Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.

A familial case of Alzheimer's disease without tau pathology may be linked with chromosome 3 markers.

Alzheimer's disease is the most common form of dementia that occurs in later years. The diagnosis is confirmed by the pathological findings of betaA4-amyloid-containing neuritic plaques and neurofibrillary tangles, the former being present in sufficient quantity commensurate with age. Other forms of dementia are more difficult to diagnose clinically; their pathology is noted for the lack of plaques and tangles. A patient with a family history of dementia presented with the clinical signs of Alzheimer's disease which lasted for 13 years. At autopsy the brain tissue had betaA4-amyloid-containing neuritic plaques, but no neurofibrillary tangles (i.e., the tissue was negative for staining with the tau antibody). Genetic analysis of DNA from family members revealed no linkage with chromosome 17 markers, indicating that this was not frontotemporal dementia. However, there was linkage with chromosome 3 markers. Thus, this form of Alzheimer's disease with a pathology of plaques only is linked with markers on chromosome 3.

Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.

We describe a progressive neurologic disorder in three sisters characterized clinically by palatal myoclonus, spastic weakness, hyperreflexia, mild cerebellar dysfunction, and ocular motor abnormalities. Postmortem examination of one patient demonstrated widespread Rosenthal fiber deposition associated with demyelination. The father previously was reported to have similar pathologic findings and carried a clinical diagnosis of multiple sclerosis. These clinical and pathologic findings describe a rare familial leukodystrophy that corresponds most closely to cases reported as adult Alexander's disease. Although similar pathologically to the well-characterized infantile variant of Alexander's disease, it is not known whether this adult variant represents the same disease process.

A closely linked gene to apolipoprotein E may serve as an additional risk factor for Alzheimer's disease.

The E4 allele of the apolipoprotein E (APOE) gene has been identified as a risk factor for Alzheimer's disease. Immediately downstream from the APOE gene on chromosome 19 is the gene for apolipoprotein CI (APOCI). We have found that the frequency of an APOCI restriction site is 0.45 for Alzheimer's patients and 0.14 for control spouses, which is similar to the frequencies for the APOE4 allele. The APOE4 allele is in linkage disequilibrium with the APOCI restriction site. Thus both the APOE4 allele and the APOCI restriction site may be considered as risk factors for Alzheimer's disease.

Association of apolipoprotein E but not B with Alzheimer's disease.

In our studies apolipoprotein E4 (APOE4) is associated with both early- and late-onset Alzheimer's disease. Alzheimer's patients from West Texas were screened for the APOE4 allele, which was found at frequencies of 0.43 and 0.59 in familial late- and early-onset cases. Sporadic cases had lower frequencies, but they still were 2-4 times higher than control spouses. To determine whether the APOE association may be a risk factor for coronary disease as well, we examined two APOB gene restriction sites that have previously been found to be associated with coronary artery disease, especially myocardial infarctions. The APOB alleles were found at similar frequencies in Alzheimer's patients and control spouses.

Apolipoprotein E and B alleles in Parkinson's patients.

Parkinson's patients were genotyped for the apolipoprotein E alleles as well as polymorphisms at the apolipoprotein B loci to determine whether they were at risk for late onset Alzheimer's disease or coronary disease. The Parkinson's patients were at no greater risk for either disease than were the control spouses. The frequency for the APOE4 allele was 11% compared with the spouses, 10%. Interestingly, 20% of the patients had the 2/3 genotype which may have a protective effect from late onset Alzheimer's disease.

MR vs CT in progressive supranuclear palsy.

Nine progressive supranuclear palsy (PSP) patients were studied with computerized tomography (CT) and magnetic resonance (MR) in order to determine the efficacy of each in detecting atrophy of the brainstem. Three additional PSP patients were evaluated with MRI for quantitative (electronic) measurements of the colliculi, pons and midbrain tegmentum. Both CT and MRI were equally effective in demonstrating midbrain atrophy. The MR was able to utilize the sagittal view to visualize thinning of the collicular (quadrigeminal) plate, a useful sign in PSP. Atrophy of the thinned collicular plate is more pronounced in the superior colliculus, one of the most common sites of pathology in PSP. The MR is able to make quantitative measurements of the degree of atrophy of the colliculi, pons and midbrain tegmentum.

A new polymorphism in the gene for the dopamine D2 receptor.

A new polymorphism has been identified in the gene for the dopamine D2 receptor. The polymorphism was found by single-stranded conformational polymorphism (SSCP) analysis. Sequencing revealed an insertion at a BsoF1 restriction site. This polymorphism in the 3'-untranslated region was found at a frequency of 0.07 in Centre d'Etude du Polymorphisme Humain (CEPH) parents.

Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.

OBJECTIVE: To study the clinical and pathological features of a kindred with an adult-onset autosomal dominant leukodystrophy. PATIENTS: Five symptomatic and nine asymptomatic at-risk members of the kindred. INTERVENTIONS: Subjects underwent detailed histories and general and neurologic examinations. Further evaluation included electroencephalography, evoked potentials, electromyography, autonomic testing, and analysis of serum, urine, and cerebrospinal fluid. One patient underwent sural nerve biopsy and analysis. Another, previously studied patient, underwent a limited autopsy. RESULTS: Cerebellar and pyramidal dysfunction began in the fourth and fifth decades of life; subtle autonomic symptoms were often present years earlier. Frontal lobe dysfunction and abnormalities of the central visual pathways were mild and of late onset. Sensorineural hearing loss was common. The peripheral nervous system was spared. Autopsy results of one patient revealed severe degeneration of the white matter at all levels of the neuraxis, but most prominent in the frontoparietal and cerebellar regions, with sparing of the subcortical U fibers. Histological and ultrastructural examinations failed to show evidence of a specific pathogenetic mechanism or etiology. CONCLUSION: This disorder seems to be a distinct type of hereditary leukodystrophy, but its exact nature remains unknown.

Association of a monoamine oxidase B allele with Parkinson's disease.

Monoamine oxidase B (MAO-B) is implicated in the cause of Parkinson's disease (PD) because of its role in metabolizing the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and forming H2O2 during dopamine metabolism. Altered MAO-B activity has been observed in PD platelets. Polymerase chain reaction was used to amplify a portion of the MAO-B gene. Polymerase chain reaction products were screened with restriction enzymes to identify fragments useful for single-stranded conformational polymorphism analysis. A single-stranded conformational polymorphism was identified in an MAO-B polymerase chain reaction product after Hae III digestion. One hundred twenty-one control individuals were allelotyped with frequencies of 0.45 and 0.55 for alleles 1 and 2, respectively. Frequencies of 0.62 and 0.38 (1 and 2, respectively) were observed in a population of 46 patients with PD. The presence of MAO-B allele 1 is associated with a relative risk for PD of 2.03-fold (confidence interval, 1.44-2.61; p < 0.02). For comparison, a monoamine oxidase A polymorphism was used to determine allelic frequencies in these same populations and no statistically significant differences were found. These results suggest that an inherited variant of MAO-B may be involved in a genetic predisposition for PD.

The middle latency auditory evoked potential may be abnormal in dementia.

The P1 potential (50 msec) of the middle latency auditory evoked potential was lacking in 12 of 31 (39%) patients with probable Alzheimer's disease and seven of 12 (58%) demented patients with Parkinson's disease. Component P1 was not present in one normal control subject and one nondemented Parkinson's disease patient. Clinical and experimental evidence suggests that abnormalities of P1 in dementia may be due to cholinergic dysfunction.

Increased glucose metabolism in the medulla of patients with palatal myoclonus.

