PPP2R5D heterozygous pathogenic variant causes early-onset parkinsonism and treatment implications: A case report.

Neurodevelopmental disorders with early-onset parkinsonism have diverse genetic aetiologies and can mimic Parkinson's disease. We report the clinical evaluation and neuroimaging studies of a woman with intellectual disability and levodopa-responsive akinetic rigid parkinsonism. Whole-genome sequencing of family trio identified a de novo missense variant in PPP2R5D in the proband.

Dyspnea in Parkinson's disease: an approach to diagnosis and management.

INTRODUCTION: Dyspnea is a complex and debilitating non-motor symptom experienced by a significant proportion of PD patients which results in limitations to physical ability and a reduction in quality of life. AREAS COVERED: The authors highlight the underlying pathophysiological mechanisms that can contribute to dyspnea in PD patients, and provide the clinician with a practical working algorithm for the management of such patients. The authors further highlight important clinical red flags that should be heeded in dyspneic PD patients and discuss therapeutic strategies for managing dyspnea. EXPERT OPINION: Although awareness of dyspnea in PD is increasing, further studies of its prevalence and natural history at different stages of the disease are needed. In particular, it is important to determine whether dyspnea could be an early or prodromal disease manifestation. Although peripheral mechanisms are likely to play a major role in the pathophysiology of dyspnea, the possibility that central changes in brainstem ventilatory control may also play a part warrants further investigation.

Pregnancy outcomes amongst multiple sclerosis females with third trimester natalizumab use.

BACKGROUND: Natalizumab, a monoclonal antibody directed against alpha-4-integrin, is an efficacious treatment used in Multiple Sclerosis (MS). Use in early pregnancy is safe but information in the third trimester is limited. Ceasing natalizumab is often associated with an increased risk in MS relapse and in some instances natalizumab continuation during pregnancy may be required. However natalizumab crosses the placenta in late pregnancy and has been associated with hematological abnormalities. We present clinical and hematological outcome data of newborns from a series of MS patients who received natalizumab during their second and third pregnancy trimesters. We describe possible methods to mitigate risks to the fetus. METHODS: Retrospective chart review of 15 births from mothers receiving natalizumab throughout pregnancy. RESULTS: Thirteen mothers with third-trimester exposure to natalizumab were identified. Median age at conception was 34 years (26-40) and median disease duration was 53.5 months (11-204). The 13 mothers gave birth to 15 newborns (2 mothers each with 2 individual births), median (SD) birth weight was 2778 gs (2100 - 3790). Congenital or laboratory abnormalities were identified in 5 which included anemia (n = 2) and thrombocytopenia (n = 3). CONCLUSIONS: Complications following natalizumab administration during the second and third trimester of pregnancy occurred in 33% of newborns. However, did not result in mortality or morbidity. Dose alterations during the third trimester, pre-delivery umbilical cord sampling and IVIG administration may reduce hematological effects on newborns. Prospective studies with larger numbers of patients are required to provide further evidence regarding the safety of Natalizumab use in pregnancy.

Brainstem ventilatory dysfunction: A plausible mechanism for dyspnea in Parkinson's Disease?

Dyspnea is an under-recognized and debilitating symptom that is reported in up to 40% of patients with Parkinson's disease and may have multiple origins. Despite its frequency, it is poorly researched, and there is a general lack of understanding of the pathophysiology of dyspnea and respiratory dysfunction in PD. Consequently, a number of PD patients are labelled as having "unexplained dyspnea." Studies to date have focused mainly on evaluating ventilatory capacity and lung volumes, and little is known about the effects of the disease on the medullary and pontine ventilatory control centers within the brainstem. This is of particular relevance in view of neuropathological studies demonstrating early involvement of the dorsal medulla and other brainstem structures by the disease process. The possibility that impaired brainstem ventilatory control is a contributory mechanism for dyspnea and could be a premotor manifestation in some PD patients therefore warrants further attention. This review focuses on clinical, pathological, and experimental evidence for the involvement of brainstem respiratory centers in PD. We highlight the need for further research, particularly in PD patients with unexplained dyspnea. © 2020 International Parkinson and Movement Disorder Society.

Dimethyl fumarate-associated transient bone marrow oedema syndrome.

BACKGROUND: Dimethyl fumarate (DMF) is a commonly used and effective treatment for relapsing and remitting multiple sclerosis. Its use results in impairment of the transcription factor nuclear factor erythroid-derived 2 (E2)-related factor (Nrf2), which is involved in both immunomodulation and bone health. DMF has not previously been reported to cause bone marrow complications, though other fumarates including tenofovir have. The mechanism of fumarate-associated bone toxicity remains unclear with altered osteoblastic gene expression and function suggested. METHODS: We present a case of a 54-year-old female with relapsing remitting multiple sclerosis (RRMS) treated for 30 months with DMF who developed relapsing atraumatic lower limb bone pain. RESULTS: Serial imaging revealed multifocal areas of bone marrow oedema and trabecular fractures. The patient was diagnosed with transient bone marrow oedema syndrome. Management consisted of cessation of therapy and treatment with the pro-osteobalstic agent denosumab. CONCLUSION: In this instance of DMF-associated bone marrow oedema, cessation of DMF and treatment with denosumab resulted in symptomatic improvement. DMF therapy may potentially result in bone marrow oedema due to inhibition of common upstream signalling pathways, including the Nrf2 signalling pathway.

A World Health Organization primer.

UNLABELLED: The World Health Organization (WHO) can be considered the primary agency of the United Nations that promotes global public health. This article provides a general overview of WHO by exploring the history, current, and future practices of the organization, and by addressing its major roles and functions in the present day. BACKGROUND: Srimathy Vijayan is a fourth-year medical student at the University of East Anglia, Norwich, United Kingdom. She interned at the WHO headquarters in Geneva during the summer of 2007.