Abstract

Olivopontocerebellar Atrophy(OPCA), is characterized by neuronal degeneration of the cerebellar cortex, the inferior olive, and the pons. The symptoms associated with it are primarily cerebellar ataxia with disturbances in equilibrium and gait. However, broader symptomology is usually seen with OPCA. Current research is focusing on three primary systems thought to be responsible for the etiology of OPCA. They are excitatory amino acid disturbances, oligodendroglial microtubular tangles, and phospholipid metabolism disorders. The only treatment for OPCA is therapy focusing on improving the dysphagia associated with the disorder.

Olivopontocerebellar Atrophy

Olivopontocerebellar Atrophy (OPCA) is a disease characterized primarily by the degeneration of neurons in the cerebellar cortex, pons, and inferior olive. It is a genetic disease, being either autosomal dominant or autosomal recessive in nature. This disorder, which usually occurs in the middle years of life, presents symptoms of cerebellar ataxia, equilibrium disturbance, nystagmus, dysphasia, dysarthria, and possibly intellectual deficits.

According to Merritt, the pathology of OPCA includes loss of Purkinje cells, reduction of the number of neurons in the molecular and granular layers of the cerebellum, degeneration of the folia and white matter of the cerebellum, atrophy of the inferior olives and of the olivo-cerebellar connections, and atrophy of the pontine nuclei, arcuate nuclei, and brachium pontis (15). In addition to this, degeneration of the spinocerebellar tracts, corticospinal tracts, and frontal and temporal lobes has been reported (15).

Biopsies on living OPCA patients have suggested that there are no foci present which would indicate an ischemic attack. These biopsies have also reported severe Purkinje cell loss with cortical architecture remaining intact. Many of the remaining Purkinje cells showed increased cell density indicating that they were dying. Pyknotic central axons in the glomeruli were present, which is consistent with the degenerated mossy fibers characteristic of OPCA (13).

Some reports show evidence that the granule cells are somewhat spared in OPCA. They suggest that this is related to the granule cell sensitivity to quinolinic acid. The enzyme responsible for the metabolism of quinolinic acid, quinolinic acid phosphoribosyltransferase(QPRT) is increased in the cerebellar cortex, presumably to protect the quinolinic acid sensitive granule cells (6).

In OPCA patients degenerative lesions have also been reported in the corpus striatum, substantia nigra, and autonomic nervous system (16). The symptoms seen in OPCA include the following: progressive cerebellar ataxia of the trunk and extremities, disturbances of equilibrium and gait, slowness of voluntary movements, scanning speech, dysarthria, dysphasia, nystagmoid jerks, and oscillatory tremor of the head and neck. Some cases report extrapyramidal symptoms such as rigidity, Parkinsonian tremor, and loss of knee and ankle jerk (15).

Some neuropsychological studies report verbal and non-verbal intelligence deficits, memory loss, and frontal lobe symptoms. They point to a confirmed cerebral cortical cholinergic reduction as the culprit (8). Other neuropsychological studies conclude that OPCA patients have greater depression, anxiety, and emotional discomfort. They claim that these disturbances are the reason these patients may appear to have intellectual or memory deficits (2).

One of the most serious symptoms seen in OPCA is dysphasia. The chief cause of death in OPCA patients in aspiration bronchopneumonia, which results from the swallowing disorder. During aspiration, oral flora from the saliva escape into the respiratory passages, inducing a gram negative pneumonia. This dysphagia is also responsible for poor nutritional balance and weight loss. The dysphagia is said to be due to incoordination of the pharyngeal muscles, especially pertaining to the elevation of the larynx (3).

Dysarthria is also a symptom seen in OPCA; It may be similar to the type in Huntington’s Chorea, and may occur together with scanning speech, a monotone type of speech, due to a problem with coordination and timing of vocal cord activity, respiration, and articulation (3).

In some more advanced cases of OPCA, the following symptoms were found: spasticity with hyperactive stretch reflexes and extensor planter responses, muscular atrophy, scoliosis, rigidity, and fasciculation’s (4).

At present the etiology of OPCA is unknown. However, most research seems to be focusing on deficits of amino acid neurotransmitters and their receptors. Researchers have found a 70% and 40% reduction in aspartate and glutamate, respectively, in the cerebellar cortex of OPCA patients on autopsy. In addition they have found reductions ranging from 10-30% in aspartate, glutamate, and GABA in extracerebellar regions. They conclude that there is some type of amino acid metabolism disorder in OPCA patients, especially of aspartate, since decreased aspartate was found in OPCA patients’ blood samples. However, they also caution against declaring a generalized amino acid metabolism disorder. since many brain structures are not plagued with a reduction of these amino acids (12).

Amino acid receptor deficits have also been cited. In one autoradiographic study, GABA receptors and Benzadiazapene (BZD) receptors were significantly reduced in the molecular and granular cell layers in the cerebellar cortex of OPCA patients. The BZD receptor is associated with the GABA receptor. Both GABA and quisqualate (QA- associated with excitatory amino acid receptors) receptors were significantly reduced in the molecular layer. The N-methyl D-aspartate receptors (NMDA) were also lowered in the granular layer (1, 14).

Consistent with the discovery of decreased amino acid receptors, some researchers link these decreases directly to the reduced Purkinje cells found in the pathology of OPCA. [H3] IP-3 (inositol tris phosphate) binding in the cerebellar cortex has been shown to be reduced by 61% in OPCA patients. Since excitatory amino acid receptors are located on Purkinje cells, and since the excitatory amino acid receptors are associated with the IP-3 second messenger system, these researchers thus explain the loss of the Purkinje cells seen in OPCA (9). Whether the loss of Purkinje cells is the primary disorder accounting for the decreased receptors or whether the receptor decrease causes the loss of Purkinje cells remains to be seen. In either case, there appears to be an important relationship here.

There are studies which attempt to explain the frontal lobe symptoms, memory loss, and intellectual deficits sometimes seen in OPCA. They cite a proven reduction in choline acetyltransferase (ChAT) activity in the cerebral cortex and in the striatum of OPCA patients (7, 11).

Still another study asserted that the cell death seen in OPCA may be due to altered cell membrane phospholipid metabolism. They discovered a 37-69% increase in glycerophosphoethanolamine (GPEA) in a number of the OPCA brains they examined (10).

Finally, the discovery of oligodendroglial microtubular tangles(OMT) in OPCA may be related to the neurodegenerative process. Especially interesting is the resemblance of these tangles to the neurofibrillary tangles seen in Alzheimer’s disease. These OMT’s are specific to OPCA patients and are also specific to the locations of neurodegeneration in the OPCA brain (16).

As far as treatment of OPCA is concerned, very little is available. One of the primary treatable symptoms suggested in the literature is the dysphasia. A combination of dietary therapy, eating behavior change, and oral cleanliness are recommended (3).

The symptoms associated with OPCA and the minimal treatment available paint a bleak picture for those afflicted with this disorder. However, the discoveries of altered excitatory amino acid neurotransmitters and their receptors, OMT’s, and phospholipid metabolism disturbances appear to be leading the researchers closer to a thorough understanding of the disease process of OPCA.

Works Cited:

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