition to ataxia, the ADSCAs cause parkinsonism and other extrapyramidal manifestations, weakness and fasciculations, spasticity, ophthalmoplegia, retinal degeneration and optic atrophy, cognitive impairment, dementia, and peripheral neuropathy. The core neuropathology is cerebellar degeneration (in some cases OPCA-see below) with additional degenerations involving the basal ganglia, substantia nigra, motor neurons of the brainstem and spinal cord, the spinocerebellar and olivocerebellar tracts, cerebral cortex, and other systems. Microscopic examination sows loss of Purkinje cells and neurons in other affected nuclei. The polyQ proteins, complexed with ubiquitin, form inclusions in the neuronal nuclei and cytoplasm, which can be detected by immunohistochemistry. The pathogenesis of neurodegeneration is unknown. It may have to do with dysfunction of the mutated proteins or with diminished proteolytic capacity of the ubiquitin-proteasome system. It has been proposed that polyglutamine repeats bind to and interfere with thefunction of inositol triphosphate receptor type 1 (ITPR1), which is the main excitatory neurotransmitter receptor in Purkinje cells.

Cerebellar ataxias. The pathology in cerebellar cortical (cerebello-olivary) degeneration consists of loss of Purkinje cells and inferior olivary neurons. Loss of Purkinje cells for whatever reason causes transsynaptic degeneration of the inferior olives. In Olivopontocerebellar atrophy (OPCA) there is, in addition, loss of neurons in the pontine nuclei, and atrophy of the transverse fibers of the pons and middle cerebellar peduncles. This pattern is also seen in some autosomal dominant spinocerebellar ataxias. For the most part, however, OPCA is a sporadic condition. Sporadic OPCA is frequently combined with striatonigral degeneration which causes parkinsonian symptoms, and degeneration of sympathetic neurons of the spinal cord (Shy-Drager syndrome), which causes orthostatic hypotension and other autonomic dysfunction. The combined neurodegeneration is called multiple system atrophy (MSA). In addition to loss of neurons in the affected nuclei, MSA shows oligodendroglial inclusions containing a-synuclein and ubiquitin. In this regard, MSA resembles PD.

Other ataxias. An autosomal recessive OPCA in infants and children is associated with a defect in glycosylation of proteins (carbohydrate deficient glycoprotein syndrome). Ataxia-telangiectasia (A-T) is a childhood disease characterized by ataxia, extrapyramidal dysfunction, peripheral neuropathy and other neurologic deficits, vascular dilatation, and immunodeficiency. It is caused by mutations of a gene that regulates the cell cycle. These mutations result in defective DNA repair. In addition to cerebellar deegeneration, there is loss of anterior horns, degeneration of brainstem nuclei, substantia nigra, and other neuronal groups, and loss of dorsal root ganglionic neurons with dorsal column degeneration. A-T patients frequently develop opportunistic infections and B-cell lymphomas.

Further reading
Pandolfo M. Fiedreich ataxia. Arch Neurol 2008;65:1296-1303. PubMed

Schorge S, van de Leemput J, Singleton A, et al. Human ataxias:a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. Trends in Neurosciences 2010;33:211-19. PubMed.

Updated: July, 2010