The Use of the Voice Trainer App for Vocal Control in People with a Degenerative Ataxia: A Pilot Intervention Study.

Dysarthria is disabling in persons with degenerative ataxia. There is limited evidence for speech therapy interventions. In this pilot study, we used the Voice trainer app, which was originally developed for patients with Parkinson's disease, as a feedback tool for vocal control. We hypothesized that patients with ataxic dysarthria would benefit from the Voice trainer app to better control their loudness and pitch, resulting in a lower speaking rate and better intelligibility. This intervention study consisted of five therapy sessions of 30 min within 3 weeks using the principles of the Pitch Limiting Voice Treatment. Patients received real-time visual feedback on loudness and pitch during the exercises. Besides, they were encouraged to practice at home or to use the Voice trainer in daily life. We used observer-rated and patient-rated outcome measures. The primary outcome measure was intelligibility, as measured by the Dutch sentence intelligibility test. Twenty-one out of 25 included patients with degenerative ataxia completed the therapy. We found no statistically significant improvements in intelligibility (p = .56). However, after the intervention, patients were speaking slower (p = .03) and the pause durations were longer (p < .001). The patients were satisfied about using the app. At the group level, we found no evidence for an effect of the Voice trainer app on intelligibility in degenerative ataxia. Because of the heterogeneity of ataxic dysarthria, a more tailor-made rather than generic intervention seems warranted.

Management of rare movement disorders in Europe: outcome of surveys of the European Reference Network for Rare Neurological Diseases.

BACKGROUND AND PURPOSE: The diagnosis of rare movement disorders is difficult and specific management programmes are not well defined. Thus, in order to capture and assess care needs, the European Reference Network for Rare Neurological Diseases has performed an explorative care need survey across all European Union (EU) countries. METHODS: This is a multicentre, cross-sectional study. A survey about the management of different rare movement disorders (group 1, dystonia, paroxysmal dyskinesia and neurodegeneration with brain iron accumulation; group 2, ataxias and hereditary spastic paraparesis; group 3, atypical parkinsonism; group 4, choreas) was sent to an expert in each group of disorders from each EU country. RESULTS: Some EU countries claimed for an increase of teaching courses. Genetic testing was not readily available in a significant number of countries. Regarding management, patients' accessibility to tertiary hospitals, to experts and to multidisciplinary teams was unequal between countries and groups of diseases. The availability of therapeutic options, such as botulinum toxin or more invasive treatments like deep brain stimulation, was limited in some countries. CONCLUSIONS: The management of these conditions in EU countries is unequal. The survey provides evidence that a European care-focused network that is able to address the unmet rare neurological disease care needs and inequalities is highly warranted.

The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

The wrong end of the telescope: neuromuscular mimics of movement disorders (and vice versa).

The rapid advances in modern neurology have led to increased specialisation in clinical practice. Being an expert in a neurology subspecialty offers advantages for diagnosing and managing specific disorders. However, specialisation also risks tunnel vision: interpreting symptoms and signs within one's own framework of reference, while ignoring differential diagnostic options from other subspecialties. This is particularly relevant when the patient's presentation potentially belongs to different neurological subspecialties. We illustrate this challenge by highlighting a series of clinical features that partially overlap between two common subspecialties: movement disorders and neuromuscular disorders. An overlap in clinical presentation is not rare, and includes, for example, involuntary eyelid closure (which could be active eye closure due to blepharospasm, or ptosis due to weakness). Other overlapping features include abnormal postures, involuntary movements and gait changes. We describe two of these overlapping features in more detail and emphasise the possible consequences of 'looking through the wrong end of the telescope' in such patients, as this may lead to a wrong differential diagnosis, unnecessary investigations and a delayed treatment start.

A gait paradigm reveals different patterns of abnormal cerebellar motor learning in primary focal dystonias.

Accumulating evidence points to a role of the cerebellum in the pathophysiology of primary dystonia. The aim of this study was to investigate whether the abnormalities of cerebellar motor learning in primary dystonia are solely detectable in more pure forms of cerebellum-dependent associative motor learning paradigms, or whether these are also present in other motor learning paradigms that rely heavily on the cerebellum but in addition require a more widespread sensorimotor network. Twenty-six patients with various forms of focal dystonia and 10 age-matched healthy controls participated in a motor learning paradigm on a split-belt treadmill. By using reflective markers, three-dimensional kinematics were recorded using a 6-camera motion analysis system. Adaptation walking parameters were analyzed offline, comparing the different dystonia groups and healthy controls. Patients with blepharospasm and writer's cramp were significantly impaired on various adaptation walking parameters. Whereas results of cervical dystonia patients did not differ from healthy controls in terms of adaptation walking parameters, differences in parameters of normal gait were found. We have here demonstrated abnormal sensorimotor adaptation with the split-belt paradigm in patients with blepharospasm and writer's cramp. This reinforces the current concept of cerebellar dysfunction in primary dystonia, and that this extends beyond more pure forms of cerebellum-dependent associative motor learning paradigms. However, the finding of normal adaptation in cervical dystonia patients indicates that the pattern of cerebellar dysfunction may be slightly different for the various forms of primary focal dystonia, suggesting that actual cerebellar pathology may not be a primary driving force in dystonia.

