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Washington University Experience | METABOLIC | Menkes disease | 2A12 Discussion of Case
2A12 Discussion of Case 2 ---- The loss of neurons in the cerebellar hemispheres is common in hypoxic/ischemic damage and in seizure disorders; however, it is uncommon for the granule cells to be nearly completely damaged in the presence of such relatively preserved Purkinje cells, typically considered more sensitive to hypoxia. Use of phenytoin (Dilantin) in this patient may also have contributed to the atrophy of cerebellar hemispheres and vermis, although in phenytoin-induced cerebellar damage, loss of both Purkinje cells and granule cells is reported. A similar pattern of granule cell loss is reported in GM2 gangliosidosis, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease and mannosidosis, although neuronal storage is not seen in the current case. Other granule cell degenerative conditions described in the literature include mercurial poisoning (Minamata disease), radiation damage, cyclophosphamide treatment, cycasin, 5 fluorodeoxyuridine and, intrauterine infection with several animal viruses. There is no evidence for any of these entities in the current case. The Purkinje cells in the current case show marked abnormality and focal swelling of the dendritic tree. Although this pattern of injury is not pathognomonic for any single disease process at least two entities should be addressed: 1) Menke’s disease The "spike-ball bodies" within the Purkinje dendrites raise the possibility of Menke’s disease. We have no record of ceruloplasmin levels and serum copper during this patient’s extensive hospital workup. Menke’s disease represents the closest fit with the pathology and much of the early course. 2) Cerebellocortical Degeneration (Jervis) This sporadic or familial disease presents with severe developmental delay and microcephaly with epilepsy and ataxia with visual failure. In cerebellocortical degeneration of Jervis, Purkinje cells exhibit prominent asteroid dendrites and axonal torpedoes and loss of granule cells, however, in distinction to the current case, significant neuron loss develops in the inferior olivary nucleus. At the time (more than 30 years ago) we also considered a variety of rare, inherited disorders with cerebellar pathology including autosomal dominant cerebellar ataxias I and II, spinocerebellar ataxias 1-7, carbohydrate-deficient glycoprotein syndrome type I and others. However, these rare entities typically have a different neuropathologic appearance than the current case, usually with substantial neuron loss involving the inferior olivary nuclei, pontine neurons and spinal cord nuclei. We have also considered if profound loss of descending fibers originating in the cerebral hemispheres could produce bilateral crossed cerebellar atrophy, however, pontine nuclei are depleted significantly as the cause of the transneuronal degeneration in that entity and in the current case the pontine nuclei appear well preserved. We will attempt to put these diagnoses to the test if the material can be located.
