Autosomal Dominant Neurological Disorders Roscoe 0. Brady, MD, and Roger N . Rosenberg, M D

Genetic disease in the United States poses an immense problem, with 6% of the population having a genetically related disease, 30% of hospitalized children having a genetically based disorder, and 80% of mental retardation directly due to a genetic entity. At least 60 defined genetic diseases inherited as autosomal recessive or sex-linked recessive traits can be diagnosed prenatally due to precise knowledge of the molecular defect and its expression in amniotic fluid or in cultures of fetal fibroblasts. Tremendous progress can be cited for a clear molecular explanation of the pathogenesis of the many recessively inherited neurological diseases, but relatively linle similar progress has been made with the dominantly inherited disorders. It is timely that these dominantly inherited disorders are properly considered. McKusick's 1975 catalogue [l] lists 583 proved autosomal dominant disorders, which represent the largest single group of mendelian inherited diseases; many of these disorders have clear neurological involvement. Further, in fjscal year 1978 the National Genetics Act will be funded for the first time, allowing for increased research in this area. In order to develop a general scientific strategy and possible molecular models of dominantly inherited diseases, a symposium was held under the combined sponsorship of the National Institute of Neurological and Communicative Disorders and Stroke, the National Institute on Aging, the National Institute of Arthritis, Metabolism, and Digestive Diseases, the National Institute of Mental Health, and the Fogarty International Center for Advanced Study in the Health Sciences, National Institutes of Health, in Bethesda, MD, on April 6 and 7, 1978. Fifty invited speakers and informal participants considered emerging and established dominantly inherited entities, examined as model approaches disorders in which the molecular pathology is reasonably well understood, considered in detail biochemical implications of genetic patterns, and discussed specific molecular mechanisms that might explain the expression of dominant diseases.

Dominance John Edwards of Maternity Hospital, Birmingham, England, addressed the issue of dominance, which he defined as a gene dominating the other allele, resulting in the heterozygote being clinically affected. He suggested the concept of repeated genetic units, analogous to cistrons in bacterial systems, which encode for differentiated functions in neurons and glia. Deletions of these functional repeated units result in microchromosomal defects that might be visible with high-resolution chromosomal staining. The result of such defects is precocious cellular dedifferentiation. Alternative neuronal circuits are developed, resulting in excessive metabolic stress of these secondarily derived pathways, which causes cell exhaustion and cytolysis. The syndrome of red blood cell elliptocytosis in Iceland is an example of a dominant disorder leading to anemia as a result of reduced red cell life span and end-cell exhaustion. Thus, dominant neurological disease may be related to a genetic predisposition that results in precocious death of postmitotic neurons, the underlying defect being a microchromosomal structural lesion. Theodore Puck of the Eleanor Roosevelt Institute for Cancer Research, Denver, emphasized the importance of cyclic adenosine monophosphate (AMP) dependent polymerization of tubulin and filamentous protein into microfilaments and neurorubules as a necessary and dependent system for neuronal and dial differentiation. Alterations in this system lead to a dedifferentiated state, which includes malignant transformation. It is clear that neuroblastoma cells differentiate under the influence of cyclic AMP, with neurite production dependent upon tubules and filaments. A dominant gene mutation disrupting this system would impair the cell-cell recognition program, resulting in loss of synapses and secondary neuronal loss. Along these lines, Arthur Robinson, working with Puck, has identified the presence of chromosomal aneuploidy in lymphocytes obtained from patients with familial Altheimer disease. Thus, major chromosomal defects may result in neuro-

From the Developmental and Metabolic Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke,National Institutes of Health, Bethesda. MD, and the DePanment of Neurolorrv. Universitv of Texas Southwestern Medical School, Dallas, TX:

Accepted for publication May 30, 1978. Address reprint requests to Dr Brady,Bldg 10, Room 3m.Nationa Iastitutes of M D 2o014.



0364-5134/78/0OO4-0611$01.25 @ 1978 by Roscoe 0.Brady

fibrillary tangles, which constitute one of the hallmarks of this disorder and in turn may cause synaptic disconnection and cell loss. Clearly, more work is needed in the area of understanding the molecular basis of membrane tubulin, polymerization of actin, microfilamentous protein, tubulin, and the intermediate filamentous protein, as these proteins are crucial for morphological and functional differentiation and are the kind of structural proteins that might be involved in a dominantly inherited disorder. Clinical Variations in Gene Mutation Three major presentations-autosomal dominant striatonigral degeneration, by Roger N. Rosenberg of the University of Texas Southwestern Medical School, Dallas, dominantly inherited CharcotMarie-Tooth disease, by Peter James Dyck of the Mayo Clinic, and dominantly inherited spinocerebellar degeneration, by Andri Barbeau of the University of Montreal-emphasized the striking clinical variations that may occur in these three separate system degenerations, presumably each due to a single gene mutation. Rosenberg described the pyramidal and extrapyramidal manifestations seen exclusively in the Joseph family, the findings of additional cerebellar involvement in the Thomas and Sousa families, and the presence of dominantly inherited parkinsonism and peripheral neuropathy in the Luz family. The Joseph, Thomas, and Sousa families can all trace their ancestry to a small island in the Azores, the Island of Flores, suggesting a common origin and a single gene mutation resulting in a marked variation in clinical expression. Dyck emphasized the importance for genetic counseling of peripheral nerve biopsy and a statistical analysis of teased nerve fiber preparations to quantify demyelination and internodal distance measurements in order to determine accurately the penetrance and expression of the dominant gene in large families. Both Dyck and Barbeau emphasized the marked variation in penetrance and expression that may be seen in Charcot-Marie-Tooth disease and in the spinocerebellar degenerations. It was suggested that such variation may be the result of a single mutant gene interacting with 70,000 other genes in a eukaryotic cell in which the overall gene pool is altered in a major way from person to person and clearly from family segment to segment, resulting in the clinical variation. Biochemical Basis Three dominant diseases in which considerable progress has been made toward understanding the biochemical basis were extensively reviewed. S. J. Enna of the University of Texas Medical School, Houston, discussed the molecular biology of Huntington dis-

ease (HD), T. L. Munsat of Tufts University, Boston, presented his data on dominantly inherited McArdle disease, and Donald Tschudy of the National Institutes of Health, Bethesda, reviewed his extensive biochemical experience with dominantly inherited acute porphyria. It is clear from a number of laboratories that frontal cortex and the striatum from HD brain are deficient in glutamic acid decarboxylase, y-aminobutyric acid (GABA), and choline acetylase, and that receptor binding for serotonin and cholinergic agents is impaired. These changes, it was believed, are biochemical correlates of the morphological alterations and are not related to a primary defect. Attempts at regeneration appear to be occurring in HD brain as there is an increase in GABA receptor density on dopamine synthesizing neurons located in the substantia nigra due to a loss of GABA afferent input, resulting in supersensitivity of these cells to applied GABA. The use of blood platelets as a potential model system to study neurotransmitter functions from patients with HD and other dominantly inherited system degenerations might prove useful. The unique occurrence of dominantly inherited McArdle disease due to myophosphorylase deficiency and the accepted fact that acute porphyria is due to a 50% loss in activity of uroporphyrinogen synthetase were emphasized to indicate that dominantly inherited disease can be the result of a simple enzyme defect. How a secondary increase in 6aminolevulinic acid synthetase with serum elevations in 8-aminolevulinic acid and porphobilinogen produce neurological impairment and a variation in the degree and kind of defects received emphasis in discussion, but the mechanism involved remains unresolved. Additional examples of dominantly inherited disorders were provided by W. H. Nyhan of the University of California, San Diego, and A. D. Roses of Duke University. Nyhan indicated that pediatricians are frequently consulted for advice concerning dominantly inherited diseases expressed in childhood, particularly those leading to mental retardation ostensibly caused by pleiotropic expression and alteration of a single gene, Using the example of the Lesch-Nyhan syndrome, he indicated how hereditary disorders are processed from clinical descriptions through discovery of abnormal quantities of one or more metabolites (e.g., uric acid) to provide an indication of the enzymatic defect in the disorder. He then cited examples in dominant disorders in which certain clues appear to be emerging, such as neurofibromatosis. In that disease, Philip J. Fialkow of the Veterans Administration Hospital, Seattle, WA, has examined women heterozygous for two X-linked genes (glucose-6-phosphate dehydrogenase isoenzymes A and B). Analysis of their tumors

