scholarly journals FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Megumi Toko ◽  
Tomohiko Ohshita ◽  
Takashi Kurashige ◽  
Hiroyuki Morino ◽  
Kodai Kume ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Skin Biopsy ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Fragile X ◽  
Brain Mri ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Cerebellar Peduncle ◽  
Ataxia Syndrome

Abstract Background Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID. Case presentation The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID. Conclusions For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

scholarly journals Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan

2021 ◽  
Author(s):  
Yujiro Higuchi ◽  
Masahiro Ando ◽  
Akiko Yoshimura ◽  
Satoshi Hakotani ◽  
Yuki Koba ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Cerebellar Ataxia ◽  
Fragile X ◽  
Genetic Diagnosis ◽  
Japanese Patients ◽  
High Signal ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Male Patients ◽  
Ataxia Syndrome

AbstractThe presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

scholarly journals NOTCH2NLC CGG Repeats Are Not Expanded and Skin Biopsy Was Negative in an Infantile Patient With Neuronal Intranuclear Inclusion Disease

2020 ◽  
Vol 79 (10) ◽  
pp. 1065-1071
Author(s):  
Ivana Jedlickova ◽  
Anna Pristoupilova ◽  
Helena Hulkova ◽  
Alena Vrbacka ◽  
Viktor Stranecky ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Neurodegenerative Disorder ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Intranuclear Inclusion ◽  
Negative Results ◽  
Developmental Regression ◽  
Cgg Repeats ◽  
Long Read ◽  
Neuronal Intranuclear Inclusion

Abstract Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder categorized into 3 phenotypic variants: infantile, juvenile, and adult. Four recent reports have linked NIID to CGG expansions in the NOTCH2NLC gene in adult NIID (aNIID) and several juvenile patients. Infantile NIID (iNIID) is an extremely rare neuropediatric condition. We present a 7-year-old male patient with severe progressive neurodegenerative disease that included cerebellar symptoms with cerebellar atrophy on brain MRI, psychomotor developmental regression, pseudobulbar syndrome, and polyneuropathy. The diagnosis of iNIID was established through a postmortem neuropathology work-up. We performed long-read sequencing of the critical NOTCH2NLC repeat motif and found no expansion in the patient. We also re-evaluated an antemortem skin biopsy that was collected when the patient was 2 years and 8 months old and did not identify the intranuclear inclusions. In our report, we highlight that the 2 methods (skin biopsy and CGG expansion testing in NOTCH2NLC) used to identify aNIID patients may provide negative results in iNIID patients.

scholarly journals NOTCH2NLC-linked neuronal intranuclear inclusion body disease and fragile X-associated tremor/ataxia syndrome

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. e69-e69
Author(s):  
Adeline S L Ng ◽  
Zheyu Xu ◽  
Zhiyong Chen ◽  
Yi Jayne Tan ◽  
Weng Khong Lim ◽  
...  
Keyword(s):  
Inclusion Body ◽  
Fragile X ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Inclusion Body Disease ◽  
Ataxia Syndrome

scholarly journals Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease

2020 ◽  
Vol 79 (12) ◽  
pp. 1293-1302
Author(s):  
Shugang Zhang ◽  
Qixing Gong ◽  
Di Wu ◽  
Yun Tian ◽  
Lu Shen ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Cerebrovascular Diseases ◽  
Pathological Examination ◽  
Positive Staining ◽  
Intranuclear Inclusion ◽  
Cgg Repeats ◽  
Genetic Features ◽  
Neuronal Intranuclear Inclusion ◽  
Ataxia Syndrome

Abstract Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5′ region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.

scholarly journals Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Atsuhiko Sugiyama ◽  
Takahiro Takeda ◽  
Mizuho Koide ◽  
Hajime Yokota ◽  
Hiroki Mukai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Repeat Expansion ◽  
Cerebellar Hemisphere ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

scholarly journals Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

2021 ◽  
Vol 22 (16) ◽  
pp. 8368
Author(s):  
Luis M. Valor ◽  
Jorge C. Morales ◽  
Irati Hervás-Corpión ◽  
Rosario Marín
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Endocrine System ◽  
Molecular Pathogenesis ◽  
Adult Women ◽  
Adult Men ◽  
Cgg Repeats ◽  
Reproductive Impairment ◽  
Ataxia Syndrome

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

Neuronal intranuclear inclusion disease cases with leukoencephalopathy diagnosed via skin biopsy

2013 ◽  
Vol 85 (3) ◽  
pp. 354-356 ◽  
Author(s):  
J. Sone ◽  
N. Kitagawa ◽  
E. Sugawara ◽  
M. Iguchi ◽  
R. Nakamura ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion

scholarly journals Case Report: Coexistence of Alzheimer-Type Neuropathology in Fragile X-Associated Tremor Ataxia Syndrome

2021 ◽  
Vol 15 ◽  
Author(s):  
Maria Jimena Salcedo-Arellano ◽  
Desiree Sanchez ◽  
Jun Yi Wang ◽  
Yingratana A. McLennan ◽  
Courtney Jessica Clark ◽  
...  
Keyword(s):  
Globus Pallidus ◽  
Late Onset ◽  
Fragile X ◽  
Amyloid Β ◽  
Middle Temporal Gyrus ◽  
Histopathological Study ◽  
Precentral Gyrus ◽  
Alzheimer Type ◽  
Mri Findings ◽  
Ataxia Syndrome

This case documents the co-occurrence of the fragile X-associated tremor ataxia syndrome (FXTAS) and Alzheimer-type neuropathology in a 71-year-old premutation carrier with 85 CGG repeats in the fragile X mental retardation 1 (FMR1) gene, in addition to an apolipoprotein E (APOE) ε4 allele. FXTAS and Alzheimer's Disease (AD) are late-onset neurodegenerative diseases that share overlapping cognitive deficits including processing speed, working memory and executive function. The prevalence of coexistent FXTAS-AD pathology remains unknown. The clinical picture in this case was marked with rapid cognitive decline between age 67 and 71 years in addition to remarkable MRI changes. Over the 16 months between the two clinical evaluations, the brain atrophied 4.12% while the lateral ventricles increased 26.4% and white matter hyperintensities (WMH) volume increased 15.6%. Other regions atrophied substantially faster than the whole brain included the thalamus (−6.28%), globus pallidus (−10.95%), hippocampus (−6.95%), and amygdala (−7.58%). A detailed postmortem assessment included an MRI with confluent WMH and evidence of cerebral microbleeds (CMB). The histopathological study demonstrated FXTAS inclusions in neurons and astrocytes, a widespread presence of phosphorylated tau protein and, amyloid β plaques in cortical areas and the hippocampus. CMBs were noticed in the precentral gyrus, middle temporal gyrus, visual cortex, and brainstem. There were high amounts of iron deposits in the globus pallidus and the putamen consistent with MRI findings. We hypothesize that coexistent FXTAS-AD neuropathology contributed to the steep decline in cognitive abilities.

Sign in / Sign up

Export Citation Format

Share Document