Neurofilament Light Chain Is a Biomarker of Neurodegeneration in Ataxia Telangiectasia.

Ataxia telangiectasia (A-T) is a progressive and life-limiting disease associated with cerebellar ataxia due to progressive cerebellar degeneration. In addition to ataxia, which is described in detail, the presence of chorea, dystonia, oculomotor apraxia, athetosis, parkinsonism, and myoclonia are typical manifestations of the disease. The study aimed to evaluate the specificity and sensitivity of neurofilament light chain (NfL) as a biomarker of neurodegeneration in relation to SARA score. In this prospective trial, one visit of 42 A-T patients aged 1.3-25.6 years (mean 11.6 ± 7.3 years) was performed, in which NfL was determined from serum by ELISA. Additionally, a neurological examination of the patients was performed. Blood was collected from 19 healthy volunteers ≥ 12 years of age. We found significantly increased levels of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs. 9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with age, AFP, and SARA. NfL is a new potential progression biomarker in blood for neurodegeneration in A-T which increases with age.

Altered Cerebrospinal Fluid (CSF) in Children with Ataxia Telangiectasia.

Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia and immunodeficiency. The neurological decline may be caused by multiple factors of which ongoing inflammation and oxidative stress may play a dominant role. The objective of the present investigation was to determine cerebrospinal fluid (CSF) proteins and possible low-grade inflammation and its relation to age and neurological deterioration. In the present study, we investigated 15 patients with A-T from 2 to 16 years. Our investigation included blood and CSF tests, clinical neurological examination, A-T score, and MRI findings. The albumin ratio (AR) was analyzed to determine the blood-brain-barrier function. In addition, inflammatory cytokines (IL-1α, IL-6, IL-8, IL-12 p40, IL-17A, IFN-γ, TNF-α) were measured by the multiplex cytometric bead array. We compared the results with those from an age-matched control group. Three of the A-T patients were analyzed separately (one after resection of a cerebral meningioma, one after radiation and chemotherapy due to leukemia, one after stem cell transplantation). Patient had significantly more moderate and severe side effects due to CSF puncture (vomiting, headache, need for anti-emetic drugs) compared with healthy controls. Total protein, albumin, and the AR increased with age indicating a disturbed blood barrier function in older children. There were no differences for cytokines in serum and CSF with the exception of IL-2, which was significantly higher in controls in serum. The AR is significantly altered in A-T patients, but low-grade inflammation is not detectable in serum and CSF.

Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy. We attempted to go beyond previous work, mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase. Thus, we now used aged Parkin-knockout (KO) mouse brain for a global quantification of ubiquitylated peptides by mass spectrometry (MS). This approach confirmed the most abundant substrate to be VDAC3, a mitochondrial outer membrane porin that modulates calcium flux, while uncovering also >3-fold dysregulations for neuron-specific factors. Ubiquitylation decreases were prominent for Hippocalcin (HPCA), Calmodulin (CALM1/CALML3), Pyruvate Kinase (PKM2), sodium/potassium-transporting ATPases (ATP1A1/2/3/4), the Rab27A-GTPase activating protein alpha (TBC1D10A) and an ubiquitin ligase adapter (DDB1), while strong increases occurred for calcium transporter ATP2C1 and G-protein subunits G(i)/G(o)/G(Tr). Quantitative immunoblots validated elevated abundance for the electrogenic pump ATP1A2, for HPCA as neuron-specific calcium sensor, which stimulates guanylate cyclases and modifies axonal slow afterhyperpolarization (sAHP), and for the calcium-sensing G-protein GNA11. We assessed if compensatory molecular regulations become insufficient over time, leading to functional deficits. Patch clamp experiments in acute Parkin-KO brain slices indeed revealed alterations of the electrophysiological properties in aged noradrenergic locus coeruleus (LC) neurons. LC neurons of aged Parkin-KO brain showed an acceleration of the spontaneous pacemaker frequency, a reduction in sAHP and shortening of action potential duration, without modulation of KCNQ potassium currents. These findings indicate altered calcium-dependent excitability in a PARK2 model of PD, mediated by diminished turnover of potential Parkin targets such as ATP1A2 and HPCA. The data also identified further novel Parkin substrate candidates like SIRT2, OTUD7B and CUL5. Our elucidation of neuron-specific mechanisms of PD pathogenesis helps to explain the known exceptional susceptibility of noradrenergic and dopaminergic projections to alterations of calcium homeostasis and its mitochondrial buffering.

Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in Spinocerebellar ataxia type 2.

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the unstable expansion of a cytosine-adenine-guanine (CAG)/cytosine-adenine-adenine (CAA) repeat in the ATXN2 gene, which normally encodes 22 glutamines (Q22). A large study was conducted to characterize the CAG/CAA repeat intergenerational instability in SCA2 families. Large normal alleles (Q24-31) were significantly more unstable upon maternal transmissions. In contrast, expanded alleles (Q32-750) were significantly more unstable during paternal transmissions, in correlation with repeat length. Significant correlations were found between the instability and the age at conception in paternal transmissions. In conclusion, intergenerational instability at ATXN2 locus is influenced by the sex, repeat length and age at conception of the transmitting parent. These results have profound implications for genetic counseling services.

Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2 (-/-)) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2 (-/-) mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.

A Genetic Mouse Model of Parkinson's Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine.

Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (L-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD.

Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2).

AIMS: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.

Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3).

The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.

Restriction of trophic factors and nutrients induces PARKIN expression.

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder and manifests at old age. While many details of its pathogenesis remain to be elucidated, in particular the protein and mitochondrial quality control during stress responses have been implicated in monogenic PD variants. Especially the mitochondrial kinase PINK1 and the ubiquitin ligase PARKIN are known to cooperate in autophagy after mitochondrial damage. As autophagy is also induced by loss of trophic signaling and PINK1 gene expression is modulated after deprivation of cytokines, we analyzed to what extent trophic signals and starvation stress regulate PINK1 and PARKIN expression. Time course experiments with serum deprivation and nutrient starvation of human SH-SY5Y neuroblastoma cells and primary mouse neurons demonstrated phasic induction of PINK1 transcript up to twofold and PARKIN transcript levels up to sixfold. The corresponding threefold starvation induction of PARKIN protein was limited by its translocation to lysosomes. Analysis of primary mouse cells from PINK1-knockout mice indicated that PARKIN induction and lysosomal translocation occurred independent of PINK1. Suppression of the PI3K-Akt-mTOR signaling by pharmacological agents modulated PARKIN expression accordingly. In conclusion, this expression survey demonstrates that PARKIN and PINK1 are coregulated during starvation and suggest a role of both PD genes in response to trophic signals and starvation stress.

Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.

OBJECTIVE: Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as paroxysmal choreoathetosis/spasticity (DYT9) and linked close to but not including the SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1 defects. METHODS: The German/Dutch family and an Australian monozygotic twin pair were clinically (re-)investigated, and 139 index cases with dominant or sporadic HSP in which relevant dominant genes were partially excluded were identified from databanks. SLC2A1 was sequenced in all cases in this observational study and the functional effects of identified sequence variations were tested in glucose uptake and protein expression assays. RESULTS: We identified causative mutations in SLC2A1 in both families, which were absent in 400 control chromosomes, cosegregated with the affection status, and decreased glucose uptake in functional assays. In the 139 index patients with HSP without paroxysmal dyskinesias, we only identified one sequence variation, which, however, neither decreased glucose uptake nor altered protein expression. CONCLUSIONS: This study shows that DYT9 and DYT18 are allelic disorders and enlarges the spectrum of GLUT1 phenotypes, now also including slowly progressive spastic paraparesis combined with PED. SLC2A1 mutations were excluded as a cause of HSP without PED in our cohort.

Enhanced vulnerability of PARK6 patient skin fibroblasts to apoptosis induced by proteasomal stress.

Proteasomal dysfunction and apoptosis are major hallmarks in the pathophysiology of Parkinson's disease (PD). PARK6 which is caused by mutations in the mitochondrial protein kinase PINK1 is a rare autosomal-recessively inherited disorder mimicking the clinical picture of PD. To investigate the cytoprotective physiological function of PINK1, we used primary fibroblasts from three patients homozygous for G309D-PINK1 as well as SHEP neuroblastoma cells stably overexpressing GFP-tagged wild type (wt) PINK1. Here we demonstrate that overexpression of wt PINK1 inhibits activation of Bax and release of cytochrome c, thereby diminishing caspase 9 processing and effector caspase activity after induction of proteasomal stress with the proteasome inhibitor (PI) MG132 in SHEP cells. Conversely, effector caspase activation induced by PIs, but not by the unrelated apoptotic stimulus staurosporine was potently enhanced in primary fibroblasts from homozygous PARK6 patients in comparison to those of heterozygous carriers or unaffected siblings. SHEP cells overexpressing wt PINK1 showed an elevated expression of the cytoprotective gene parkin, whereas PARK6 fibroblasts displayed significantly decreased expression of parkin in comparison to wild type control cells. Interestingly, overexpressed GFP-PINK1 was exclusively localized in the mitochondria of SHEP cells, but was redistributed to the cytoplasm under conditions of proteasomal stress. Our data indicate that PINK1 plays an important and specific physiological role in protecting cells from proteasomal stress, and suggest that PINK1 might exert its cytoprotective effects upstream of mitochondria engagement.

Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis.