Summary: Brady and Rosenberg: Autosomal Dominant Neurological Disorders 549

showed that they contained both isoenzymes, contrary to the expectation that either the A or the B form would be expressed, and indicated that the tumors were of multicellular origin. Thus the dominant neurofibromatosis gene is able to condition a large number of cells to develop tumors, and experiments are underway in vitro to try to learn how the dominantly produced gene product exerts its effect. A possibly relevant finding is that nerve growth factor is increased in the serum of patients with neurofibromatosis. In contrast, patients with multiple mucosal neuromas have medullary carcinomas of the thyroid that are derived from the neural crest and are monoclonal in origin. These data are suggestive of the two-hit theory of nunorigenesis, in which the initial mutation is dominantly inherited in each cell of the body and tumors arise from subsequent environmental alterations producing the mutant clone. Another example that may be useful to study in order to obtain a biochemical handle in a dominant disorder may be derived from patients with the linear sebaceous nevus syndrome who have vitamin Dresistant rickets. It is conceivable that the nevus may be secreting a factor causing the tickets as a result of a block in the conversion of 25-hydroxyvitamin D to 1-2,dihydroxyvitamin D. Still another approach was the suggestion that metabolic processes involved in premature aging in the Hallermann-Streiff syndrome might be amenable to comparative biochemical investigation in cultured cells derived from affected individuals. Roses and co-workers approached the molecular basis of dominant myotonic muscular dystrophy by examining alterations in erythrocyte membranes as a model of a possible lesion in the affected sarcolemmal membrane. To d o this, they investigated cyclic AMP-stimulated protein phosphorylation using endogenous erythrocyte proteins as acceptors. They found diminished phosphorylation of a particular glycoprotein in erythrocyte ghosts obtained from patients with myotonic dystrophy even though the recovery of the protein itself was the same as in control samples. It was further observed that the stoichiometry of the ouabain-sensitive sodium efflux to potassium influx decreased from 3:2 in controls to 2:2 in myotonic dystrophy. A phosphorylation abnormality has also been found in muscles of pstients with myotonic dystrophy. An interesting sidelight was the finding that there is always diminished phosphorylation in myotonic patients, but it is not always of the same peptide fragment. However, the abnormality does run true in families and between families with the disorder. In order to clarify this situation, it will be necessary to analyze the amino acid sequence in the various pep-

550 Annals of Neurology Vol 4 N o 6

tides to determine whether there really is a consistent difference. More recent investigations are centered on how such a change may be related to the abnormal physiology of muscle dysfunction and how other systems are affected in myotonic dystrophy, with the hope that acquisition of this information will provide a lead to effective therapeutic measures.

Viral Factors Colin Masters of the National Institute of Neurological and Communicative Disorders and Stroke discussed degenerative diseases caused by unconventional viruses comprising the subacute spongiform encephalopathies, such as Creunfeldt-Jakob disease and kuru in man and scrapie and transmissible mink encephalopathy in animals. N o evidence of vertical transrhission has been obtained, and it is believed that the familial cases are most likely due to environmental spread. There may be increased susceptibility on a genetic basis, however, as evidenced by the abnormally high incidence of CreutzfeldtJakob disease in Libyan Jews in Israel. These observations are consistent with the long-recognized marked variation in susceptibility of various strains of sheep to scrapie. Masters also pointed out the necessity for careful pathological examination since Creutzfeldt-Jakob disease has now been diagnosed in a family with Huntington chorea and is suspected in a family with Alzheimer disease. Inoculation of biopsy material from some Alzheimer patients has caused spongiform encephalopathy in animals.

