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The American Journal of Case Reports Dec 2021BACKGROUND The interference of biotin administration with thyroid function tests has been reported; however, it remains unclear in clinical practice. In this report, we...
BACKGROUND The interference of biotin administration with thyroid function tests has been reported; however, it remains unclear in clinical practice. In this report, we present the case of a neonate with a diagnosis of pontocerebellar hypoplasia type 6 (PCH6) treated with biotin who developed biotin interference with laboratory thyroid function tests. CASE REPORT A 1-day-old male infant with hypothermia, tachypnea, and lactic acidosis had a suspected diagnosis of mitochondrial disease. Biotin and several vitamins were administered to improve his condition. On day 14, his laboratory tests revealed a free triiodothyronine level of 4.7 pg/mL, free thyroxine level of 3.7 ng/dL, thyroid-stimulating hormone level of 0.07 μIU/mL, and thyroid-stimulating hormone receptor antibody (TRAb) level of 37.6 IU/L, suggesting Graves' disease. No goiter or tachycardia developed. The maternal thyroid function was not measured during pregnancy, while the maternal TRAb was negative on the same day. After methimazole administration, the patient's thyroid function normalized, and methimazole was therefore discontinued. All thyroid function tests were conducted using immunoassay methods with avidin and biotin. Later, reduced oxygen consumption under aerobic conditions in skin fibroblasts and compound heterozygous variants of the mitochondrial arginine tRNA synthetase gene were identified, and the patient was diagnosed with PCH6. CONCLUSIONS In this case, the clinical symptoms and physical findings were incompatible with the thyroid function. These laboratory findings could have mimicked Graves' disease due to the biotin interference with immunoassays. Therefore, caution is required when evaluating similar cases.
Topics: Biotin; Female; Humans; Infant, Newborn; Laboratories; Male; Olivopontocerebellar Atrophies; Pregnancy; Thyroid Function Tests
PubMed: 34930889
DOI: 10.12659/AJCR.934417 -
Journal of Neural Transmission (Vienna,... Oct 2021Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and... (Review)
Review
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.
Topics: Animals; Inclusion Bodies; Models, Animal; Multiple System Atrophy; Nerve Degeneration; alpha-Synuclein
PubMed: 34613484
DOI: 10.1007/s00702-021-02419-8 -
Journal of Neural Transmission (Vienna,... Oct 2021Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no... (Review)
Review
Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are α-synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. Since the original descriptions of this multifaceted disorder, several steps forward have been made to clarify its neuropathological hallmarks and key pathophysiological mechanisms. The Austrian neuropathologist Kurt Jellinger substantially contributed to the understanding of the underlying neuropathology of this disease, to its standardized assessment and to a broad systematical clinic-pathological correlation. On the occasion of his 90th birthday, we reviewed the current state of the art in the field of MSA neuropathology, highlighting Prof. Jellinger's substantial contribution.
Topics: Austria; Humans; Inclusion Bodies; Multiple System Atrophy; Neuropathology; alpha-Synuclein
PubMed: 34319460
DOI: 10.1007/s00702-021-02383-3 -
Brain Pathology (Zurich, Switzerland) Jan 2022The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and...
The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann-Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann-Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.
Topics: Brain; Female; Hippocampus; Humans; Inclusion Bodies; Multiple System Atrophy; Neurons; alpha-Synuclein
PubMed: 34255887
DOI: 10.1111/bpa.13002 -
JPMA. the Journal of the Pakistan... Apr 2021Hypertrophic olivary degeneration is a kind of trans-synaptic degeneration, caused by the interruption of dentato rubro olivary pathway. Magnetic resonance imaging (MRI)...
Hypertrophic olivary degeneration is a kind of trans-synaptic degeneration, caused by the interruption of dentato rubro olivary pathway. Magnetic resonance imaging (MRI) has been the best modality to show the signals of olivary nucleus hypertrophy. It appears on T2-weighted magnetic resonance imaging as hyper-intensities. Here we present a unique case of a 27-year-old male with traumatic brain injury causing multiple intracranial haemorrhages and functional impairment, which was revealed on computerised tomography. Tracheotomy and thoracic drainage were performed immediately. Anti-infection therapy, brain protection, and comprehensive arousal therapy were part of the intervention along with a comprehensive rehabilitation programme including occupational therapy, balance training, coordination, bed mobility training, and strengthening exercises. A holistic diagnostic approach can reduce the chances of misdiagnosing post-traumatic Hypertrophic Olivary Degeneration cases. We concluded that a comprehensive physical rehabilitation programme and medical treatment works best to heal the lesion and its resulting traumatic symptoms in cases of Hypertrophic Olivary Degeneration cases.
Topics: Adult; Brain Injuries, Traumatic; Humans; Hypertrophy; Magnetic Resonance Imaging; Male; Olivary Nucleus
PubMed: 34125782
DOI: 10.47391/JPMA.1124 -
Orphanet Journal of Rare Diseases May 2021Rare and severe neurological disorders in childhood not only heavily affect the life perspective of the patients, but also their caregivers and families. The aim of this...
BACKGROUND
Rare and severe neurological disorders in childhood not only heavily affect the life perspective of the patients, but also their caregivers and families. The aim of this study was to investigate the impact of such diseases on the family, especially on the quality of life and life perspectives of parents, but also on the families' everyday life, based on the model of two diseases which have been well described in recent years with respect to symptoms and course: metachromatic leukodystrophy (MLD) and pontocerebellar hypoplasia type 2 (PCH2). PCH2 is a primary severe developmental disorder, while children with MLD initially develop normally and then progressively deteriorate.
METHODS
Using a semi-standardized questionnaire, 43 families with children suffering from MLD (n = 30) or PCH2 (n = 19) reported data on the severity of the illness/symptoms, on family support and the care situation, as well as on the circumstances of non-affected siblings and the parents' work situation. In addition, the quality of life of parents and general family functioning was assessed using the PedsQL™ Family Impact Module [23]. Results for the latter were compared to published data from families with children without any chronic condition using student's t-tests for independent samples. Potential factors influencing the PedsQL™ scores were analyzed using Spearman's rank correlation.
RESULTS
Parents of children with MLD and PCH2 reported significantly lower health-related quality of life (HRQOL) compared to parents of healthy children (P < 0.001). Mothers showed significantly poorer HRQOL (P < 0.05) and were significantly more dissatisfied with their professional development (P < 0.05) than fathers, and this was seen in relation to their child's disease. Neither the form of disease ('primary' symptomatic PCH2 or 'secondary' symptomatic MLD), nor the severity of the child's illness (in terms of gross motor and speech function) had a specific impact on HRQOL in families. However, the time from diagnosis and advanced symptoms in the terminal disease stage were experienced as especially distressing.
CONCLUSIONS
This study illustrates that MLD and PCH2 affect mothers in particular, but also the entire family. This underlines the need for personalized care and counselling of parents and families, especially following diagnosis and during the end stage in a child with a severe, rare chronic neurological disorder.
Topics: Child; Chronic Disease; Female; Humans; Leukodystrophy, Metachromatic; Olivopontocerebellar Atrophies; Parents; Quality of Life; Surveys and Questionnaires
PubMed: 33971942
DOI: 10.1186/s13023-021-01828-y -
Movement Disorders : Official Journal... Feb 2021Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and...
BACKGROUND
Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.
METHODS
Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.
RESULTS
We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts.
CONCLUSION
Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Animals; Genome-Wide Association Study; Humans; Inflammatory Bowel Diseases; Mice; Mice, Transgenic; Multiple System Atrophy; alpha-Synuclein
PubMed: 33107653
DOI: 10.1002/mds.28338 -
Genetics and Molecular Biology Aug 2020The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow...
The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. The mother aged 27 years-old presented progressive cerebellar ataxia, dysarthria, dysmetria, dysdiadochokinesis, limb ataxia and olivopontocerebellar atrophy. The molecular analysis was made by identifying the expansion repeats in tandem by long PCR to analyze the repeats in the ATXN2 gene. We found an extreme CAG expansion repeats of ~884 repeats in the child. We describe a Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon.
PubMed: 32870233
DOI: 10.1590/1678-4685-gmb-2019-0325 -
Free Neuropathology Jan 2020Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of...
Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed.
PubMed: 37283673
DOI: 10.17879/freeneuropathology-2020-2813 -
Frontiers in Neurology 2020Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe...
Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. A total of 48 patients with SCA3 and 50 sex- and age-matched healthy individuals, as the control group, participated in this study. The 3D-FD method was proposed to distinguish 97 automatic anatomical label regions of gray matter (left cerebrum: 45, right cerebrum: 45, cerebellum: 7) between healthy individuals and patients with SCA3. Patients with SCA3 exhibited reduced brain complexity within both the traditional olivopontocerebellar atrophy (OPCA) pattern and specific supratentorial regions. The study results confirmed the extensive involvement of extracerebellar regions in SCA3. The atrophied regions of SCA3 in infratentorial and supratentorial cortex showed a wide range of overlapped areas as in two functional cortexes, namely cerebellum-related cortex and basal ganglia-related cortex. Our results found that the atrophy of the SCA3 are not only limited in the infratentorial regions. Both cerebellar related cortex and basal ganglia related cortex were affected in the disease process of SCA3. Our findings might correlate to the common symptoms of SCA3, such as ataxia, Parkinsonism, dysarthria, and dysmetria. SCA3 should no longer be considered a disease limited to the cerebellum and its connections; rather, it should be considered a pathology affecting the whole brain.
PubMed: 32194495
DOI: 10.3389/fneur.2020.00124