The clinical utility of botulinum toxin injections targeted at the motor endplate zone in cervical dystonia.

BACKGROUND AND PURPOSE: Cervical dystonia (CD) patients usually receive repeated botulinum neurotoxin (BoNT) injections. The aims of this study were to evaluate the feasibility of motor endplate zone (MEZ) detection of relevant cervical muscles in CD patients receiving chronic BoNT treatment and to compare the treatment effect of half-dosed, endplate-targeted injections to standard BoNT injections. METHODS: In study 1, high-density surface electromyography (HD-sEMG) was recorded from the sternocleidomastoid (SCM) and splenius capitis (SC) muscles in 18 CD patients with ongoing BoNT treatment, by which the location of the MEZ was determined. In study 2, nine additional patients with rotational-type CD participated in a treatment effect study where they received either half of their regular BoNT dose through endplate-targeted injections or their normal BoNT dose through standard injections (crossover design). Dystonia severity was recorded before and 4 weeks after each treatment session (Toronto Western Spasmodic Torticollis Rating Scale severity subscore). RESULTS: In the SCM muscle the MEZ was located at the lower border of the superior third part of the muscle, and in the SC muscle at half muscle length. Endplate-targeted, half-dosed BoNT injection resulted in a similar treatment effect to injecting the full dose in the standard technique. CONCLUSIONS: Half-dosed, endplate-targeted BoNT injections lead to a similar treatment effect to the standard BoNT injection protocol. MEZ detection confronts the clinician with some technical challenges, such as the ability of accurate and technically optimal placement of the electrode grid and correct interpretation of the HD-sEMG signal.

EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.

BACKGROUND AND OBJECTIVES: The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. METHODS: This guideline is based on systematic evaluations of the relevant literature and on three consensus meetings of the task force. DIAGNOSIS: If acquired causes are ruled out, and if the disease course is rather slowly progressive, a (heredo)degenerative disease is likely. A positive family history gives much guidance. In the case of a dominant family history, first line genetic screening is recommended for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 (level B), and in Asian patients also for dentatorubral-pallidoluysian atrophy (DRPLA). In the case of recessive disease, a stepwise diagnostic work-up is recommended, including both biochemical markers and targeted genetic testing, particularly aimed at Friedreich's ataxia, ataxia telangiectasia, ataxia due to vitamin E deficiency, polymerase gamma gene (POLG gene, various mutations), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and ataxia with oculomotor apraxia (AOA) types 1 and 2. If family history is negative, we still advise to screen for the more common dominant and recessive ataxias. In addition, if onset is below 45 years we recommend the full work-up for recessive ataxias; if onset is above 45 years we recommend to screen for fragile X mental retardation 1 FMR1 premutations (good practice points). In sporadic cases with an onset after 30 years, a diagnosis of multiple system atrophy should be considered (good practice point). In particular the genetic work-up will change over the upcoming years due to the diagnostic utility of new techniques such as gene panel diagnostics based on next generation sequencing for routine work-up, or even whole exome and genome sequencing for selected cases. TREATMENT: Some of the rare recessive ataxias are treatable, but for most of the heredodegenerative ataxias treatment is purely symptomatic. Idebenone is not effective in Friedreich's ataxia (level A). Riluzole (level B) and amantadine (level C) might provide symptomatic relief, irrespective of exact etiology. Also, varenicline for SCA3 patients (level B) can be considered. There is level Class II evidence to recommend physiotherapy, and Class III data to support occupational therapy.

Cerebellum-dependent associative learning deficits in primary dystonia are normalized by rTMS and practice.

Eyeblink classical conditioning (EBCC) is a cerebellum-dependent paradigm of associative motor learning, and abnormal EBCC is a neurophysiological indicator of cerebellar dysfunction. We have previously demonstrated impaired EBCC in patients with primary dystonia, but it remains uncertain if this represents actual cerebellar pathology or reflects a functional cerebellar disruption. We examined this further by: (1) studying acquisition and retention of EBCC in a second session in eight patients with cervical dystonia (CD) who had a first session 7-10 days earlier; and (2) by investigating the potential of continuous theta burst stimulation (cTBS) over the right cerebellar hemisphere to modify a first-ever EBCC session in 11 patients with CD. EBCC data of eight healthy controls previously studied were used for additional between-group comparisons. We observed an improvement of EBCC in a second session in patients with CD, which is in contrast to patients with proven cerebellar pathology who do not show further improvement of EBCC in additional sessions. We also found that cerebellar cTBS paradoxically normalized EBCC in patients with CD, while we previously showed that it disrupts EBCC in healthy volunteers. Combined, these two experiments are in keeping with a functional and reversible disruption of the cerebellum in dystonia, a phenomenon that is probably secondary to either cerebellar compensation or to cerebellar recruitment in the abnormal sensorimotor network.

Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument.

Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter-rater reliability and another trial of 28 SCA patients to assess short-term intra-rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials.

Prospective analysis of falls in dominant ataxias.

In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence.

Autosomal recessive cerebellar ataxias: the current state of affairs.

Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, and the genetic heterogeneity often complicate the clinical management of such patients. Despite the steady increase in newly discovered ARCA genes, many patients with a putative ARCA cannot be genotyped yet, proving that more genes must be involved. This review presents an updated overview of the various ARCAs. The clinical and genetic characteristics of those forms with a known molecular genetic defect are discussed, along with the emerging insights in the underlying pathophysiological mechanisms.

Neurofilament light chain: A novel blood biomarker in patients with ataxia telangiectasia.

AIM: Neurofilament light chain (NfL) is recognized as a blood biomarker in several neurodegenerative disorders, but its possible relevance in Ataxia Telangiectasia (A-T) has not been examined. The aim of this study was to investigate the biomarker potential of blood NfL concentrations in patients with A-T. METHOD: Blood (serum/plasma) NfL concentrations were measured in a Dutch and an American cohort of patients with A-T and compared to control values. Additionally, correlations between NfL concentrations and disease phenotype (classic versus variant A-T) were studied. RESULTS: In total 40 (23 Dutch and 17 American) patients with A-T (32 patients with classic A-T and 7 patients with variant A-T) and 17 age- and gender-matched (to the American cohort) healthy controls were included in this study. Blood (serum/plasma) NfL concentrations in patients with classic A-T and age ≤ 12 years were elevated compared to age matched controls. Patients with classic A-T > 12 years also had higher blood (serum/plasma) NfL concentrations (here: compared to age-dependent reference values found in the literature). Patients with classic A-T had higher blood (serum/plasma) NfL concentrations than patients with the variant phenotype. CONCLUSION: Blood (serum/plasma) NfL concentrations are elevated in patients with classic A-T and appear to correlate with the disease phenotype (classic versus variant). Therefore, blood (serum/plasma) NfL may be a promising biomarker in A-T.

New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype.

Sandhoff disease is a lipid-storage disorder caused by a defect in ganglioside metabolism. It is caused by a lack of functional N-acetyl-beta-d-glucosaminidase A and B due to mutations in the HEXB gene. Typical, early-onset Sandhoff disease presents before 9 months of age with progressive psychomotor retardation and early death. A late-onset form of Sandhoff disease is rare, and its symptoms are heterogeneous. As drug trials that aim to intervene in the disease mechanism are emerging, the recognition and identification of Sandhoff disease patients-particularly those with atypical phenotypes-are becoming more important. The authors describe six new late-onset Sandhoff cases demonstrating cerebellar ataxia or lower motor neuron (LMN) involvement combined with, mostly subclinical, neuropathy. Two different mutations were found: IVS 12-26 G/A and c.1514G-->A. In patients with either progressive cerebellar ataxia or LMN disease in the setting of a possibly recessive disorder, Sandhoff disease should be suspected, even when the onset age is over 45 years.

Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations.

BACKGROUND: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form. OBJECTIVE: To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4). METHODS: SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed. RESULTS: 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype. CONCLUSIONS: Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.

Postural instability in cerebellar ataxia: correlations of knee, arm and trunk movements to center of mass velocity.

The aim of this study was to investigate the correlations between body segment movements and center of mass (COM) velocity during pathological balance corrections of spinocerebellar ataxia (SCA) patients compared with controls, and to relate correlations indicating instability to EMG activity differences. Eighteen SCA patients and 21 age-matched controls were tested. Upright standing was perturbed using rotations of the support surface. We recorded body motion and surface EMG. For lateral perturbations peaks in COM lateral velocity were larger in SCA patients than controls. These peaks were correlated with increased ("hypermetric") trunk roll downhill and reduced uphill knee flexion velocity. Subsequent arm abduction partially corrected the lateral instability. Early balance correcting responses in knee and paraspinal muscles showed reduced amplitudes compared with normal responses. Later responses were consistent with compensation mechanisms for the lateral instability created by the stiffened knee and pelvis. We conclude that truncal hypermetria coupled with insufficient uphill knee flexion is the primary cause of lateral instability in SCA patients. Holding the knees and pelvis more rigid possibly permits a reduction in the controlled degrees of freedom and concentration on arm abduction to improve lateral instability. For backwards perturbations excessive posterior COM velocity coincided with marked trunk hypermetric flexion forwards. We concluded that this flexion and the ensuing backwards shift of the pelvis result from rigidity which jeopardizes posterior stability. Timing considerations and the lack of confirmatory changes in amplitudes of EMG activity suggest that lateral and posterior instability in SCA is primarily a biomechanical response to pelvis and knee rigidity resulting from increased muscle background activity rather than changed evoked responses.