Previous studies have investigated the close association that exists between CAG repeat number and the age at onset in SCA2 = spinocerebellar ataxia type 2. These studies have focused on affected individuals. To further characterize this association and estimate the risk of a carrier developing SCA2 at a particular age as a function of a specific CAG repeat size, we have analyzed a large group of 924 individuals, including 394 presymptomatic and 530 affected individuals with a CAG repeat length of 32-79 units. Using a Kaplan-Meier survival analysis, we obtained cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34-45 range. These curves were significantly different (p < 0.001) and showed small overlap. All these information may be very valuable in predictive-testing programs, in the planning of studies for the identification of other genetic and environmental factors as modifiers of age at onset, and in the design of clinical trials for people at enlarged risk for SCA2.

Alpha-synuclein deficiency affects brain Foxp1 expression and ultrasonic vocalization.

Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected.

Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2.

OBJECTIVE: A characteristic feature of spinocerebellar ataxia type 2 (SCA2) is saccadic slowing at early disease stages. We sought to determine whether this sign is detectable before clinical manifestation and quantifies the disease progression throughout life in linear fashion. METHODS: In a specialized ataxia clinic, 54 presymptomatic carriers of SCA2 polyglutamine expansions and 56 relatives without mutation were documented with regard to their maximal saccade velocity (MSV). RESULTS: Among the control individuals, a significant effect of aging on MSV was observed. After elimination of this age influence through a matched-pair approach, a presymptomatic decrease of MSV could be shown. The MSV reduction was stronger in carriers of large expansions. In the years before calculated disease manifestation, the MSV impairment advanced insidiously. CONCLUSION: Saccade velocity is a sensitive SCA2 endophenotype that reflects early pontine degeneration and may be a useful diagnostic parameter before the onset of ataxia. SIGNIFICANCE: Future neuroprotective therapies of polyglutamine neurodegeneration may be assessed by MSV from earliest to prefinal disease stages.

Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy.

INTRODUCTION: Autosomal dominant optic atrophy (ADOA) is considered as the most common form of hereditary optic neuropathy. Although genetic linkage studies point to the OPA1 locus on chromosome 3q28-q29 as by far the most common gene locus, previous screening studies-based on sequencing of the coding exons-detected OPA1 mutations in only 32-70% of ADOA patients. We therefore hypothesised that larger deletions or duplications that remained undetected in previous screening approaches may substantially contribute to the prevalence of OPA1 mutations in ADOA. METHODS: 42 independent ADOA patients were analysed for the presence of genomic rearrangements in OPA1 by means of multiplex ligation probe amplification (MLPA). Deletions or duplications were confirmed either by long distance polymerase chain reaction (PCR) and breakpoint sequencing or loss of heterozygosity analyses with flanking microsatellite markers. Patients underwent ophthalmological examination including visual acuity, colour vision testings, perimetry and funduscopy. RESULTS: We identified genomic rearrangements in 8 of 42 patients, including single exon deletions of exon 9 and exon 24, respectively, a deletion of exons 1-5, two different deletions of the complete OPA1 gene as well as a duplication of the exons 7-9, with the latter being present in three unrelated families. Patients' phenotypes were highly variable, similar to patients with point mutation in OPA1. DISCUSSION: Our findings show that gross genomic aberrations at the OPA1 gene locus are frequent in ADOA and substantially contribute to the spectrum and prevalence of OPA1 mutations in ADOA patients. They further strengthen the hypothesis that haploinsufficiency is a major pathomechanism in OPA1 associated ADOA.

Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7).

AIMS: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7. METHODS: We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients. RESULTS: Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients. CONCLUSIONS: The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients.

Sleep quality in a family with hereditary parkinsonism (PARK6).

OBJECTIVES: The autosomal recessive disorder PARK6 manifests as early-onset Parkinson's disease (PD) with a particularly mild progression. PARK6 is of particular scientific interest, since it is caused by loss-of-function mutations in the mitochondrial protein kinase PINK1 and may thus serve as a model for oxidative damage in PD and in other basal ganglia disorders. Sleep disturbances are very common in PD but have not yet been reported for PARK6 patients. The present study reports on sleep of a Spanish family with PARK6. Of the 5 siblings, 3 were homozygous and severely affected, and 2 were heterozygous and clinically asymptomatic. Research questions concerned possible differences in sleep recordings between homozygote and heterozygote siblings and similarities between PARK6 and sporadic PD sleep profiles. METHOD: The data from detailed clinical interviews of the patients and their bedpartners are reported and compared with polysomnographic data from second-night recordings. CONCLUSIONS: All siblings had good subjective and objective sleep quality. Restless legs syndrome and rapid eye movement (REM) sleep behaviour disorder (RBD) were not observed, suggesting that sleep disturbances are not commonly found in PARK6 patients. Good sleep quality and the absence of RBD might be a useful diagnostic guide in the differential diagnosis of sporadic PD versus PARK6.

Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia.

BACKGROUND: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. METHODS: We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had MR-1 mutations and 6 did not. RESULTS: Patients with PNKD with MR-1 mutations had their attack onset in youth (infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. CONCLUSIONS: Paroxysmal nonkinesigenic dyskinesia (PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation (which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 (MR-1) gene mutations. Other "PNKD-like" families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia.