Clinical and Cell-Molecular Understandings of Two Dominantly Inherited Neurological Diseases


Sources: Maher ER, Kaelin WG, Jr. von Hippel-Lindau disease. Medicine 1997;76:381-391; Ross CA, et al. Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA). Medicine 1997;76:305-338.

Note-Two important reviews in a not widely circulated journal provide clear summaries of the rapid advancement of the clinical and advancing cell-molecular understandings of two major dominantly inherited neurological diseases. -fp

von Hippel-Lindau disease (vhl) is represented by angiomas of the retina and hemangioblastomas of the cerebellum. The gene was mapped on the short arm of Cr3 in 1988 (Seizinger, et al. Nature 1988; 332:268-269) and isolated in 1993 by Latif (Science 1993;260:1317-1320). Clinical representation is often initially confined to above lesions, but CNS lesions occur in multiple sites and can enlarge but not metastasize. Lifetime risk for renal clear cell (RCC) carcinoma amounts to 70% and is the most frequent cause of death. Pheochromocytomas affect 7-20% of reported cases and can be bilateral or malignant. Non secretory pancreatic islet cell tumors affect a minority but run a malignant risk. Endolymphatic sac tumors affect about 10% of cases but need attention only if symptomatic. VHL should be considered in all persons with retinal or CNS hemangiomas, familial or bilateral pheochromocytomas, familial, multiple or early RCC, and/or bilateral endolymphatic sac tumors.

Geneline mutations of the VHL tumor suppressor gene located on chromosome 3p25 cause the disease by inactivating or omitting the remaining wild-type allele in a susceptible cell. Normally, the VHL gene product inhibits the generation of vascular endothelial growth factor (VEGF). Loss of this inhibition enhances VEGF production and vascular proliferation, the trademark of the hemangioblastomas and their cerebellar secretion of erythropoietin. Combined mutation of other genes may explain the non-vascular effects of the 3p25 abnormality. Although clinical detection of the various effects of 3p25 gene mutations include 1) retina, 2) cerebellum, 3) spinal cord hemangioblastomas, 4) renal cell carcinoma, and 5) pheochromocytoma, which can be identified as late as the seventh decade. The mean age of recognition of numbers 1, 2, and 5 are below 30 years, especially in multi-focal disease.

As noted, cerebellar hemangiomas carry the highest organic incidence of the disease and are the most easy to remove. Unfortunately, however, such early appearances relatively often are followed by the more serious lesions later in life. Intense efforts by academic and pharmaceutical laboratories are attempting to block the process that stimulates the vascular proliferation.

Neurologists are all too familiar with the unfortunate clinical course of Huntington disease, which is marked by varying degrees of chorea, dementia, and emotional disturbances and usually affects its sufferers between the ages of adolescence and the sixth decade. In 1983, Gusella et al localized the Huntington gene (Nature 1983;306:234-238); the actual gene was identified in 1993 (Cell 1993;72:971-983) on chromosome 4p16.3. It belongs to a group of triplet repeat disorders with a mutation that abnormally generated an abnormal form of the protein huntinen terminated by a long chain of repeated amino acid triplet CA glutamate repeats.

The clinical profile of DRPLA was first described in a single case by Smith in 1958 (Neurology 1958;8:205-209) and remains rare outside of Asia. Relatively young adults, as well as children, display progressive chorea, cerebellar ataxia, abnormal oculomotor movements, motor defects, and dementia. Neuropathology at death is similar to Huntington chorea but with greater degeneration of the cerebellar dentate nucleus. The illness can be tracked to several pedigrees but is rare in the United States. Affected children are afflicted by progressive myoclonic epilepsy and mental retardation. Adult suffers may resemble Huntington disease in their phenotype. The gene, named atrophin-1, is located on Cr12 and, like the Huntington gene, is also marked by an excess of terminal triple repeats. The table, adapted from Bird, lists the presently identified triple repeat disorders" along with the vulnerable chromosome and the number of specific triple repeats usually found in sufferers of the diseases.


Currently identified "triple repeat disorders"



Trinucleotide Repeat


Abnormal Repeat Number












Spinocerebellar ataxias 1-3


Ataxin 1-3

40, 33, 58-83, 77, 86


Spinobulbar muscular atrophy


Androgen receptor



Machado Joseph Disease





Myotonic Dystrophy


Myotonin kinase



Fragile-X Syndrome




Modified from: Bird TD. In: Bradley, et al (eds). Neurology in Clinical Practice, 2nd ed. Boston: Butterworth-Heinemann; 1996:699.

The above features of Huntington's disease and its somewhat similar cousin may be well known to Alert's readers, but Ross et al's review contains a brief but enlightening summary of recent research that identifies intranuclear inclusion bodies in the cerebral cortex and striatum of HD brains obtained post-mortem, but not in controls. The number of inclusions correlates with the length of the individual's CAG repeat. Furthermore, bench studies indicate that protein aggregates similar to the inclusions can be synthesized by huntinen from brains with long triple repeats but not in brains associated with normal repeats. Similar inclusions have also been found by the Ross group in at least three of the other glutamine repeat diseases, including DRPLA, SCA1, and SCA3 (see Ross CA. Neuron 1997;19:1147-1150). Other laboratories have reproduced the phenomenon with suggestive evidence that the inclusions may have a fatal influence on their parent neurons.


Neurology Alert usually avoids reviews of reviews, but these two important studies of inherited neurological illness are clearly written, include the latest evidence about the cell-genetic-molecular nature of the diseases in question, and, in both instances, point to possibly causative mechanisms of the diseases they review. The Ross et al laboratory especially provides us with not only a thorough understanding of what has already been done but also a hopeful hint that a key for HD may be found at the molecular level. Meanwhile, our younger readers may find these reviews useful as they prepare for the Board exams. -fp