SPG10 is a rare cause of spastic paraplegia in European families

Background: SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date.Objective: To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype.Patients and methods: 80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families.Results: Three novel KIF5A mutations were detected in German families, including one missense mutation (c.759G>T, p.K253N), one in frame deletion (c.768_770delCAA, p.N256del) and one splice site mutation (c.217G>A). Onset of gait disturbance varied from infancy to 30 years of age. All patients presented clinically with pure HSP, but a subclinical sensory--motor neuropathy was detected by neurophysiology studies.Conclusions: SPG10 accounts for approximately 3% of European autosomal dominant HSP families. All mutations affect the motor domain of kinesin and thus most likely impair axonal transport. Clinically, SPG10 is characterised by spastic paraplegia with mostly subclinical peripheral neuropathy

Induced pluripotent stem cells (iPSCs) derived from cerebrotendinous xanthomatosis (CTX) patient's fibroblasts carrying a R395S mutation

AbstractInduced pluripotent stem cells (iPSCs) were generated from dermal fibroblasts from a 60-year-old cerebrotendinous xanthomatosis (CTX) patient, carrying a homozygous mutation c. [1183C>A]; p. R395S in CYP27A1. Episomal plasmids encoding the pluripotency genes OCT4, SOX2, KLF4, L-MYC and LIN28 were introduced via electroporation. The generated line iPS-CTX-R395S has no sign of plasmid integration or chromosomal aberration and retained the mutation site in CYP27A1. Furthermore, iPSCs express pluripotency markers and are able to differentiate in all germ layers in vitro. The generated line may be a useful tool for disease modelling of CTX

Generation of the CRISPR/Cas9-mediated KIF1C knock-out human iPSC line HIHRSi003-A-1

Bi-allelic loss-of-function mutations in the gene encoding the motor protein KIF1C are associated with Hereditary Spastic Paraplegia (HSP) type SPG58, a slowly progressive neurodegenerative motoneuron disease. The biological role of KIF1C is incompletely understood. We used a protein-based CRISPR/Cas9 genome editing approach to generate a homozygous KIF1C knock-out iPSC line (HIHRSi003-A-1) from a healthy control. This iPSC-KIF1C$^{-/-}$ line and the corresponding isogenic control are a useful model to study the physiological function of KIF1C and the pathophysiological consequences of KIF1C dysfunction in human disease

Hereditary spastic paraplegia Type 4 (SPG4): Disease pattern, disease progression and prognostic factors

Hereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by a progressive spastic gait disorder and caused by variants in a wide variety of genes. The most common subtype is Spastic paraplegia 4 (SPG4). We performed a longitudinal natural history study in a large cohort of 276 patients with genetically proven SPG4 to 1) describe the phenotypic spectrum and frequency of complicating symptoms, 2) assess variability in age of onset, 3) calculate time to dependency on walking aids, 4) provide prospective data on disease progression using the Spastic Paraplegia Rating Scale (SPRS), and 5) determine potential disease modifying factors. Patients were recruited via HSP outpatient clinics of the German Center for Neurodegenerative Diseases (DZNE) as well as the BMBF-funded GeNeMove network. Longitudinal data available in the HSP Registry, including detailed demographic, phenotypic and mutation data as well as the SPRS were analyzed. Average self-reported disease onset in SPG4 is at 31.6 years; in addition to a spastic gait pattern, lower limb spasticity, lower limb weakness, contractures, neurogenic bladder disorder and impairment of vibration sense were the most frequently observed features. Pyramidal motor affection of the upper limbs was observed in half of our cohort. Loss of independent walking is perceived as a negative milestone by many HSP patients. Half of our cohort regularly used a walking aid at baseline (average loss of independent walking ability at 47.4 years). 20% were wheelchair dependent (median age of onset 48.4 years). Hereby, missense variant carriers used a wheelchair at a significantly younger age than carriers of truncating SPAST variants (38.5 vs 50.3 years). Additionally, disease duration until walking aid and wheelchair dependency was influenced by the age of onset. In early onset SPG4 (40 years; 13/25 years). We used longitudinal SPRS follow-up examinations and linear mixed models to determine the disease progression. SPG4 progresses with an average progression rate of 1 point in SPRS total score per year. Age of disease onset significantly determined disease progression with slower progression in early onset cases. In conclusion we here establish progression rates of SPG4 using both patient-centered outcomes (walking aid/wheelchair use) as well as the clinician-reported SPRS. Age of onset significantly influences disease progression and therefore needs to be considered in clinical trials. Based on our results trial sample sizes and trial duration can be determined that are required to demonstrate effectiveness of new therapies in clinical trials.Hereditäre Spastische Paraplegien (HSP) sind eine Gruppe von seltenen neurodegenerativen Erkrankungen, die durch eine fortschreitende spastische Gangstörung gekennzeichnet sind. Mutationen in über 80 verschiedenen Genen können zu einer HSP führen. Der häufigste genetische Subtyp ist die Spastische Paraplegie Typ 4 (SPG4). Wir haben eine longitudinale Verlaufsstudie an einer großen Kohorte von 276 Patienten mit genetisch gesicherter SPG4 durchgeführt, um 1) das phänotypische Spektrum und die Häufigkeit komplizierender Zusatzsymptome zu beschreiben, 2) die Variabilität des Erkrankungsalters zu untersuchen, 3) die Zeit bis zum Verlust der freien Gehfähigkeit zu bestimmen, 4) prospektive Daten zum Krankheitsverlauf zu liefern und 5) mögliche krankheitsmodifizierende Faktoren zu identifizieren. Die Patienten wurden aus HSP-Spezialambulanzen des Deutschen Zentrums für Neurodegenerative Erkrankungen (DZNE) sowie des BMBF-geförderten GeNeMove-Netzwerkes rekrutiert. Wir analysieren statistisch die Längsschnittdaten von Untersuchungen auf Grundlage der Spastic paraplegia rating scale (SPRS). Der durchschnittliche Erkrankungsbeginn liegt bei 31,6 Jahren. Neben der spastischen Gangstörung sind Spastik und Schwäche der unteren Extremitäten, Kontrakturen, neurogene Blasenstörungen und Beeinträchtigung des Vibrationsempfindens häufige Symptome. Wir fanden in der Hälfte unserer Kohorte Anzeichen für eine motorische Beeinträchtigung auch der oberen Extremität. Ein Meilenstein der Beeinträchtigung bei SPG4 ist der Verlust der freien Gehfähigkeit. Die Hälfte unserer Kohorte war angewiesen auf Gehhilfen (Beginn durchschnittlich mit 47,4 Jahren). 20% waren auf einen Rollstuhl angewiesen (Beginn durchschnittlich mit 48,4 Jahren); Träger von Missensmutationen nutzten einen Rollstuhl hierbei in signifikant jüngerem Alter als Träger trunkierender Mutationen (38,5 vs. 50,3 Jahre). Des Weiteren trat der Verlust der freien Gehfähigkeit und die Rollstuhlabhängigkeit bei früh einsetzender SPG4 (40 Jahre; 13/25 Jahre). Wir setzen longitudinale SPRS-Verlaufsuntersuchungen und lineare gemischte Modelle ein, um die Erkrankungsprogression zu bestimmen. Die SPG4 nimmt hierbei um durchschnittlich einen Punkt auf der SPRS-Skala pro Jahr zu. Das Erkrankungsalter bestimmt signifikant die Krankheitsprogression mit einer langsameren Progressionsrate bei früh-beginnender SPG4. Zusammenfassend berichten wir hier die Progressionsrate der SPG4 unter Verwendung Patienten-zentrierter Outcomes (Abhängigkeit von Gehhilfe/Rollstuhl) und sog. „clinician-reported“ Outcomes (SPRS). Das Alter bei Erkrankungsbeginn beeinflusst signifikant die Erkrankungsprogression und muss daher bei der Planung klinischer Studien berücksichtigt werden. Basierend auf unseren Ergebnissen sind Kalkulation von Fallzahlen sowie Studiendauer für künftige Therapiestudien möglich

Real-time use of audio-biofeedback can improve postural sway in patients with degenerative ataxia

Abstract Objective Cerebellar ataxia essentially includes deficient postural control. It remains unclear whether augmented sensory information might help cerebellar patients, as the cerebellum underlies processing of various sensory modalities for postural control. Here, we hypothesized that patients with cerebellar degeneration can still exploit audio‐biofeedback (ABF) of trunk acceleration as a real‐time assistive signal to compensate for deficient postural control. Methods Effects on postural sway during stance were assessed in an ABF intervention group versus a no‐ABF disease control group (23 vs. 17 cerebellar patients) in a clinico‐experimental study. A single‐session ABF paradigm of standing plus short exergaming under ABF was applied. Postural sway with eyes open and eyes closed was quantified prior to ABF, under ABF, and post ABF. Results Postural sway in the eyes closed condition was significantly reduced under ABF. Both benefit of ABF and benefit of vision correlated with the extent of postural sway at baseline, and both types of sensory benefits correlated with each other. Patients with strongest postural sway exhibited reduced postural sway also with eyes open, thus benefitting from both vision and ABF. No changes were observed in the no‐ABF control group. Interpretation Our findings provide proof‐of‐principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors

ADHD candidate gene (DRD4 exon III) affects inhibitory control in a healthy sample

<p>Background</p> <p>Dopamine is believed to be a key neurotransmitter in the development of attention-deficit/hyperactivity disorder (ADHD). Several recent studies point to an association of the dopamine D4 receptor (DRD4) gene and this condition. More specifically, the 7 repeat variant of a variable number of tandem repeats (VNTR) polymorphism in exon III of this gene is suggested to bear a higher risk for ADHD. In the present study, we investigated the role of this polymorphism in the modulation of neurophysiological correlates of response inhibition (Go/Nogo task) in a healthy, high-functioning sample.</p> <p>Results</p> <p>Homozygous 7 repeat carriers showed a tendency for more accurate behavior in the Go/Nogo task compared to homozygous 4 repeat carriers. Moreover, 7 repeat carriers presented an increased nogo-related theta band response together with a reduced go-related beta decrease.</p> <p>Conclusions</p> <p>These data point to improved cognitive functions and prefrontal control in the 7 repeat carriers, probably due to the D4 receptor's modulatory role in prefrontal areas. The results are discussed with respect to previous behavioral data on this polymorphism and animal studies on the impact of the D4 receptor on cognitive functions.</p

Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials