Elena Lezcano

The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to α‐synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the α‐synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary α‐synucleinopathies, dementia with Lewy bodies is related to mutation of α‐synuclein.

A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease

Background: Frontotemporal dementia with parkinsonism is often linked to chromosome 17 and is related to mutations in the MAPT gene. In some families the genetic basis is still unknown. The authors report two pedigrees with FTDP-17 harboring a novel mutation (K317M) in exon 11 in the MAPT gene. Methods: The authors identified two apparently unrelated pedigrees with an autosomal dominant neurodegenerative condition. Thirteen patients were examined and eight autopsies were performed. Results: Mean age at onset was 48 years. Mean disease duration was 6 years. Dysarthria often heralded the disease. All cases had parkinsonism and pyramidalism and half of them had amyotrophy. Behavioral or personality changes were not a prominent feature. Cognitive decline appeared late in the evolution. Neuropathologically, a massive degeneration of the substantia nigra without Lewy bodies was a constant finding. A variable degree of frontotemporal atrophy was found. Corticospinal tract degeneration and anterior horn neuron loss were present in six of seven autopsies in which the spinal cord was examined. An extensive deposition of abnormal tau protein in a mixed pattern (neuronal, glial) was observed. Pick’s bodies were not seen. Biochemical analysis of tau revealed two bands of 64 and 68 kDa. Conclusion: Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.

Phenotypic variability in familial prion diseases due to the D178N mutation

Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

Use of ziprasidone in parkinsonian patients with psychosis.

Twelve patients with Parkinson disease and psychosis were included in an open-label 12-week trial of ziprasidone. Two patients withdrew from the treatment because of adverse effects. The remaining 10 patients reported a significant improvement in psychiatric symptoms. Altogether, there was no deterioration of motor symptoms (UPDRS III score: basal 40.4 ± 11, 1, first month 41.1 ± 10.8; final visit, 37.7 ± 13.3). Two patients (20%) suffered a slight deterioration in motor symptoms and another patient suffered deterioration of gait. No analytic alterations or serious adverse effects that could limit the use of ziprasidone were observed. Although controlled trials are needed, the findings suggest that ziprasidone may be effective in parkinsonian patients with psychosis.

Cardiac sympathetic denervation precedes nigrostriatal loss in the E46K mutation of the α-synuclein gene (SNCA)

IntroductionHere we report the case of an asymptomatic carrier of the E46K substitution in α-synuclein gene where we have documented that cardiac sympathetic denervation precedes nigrostriatal dopaminergic loss.Material and methodsShe has been followed up regularly with standard neurological examination, UPDRS, neuropsychological formal testing, parkinson disease sleep scale-PDSS, Epworth scale, Hamilton-D scale, SCOPA Aut, orthostatic hypotension test, brief smell identification test, polysomnography, cerebral 123-I-FP-CIT SPECT, and, 123I-MIBG cardiac scintigraphy.ResultsShe shows no presence of orthostatic hypotension. Olfactory test results demonstrate normal limits. In the PSG the nocturnal sleep shows mild abnormalities although the sleep efficiency and stage proportion remain under normal limits. The 123-I-FP-CIT SPECT is normal; in contrast, the 123I-MIBG cardiac scintigraphy shows a complete lack of isotopic uptake compatible with a severe sympathetic myocardial denervation.ConclusionThis example of monogenic autosomal dominant parkinsonism due to an α-synuclein mutation favours the hypothesis that peripheral autonomous nervous system involvement occurs earlier than the CNS degeneration.

Parkinson's disease‐like presentation of multiple system atrophy with poor response to STN stimulation: A clinicopathological case report

We report on a clinicopathological case of multiple system atrophy with good response to levodopa and subsequent development of motor complications. Because the subject complied with all the inclusion criteria (Core Assessment Program for Surgical Interventional Therapies in Parkinsons Disease), bilateral subthalamic nucleus deep brain stimulation electrodes were implanted.

Sleep complaints and their relation with drug treatment in patients suffering from Parkinson's disease.

The aim of this research was to quantify sleep problems in patients suffering from Parkinsons disease by means of the new Parkinsons Disease Sleep Scale (PDSS) and to correlate such problems with the possible influence of current drug treatment. A total of 70 patients (36 men and 34 women) with a diagnosis of Parkinsons disease were enrolled. Their mean age was 69.7 ± 8.2 years, and duration of disease was 7.4 ± 4.8 years. All patients completed the PDSS and the Unified Parkinsons Disease Rating Scale (UPDRS Parts I–IV). Drug consumption and doses were registered. The mean score on the PDSS scale was 109.23 ± 19.75 and on the UPDRS III scale was 25.24 ± 11.35. The lowest scores were obtained in Item 3 (sleep fragmentation): 5.53 (2.46); and in Item 8 (nocturia): 5.75 (2.91). There was a weak correlation between the PDSS and UPDRS III (cc = −0.355, P = 0.003), PDSS and UPDRS I (cc = −0.272, P = 0.02), and PDSS and UPDRS IV (cc = −0.416, P < 0.001). Motor conditions, mental state, and drug complications influence sleep quality. Although this effect was significant, it was not of a great magnitude. Dopaminergic drugs did not increase daytime sleepiness. As a whole, sleep quality in patients who took dopaminergic agonists did not differ from that of patients who took levodopa in monotherapy.

Initial neuropsychological impairments in patients with the E46K mutation of the α-synuclein gene (PARK 1).

INTRODUCTION In 2004 we described the mutation E46K of the α-Synuclein (SNCA). These patients show Parkinsons disease with early cognitive impairment, sleep disorders and autonomic dysfunction. OBJECTIVE The main objective is to identify early neuropsychological impairments in patients with the E46K mutation. METHODS This is a longitudinal neuropsychological study of 4 of the 5 surviving patients with E46K mutation by semi-structured interviews and the following scales: Mattis Dementia Rating Scale (MDRS), semantic and phonemic verbal fluency tests (VFT), Benton Visual Retention Test (BVRT), Stroop Test (STROOP), Clock drawing test (CLOCK), WAIS III Letter and Number sequencing (WAIS III LN), Rey Auditory Verbal Learning Test (RAVLT) and Benton Judgement of Line Orientation Test (BJLOT). Motor status was assessed by UPDRS III. RESULTS Motor status: Patients 1, 2 and 3 present mild to moderate Parkinson disease of 7, 8 and 3years of evolution respectively, patient 4 is asymptomatic. Cognitive status: Patient 2 and 3 both refer cognitive decline while patient 1 presents no cognitive complaints, however they all show a progressive cognitive decline across various tasks. Tests of frontal function showed the first alterations in all patients but fluctuate. The first cognitive complaints coincide with deterioration of tasks of posterior cortical basis. Patient 4 presents a normal performance on all tests. Patient 1, 2 and 3 have all presented visual hallucinations. CONCLUSIONS A fluctuating frontal impairment is observed at early stages. Prominent visuospatial alterations and visual hallucinations suggest that posterior cortical dysfunction might be a distinct early feature of the cognitive impairment observed in patients with this mutation.

Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the α synuclein gene

OBJECTIVE The aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene (SNCA) mutation. PATIENTS AND METHODS Autonomic function tests were performed in six patients, four of whom were symptomatic carriers (ages: 46, 59, 52 and 28-years) and two who were asymptomatic carriers (ages: 52 and 29 years). Autopsy studies were performed on an additional two symptomatic carriers not eligible for autonomic testing. Patients completed the SCOPA autonomic questionnaire, and underwent the head-up tilt test accompanied by measurements of plasma norepinephrine. Valsalva maneuver and deep breathing tests, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy were carried out. Myocardial tissue sections removed from the two autopsied cases were subjected to routine histological staining and immunohistochemical processing with monoclonal antibodies against tyrosine hydroxylase and alpha-synuclein. RESULTS Both the four symptomatic and the older asymptomatic carriers reported abnormalities in the SCOPA questionnaire and had markedly diminished cardiac MIBG uptake. Plasma norepinephrine in the supine and tilted positions was normal in all subjects. Only one patient had significant orthostatic hypotension. There was a complete absence of tyrosine hydroxylase immunostaining in the myocardium of the two autopsied cases. INTERPRETATION We have found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene mutation. The sympathetic denervation appears to be organ-specific, with selective affectation of the heart given that plasma norepinephrine levels and blood pressure were normal.

Abnormal sleep architecture is an early feature in the E46K familial synucleinopathy.

We examined 7 patients from a family harboring a novel mutation in the α‐synuclein gene (E46K) that segregated with a phenotype of parkinsonism and dementia with Lewy bodies. An abnormal restless sleep was the presenting symptom in 2 of them. Polysomnographic (PSG) studies were performed in 4 of the 7 patients and in 2 asymptomatic carriers of the mutation. A severe loss of both rapid eye movement (REM) and non‐REM sleep was observed in 2 patients complaining of insomnia and in a third parkinsonian member of the family who did not complain of trouble with sleeping. Another parkinsonian family member had a mild disorganization of the sleep architecture. The 2 asymptomatic carriers also had minor changes in the PSG findings. Episodes of bizarre behavior at night were reported historically in the 2 symptomatic patients, but we did not observed the behaviors during the PSG studies. REM sleep behavior disorder could not be recorded in any case. Our findings expand the spectrum of sleep disorders reported in synucleinopathies whether sporadic or familial.