PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240.

The long-term outcome of orthostatic tremor.

OBJECTIVES: Orthostatic tremor is a rare condition characterised by high-frequency tremor that appears on standing. Although the essential clinical features of orthostatic tremor are well established, little is known about the natural progression of the disorder. We report the long-term outcome based on the largest multicentre cohort of patients with orthostatic tremor. METHODS: Clinical information of 68 patients with clinical and electrophysiological diagnosis of orthostatic tremor and a minimum follow-up of 5 years is presented. RESULTS: There was a clear female preponderance (76.5%) with a mean age of onset at 54 years. Median follow-up was 6 years (range 5-25). On diagnosis, 86.8% of patients presented with isolated orthostatic tremor and 13.2% had additional neurological features. At follow-up, seven patients who initially had isolated orthostatic tremor later developed further neurological signs. A total 79.4% of patients reported worsening of orthostatic tremor symptoms. These patients had significantly longer symptom duration than those without reported worsening (median 15.5 vs 10.5 years, respectively; p=0.005). There was no change in orthostatic tremor frequency over time. Structural imaging was largely unremarkable and dopaminergic neuroimaging (DaTSCAN) was normal in 18/19 cases. Pharmacological treatments were disappointing. Two patients were treated surgically and showed improvement. CONCLUSIONS: Orthostatic tremor is a progressive disorder with increased disability although tremor frequency is unchanged over time. In most cases, orthostatic tremor represents an isolated syndrome. Drug treatments are unsatisfactory but surgery may hold promise.

Mental rotation and working memory in musicians' dystonia.

BACKGROUND: Mental rotation of body parts engages cortical-subcortical areas that are actually involved in the execution of a movement. Musicians' dystonia is a type of focal hand dystonia that is grouped together with writer's cramp under the rubric of "occupational dystonia", but it is unclear to which extent these two disorders share common pathophysiological mechanisms. Previous research has demonstrated patients with writer's cramp to have deficits in mental rotation of body parts. It is unknown whether patients with musicians' dystonia would display similar deficits, reinforcing the concept of shared pathophysiology. METHODS: Eight patients with musicians' dystonia and eight healthy musicians matched for age, gender and musical education, performed a number of tasks assessing mental rotation of body parts and objects as well as verbal and spatial working memories abilities. RESULTS: There were no differences between patients and healthy musicians as to accuracy and reaction times in any of the tasks. CONCLUSIONS: Patients with musicians' dystonia have intact abilities in mentally rotating body parts, suggesting that this disorder relies on a highly selective disruption of movement planning and execution that manifests only upon playing a specific instrument. We further demonstrated that mental rotation of body parts and objects engages, at least partially, different cognitive networks.

Rest and other types of tremor in adult-onset primary dystonia.

INTRODUCTION: Knowledge regarding tremor prevalence and phenomenology in patients with adult-onset primary dystonia is limited. Dystonic tremor is presumably under-reported, and we aimed to assess the prevalence and the clinical correlates of tremor in patients with adult-onset primary dystonia. METHODS: We enrolled 473 consecutive patients with different types of adult-onset primary dystonia. They were assessed for presence of head tremor and arm tremor (rest, postural and kinetic). RESULTS: A total of 262 patients (55.4%) were tremulous: 196 patients presented head tremor, 140 patients presented arm tremor and 98 of them had a combination of head and arm tremor. Of the 140 patients with arm tremor, all presented postural tremor, 103 patients (73.6%) presented also a kinetic component, whereas 57 patients (40.7%) had rest tremor. Rest tremor was unilateral/asymmetric in up to 92.9% of them. Patients with segmental and multifocal dystonia were more likely tremulous than patients with focal dystonia. Dystonic symptoms involving the neck were more frequently observed in patients with head tremor, whereas dystonic symptoms involving the arms were more frequently observed in patients with arm tremor. DISCUSSION: Here we show that tremor is a common feature of patients with adult-onset primary dystonia. It may involve different body segments, with the head being the most commonly affected site. Arm tremor is also frequent (postural>kinetic>rest), occurring in up to one-third of cases. There is a suggestion of a stronger tendency for spread of dystonic features in patients with associated tremor. Dystonic tremor is under-reported and this underscores the importance of careful clinical examination when assessing tremulous patients without overt dystonia.

The phenotypic spectrum of DYT24 due to ANO3 mutations.

Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations.

Secondary and primary dystonia: pathophysiological differences.

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

Clinical diagnosis of propriospinal myoclonus is unreliable: an electrophysiologic study.