Neurophysiological evidence for cerebellar dysfunction in primary focal dystonia.

Recent studies have suggested that there may be functional and structural changes in the cerebellum of patients with adult onset primary focal dystonia. The aim of this study was to establish whether there is any neurophysiological indicator of abnormal cerebellar function, using the classic eyeblink conditioning paradigm. This paradigm at short intervals is dependent on the olivo-cerebellar circuit and does not require cerebral and basal ganglia structures. Eyeblink conditioning was performed by pairing an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms in 12 patients with primary focal dystonia (seven cervical dystonias, five focal hand dystonias) and eight healthy controls. Healthy controls produced more conditioned eyeblink responses than patients with focal dystonia, indicating an abnormality of associative learning in this patient population. This study provides neurophysiological evidence for functional changes in the olivo-cerebellar pathway of patients with primary focal dystonia. Further work needs to be done to determine if these changes are primary, secondary or epiphenomenal to the disease.

Excessive short-latency stretch reflexes in the calf muscles do not cause postural instability in patients with hereditary spastic paraplegia.

OBJECTIVE: To identify the role of hyperexcitable short-latency stretch reflexes (SLRs) on balance control in people with hereditary spastic paraplegia (PwHSP). METHODS: Sixteen PwHSP with triceps surae spasticity and 9 healthy control subjects were subjected to toes-up support-surface perturbations. EMG data were recorded from gastrocnemius, soleus and tibialis anterior. Furthermore, center-of-mass trajectories were recorded. RESULTS: PwHSP were less able to withstand the perturbations. Triceps surae SLRs (40-80 ms post perturbation) in PwHSP were increased compared to healthy subjects. Furthermore, a sustained triceps surae EMG activity at 220-320 ms post perturbation was observed in PwHSP, whereas control subjects demonstrated suppression of triceps surae activity. Center of mass trajectories started to diverge between PwHSP and controls only after ∼500 ms, with greater excursions being observed in the PwHSP. CONCLUSIONS: The present results confirm that balance control is impaired in PwHSP. However, the late instant of center of mass divergence argues against a direct, causative role of hyperexcitable SLRs in the triceps surae. SIGNIFICANCE: We postulate that enhanced short-latency stretch reflexes of the triceps surae do not underlie poor balance control in PwHSP. Instead, we suggest the lack of suppression of later triceps surae activity to be the main cause.

"Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia.

BACKGROUND AND PURPOSE: The "ears of the lynx" MR imaging sign has been described in case reports of hereditary spastic paraplegia with a thin corpus callosum, mostly associated with mutations in the spatacsin vesicle trafficking associated gene, causing Spastic Paraplegia type 11 (SPG11). This sign corresponds to long T1 and T2 values in the forceps minor of the corpus callosum, which appears hyperintense on FLAIR and hypointense on T1-weighted images. Our purpose was to determine the sensitivity and specificity of the ears of the lynx MR imaging sign for genetic cases compared with common potential mimics. MATERIALS AND METHODS: Four independent raters, blinded to the diagnosis, determined whether the ears of the lynx sign was present in each of a set of 204 single anonymized FLAIR and T1-weighted MR images from 34 patients with causal mutations associated with SPG11 or Spastic Paraplegia type 15 (SPG15). 34 healthy controls, and 34 patients with multiple sclerosis. RESULTS: The interrater reliability for FLAIR images was substantial (Cohen κ, 0.66-0.77). For these images, the sensitivity of the ears of the lynx sign across raters ranged from 78.8 to 97.0 and the specificity ranged from 90.9 to 100. The accuracy of the sign, measured by area under the receiver operating characteristic curve, ranged from very good (87.1) to excellent (93.9). CONCLUSIONS: The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history.

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.

[From psychiatric symptoms to paraneoplastic syndrome]. / Van psychiatrisch symptoom tot paraneoplastisch syndroom.

Two patients, a 38-year-old man and a 32-year-old woman, were admitted to a psychiatric ward. The first patient suffered from a mood disorder, personality changes and complained of several, hitherto unexplained physical symptoms. Finally the patient was diagnosed with paraneoplastic cerebellar degeneration associated with Hodgkin's disease. The second patient presented with psychosis and panic disorders, but the condition was later found to be caused by paraneoplastic limbic encephalitis due to ovarian teratomas. These cases illustrate that patients with paraneoplastic neurological syndromes may present with psychiatric symptoms which can hamper an early diagnosis.