DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

Exploring Parkinson's disease prevalence in regional, rural and remote Australia: A systematic scoping review.

INTRODUCTION: Idiopathic Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Due to ageing populations, prevalence estimates for PD are set to increase in western countries including Australia. OBJECTIVE: This study aims to investigate the prevalence of PD in regional, rural and remote areas of Australia, to inform the provision of equitable PD-specific care. DESIGN: A scoping review, following the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), was conducted. An electronic search of four databases and the search engine google scholar was completed in May 2022 and updated in September 2023. Article screening and quality appraisal were undertaken independently by at least two reviewers. FINDINGS: Of 514 records screened, six articles (between 1966 and 2019) were identified and included for review. Wide variations in PD prevalence were evident, ranging from 0.58 to 8.5 per 1000 people. Two studies suggested prevalence may be higher in regional, rural and remote areas of Australia than in urban localities. DISCUSSION: The limited number of studies identified, and wide variation in prevalence rates makes it difficult to draw firm conclusions to inform heath care planning and resource allocation. CONCLUSION: A paucity of reliable prevalence data indicates the need for well-designed, country-specific epidemiological studies to be conducted to estimate the actual impacts of the disease to inform public health planning, particularly in regional, rural and remote areas where access to PD-specific care is already inequitable.

A single centre prospective study of three device-assisted therapies for Parkinson's disease.

Comparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson's disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.

Possible EIF2AK2-Associated Stress-Related Neurological Decompensation with Combined Dystonia and Striatal Lesions.

BACKGROUND: Variants in EIF2AK2 have been recently associated with a spectrum of neurological disease encompassing isolated dystonia to fever-related neurological decompensation, movement disorders and leukodystrophy. CASE: A 32-year old patient presented with childhood-onset episodes of neurological decompensation after febrile illness, progressive anarthria, dystonia and spasticity. The T2/FLAIR MRI showed bilateral posterolateral putamen hyperintensities and white matter changes suggestive of leukodystrophy. Initial extensive metabolic workup and whole genome sequencing (WGS) was unremarkable. Re-analysis of the WGS data revealed a variant in exon 3 of the EIF2AK2 gene [(NM_001135651.3): c.92C > G (p.Pro31Arg)]. EIF2AK2-associated disorders should be incorporated into the differential diagnosis of the syndrome of fever-related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging. LITERATURE REVIEW: Disease-causing variants in EIF2AK2 have been reported in 24 individuals from 16 families in the literature to date. Two broad phenotypes have been described, including: (1) childhood-onset generalized dystonia and a normal brain MRI; and (2) early childhood-onset developmental delay combined with movement disorders, spasticity, and seizures in some. Notably, 92% of these patients have neurological deterioration after febrile illness or other physiological stress. Hypomyelination or delayed myelination and thin corpus callosum are seen in most patients and lower medullary lessions are common. Basal ganglia lesions have been reported previously in one case. CONCLUSIONS: EIF2AK2-associated disorders should be incorporated into the differential diagnosis of the syndrome of fever-related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging.

Parkinsonism and dystonia: Clinical spectrum and diagnostic clues.

The links between the two archetypical basal ganglia disorders, dystonia and parkinsonism, are manifold and stem from clinical observations, imaging studies, animal models and genetics. The combination of both, i.e. the syndrome of dystonia-parkinsonism, is not uncommonly seen in movement disorders clinics and has a myriad of different underlying aetiologies, upon which treatment and prognosis depend. Based on a comprehensive literature review, we delineate the clinical spectrum of disorders presenting with dystonia-parkinsonism. The clinical approach depends primarily on the age at onset, associated neurological or systemic symptoms and neuroimaging. The tempo of disease progression, and the response to L-dopa are further important clues to tailor diagnostic approaches that may encompass dopamine transporter imaging, CSF analysis and, last but not least, genetic testing. Later in life, sporadic neurodegenerative conditions are the most frequent cause, but the younger the patient, the more likely the cause is unravelled by the recent advances of molecular genetics that are focus of this review. Here, knowledge of the associated phenotypic spectrum is key to guide genetic testing and interpretation of test results. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

The initial diagnosis and management of Parkinson's disease.

BACKGROUND: Parkinson's disease is a common, progressive neurodegenerative disorder, the prevalence of which is on the rise. The diagnosis and management of Parkinson's disease is therefore likely to become increasingly frequent in general practice. OBJECTIVE: The aim of this article is to provide a practical overview for the general practitioner of the initial diagnosis and management of Parkinson's disease. DISCUSSION: Parkinson's disease is a multisystem disorder, and the way the diagnosis is delivered, as well as the early management, can have a lasting impact on the patient experience. In this article, the authors present their preferred approach to diagnosis and initial treatment, while highlighting common pitfalls and some useful simple strategies for communicating the diagnosis.

Levodopa/dopa decarboxylase inhibitor associated microscopic colitis: An under-recognized drug reaction.

BACKGROUND: Microscopic colitis is a form of inflammatory bowel disease characterized by profuse non-bloody watery diarrhea. Macroscopic abnormality is not present on colonoscopy, and it requires biopsy for diagnosis. Few cases have been attributed to levodopa/dopa-decarboxylase inhibitor therapy. METHOD: A retrospective cohort study of 21 patients on levodopa/benserazide and one patient on levodopa-carbidopa intestinal gel with clinically suspected or biopsy proven microscopic colitis. RESULTS: All 21 patients on oral levodopa/benserazide had resolution of diarrhea with cessation of the medication. Four patients discontinued levodopa permanently. Two were rechallenged with levodopa/benserazide without symptom recurrence. One patient on oral levodopa/carbidopa developed diarrhea only with intermittent dispersible levodopa/benserazide. 14 were switched to levodopa/carbidopa with resolution of diarrhea in 9 but symptom recurrence in 5. One patient on oral levodopa/benserazide developed profuse diarrhea when switched to levodopa-carbidopa intestinal gel. Of 7/22 patients who had colonoscopy and biopsy, 5 had histopathological proven microscopic colitis. CONCLUSION: levodopa/dopa-decarboxylase inhibitor induced microscopic colitis may be more common than previously suspected, with the potential to affect treatment compliance and therapeutic options.

Rest tremor correlates with reduced contralateral striatal dopamine transporter binding in Parkinson's disease.

INTRODUCTION: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor. METHODS: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI). RESULTS: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions. CONCLUSION: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.

The Head Retraction Reflex in Niemann-Pick Type C: A Novel Diagnostic Clue.

BACKGROUND: The head retraction reflex (HRR) is characterized by the extension of the neck after percussion stimulation of the central facial region. It is either absent or habituates in normal individuals and can become exaggerated and persistent in certain pathological conditions, having been most commonly reported in hyperekplexia and stiff-person syndrome disorders. It has not, however, been reported in Niemann-Pick type C (NPC), a lipid storage disorder with a variety of neurologic and systemic manifestations. The diagnosis of NPC is often delayed because of the rarity of the condition and the subtlety of clinical signs. CASES: We present 3 consecutive cases of genetically confirmed NPC with a pathological HRR, which was not present in controls. Neurophysiological analysis showed findings suggestive of myoclonus of brainstem origin. CONCLUSION: We propose that the presence of a pathological HRR, an easily performed clinical test, may provide a clue to the diagnosis of NPC.