Propriospinal myoclonus is a rare movement disorder that is hypothesized to arise from a spinal generator that transmits activity up and down the spinal cord via long propriospinal pathways. Polymyography is mandatory for the diagnosis, but the typical electrophysiological pattern described for propriospinal myoclonus has been also found in patients with psychogenic axial jerks, supported by the presence of a Bereitschaftspotential (BP; from German, "readiness potential," also called the premotor potential). We evaluated polymyographic findings in 65 patients referred to us with a clinical diagnosis of propriospinal myoclonus and also looked for the presence of the BP, as detected by jerk-locked back-averaging. At clinical reassessment by a movement disorder specialist, nearly one-half of the patients had clinical clues suggestive of a psychogenic cause of the jerks. Electrophysiological studies were carried out on all 65 patients. Polymyography findings revealed an incongruent electromyographic pattern for propriospinal myoclonus in 84.6% of patients and the presence of the BP in 86.1% of the entire cohort. When taking into account either the presence of BP and/or incongruence of polymyographic features, all patients, including the approximately 50% clinically diagnosed as organic propriospinal myoclonus by a movement disorder expert, had strong neurophysiological evidence for a psychogenic origin of their jerks. The clinical distinction of propriospinal myoclonus from psychogenic axial jerks is unreliable. This is the largest cohort of patients with axial jerks reported so far and we suggest that most of the patients with a clinical picture that clinically resembles propriospinal myoclonus are likely to be psychogenic.

Late-onset asymmetric myoclonus: an emerging syndrome.

BACKGROUND: Asymmetric cortical myoclonus is typically thought to be associated with either contralateral cortical structural lesions or degenerative disorders such as corticobasal degeneration when onset is in middle-aged or aged adults. This view has been challenged after a recent case series brought to light a syndrome of senile-onset, asymmetric cortical myoclonus not associated with any such identifiable disorders, thus, named "primary progressive myoclonus of aging." This is rare and no other reports have been published; hence, further such cases need to be highlighted. CASE REPORTS: Here, we describe 3 patients with some similarities, namely, adult-onset, asymmetric myoclonus that is most likely to be cortical, with an unremarkable thorough diagnostic workup, but with younger age at onset and longer follow-up time. CONCLUSIONS: This report expands on previous phenotypical descriptions attempting to further develop and refine this possible diagnostic entity.

Moving toward "laboratory-supported" criteria for psychogenic tremor.

A confident clinical diagnosis of psychogenic tremor is often possible, but, in some cases, a "laboratory-supported" level of certainty would aid in early positive diagnosis. Various electrophysiological tests have been suggested to identify patients with psychogenic tremor, but their diagnostic reliability has never been assessed "head to head" nor compared to forms of organic tremor other than essential tremor or PD. We compared baseline tremor characteristics (e.g., frequency and amplitude) as well as electrophysiological tests previously reported to distinguish psychogenic and organic tremor in a cohort of 13 patients with psychogenic tremor and 25 patients with organic tremor, the latter including PD, essential-, dystonic-, and neuropathic tremors. We assessed between-group differences and calculated sensitivity and specificity for each test. A number of tests, including entrainment or frequency changes with tapping, pause of tremor during contralateral ballistic movements, increase in tremor amplitude with loading, presence of coherence, and tonic coactivation at tremor onset, revealed significant differences on a group level, but there was no single test with adequate sensitivity and specificity for separating the groups (33%-77% and 84%-100%, respectively). However, a combination of electrophysiological tests was able to distinguish psychogenic and organic tremor with excellent sensitivity and specificity. A laboratory-supported level of diagnostic certainty in psychogenic tremor is likely to require a battery of electrophysiological tests to provide sufficient specificity and sensitivity. Our data suggest such a battery that, if supported in a prospective study, may form the basis of laboratory-supported criteria for the diagnosis of psychogenic tremor.

Modulatory effects of 5Hz rTMS over the primary somatosensory cortex in focal dystonia--an fMRI-TMS study.

Dystonia is associated with impaired somatosensory ability. The electrophysiological method of repetitive transcranial magnetic stimulation (rTMS) can be used for noninvasive stimulation of the human cortex and can alter cortical excitability and associated behavior. Among others, rTMS can alter/improve somatosensory discrimation abilities, as shown in healthy controls. We applied 5Hz-rTMS over the left primary somatosensory cortex (S1) in 5 patients with right-sided writer's dystonia and 5 controls. We studied rTMS effects on tactile discrimination accuracy and concomitant rTMS-induced changes in hemodynamic activity measured by functional magnetic resonance imaging (fMRI). Before rTMS, patients performed worse on the discrimination task than controls even though fMRI showed greater task-related activation bilaterally in the basal ganglia (BG). In controls, rTMS led to improved discrimination; fMRI revealed this was associated with increased activity of the stimulated S1, bilateral premotor cortex and BG. In dystonia patients, rTMS had no effect on discrimination; fMRI showed similar cortical effects to controls except for no effects in BG. Improved discrimination after rTMS in controls is linked to enhanced activation of S1 and BG. Failure of rTMS to increase BG activation in dystonia may be associated with the lack of effect on sensory discrimination in this group and may reflect impaired processing in BG-S1 connections. Alternatively, the increased BG activation seen in the baseline state without rTMS may reflect a compensatory strategy that saturates a BG contribution to this task.

Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation.

