Adult-onset neuronal intranuclear hyaline inclusion disease

We studied the clinical and pathologic features of two cases of neuronal intranuclear hyaline inclusion disease. The cases were unique in late onset, presentation with dementia, possible autosomal dominant pattern of inheritance (in one patient), predominance of inclusions in glial cells, and mineral deposits within some inclusions. Differences from other reported cases indicate that this is probably not a homogeneous entity.     

FUS immunoreactivity of neuronal and glial intranuclear inclusions in intranuclear inclusion body disease

F. Mori, K. Tanji, T. Kon, S. Odagiri, M. Hattori, Y. Hoshikawa, C. Kono, K. Yasui, S. Yokoi, Y. Hasegawa, M. Yoshida and K. Wakabayashi (2012) Neuropathology and Applied Neurobiology 38, 322–328 FUS immunoreactivity of neuronal and glial intranuclear inclusions in intranuclear inclusion body disease Aims: Recent studies have shown that fused‐in‐sarcoma (FUS) protein is a component of ‘neuronal’ intranuclear inclusion bodies (INIBs) in the brains of patients with intranuclear inclusion body disease (INIBD). However, the extent and frequency of FUS‐immunoreactive structures in INIBD are uncertain. Methods: We immunohistochemically examined the brain, spinal cord and peripheral ganglia from five patients with INIBD and five control subjects, using anti‐FUS antibodies. Results: In controls, the nuclei of both neurones and glial cells were intensely immunolabelled with anti‐FUS and neuronal cytoplasm was weakly positive for FUS. In INIBD, neuronal and glial INIBs in the brain and spinal cord were positive for FUS. FUS‐positive INIBs were also found in the peripheral ganglia. The proportion of FUS‐positive neuronal INIBs relative to the total number of inclusion‐bearing neurones ranged from 55.6% to 83.3% (average 73.2%) and that of FUS‐positive glial INIBs ranged from 45.9% to 85.7% (average 62.7%). The nucleus and cytoplasm of inclusion‐bearing neurones and glial cells showed no FUS immunoreactivity. Conclusions: These findings suggest that FUS is incorporated into INIBs in both neurones and glial cells and that loss of normal FUS immunoreactivity may result from reduced protein expression and/or sequestration within inclusions.     

Characteristics of ocular findings of patients with neuronal intranuclear inclusion disease

Neurological Sciences - This study aimed to explore the ocular characteristics of neuronal intranuclear inclusion disease (NIID), caused by GGC repeat expansion in the NOTCH2NLC gene, combined with...     

Recruitment of nonexpanded polyglutamine proteins to intranuclear aggregates in neuronal intranuclear hyaline inclusion disease

Recruitment of polyglutamine-containing proteins into nuclear inclusions (NIs) was investigated in neuronal intranuclear hyaline inclusion disease (NIHID). Some polyglutamine-containing proteins, ataxin-2, ataxin-3, and TATA box binding protein (TBP), as well as unidentified proteins with expanded polyglutamine tracts were recruited into NIs with different frequencies. Ataxin-3 was incorporated into most of the NIs and disappeared from its normal cytoplasmic localization, whereas only a small fraction of NIs contained ataxin-2 and TBP. The consistent presence of ataxin-3 in NIs could reflect a biological feature of wild-type ataxin-3, which is translocated into the nucleus under pathological conditions and participates in the formation of aggregates. Ataxin-2 also accumulated in the nucleus, but was not necessarily incorporated into NIs, suggesting that transport of these cytoplasmic proteins into the nucleus and their recruitment into NIs are not wholly explained by an interaction with a polyglutamine stretch and must be regulated in part by other mechanisms. The prevalence of ubiquitin-immunopositive NIs was inversely correlated to neuronal loss in all cases examined. This correlation could be explained if NI formation is a protective mechanism involving the ubiquitin-proteasome pathway. This hypothesis is supported by the finding that the polyglutamine epitope in the center of NIs was surrounded by ubiquitin.     