Experimental Studies R L. Sidman of Children’s Hospital Medical Center, Boston, discussed several advantages of using inbred strains of mice that carry stable genetic mutations with consistent syndromes. These studies have the added advantage that the effects of intrinsic versus extrinsic factors can often be sorted o u t - a n important aspect that generally defies solution in human situations. Furthermore, certain of the mouse conditions can be clearly identified in which phenotypic expression is the result of cell-cell interaction, a phenomenon of particular relevance to the nervous system. In addition, genetic mapping and ancillary phenotypic markers, such as pigmentary changes or tail size, are frequently available and are evident long before the neurological syndrome appears. This fortunate occurrence provides the important capability of examining the time of gene action, which is generally impossible in human conditions (with the possible exception of the appearance of caf6-au-laic spots and axillary freckles in neurofibromatosis). Perhaps

December 1978

an even greater advantage is the possibility of obtaining tissue from the central nervous system of these animals and examining their characteristics in tissue culture under carefully defined conditions. Sidman cited specific examples including the dominant trembler J mouse, in which the disorder resembles inherited hypertrophic neuropathy with onion bulb formation in man. Albert J. Aguayo of McGill University, Montreal, has found that Schwann cells from the trembler mouse carry the disease and that the neuropathy is independent of nerve cell genotype. The lurcher mouse is another autosomal mutant in which selective destruction of the Purkinje cells occurs in late adolescence. Here there may be an abnormal protein on the membrane of the Purkinje cell or on some other cells with which Purkinje cells critically interact. Sidman further pointed out one of the recurring themes of the meeting: that as one learns more about an abnormal status, the definition of a recessive disorder frequently becomes imprecise. He cited the example of the weaver mouse, in which granule cells of the cerebellum fail to migrate to their normal residence in the granular cell layer. In the weaver mutant, synaptic connection fails and the granule cells die. The cerebellum is smaller than normal, and the animals become ataxic. In the heterozygote there is an intermediate pattern by which it takes five times longer for the cells to migrate. Some cells fail to arrive at their destination and die off, and the cerebellum is slightly smaller, though the animals are behaviorally normal. The condition is therefore that of a semidominant trait. Sidman believes that the granule cells are really normal but that the glial cells fail to provide an appropriate scaffolding for the granule cells to migrate along, and that the actual defect is expressed at the surface of the glial cell. However, it is not yet possible to distinguish whether the requisite factor is incorporated into the cell membrane or is something that is released from the cell and acts very locally. Still another phenomenon has been detected in the staggerer mutant, in which the granule cells die off because of an abnormality in the Purkinje cell that prevents proper synapse formation with the granule cells. Thus, these extraordinarily lucid examples of mutational mechanisms provide insight into various intercellular relationships that seem virtually certain to be mimicked in human neurological disorders. Dominant versus Recessive Disorders Charles Epstein of the University of California, San Francisco, emphasized the present perplexity concerning the terms dominant and recessive. Although their continued use may be helpful for clinical pur-

poses such as prognostication and genetic counseling, they may be misleading when one is attempting to understand the genetic basis of a disorder. Thus, the problem of dominant versus recessive disorder hinges on the relative severity of effect, so that in the dominant diseases, the heterozygote is affected. The question of whether all autosomal recessive disorders involve enzyme defects and all autosomal dominant disorders are due to defects in structural proteins was considered. Examples of circulating protein deficiencies in recessive disorders were cited to refute the enzyme deficiency theory. Further, the possibility was raised that a membrane component is missing in hereditary spherocytosis and a platelet antigen in the thrombasthenic platelet syndrome. Environmental factors appear to play major roles in the dominant disorders since it might be quite possible to go through life without manifesting a disease even though the trait is present, as in acute intermittent porphyria. Environmental factors might also affect penetrance and expressivity of recessive and X-linked conditions such as sickle cell anemia, which is manifest in anoxic situations, pharmacogenetic disorders in which drug ingestion is the precipitating factor, and even in metabolic defects such as those which respond to dietary restriction.

Mechanisms of Dominant Disorders William Johnson of Columbia University, New York, addressed the concept of whether we need to examine novel mechanisms to explain dominant diseases. As examples, he postulated that a mutational alteration of a protein might result in the following types of molecular aberrations: (1) the gene product might become an inhibitor of a reaction; (2) an enzyme may acquire new substrate specificity; or (3) an enzyme could be mutationally altered so that it produces a toxin or an inhibitor. In examples 2 and 3, the presence of the normal gene could not protect against the harmful effect of the mutation. Further, if the normal enzyme o r other protein such as hemoglobin is a tetramer, the presence of the abnormal component would cause a deleterious distortion of the molecule, and the presence of the abnormal product would defy compensation. For example, pores on the cell membrane could be affected, and abnormally permeable ion channels might result. Similarly, large numbers of normal receptors could not prevent increased susceptibility to disease at modified virus sites. Surface antigens could be changed, membrane receptors could be altered, and abnormalities of receptor-effector mechanisms involved in regulating cell growth might result in increased susceptibility to tumors, as in neurofibromatosis.

