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This Month in Archives of Neurology
May 2003

This Month in Archives of Neurology

Arch Neurol. 2003;60(5):657-659. doi:10.1001/archneur.60.5.657

The sense of taste is generally regarded as less important when compared with vision and hearing. However, gustatory disorders considerably diminish the pleasures of life. Heckmann and colleagues provide a timely review of the physiology and neurologic syndromes related to disorders of taste and therapies for specific syndromes.

Genomic Neurology

We now know that there are about 35 000 genes in the human genome, owing to the recent publication of the sequence and analysis of the human genome by the International Human Genome Consortium and Celera Genomics. As Sturla and colleagues point out in this exciting review, the identification of specific genes responsible for neurologic disease and the expression of normal brain functions is now possible using microarrays. Thousands of genes can be analyzed simultaneously for their level of expression in specific neurologic disorders, including multiple sclerosis, Huntington disease, Parkinson disease, Alzheimer disease, and brain tumors. Detecting the at-risk status of patients for familial disease to predict and prevent progression of a neurologic disorder is also anticipated using microarrays. The revolution in neurologic genomics has just begun, and microarray technology will define the patterns of genetic expression of disease and normal brain function. Neurologists will want to know more about the power and precision of this new technology.

Genotypes vs Phenotypes

The calcium channel gene, CACNA1A, on chromosome 19, has been described with missense and nonsense mutations and with CAG unstable DNA triplet repeat expansions. The clinical neurologic syndromes that correspond to these mutations are familial hemiplegic migraine, episodic ataxia, and progressive ataxia. Kors and colleagues, in an elegant and compelling study, demonstrate the expanding phenotypic spectrum of this CACNA1A gene in 5 families with familial hemiplegic migraine. They define the T666M mutation in this gene in 5 unrelated families with familial hemiplegic migraine. In 3 of the families, the patients displayed cerebellar ataxia. In 1 family, some members who were affected with the mutation experienced attacks with confusion but without hemiparesis. In 1 family, patients had progressive cognitive dysfunction. Clearly, the genotype defines the issue and is the reliable marker to use in identifying the genetic basis of familial neurologic disease. Editorial perspective provided by Arnulf H. Koeppen, MD.

Subthalamic Stimulation in Parkinson Disease: Predicting the Future

Intraoperative clinical and electrophysiologic data were obtained from 41 patients with Parkinson disease who underwent bilateral implanation of electrodes for subthalamic nucleus (STN) stimulation. The state of parkinsonian function was assessed 6 months after the operation in these patients by Houeto and colleagues. They found that intraoperative improvement in segmental akinesia, but not in rigidity, predicted postoperative improvement in parkinsonian motor disability and reduction in daily levodopa-equivalent dosage. Postoperative motor disability was lower in patients in whom intraoperative stimulation induced dyskinesias. These findings will be of considerable value in assessing the subsequent function of patients with bilateral STN stimulation.

Effect of stimulation-induced unilateral or bilateral dyskinesias during the operation on postoperative parkinsonian disability and motor fluctuation scores (on stimulation and on drug). Values are mean ± SEM. UPDRS indicates Unified Parkinson's Disease Rating Scale; asterisk, P<.05 compared with patients without intraoperative stimulation-induced dyskinesias.

Effect of stimulation-induced unilateral or bilateral dyskinesias during the operation on postoperative parkinsonian disability and motor fluctuation scores (on stimulation and on drug). Values are mean ± SEM. UPDRS indicates Unified Parkinson's Disease Rating Scale; asterisk, P<.05 compared with patients without intraoperative stimulation-induced dyskinesias.

Tau and Frontotemporal Dementia

The tau gene was studied in patients with familial and sporadic frontotemporal dementia (FTD) by Sobrido and colleagues. The P301L mutation was detected in 11% of familial FTD cases. The H1 haplotype was not overrepresented in FTD patients, but the P301L mutation did appear on the background of the H2 tau haplotype. They identified 4 novel single nucleotide polymorphisms in intron 9 and a 9–base pair deletion in intron 4A. Further, a C-to-T transition 177 base pairs upstream from exon 10 was significantly increased in FTD patients compared with controls. These findings extend and confirm previous observations concerning sequence variations in intronic or regulatory regions with tau and define the degree of the mutations present in a cohort of patients with familial FTD.

Incipient CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by a mutation in the NOTCH3 gene. Our current knowledge of disease expression in young adults with the NOTCH mutation has been limited in this study. Oberstein and colleagues have characterized the clinical neuropsychologic and radiologic findings in NOTCH mutation carriers younger than 35 years. They found that 6 individuals from 5 families had the NOTCH3 gene mutation. Clinical symptoms included migraine with aura, stroke, and stroke-like episodes. A characteristic lesion pattern on magnetic resonance imaging was present in all mutation carriers. This comprised white matter hyperintensities in the anterior temporal lobes, frontal lobes, and periventricular frontal caps. Early diagnosis and informed genetic counseling are possible with awareness of the clinical and radiologic features of CADASIL in individuals younger than 35 years.