Hypertrophic degeneration of the inferior olivary nuclei is the pathologic substrate for palatal myoclonus, but the physiologic correlate of this finding is uncertain. Using the 2-[18F]fluoro-2-deoxy-D-glucose and PET method, we determined the local cerebral metabolic rate of glucose utilization in seven patients with palatal myoclonus (following stroke or infection, or idiopathic), one patient with oculopalatal myoclonus (following a stroke affecting the brainstem), and nine normal subjects. The metabolism of glucose in the medulla of the patients with palatal myoclonus was significantly greater than that of the normal subjects. This may well have been due to increased metabolism of the inferior olivary nuclei. Glucose metabolism in the medulla of the patient with oculopalatal myoclonus was normal. These findings suggest that the inferior olivary nuclei, or a region of the brainstem encompassing the inferior olivary nuclei, are hypermetabolic in palatal myoclonus and may be the generators of the involuntary movements in palatal myoclonus.

Abnormalities in visual spatial attention in men with mirror movements associated with isolated hypogonadotropic hypogonadism.

We studied spatial attentional performance on a visually cued reaction time task in men with isolated hypogonadotropic hypogonadism. A subset of these patients, who displayed mirror movements, have spatial attentional abnormalities. They were slow to respond to targets in the right visual field and especially slow when those targets followed incorrect or diffuse cues. This slowing was present for at least 500 msec after cue onset. They responded equally to targets in the left visual field independent of the spatial cues. The patient population as a whole was significantly faster than controls across all experimental conditions, although the speed of their attentional movement was normal. These data suggest that patients with isolated hypogonadotropic hypogonadism perform reaction time tasks quickly, that faster reaction times do not reflect superior attentional performance, and that a subset of these patients has a spatial attentional abnormality.

Eye movement disorders in men with isolated hypogonadotropic hypogonadism.

The eye movement abnormalities in two men with isolated hypogonadotropic hypogonadism were studied clinically and electro-oculographically. Both demonstrated striking saccadic dysmetria. Subsequent neuroradiologic investigation confirmed atrophy of the cerebellar vermis in one of the patients. This is in concert with other midline structural abnormalities described in patients with isolated hypogonadotropic hypogonadism and suggests that this syndrome may arise from a genetically linked developmental abnormality of midline central nervous system structures.

Primidone/phenobarbital-induced periodic alternating nystagmus.

A 37-year-old man with a history of seizures developed periodic alternating nystagmus (PAN) along with other signs of primidone/phenobarbital toxicity. The PAN gradually diminished in cycle length and intensity, finally resolving with gradual discontinuation of the drugs.

Neurologic findings in men with isolated hypogonadotropic hypogonadism.

We studied the neurologic abnormalities in 41 men with isolated hypogonadotropic hypogonadism. Findings included anosmia, hyposmia, mirror movements, ocular motor abnormalities, cerebellar dysfunction, and pes cavus foot deformity. One-third of the subjects had a family history of delayed sexual maturation. Patients with a family history of delayed sexual maturation had a significantly higher incidence of olfactory dysfunction, mirror movements, and pes cavus foot deformity. Our data suggest that isolated hypogonadotropic hypogonadism and its accompanying neurologic abnormalities may arise from a genetically linked developmental abnormality of CNS structures.

Computed tomography and magnetic resonance imaging in adult-onset leukodystrophy.

Five clinically affected and nine at-risk members of a kindred with an autosomal dominant adult-onset leukodystrophy simulating chronic progressive multiple sclerosis were studied with computed tomography (CT) and magnetic resonance imaging (MRI). Computed tomographic scans showed white matter lucencies occurring earliest and most prominently in the frontoparietal region. The lesions were nondiscrete, diffuse, and bilaterally symmetric. These changes were more clearly visualized as areas of increased signal intensity with T2-weighted MRI. Magnetic resonance imaging also showed increased signal intensity in the brain stem, cerebellar white matter, or both of four patients. Both MRI and CT differentiated this entity from multiple sclerosis, but MRI was superior to CT in detailing the extent of white matter involvement.

Ophthalmic midline dysgenesis in Kallmann syndrome.

Partial coloboma, observed only with transillumination techniques, occur in 16% of male patients diagnosed with Kallmann syndrome. This sign represents an additional midline defect in this multisystem disorder noted for midline dysgenesis. Its high incidence may be helpful in the diagnosis of this disorder although it does not appear to be the harbinger of any other ocular abnormality.