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Tomography (Ann Arbor, Mich.) Feb 2022MRI shows the three archetypal patterns of CNS volume loss underlying progressive ataxias in vivo, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and... (Review)
Review
MRI shows the three archetypal patterns of CNS volume loss underlying progressive ataxias in vivo, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and olivopontocerebellar atrophy (OPCA). The MRI-based CNS atrophy pattern was reviewed in 128 progressive ataxias. A CNS atrophy pattern was identified in 91 conditions: SA in Friedreich's ataxia, CCA in 5 acquired and 72 (24 dominant, 47 recessive,1 X-linked) inherited ataxias, OPCA in Multi-System Atrophy and 12 (9 dominant, 2 recessive,1 X-linked) inherited ataxias. The MRI-based CNS atrophy pattern may be useful for genetic assessment, identification of shared cellular targets, repurposing therapies or the enlargement of drug indications in progressive ataxias.
Topics: Ataxia; Atrophy; Cerebellar Ataxia; Humans; Magnetic Resonance Imaging; Spinocerebellar Degenerations
PubMed: 35202200
DOI: 10.3390/tomography8010035 -
Archivos Argentinos de Pediatria Feb 2022The latest method of next-generation sequencing has allowed the characterization and identification of genetic variants associated to diverse pathologies. In this...
The latest method of next-generation sequencing has allowed the characterization and identification of genetic variants associated to diverse pathologies. In this article, we present the case of female patient with a mutation of the RARS2 gene that encodes the enzyme for arginyl tRNA synthetase for coding of proteins. This genetic alteration manifests in pontocerebellar hypoplasia type 6, with a prevalence of<1/1,000,0000, characterized by a cerebellum and pons that are smaller in size and are associated with severe neurodevelopmental delay. The analysis of the case of this patient provides better knowledge of diseases of genetic origin; specifically, regarding genetic diseases of autosomal recessive patterns of inheritance from non-consanguineous parents. The impact of these studies; specially within the family, social, economic and genetic aspects helps provide a better quality of life for these patients and their family.
Topics: Arginine-tRNA Ligase; Colombia; Consanguinity; Female; Humans; Magnetic Resonance Imaging; Mutation; Parents; Quality of Life
PubMed: 35068129
DOI: 10.5546/aap.2022.e39 -
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 -
Acta Neurologica Belgica Feb 2023
Topics: Humans; Cerebellar Diseases; Mutation; India; Olivopontocerebellar Atrophies; AMP Deaminase
PubMed: 34826127
DOI: 10.1007/s13760-021-01800-4 -
Cerebellum (London, England) Aug 2022The aim of this paper is to carry out a historical overview of the evolution of the knowledge on degenerative cerebellar disorders and hereditary spastic paraplegias,... (Review)
Review
The aim of this paper is to carry out a historical overview of the evolution of the knowledge on degenerative cerebellar disorders and hereditary spastic paraplegias, over the last century and a half. Original descriptions of the main pathological subtypes, including Friedreich's ataxia, hereditary spastic paraplegia, olivopontocerebellar atrophy and cortical cerebellar atrophy, are revised. Special attention is given to the first accurate description of striatonigral degeneration by Hans Joachim Scherer, his personal and scientific trajectory being clarified. Pathological classifications of ataxia are critically analysed. The current clinical-genetic classification of ataxia is updated by taking into account recent molecular discoveries. We conclude that there has been an enormous progress in the knowledge of the nosology of hereditary ataxias and paraplegias, currently encompassing around 200 genetic subtypes.
Topics: Ataxia; Atrophy; Cerebellar Ataxia; Humans; Neurodegenerative Diseases; Paraplegia; Spastic Paraplegia, Hereditary; Striatonigral Degeneration
PubMed: 34731448
DOI: 10.1007/s12311-021-01328-6 -
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 -
Neuropediatrics Dec 2021Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as...
INTRODUCTION
Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as gastroesophageal reflux (GERD) and failure to thrive, are major contributors to this burden.
METHODS
We report three patients with genetically confirmed PCH2A and significant gastrointestinal (GI) symptoms.
RESULTS
Apart from impaired swallowing and GERD, which are frequently reported in patients with PCH2, all three patients suffered from episodes of spasmodic abdominal pain and restlessness. In one severely affected patient, lack of intestinal alkaline phosphatase (IAP) is demonstrated.
CONCLUSION
GI symptoms are common in PCH2. We draw attention to episodes of spasmodic abdominal pain seriously, aggravating the condition of the patients, especially their movement disorder, and discuss the role of IAP.
Topics: Abdominal Pain; Gastroesophageal Reflux; Humans; Olivopontocerebellar Atrophies
PubMed: 34255333
DOI: 10.1055/s-0041-1730445 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jul 2021To explore the genetic basis for a fetus with cerebellar dysplasia and widened lateral ventricles.
OBJECTIVE
To explore the genetic basis for a fetus with cerebellar dysplasia and widened lateral ventricles.
METHODS
The couple have elected induced abortion after careful counseling. Skin tissue sample from the abortus and peripheral venous blood samples from both parents were collected for the extraction of genomic DNA, which was then subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing.
RESULTS
Prenatal ultrasonography showed increased nuchal translucency (0.4 cm) and widened lateral ventricles. Magnetic resonance imaging revealed infratentorial brain dysplasia. By DNA sequencing, the fetus was found to carry compound heterozygous variants c.1A>G and c.1564G>A of the RARS2 gene, which were inherited from its father and mother, respectively. Among these, c.1A>G was known to be pathogenic, but the pathogenicity of c.1564G>A was unreported previously. Based on the American College of Medical Genetics and Genomics guidelines, the c.1564G>A variant of RARS2 gene was predicted to be likely pathogenic(PM2+PM3+PP3+PP4).
CONCLUSION
The compound heterozygous variants c.1A>G and c.1564G>A of RARS2 gene contributed to the fetus suffering from pontocerebellar hypoplasia type 6, which expanded variant spectrum of RARS2 gene.
Topics: Female; Fetus; Genomics; Humans; Mutation; Olivopontocerebellar Atrophies; Pregnancy; Exome Sequencing
PubMed: 34247374
DOI: 10.3760/cma.j.cn511374-20200512-00340