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This Month in Archives of Neurology
November 2001

This Month in Archives of Neurology

Arch Neurol. 2001;58(11):1736-1738. doi:10.1001/archneur.58.11.1736

A New Era Begins

With the publication of the initial sequence and analysis of the human genome by the International Human Genome Consortium and the National Institutes of Health in Nature and by Celera Genomics in Science in February 2001, a new era for neuroscience and clinical neurology was initiated. This issue of the ARCHIVES marks this new beginning for neurogenomics. The impact of the neurogenomic revolution is discussed in separate editorials by Rosenberg, Hardy, Puls and colleagues, Pulst, Tsuji, Bird, and Roses. Each editorial provides a fresh and unique perspective on the new field of genomic neurology.

Circadian Neurology

Turek and colleagues define the critical importance of diurnal rhythms and alterations in the central circadian clock of the brain that regulates the timing of sleep and wakefulness and other circadian effects on normal brain function. Genetic changes in the expression of the suprachiasmatic nucleus have sequential effects on several biological rhythms. This is a critical area of neurogenetics that is just beginning to be developed. Potential new areas of research are reviewed.

Polymorphisms and Alzheimer Disease

Polymorphisms involving inflammatory cytokine genes, acute-phase reactants, and the enhanced risk of developing Alzheimer disease are described by P. L. McGeer and E. G. McGeer. Identification of single-nucleotide polymorphisms in the human genome will be of great importance to define an individual's risk for developing Alzheimer disease.

Gene Therapy for Lipofuscinosis

Sondhi and colleagues summarize new therapies under consideration for late infantile neuronal ceroid lipofuscinosis. They focus on strategies involving in vivo gene therapy for both the retinal and central nervous system manifestations of this disease.

Frontotemporal Dementia: A New Classification

McKhann and colleagues report the results of the Work Group on Frontotemporal Disease and Pick Disease. The frontotemporal dementias (FTDs) are in an increasing group of degenerative disorders commonly mistaken for Alzheimer disease. Specific gene loci and mutations have been described for several of the FTDs. They have provided a unique set of recommendations for classification of the FTDs, which will be of great value for clinicians to recognize patients with FTDs and to establish specific neuropathologic criteria for diagnosis. The molecular and genetic findings in the FTDs are incorporated for future research correlations and may serve for the development of a future genotype classification.

Familial Frontotemporal Dementia

Morris and colleagues describe 22 families with frontotemporal dementia (FTD) and find that one half of the families had mutations in the TAU gene. Specific pathologic diagnosis were made in 17 of 22 families. This study illustrates the value of TAU sequencing in FTD and suggests that about one half of individuals with familial FTD have TAU mutations and TAU pathologic dementia. Of interest is that each FTD tau family had a TAU mutation, whereas TAU mutations were not identified in FTD families with ubiquitin inclusions and FTD with neuronal loss and spongiosis. This study illustrates that the FTDs are a diverse set of disorders owing to different genetic and other multifactorial issues.

α-Synuclein in Alzheimer Disease

Lippa and colleagues have studied the α-synuclein epitope mapping properties of Lewy bodies in familial Alzheimer disease. They find that the epitope profile of the α-synuclein in Lewy bodies was consistent in familial Alzheimer disease cases and similar to that in Parkinson disease and dementia with Lewy body disease but different from α-synuclein aggregates that occurred in multiple-system atrophy. These findings support the general hypothesis that the mechanism of α-synuclein aggregation is the same within cell types, but distinctive between cell types.

Molecular Diagnosis of Machado-Joseph Disease

Maciel and colleagues describe their current molecular genetic findings in Machado-Joseph disease, which is now the most frequent cause of autosomal-dominant spinocerebellar ataxia worldwide. They address the issues of alleles of a size between the known normal and pathologic ranges (intermediate alleles) and the issue of homoallelism, that is, homozygosity for 2 normal alleles with exactly the same CAG length. The study of the family in which the 51 CAG allele was found suggested that it was not associated with disease. These clinical molecular correlation studies examining intermediate allele expansion are critically important in conducting presymptomatic and prenatal diagnosis of Machado-Joseph disease.

DNA Testing for Alzheimer Disease and Frontotemporal Dementia

Steinbart and colleagues describe their experience in conducting DNA testing of persons at risk for familial Alzheimer disease (FAD) and frontotemporal dementia (FTD). Twenty-one (8.4%) of 251 persons at risk for FAD or FTD requested genetic testing. Twelve subjects had positive DNA test results and 6 of these had early symptoms of dementia. Eight persons had negative test results. Of the 14 asymptomatic subjects completing the testing, 13 felt the testing had been of benefit. Clearly, genetic testing in early-onset FAD and FTD can be successfully completed and is of great medical and personal value to a segment of the population at risk for these inherited dementias.