Idiopathic basal ganglia calcification (IBGC) or primary familial brain calcification is a rare genetic condition characterized by an autosomal dominant inheritance pattern and the presence of bilateral calcifications in the basal ganglia, thalami, cerebellum and cerebral subcortical white matter. The syndrome is genetically and phenotypically heterogeneous. Causal mutations have been identified in four genes: SLC20A2, PDGFRB, PDGFB and XPR1. A variety of progressive neurological and psychiatric symptoms have been described, including cognitive impairment, movement disorders, bipolar disorder, chronic headaches and migraine, and epilepsy. Here we describe a family with a novel SLC20A2 mutation mainly presenting with neurological symptoms including cortical myoclonus and epilepsy. While epilepsy, although rare, has been reported in patients with IBGC associated with SLC20A2 mutations, cortical myoclonus seems to be a new manifestation.

Tremor on smiling.

Facial tremor occurring on smiling is a rare phenomenon and has been described (to the best of our knowledge) in the literature only once. We describe two patients who presented with a bilateral facial tremor that occurred only on smiling and other activation of therisorii muscles and had a high frequency of 9 Hz. One patient additionally suffered from young-onset Parkinson's disease, whereas the other had no further neurological symptoms or signs apart from this tremor. Anti-parkinsonian medication was unhelpful for the facial tremor in the patient with Parkinson's disease. Tremor on smiling may be a discrete entity or may be associated in some cases of Parkinson's disease.

Idiopathic spinal myoclonus: a clinical and neurophysiological assessment of a movement disorder of uncertain origin.

Spinal Myoclonus (SM) is characterized by brief and sudden movements caused by the activation of muscles belonging to adjacent spinal myotomes. Recent reports have indicated that "typical" clinical and electrophysiological features of SM can be mimicked voluntarily. A useful tool that can distinguish between organic and psychogenic jerks is the detection of a Bereitschaftspotential (BP). In this study, we looked for evidence of a BP in a cohort of patients with idiopathic SM. A clinical and neurophysiological assessment of 20 patients affected by idiopathic SM was performed. A video EEG-EMG multichannel recording was performed in each patient to detect BP. An expert neurophysiologist (PB) reviewed the BP recordings and divided them into those showing a definite, possible, and no BP. A clinical assessment of the videoed movements was performed by two neurologists expert in movement disorders (KB and MJE) who indicated if the movements were compatible with organic or psychogenic myoclonus. A definite or possible BP was recorded in 15 out of 20 patients. Clinical raters agreed in their clinical opinion on 15 patients (75%). All patients where both raters agreed the movements appeared to be organic had definite or possible BP. BP are commonly seen in patients with idiopathic SM. There is discordance between clinicians in their clinical rating of SM as organic or psychogenic, but even in those patients where movements appear clinically to be organic, a BP is commonly detected, indicating that the aetiology is psychogenic. This suggests that BP recordings are a useful adjunct to clinical assessment in the accurate diagnosis of patients with idiopathic SM.

Brachial Neuritis After Botulinum Toxin Injections for Cervical Dystonia: A Need for a Reappraisal?

BACKGROUND: Brachial neuritis has previously been described as a rare occurrence in patients receiving botulinum toxin for cervical or writing/focal arm dystonia. METHODS: We report four cases of patients with a long history of cervical dystonia treated with botulinum toxin injections. RESULTS: All patients developed pain and muscular weakness around the shoulder, with EMG studies suggesting brachial neuritis. CONCLUSIONS: In the context of these observations, we discuss the question of an association between brachial neuritis and botulinum toxin treatment.

Unusual familial presentation of epsilon-sarcoglycan gene mutation with falls and writer's cramp.

Inherited myoclonus dystonia (M-D, DYT11) is an autosomal dominant dystonia-plus syndrome, which in many families is caused by mutations in the SGCE/(epsilon-sarcoglycan gene. We present a family with M-D, with an unusual presentation characterized by infantile onset with falls in two sisters and adult-onset writer's cramp in their father. Myoclonus dystonia is typically characterized by a variable mixture of alcohol-sensitive myoclonic jerks and dystonia classically affecting mainly the proximal arms and neck. Leg involvement is less frequent, and to our knowledge, initial presentation with falls has not previously been described. The unusual phenotype of the family is discussed.

Altered dorsal premotor-motor interhemispheric pathway activity in focal arm dystonia.

Given the possible role of dorsal premotor cortex (PMd) in the pathophysiology of dystonia, we used transcranial magnetic stimulation (TMS) methods to study PMd and PMd-primary motor cortex (M1) interactions in patients with focal arm dystonia. Here, we tested the connectivity between left PMd and right M1 as well as the intracortical excitability of PMd in 11 right-handed patients with focal arm/hand dystonia and nine age-matched healthy controls. The results showed that excitability of the inhibitory connection between PMd and M1 was reduced in patients, but there was no significant difference to healthy subjects in the excitability of the facilitatory connection. A triple stimulation technique in which pairs of TMS pulses are given over PMd and their interaction measured in terms of the effect on the baseline PMd-M1 connection failed to reveal the usual pattern of interaction between the pairs of PMd stimuli. Indeed, the results in patients were similar to those seen in a group of young healthy subjects after the excitability of PMd had been changed by pretreatment with high-frequency rTMS. We suggest that reduced transcallosal inhibition from the PMd may be involved in the altered pattern of abnormal muscle contractions of agonists and antagonists (overflow).