Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Targeted resequencing reveals high-level mosaicism for a novel frameshift variant in WDR45 associated with beta-propeller protein-associated neurodegeneration.

OBJECTIVES: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant neurodegenerative disease, which is characterized by iron accumulation in the basal ganglia. BPAN is associated with pathogenic variation in WDR45, which has been reported almost exclusively in females most probably due to male lethality in the hemizygous state. METHODS: Whole exome sequencing (WES) and targeted deep sequencing were performed for a male with a clinical diagnosis of BPAN at the age of 37. RESULTS: The novel frameshift variant in WDR45 detected by WES was further analyzed with targeted resequencing to detect a mosaic variant with a level of 85.5% in the blood sample of the proband. DISCUSSION: Although the main role of WDR45 remains elusive, recent studies show that WDR45 may contribute to neurodegeneration through defects in autophagy, iron storage and ferritin metabolism, mitochondria organization, and endoplasmic reticulum homeostasis. The extend of spatiotemporal haploinsufficiency of WDR45 frameshifting variants caused by mosaicism in males may lead to variable clinical severity, which may be hard to elaborate clinically. Promising genetic analysis strategies using targeted deep sequencing may help determine the clinical outcome of somatic mosaicism in neurological disorders including BPAN. Additionally, we suggest that deep sequencing should be conducted in cerebrospinal fluid samples to provide more reliable results in terms of reflecting the mosaicism level in the brain for future studies.

Intermittent Subcutaneous Injections of Apomorphine in Parkinson's Disease.

The intermittent subcutaneous injection of apomorphine is highly effective in the management of motor and non-motor symptoms of Parkinson's disease. Although it has been shown that apomorphine injection can be safely used in selected cases at all stages of the disease, there is no consensus regarding intermittent administration strategies. This review aimed to discuss the indications for intermittent subcutaneous apomorphine use in clinical practice, possible side effects and their management, and contraindicated cases in light of the literature and to present practical recommendations for clinical practice.

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

BACKGROUND: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. OBJECTIVE: To survey the accessible MD clinical training in these regions. METHODS: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. RESULTS: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. CONCLUSION: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series.

Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [18F]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

Modelling cognitive deficits in Parkinson's disease: Is CA2 a gateway for hippocampal synucleinopathy?

BACKGROUND: Cognitive dysfunction is one of the most disabling non-motor symptoms of Parkinson's disease (PD), though its pathological correlates still remain elusive. Hippocampal Lewy pathology has recently been correlated by compelling evidence from post-mortem and imaging studies. Animal models recapitulating cognitive impairment in PD are essential to better understand the underlying pathophysiology. To investigate the hippocampal involvement in cognitive dysfunction of PD, we generated an experimental model by inducing midbrain and hippocampal α-synuclein pathology simultaneously. METHODS: Rats were injected either with human α-synuclein or green fluorescent protein (GFP) expressing adeno-associated viral vectors (AAV), or saline bilaterally into substantia nigra (SN) and dentate gyrus (DG). A group of untreated animals were used as naïve controls. Cognitive and behavioral changes were evaluated with tests probing for spatial learning, short-term memory, anxiety and hedonistic behavior. Immunohistochemical staining, immunoblotting and stereological analysis were performed for pathological characterization. RESULTS: Bilateral α-synuclein overexpression in SN and DG led to mild but significant motor impairment as well as dysfunctions in short-term memory and spatial learning. There was no hedonistic deficit, whereas a hypo-anxious state was induced. While stereological analysis revealed no significant neuronal loss in any sectors of cornu ammonis, there was considerable decrease (43%) in TH+-neurons in SN pars compacta supporting the well-known vulnerability of nigral dopaminergic neurons to α-synuclein mediated neurodegeneration. On the other hand, synaptophysin levels decreased in similar amounts both in striatum and hippocampus, suggesting comparable synaptic loss in target areas. Interestingly, phosphorylated-S129-α-synuclein staining revealed significant expression in CA2 characterized by more mature and dense cellular accumulations compared to CA1-CA3 sub-regions displaying more diffuse grain-like aggregates, suggesting preferential susceptibility of CA2 to produce α-synuclein induced pathology. CONCLUSION: Bilateral α-synuclein overexpression in DG and SN reproduced partial motor and hippocampus related cognitive deficits. Using this model, we showed a predisposition of CA2 for pathological α-synuclein accumulation, which may provide further insights for future experimental and clinical studies.

Macrocytic anemia in Lesch-Nyhan disease and its variants.

PURPOSE: Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was  to describe macrocytic erythrocytes as another common aspect of the phenotype. METHODS: The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly. RESULTS: Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants. After excluding cases with iron deficiency because it might pseudonormalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia. CONCLUSION: These results establish macrocytic erythrocytes as a very common aspect of the clinical phenotype of Lesch-Nyhan disease and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process, such as iron deficiency. Because macrocytosis is uncommon in unaffected children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.

Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia.

Striatal cholinergic dysfunction is a common phenotype associated with various forms of dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this study, we used a recently developed knock-in mouse model of dopamine-responsive dystonia (DRD) with strong symptomatic responses to anti-cholinergic drugs, to assess changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs) in a model of generalized dystonia. Unbiased stereological neuronal counts and Sholl analysis were used to address these issues. To determine the potential effect of aging on the number of ChIs, both young (3 months old) and aged (15 months old) mice were used. For purpose of comparisons with ChIs, the number of GABAergic parvalbumin (PV)-immunoreactive striatal interneurons was also quantified in young mice. Overall, no significant change in the prevalence of ChIs and PV-immunoreactive cells was found throughout various functional regions of the striatum in young DRD mice. Similar results were found for ChIs in aged animals. Subtle changes in the extent and complexity of the dendritic tree of ChIs were found in middle and caudal regions of the striatum in DRD mice. Additional immunohistochemical data also suggested lack of significant change in the expression of striatal cholinergic M1 and M4 muscarinic receptors immunoreactivity in DRD mice. Thus, together with our previous data from a knock-in mouse model of DYT-1 dystonia (Song et al., 2013), our data further suggest that the dysregulation of striatal cholinergic transmission in dystonia is not associated with major neuroplastic changes in the morphology or prevalence of striatal ChIs. Highlights -There is no significant change in the number of striatal ChIs in young and aged mice model of DRD-There is no significant change in the prevalence of striatal GABAergic PV-containing interneurons in the striatum of young mice models of DRD-Subtle morphological changes in the dendritic arborization of striatal ChIs are found in the middle and caudal tiers of the striatum in young mice models of DRD-The levels of both M1 and M4 muscarinic receptors immunoreactivity are not significantly changed in the striatum of DRD mice-Major changes in the prevalence and morphology of striatal ChIs are unlikely to underlie striatal cholinergic dysfunction in DRD.

Use of anti-Parkinson medication during pregnancy: a case series.

INTRODUCTION: Experience about the use and safety of anti-Parkinson (anti-PD) medication during pregnancy is scarce. METHODS: We have retrospectively evaluated the course and outcome of pregnancy in PD patients who used anti-PD medication during their pregnancy. RESULTS: 14 PD patients who used anti-PD medication during part or whole of their pregnancy were included. Dopamine agonists were used in 13 patients, levodopa/benserazide in 4, levodopa/carbidopa/entacapone in 1, rasagiline in 7, amantadine in 4, and biperiden in 1 patient. Nine patients were on combination treatment at the time of their pregnancy. During their whole pregnancy, dopamine agonists had been used in six patients, levodopa in four, and rasagiline in one. Four patients experienced adverse outcomes: one had spontaneous abortion while receiving pramipexole, one elderly mother gave birth to a child with Down syndrome, while receiving pramipexole and rasagiline, in one case, there was fetal distress under levodopa/benserazide, piribedil, and rasagiline which resolved spontaneously, in one case, one of the twins did not survive after the birth while the mother was receiving pramipexole and rasagiline. In none of these cases an association with the use of anti-PD medication and adverse outcomes was clearly established. In one patient, motor symptoms worsened despite high dose levodopa, four others experienced transient worsening upon dose reduction. CONCLUSION: Results in our case series suggest that levodopa, rasagiline, pramipexole, and ropinirole alone or in combination with each other may be considered relatively safe during pregnancy. Expected benefits and risks should be considered when prescribing anti-PD medication in pregnant women.

A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism.

Juvenile parkinsonism can be caused by recessive mutations in several genes. Among these, homozygous or compound heterozygous mutations in the F-box only protein 7 gene (FBXO7) cause juvenile parkinsonism with variable degrees of pyramidal disturbances (PARK15). So far, only five families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported with this form. Here, we describe a new Turkish family with homozygous FBXO7 mutation (c.1492C > T, p.Arg498*). Three out of nine siblings born from consanguineous parents suffered from juvenile-onset progressive parkinsonism. Mental retardation was also documented in two of them. Of note, pyramidal signs were absent. The response to dopaminergic medications was present, but limited by dyskinesias and psychiatric side effects. Further genetic analysis of this Turkish family and the Italian PARK15 family reported previously revealed that the c.1492C > T mutation is present on two different haplotypes in the Italian family, and one of these haplotypes is shared in homozygous state in the Turkish patients. These findings contribute to the ongoing delineation of the genetic and clinical spectrum of PARK15.