Spinocerebellar Ataxia Type 12

Cholfin and colleagues describe their experience with spinocerebellar ataxia type 12 (SCA12). They used the polymerase chain reaction to analyze CAG repeat size in a series of patients from a reference ataxia clinic. Two hundred eleven patients from 180 families with inherited or sporadic ataxia were studied. The SCA12 expansion was not detected in any of the patients studied. Thus, SCA12 is a rare cause of dominantly inherited ataxia in their clinic population and should be considered in cerebellar ataxia patients mainly having an atypical clinical phenotype, such as when tremor is initially present, as has been described in SCA12.

Spinocerebellar Ataxia Type 6

Sinke et al confirmed SCA6 in 24 families comprising 30 familial and 4 sporadic cases. Expanded CAG repeats with sizes 22, 23, and 25 were found. These sizes inversely correlated with age at onset. Two of the families showed clinical anticipation. Their study provides the first detailed description of SCA6 in Dutch patients. Episodic features such as headache and nausea were present in a few of their patients, suggesting that SCA6 can present with similar manifestations as seen in episodic ataxia type 2 and familial hemiplegic migraine (Table 1).

Table 1 
Characteristics of the 14 Different SCA Loci*
Characteristics of the 14 Different SCA Loci*
Familial Progressive Supranuclear Palsy

Piccini and colleagues describe their experience with familial progressive supranuclear palsy (PSP). Patients with PSP were scanned with 18F-dopa and 18fluorodeoxyglucose positron emission tomography (PET). Similarly, 15 asymptomatic first-degree relatives were scanned. All 3 clinically affected PSP patients showed a significant reduction in their PET scan. In 4 of the 15 asymptomatic relatives, caudate and putamen 18F-dopa fell more than 2.5 SDs below the mean value. Thus, preclinical abnormalities on PET scanning were identified in individuals potentially at risk for PSP, suggesting that PET scanning may be a useful approach for characterizing the pattern of aggregation in PSP kindreds and specific individuals who are at risk for developing PSP.

Genetic Ataxia

Cellini and colleagues have described their experience with SCA8 due to CTA/CTG repeat expansions. They found these expansions in 5 ataxic patients, 3 of whom had pure cerebellar ataxia. More than 400 subjects were screened for this genetic mutation and the results indicate that in Italy SCA8 is a rare form of ataxia, occurring in 3% of all ataxic patients examined.

Williams Syndrome

Galaburda and colleagues describe their findings in 21 subjects with clinically and genetically diagnosed Williams syndrome using high-resolution structural magnetic resonance imaging. The extent of the central sulcus was quantitatively assessed via surface projections of the cerebral cortex. The central sulcus was less likely to reach the interhemispheric fissure in subjects with Williams syndrome than controls for both the left and right hemispheres. This important finding provides further structural, anatomical evidence for functional alterations present in this syndrome associated with a hemideletion in the long arm of chromosome 7 (7q11.23).

TAU Gene and the Amyotrophic Lateral Sclerosis–Parkinson Dementia Complex of Guam

Poorkaj and colleagues have analyzed the TAU gene and its potential role in causing the amyotrophic lateral sclerosis–Parkinson dementia complex of Guam (ALS-G/PDC-G). The TAU gene was evaluated by DNA sequence analysis in patients and control subjects, by linkage analysis of TAU polymorphisms, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within the TAU gene. DNA sequence analysis of the TAU coding regions did not reveal a mutation responsible for this syndrome. Linkage analysis of a large pedigree from Guam indicated that the TAU gene is not a major gene for this syndrome. Analysis of tau genotypes in an extended pedigree indicated obligate recombinants between the TAU gene and affected individuals. They conclude that a genetic association with ALS-G/PDC-G implicates the TAU gene as a genetic susceptibility factor for this syndrome. TAU may be a modifying gene increasing risk for the syndrome in the presence of other, unlinked, causative mutations. This thorough and comprehensive study is essential to begin to narrow the genetic factors involved in this complex genetic syndrome.

Wilson Disease in a Chinese Population

Xu and colleagues have screened Chinese patients with Wilson disease (WD) to establish a DNA diagnostic method for WD. Screening was conducted for a mutation at exon 8 of the ATP7B gene by fluorescent polymerase chain reaction analysis. Five homozygotes and 32 heterozygotes were identified. Sequence analysis showed a missense mutation with a nonsense mutation together in exon 8. The rate of the gene mutation in 106 cases was 34.9%, in which 4.7% were homozygous and 30.2% were heterozygous. Thus, a high frequency of mutation of exon 8 of the ATP7B gene exists in a Chinese population, and the fluorescent polymerase chain reaction analysis may be an effective and accurate assay for the detection of the WD gene.

Hearing Loss in a Mitochondrial DNA Mutation

Deschauer and colleagues describe the finding of the A3243G mitochondrial mutation in 16 patients. Six of 16 patients presented with stroke-like symptoms and met the classic criteria of the MELAS syndrome. In 11 of these 16 patients, hearing impairment was obvious on clinical examination. All 5 patients with normal hearing on clinical examination showed some subclinical hearing loss. Hearing impairment was a common symptom in these patients that was clinically or subclinically present in 15 (94%) of 16 patients. Thus, the MELAS syndrome can be associated with significant hearing impairment, and audiology should be part of the clinical evaluation.