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Neurology AND Movement disorders [keywords]
- Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia. [JOURNAL ARTICLE]
- J Neurol 2014 Sep 30.
PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.
- Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. [JOURNAL ARTICLE]
- Exp Neurol 2014 Sep 25.
Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinson's disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD.
- Levodopa-carbidopa intestinal gel (LCIG) infusion during pregnancy and delivery: First documented case. [LETTER]
- Parkinsonism Relat Disord 2014 Sep 17.
- Globus pallidus deep brain stimulation for adult-onset axial dystonia. [JOURNAL ARTICLE]
- Parkinsonism Relat Disord 2014 Sep 16.
Generalized dystonia, both primary and secondary forms, and axial dystonias such as tardive dystonia, and idiopathic cervical dystonia are responsive to globus pallidus interna (GPi) DBS. There is a paucity of investigations probing the impact of DBS on adult-onset axial dystonia. We assessed the efficacy of GPi DBS in four patients with rare adult-onset axial dystonia.Primary outcome measure was improvement in the motor component of the Burke-Fahn-Marsden (BFM) rating scale. Secondary outcome measures were quality of life as determined by the SF-36 questionnaire, time to achieve best possible benefit and DBS parameters that accounted for the best response. In patients with prominent concomitant cervical dystonia we also used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).GPi DBS improved BFM scores by 87.63 ± 11.46%. Improvement in total severity scale of TWSTRS was 71.5 ± 12.7%. Quality of life also remarkably improved as evidenced by 109.38 ± 82.97 and 7.05 ± 21.48% percent change in psychometrically-based physical component summary (PCS), and a mental component summary (MCS) score respectively.GPi DBS is a very effective treatment for adult-onset axial dystonia. Considering its refractoriness to medical therapy and significant impact on quality of life DBS should be considered for this disorder.
- The Cognition and Emotional Well-being indices of the Parkinson's disease questionnaire-39: What do they really measure? [JOURNAL ARTICLE]
- Parkinsonism Relat Disord 2014 Sep 18.
The Parkinson's disease questionnaire-39 (PDQ-39) is a common measure of health related quality of life (HRQoL) that is widely used with Parkinson disease (PD) patients. Previous evidence suggests that the PDQ-39 reflects at least 8 dimensions (i.e., Emotion, Cognitions, Mobility, etc). To date, little research has examined the external/convergent validity of the Cognitions and Emotional Well-being domains of the PDQ-39.A convenience sample of 303 PD patients underwent a comprehensive multi-domain neuropsychological evaluation, including tests of execution function, episodic verbal memory, processing speed, language and working memory, as well as completing measures of depression, apathy, state and trait anxiety and HRQoL (PDQ-39). Hierarchical regressions were conducted in order to examine the relationship between scores on neuropsychological tests and the Cognitions index, as well as mood measures and the Emotional Well-being index of the PDQ-39.Neuropsychological test performance did not account for a significant amount of variance in the PDQ-39 Cognitions index scores. Instead, it was depression that significantly contributed to the Cognitions index, above and beyond neuropsychological performance. The PDQ-39 Emotional Well-being index was also related to mood measures, primarily depression and trait anxiety.The PDQ-39 Cognition index may be more related to mood functioning, as opposed to cognitive functioning, and should not be considered a "proxy" for cognitive functioning. Future studies are needed to better explain the construct of this index.
- "Medical marijuana" use in a movement disorders clinic in Rhode Island. [LETTER]
- Parkinsonism Relat Disord 2014 Jul 19.
- Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features. [JOURNAL ARTICLE]
- Neurobiol Aging 2014 Aug 27.
The cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is because of NOTCH3 mutations affecting the number of cysteine residues. In this view, the role of atypical NOTCH3 mutations is still debated. Therefore, we investigated a family carrying a NOTCH3 nonsense mutation, with dominantly inherited recurrent cerebrovascular disorders. Among 7 family members, 4 received a clinical diagnosis of CADASIL. A heterozygous truncating mutation in exon 3 (c.307C>T, p.Arg103X) was found in the 4 clinically affected subjects and in one 27-year old lady, only complaining of migraine with aura. Magnetic resonance imaging scans found typical signs of small-vessel disease in the 4 affected subjects, supporting the clinical diagnosis. Skin biopsies did not show the typical granular osmiophilic material, but only nonspecific signs of vascular damage, resembling those previously described in Notch3 knockout mice. Interestingly, messenger RNA (mRNA) analysis supports the hypothesis of an atypical NOTCH3 mutation, suggesting a nonsense-mediated mRNA decay. In conclusion, the present study broadens the spectrum of CADASIL mutations, and, therefore, opens new insights about Notch3 signaling.
- Clinical Evaluation of Eye Movements in Spinocerebellar Ataxias: A Prospective Multicenter Study. [JOURNAL ARTICLE]
- J Neuroophthalmol 2014 Sep 25.
Ocular motor abnormalities reflect the varied neuropathology of spinocerebellar ataxias (SCAs) and may serve to clinically distinguish the different SCAs. We analyzed the various eye movement abnormalities detected prospectively at the baseline visit during a large multicenter natural history study of SCAs 1, 2, 3, and 6.The data were prospectively collected from 12 centers in the United States in patients with SCAs 1, 2, 3, and 6, as part of the Clinical Research Consortium for Spinocerebellar Ataxias (NIH-CRC-SCA). Patient characteristics, ataxia rating scales, the Unified Huntington Disease Rating Scale functional examination, and clinical staging were used. Eye movement abnormalities including nystagmus, disorders of saccades and pursuit, and ophthalmoparesis were recorded, and factors influencing their occurrence were examined.A total of 301 patients participated in this study, including 52 patients with SCA 1, 64 with SCA 2, 117 with SCA 3, and 68 with SCA 6. Although no specific ocular motor abnormality was pathognomonic to any SCA, significant differences were noted in their occurrence among different disorders. SCA 6 was characterized by frequent occurrence of nystagmus and abnormal pursuit and rarity of slow saccades and ophthalmoparesis and SCA 2 by the frequent occurrence of slow saccades and infrequent nystagmus and dysmetric saccades. SCA 1 and SCA 3 subjects had a more even distribution of eye movement abnormalities.Prospective data from a large cohort of patients with SCAs 1, 2, 3, and 6 provide statistical validation that the SCAs exhibit distinct eye movement abnormalities that are useful in identifying the genotypes. Many of the abnormalities correlate with greater disease severity measures.
- Diagnostic accuracy of Parkinson's disease and atypical parkinsonism in nursing homes. [JOURNAL ARTICLE]
- Parkinsonism Relat Disord 2014 Aug 28.
Management of Parkinson's disease (PD) and atypical parkinsonism in nursing homes depends on a timely and accurate diagnosis. However, little is known about the diagnostic accuracy of these parkinsonian syndromes in nursing homes. We examined this issue in a large group of Dutch nursing home residents.Twelve large nursing home organizations in the Netherlands accounting for 100 nursing homes with a total population of 5480 residents participated. Residents with PD or atypical parkinsonism were identified according to their nursing home medical chart diagnosis. Additionally, local pharmacists provided a list of all residents using antiparkinson medication. We compared the admission diagnosis to a clinical diagnosis made in the study, based upon interview and detailed neurological examination by movement disorders experts. Diagnoses were based on accepted clinical criteria for PD and atypical parkinsonism.In the total population of 5480 residents, 258 had previously been diagnosed with a form of parkinsonism according to their medical record. In 53 of these residents (20.5%) we changed or rejected the diagnosis. Specifically, we found no parkinsonism in 22 of these 53 residents (8.5% of all patients with suspected parkinsonism). In the remaining 31 residents (12%), we established a new diagnosis within the parkinsonian spectrum.In a large population of Dutch nursing home residents, 20% of diagnoses within the parkinsonian spectrum were inaccurate. Almost 9% of residents had inadvertently received a diagnosis of parkinsonism. Better recognition of parkinsonism in nursing homes is important, because of the consequences for management and prognosis.
- New susceptibility variants to narcolepsy identified in HLA class II region. [JOURNAL ARTICLE]
- Hum Mol Genet 2014 Sep 25.
Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10%-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3,131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P=1.4×10(-10), OR=0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P=2.5×10(-9), OR=1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single nucleotide polymorphism (SNP)-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P=4.1×10(-5), OR=2.45; DPB1*05:01, P=8.1×10(-3), OR=1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.