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.

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.

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.

Adult Periodic Alternating Nystagmus Masked by Involuntary Head Movements.

Acquired periodic alternating nystagmus (PAN) describes a horizontal jerk nystagmus that reverses its direction with a predictable cycle, and is thought to arise from lesions involving the brainstem and cerebellum. We report a 20-year-old patient with PAN who presented with an acute vertiginous episode and developed an involuntary head movement that initially masked the PAN. The involuntary head movements were abolished with a subtherapeutic dose of botulinum toxin to the neck muscles. We propose that the head movements initially developed as a compensatory movement to the nystagmus, to maintain visual fixation in the presence of the underlying nystagmus, and became an entrained involuntary behavior. This case highlights the importance of disambiguating psychogenic from organic pathology as this may have clinical therapeutic implications, in this case resolution of the most disabling symptom which was her head oscillations, leading to improved day-to-day function despite PAN.

A Pilot Study of Botulinum Toxin for Jerky, Position-Specific, Upper Limb Action Tremor.

BACKGROUND: We aimed to investigate the efficacy and safety of botulinum toxin (BT) injections for jerky action tremor of the upper limb. METHODS: We performed an uncontrolled, prospective study of electromyography (EMG)-guided BT injections for jerky, position-specific, upper limb action tremor. The primary outcome was clinical global impression at 3-6 weeks after baseline. RESULTS: Eight patients with jerky, position-specific action tremor involving the upper limb were consecutively recruited. After a median follow-up of 4.4 weeks (interquartile range [IQR] 3.6-6 weeks), four of them rated themselves as "improved" and two as "much improved." Five of these six subjects reported improvements in specific activities of daily living (bringing liquids to mouth, feeding, shaving, and dressing). Upper limb subscore of the Fahn-Tolosa-Marin Tremor Rating Scale (FTM) significantly decreased from 4.5 (4-6) to 3 (2-5) (p = 0.01). DISCUSSION: This pilot, prospective cohort study suggests that EMG-guided BT injections may improve jerky, position-specific, upper limb action tremor. Placebo-controlled studies evaluating larger samples of patients are warranted to confirm these findings.

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.

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.

Propriospinal myoclonus: clinical reappraisal and review of literature.

OBJECTIVE: Propriospinal myoclonus (PSM) is a rare disorder with repetitive, usually flexor arrhythmic brief jerks of the trunk, hips, and knees in a fixed pattern. It has a presumed generation in the spinal cord and diagnosis depends on characteristic features at polymyography. Recently, a historical paradigm shift took place as PSM has been reported to be a functional (or psychogenic) movement disorder (FMD) in most patients. This review aims to characterize the clinical features, etiology, electrophysiologic features, and treatment outcomes of PSM. METHODS: Re-evaluation of all published PSM cases and systematic scoring of clinical and electrophysiologic characteristics in all published cases since 1991. RESULTS: Of the 179 identified patients with PSM (55% male), the mean age at onset was 43 years (range 6-88 years). FMD was diagnosed in 104 (58%) cases. In 12 cases (26% of reported secondary cases, 7% of total cases), a structural spinal cord lesion was found. Clonazepam and botulinum toxin may be effective in reducing jerks. CONCLUSIONS: FMD is more frequent than previously assumed. Structural lesions reported to underlie PSM are scarce. Based on our clinical experience and the reviewed literature, we recommend polymyography to assess recruitment variability combined with a Bereitschaftspotential recording in all cases.

Facial tremor in dystonia.

BACKGROUND: Tremor of the upper/middle part of the face, including the perinasal region and the forehead has been very rarely described in some patients with Parkinson's disease or Essential Tremor. It has not yet been reported in patients with idiopathic dystonia. METHODS: We describe here a series of 8 patients with common forms of idiopathic focal/segmental dystonia with tremor involving the upper/middle part of the face, along with demonstrative videos and electrophysiological recordings. RESULTS: The distribution of the tremor was confined to the face in two patients, whereas in six patients tremor was also evident either in the head/lower part of the face or in their upper limbs. Electrophysiological recordings disclosed a slightly irregular tremor with a frequency at about 3-5 Hz. CONCLUSIONS: A number of patients with classical forms of dystonia can show a tremor involving the upper/middle part of the face.

Psychogenic axial myoclonus: clinical features and long-term outcome.

BACKGROUND: It has been increasingly recognized that the majority of patients with a diagnosis of idiopathic propriospinal myoclonus have either a subsequent clinical course or electrophysiological features indicating that the likely etiology is psychogenic. However, the clinical features of psychogenic axial myoclonus and the long-term outcome have not yet well characterized. PATIENTS AND METHODS: Here we describe clinical findings with representative videos and long term outcomes of 76 patients with an electrophysiologically established diagnosis of psychogenic axial myoclonus. RESULTS: Thirty-seven patients were male. Mean age at onset of symptoms was 40.1 ± 15.1 years. Thirty-two patients (42.1%) presented with isolated axial myoclonus, while 44 patients (57.9%) presented additional features, including involvement of face or limb. In all patients but six (7.9%), the axial myoclonus was in flexion. In more than one-third of patients (42.1%), jerks were multifocal, meaning that there was no clear stereotyped pattern of jerks. Comparison between groups stratified according to the clinical outcome, revealed "delay of diagnosis" as the only predictor of worse outcome. DISCUSSION: We describe here the clinical features and long-term outcome on the largest series of patients with psychogenic axial myoclonus reported in the literature. The description of our series highlights a number of clinical features, which may help neurologists to reach a correct diagnosis on clinical grounds alone. Delay in diagnosis of a psychogenic disorder has a negative effect on long-term outcome.

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.