Summary: Brady and Rosenberg: Aurosornal Dominant Neurological Disorders 551

Johnson then advanced the proposition that novel modes of inheritance might exist that are neither dominant nor recessive. It was suggested that a situation could arise in which malfunction might occur of a heteropolymer derived from a mutation in which both homopolymers were functioning normally. In this case, the disease would be expressed only in the heterozygote. Mating of heterozygotes would result in half of the offspring being normal, rather than one-fourth as in conventional autosomal recessive disorders. Furthermore, when mating occurred between two types of homozygotes, all of the progeny would be affected. Gilbert Omenn of the Office of Science and Technology Policy, Washington, DC, cited the example that certain electroencephalographic phenotypes are inherited in an autosomal dominant pattern. He made the reasonable suggestion that an approach to the molecular basis of inherited neural disorders might focus on the pathophysiology in other involved tissues that are more readily available for analysis and manipulation. He also pointed out the extreme desirability of identifying homozygotes for qualitative and subsequent analytical investigations. Once the appropriate indices have been established in homozygotes, quantitation in heterozygotes may be much more feasible. Omenn pointed out that the previously held tenet that the flow of genetic information only occurs from D N A and R N A to proteins has been disproved with the demonstration of reverse transcriptase. Here, RNA carries the modification that is ultimately reiterated in the progeny by causing an alteration in DNA. Although the implication of the finding for human genetic disorders is not yet apparent, this novel mechanism of genetic information transfer should not be overlooked in considerations of the pathogenesis of heritable derangements. Omenn raised the further important point that the colineariry principle of one gene, one polypeptide product has been disproved in several bacterial virus systems such as q174 and Simian virus 40, in which there may be double transcription (DNA to RNA) of certain sequences of the DNA. This means that along the DNA molecule there is a starting point, and the messenger R N A for the ultimate gene product (polypeptide) is synthesized. In different ways-such as along the opposite DNA strand, starting at a dif-


Annals of Neurology VoI 4

ferent point-another stretch of the overlapping sequence is transcribed and translated. Alternatively, transcription may occur more than once along the same D N A strand but in frame shift (starting at another point on the DNA). The result from either of these phenomena is that two entirely different gene products are made. Omenn raised the interesting point that in diseases with multisystemic manifestations such as myotonic dystrophy, it might be heuristically interesting to consider the possibility that two or more gene products are affected by a single base change in the DNA molecule. This phenomenon might be examined in families of diverse origins in which the disease has occurreJ ,by looking for greater interfamilial versus intrafamilial variation of expression. One might begin by searching for differences in affected organ systems rather than degrees of severity of symptoms. Another novel genetic issue mentioned by Omenn was the recent demonstration of spacer sequences in the D N A code for P-globin, ovalbumin, and immunoglobulins. The spacer is not transcribed into messenger RNA and ultimately into amino acid sequences, another violation of the colinearity of DNA-to-polypeptide principle. The function of the spacer D N A is not known, but it might be anticipated that mutations in these sequences could result in a whole new class of abnormalities in which the protein products would be normal, but the efficiency of their transcription and processing would be defective. Conclusion The conference served well its primary functions, which were to acquaint investigators established in other aspects of neurological disease and younger uncommitted individuals with (1) the thinking that has gone into genetic research, (2) an overview of the achievements of previous research, and (3) glimpses of new directions in the area. The insight obtained from this undertaking should lead to profitable approaches to the solution of heritable autosomal neurological disorders. Reference 1. McKusick VA: Mendelian Inheritance in Man. Fourth edition. Baltimore, Johns Hopkins University Press, 1975

No 6 December 1978

Autosomal dominant neurological disorders.

SUMMARY Autosomal Dominant Neurological Disorders Roscoe 0. Brady, MD, and Roger N . Rosenberg, M D Genetic disease in the United States poses an im...
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