Parkin Gene Mutations: An 18F-dopa Positron Emission Tomography Study

Thobois and colleagues performed positron emission tomography (PET) with 18F-dopa in 19 patients with young-onset Parkinson disease (PD) with a parkin gene mutation, 6 young-onset PD patients without parkin gene mutations, and 9 healthy control subjects. In summary, they find that the pattern of 18F-dopa uptake in the striatum of young-onset PD patients is similar to that of patients with idiopathic PD and is not dependent on the presence or absence of mutation in the parkin gene. This study showed the absence of direct relationships among genotype, phenotype, and imaging pattern using 18F-dopa PET scans in patients with young-onset PD. These baseline studies will be useful for the long-term follow-up with patients.

NURR1 Polymorphisms and Parkinson Disease

NURR1 plays a key role in midbrain dopaminergic neuron development and survival. A homozygous NURR1 polymorphism (single base pair insertion in intron 6) has been reported to be associated with Parkinson disease (PD). Zheng and colleagues have determined the association of the NURR1 intron 6 polymorphism (NI6P) with PD and also with Lewy body disease (DLB). They find that almost 40% of patients with PD were heterozygotes for the NI6P polymorphism compared with 25% of controls, with a relative risk of 2.0 for heterozygotes vs wild type. Heterozygotes were more frequent in the subgroup of pathologically confirmed PD patients compared with control subjects, with a risk factor for PD of 2.8 for heterozygotes vs wild type. The homozygous NI6P was not associated with PD but was present in 17.1% of patients with DLB compared with 5.2% of controls (P = .06). Thus, the heterozygous NURR1 polymorphism is a significant risk factor for PD and may be of significance as a risk factor for DLB as well. These findings are of significance in defining the multifactorial, polygenetic influences that underlie the molecular expression of these 2 complex late-onset diseases.

Tangles, Amyloid, and Memory

The distribution pattern of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) was measured by Guillozet and colleagues to determine the association of these lesions with memory performance in nondemented individuals. Specifically, the regional distribution and neuropsychologic correlates of NFTs and amyloid plaques in cognitively normal elderly subjects and in persons with mild cognitive impairment (MCI) were investigated. Of great interest, they found that the distribution of the NFTs followed a rigorous and hierarchical pattern, but the distribution of amyloid plaques varied between individuals. Patients with MCI had higher densities of NFTs than nonimpaired subjects. Neurofibrillary tangle density in the temporal lobe correlated with the memory scores, whereas the density of amyloid plaques did not. Clearly, NFTs are of importance as a pathologic substrate for memory loss in persons with normal aging and MCI and as an early substrate for the subsequent occurrence of Alzheimer disease.

Treating Presymptomatic Wilson Disease

Wu and colleagues studied patients with presymptomatic Wilson disease (WD) established by DNA diagnosis and evaluated the efficacy of zinc therapy. Seventy-eight clinically unaffected siblings were studied from 51 unrelated families with WD that were ascertained by affected individuals. Presymptomatic patients established by DNA analysis were treated with 50 mg of elemental zinc taken twice daily from the time of molecular diagnosis and followed up for 3 to 5 years. Seventeen of the 78 siblings were diagnosed as having presymptomatic WD. Ceruloplasmin values increased, and 24-hour urinary copper values decreased during zinc therapy. No individuals developed clinical symptoms of WD or adverse effects from zinc therapy. Zinc is recommended for use as maintenance therapy for presymptomatic patients with WD.

POEMS and Stroke

Visceromegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare variant of plasma cell dyscrasia, with multisystemic manifestations. Stroke as part of the POEMS syndrome has rarely been reported. Kang and colleagues describe neuroimaging findings and fibrinogen levels in patients with POEMS syndrome. Three patients with acute cerebral infarction associated with POEMS were identified. All 3 patients had an elevated fibrinogen level, and 2 patients had unilateral or bilateral end artery border-zone infarctions, as seen on magnetic resonance imaging. Serum fibrinogen levels were high before the stroke in 2 patients. Thus, POEMS syndrome can be associated with stroke and border-zone infarctions. An elevated fibrinogen level may play a role in the pathogenesis of the stroke syndome.

Depression and Alzheimer Disease: The MIRAGE Study

The association between depression and the risk for Alzheimer disease (AD) and the temporal aspects of this association were studied by Green and colleagues in the MIRAGE study. One thousand nine hundred fifty-three subjects with AD and 2093 of their unaffected relatives were enrolled in the MIRAGE study, a genetic epidemiologic study of AD. They found that there was a significant association between depression symptoms and AD (adjusted odds ratio, 2.13; 95% confidence interval, 1.71-2.67). They conclude that depression symptoms prior to the onset of AD are associated with the development of AD, even in families whose onset of depression symptoms occurred more than 25 years prior to the onset of AD. Further, they conclude that depression symptoms are a significant risk factor for the later development of AD and that if patients develop AD within a year of symptoms of depression, these early symptoms may represent findings of AD. Depression as it relates to AD is an important issue that requires further intensive study, both as a potential predictive risk factor and as a readily treated one, which perhaps could influence the subsequent occurrence of AD.