Hyponatremic encephalopathy after excessive water ingestion prior to pelvic ultrasound: neuroimaging findings.

We report two patients with acute hyponatremic encephalopathy which developed after massive water ingestion for pelvic ultrasound and emphasize the findings of magnetic resonance (MR) imaging including diffusion-weighted imaging (DWI). Both subjects had completely recovered within 24 hours following fluid restriction and salt replacement. MR imaging revealed cortical sulcal narrowing, restricted diffusion and sulcal T2 hyperintensity along with diffuse pial enhancement suggesting diffuse cerebral cortical cytotoxic edema and blood-brain barrier breakdown. In addition to the first illustration of multimodality MR imaging features of water-intoxication, these two cases also highlight the need for standardized practice on the quantity of water intake recommended to distend the bladder for pelvic ultrasound, especially in patients at risk for serum inappropriate ADH syndrome-related hyponatremia.

Recurrent optic neuritis: clues from a long-term follow up study of recurrent and bilateral optic neuritis patients.

BACKGROUND AND AIM: Optic neuritis (ON) can be recurrent, with unilateral or bilateral presentation. Diagnosis of recurrent cases may be challenging. In this study long-term follow-up of recurrent and/or bilateral ON patients is reported in an effort to guide differential diagnosis and treatment. METHODS: The study included 474 optic neuropathy patients. Of these, 70 patients with recurrent unilateral or bilateral, and nonrecurrent bilateral ON were assessed. The characteristics of each ON attack, laboratory and magnetic resonance imaging (MRI) findings, associated diseases and response to treatment were noted for each patient. Most of the patients were reevaluated in the outpatient clinic. Seven patients were investigated for neuromyelitis optica (NMO)-immunoglobulin G (IgG) seropositivity. RESULTS: Forty-seven patients had recurrent unilateral ON and 23 had bilateral ON. Mean follow-up was 7.55 years. Final diagnoses for recurrent unilateral group were multiple sclerosis (MS) (n = 29), chronic relapsing inflammatory optic neuritis (CRION) (n = 11), NMO (n = 4), or autoimmune thyroid disease (n = 3); and for bilateral ON group, MS (n = 4), vasculitis (n = 13), postinfectious ON (n = 4), and sarcoidosis (n = 2). Three patients were positive for NMO antibodies. CONCLUSION: Based on the data collected, we conclude when recurrent ON causes moderate to severe visual loss in the absence of cranial MRI findings typical of MS, other diagnoses should be considered, including NMO.

Right internal carotid artery occlusion during intravenous thrombolysis for left middle cerebral artery occlusion.

Thrombolysis with recombinant tissue plasminogen activator is the only established treatment for acute ischemic stroke. Recurrent ischemic stroke involving an initially unaffected arterial territory during the course of thrombolysis has been reported but remains exceptionally rare. Here we report a 75-year-old woman with acute left middle cerebral artery occlusion who developed right internal carotid artery occlusion during the last minutes of recombinant tissue plasminogen activator infusion. Although the transthoracic echocardiography did not reveal an intra-atrial thrombus, cardioembolism due to disintegration of a pre-existing thrombus was thought to be the underlying mechanism because the patient had atrial fibrillation. Arterial occlusion due to intraplaque hemorrhage and de novo thrombosis caused by thrombin-mediated platelet aggregation are also discussed as potential mechanisms of arterial occlusion.

An unusual central nervous system involvement in rheumatoid arthritis: combination of pachymeningitis and cerebral vasculitis.

Severe primary central nervous system (CNS) involvement such as vasculitis and pachymeningitis can rarely occur in rheumatoid arthritis (RA) even in the absence of systemic disease activation. The authors illustrate a female patient with well-controlled RA who presented with headaches, encephalopathy, seizures and relapsing focal neurological deficits. Primary rheumatoid cerebral vasculitis and pachymeningitis were diagnosed based on suggestive brain magnetic resonance (MR) imaging, MR angiography, cerebrospinal fluid analysis and cerebral angiography. MR showed abnormal leptomeningeal enhancement and hyperintense FLAIR signal in the cortical subarachnoid spaces consistent with pachymeningitis. Cerebral angiography findings were consistent with vasculitis. Aggressive treatment resulted in significant clinicoradiological resolution. Cerebral vasculitis is a rare but certain manifestation of RA. This complication can be diagnosed in the presence of suggestive angiographic and CSF findings. The condition may be steroid resistant, and needs to be treated more aggressively.