Ataxin 1 and ataxin 3 in neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a multisystem neurodegenerative disorder characterized by large intranuclear aggregates in neurons of the central and peripheral nervous system. These ubiquitinated intranuclear inclusions are morphologically similar to the intraneuronal aggregates that have been identified in the CAG/polyglutamine expansion diseases. As rare aggregates in NIID contain a polyglutamine epitope, we further investigated the relationship between this disease and the CAG/polyglutamine expansion diseases. Here, we show that ataxin 1 and ataxin 3 proteins are recruited into aggregates in NIID in the absence of a CAG expansion in the SCA1 and SCA3 genes. These data support an association of NIID with the polyglutamine disorders and provide evidence of in vivo recruitment of proteins with polyglutamine tracts into intraneuronal aggregates.     

散发成年型神经元核内包涵体病的临床及病理特点分析

目的 分析散发成年型神经元核内包涵体病（NIID）患者的临床表型、影像特点及皮肤病理改变。方法 回顾性分析2018年3月至2021年3月就诊于北京大学人民医院的7例经NOTCH2NLC基因检测确诊的成年型NIID患者的临床、影像学及皮肤病理特点。结果 该组患者起病年龄33～73岁,平均（54.43±15.47）岁。主要临床表现除认知功能障碍、发作性脑病等核心症状外,前期发生恶心、呕吐及腹痛、腹泻等消化道症状比较突出。7例患者中,有5例患者颅脑磁共振成像显示弥散加权成像皮髓质交界区呈异常高信号。7例患者均被发现NOTCH2NLC基因非编码区中存在GGC异常重复扩增,重复扩增次数为93～177次。皮肤活检可见汗腺导管的上皮细胞和成纤维细胞中有酸性核内包涵体。免疫组织化学染色显示为p62阳性;电镜下呈不具膜结构的细丝状物质。结论 散发成年型NIID具有高度临床异质性,皮肤病理检查和基因检测是明确诊断的必要手段。     

Clinicopathological features of neuronal intranuclear inclusion disease diagnosed by skin biopsy

Neurological Sciences - Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder, with complex and diverse of clinical manifestations characterized by...     

Rectal biopsy in the diagnosis of neuronal intranuclear hyaline inclusion disease

Neuronal intranuclear hyaline inclusion disease is a neurodegenerative disorder of childhood characterized by eosinophilic intranuclear inclusions and neuronal loss throughout the nervous system. Although most cases have been diagnosed postmortem, rectal biopsy may be diagnostic during life. We identified two patients: an 11-year-old boy (P1) with new-onset bulbar weakness and parkinsonism and a 15-year-old boy (P2) with severe cognitive and motor deterioration of uncertain etiology who presented at 4 years of age with a gait disturbance and motor slowing. Both patients had a history of behavioral problems marked by frequent temper tantrums. Both had nondiagnostic magnetic resonance imaging of the head and metabolic work-ups. Rectal biopsy was diagnostic 1 year (P1) and 11 years (P2) after the initial evaluation. Rectal biopsies should be considered in children presenting with otherwise unexplained multisystem degeneration, particularly in the presence of both upper and lower motoneuron signs accompanied by behavioral problems.     

SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by progressive ataxia and neuronal nuclear inclusions (NIs), similar to the inclusions found in expanded CAG repeat diseases. NIID may be familial or sporadic. The cause of familial NIID is poorly understood, as no CAG expansion has been detected. We examined three cases, from two unrelated families, who had autosomal dominant NIID but normal CAG repeats in genes involved in polyglutamine neurodegenerative diseases. We found that NIs in all three cases were intensely immunopositive for SUMO-1, a protein which covalently conjugates to other proteins and targets them to the nuclear regions (nuclear bodies) responsible for nuclear proteasomal degradation. Electron microscopy demonstrated that SUMO-1 was located on the 10-nm fibrils of NIs. In cultured PC12 cells, we found that inhibition of proteasome function by specific inhibitors resulted in the appearance of SUMO-1-immunopositive nuclear inclusions. Our study suggests that recruitment of SUMO-1 modified proteins into insoluble nuclear inclusions and proteasomal dysfunction may be involved in the pathogenesis of NIs in familial NIID cases.     

Neuronal intranuclear hyaline inclusion disease

Neuronal intranuclear hyaline inclusion disease (NIHID) is a rare neurodegenerative disorder characterized pathologically by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells. It has been considered to be a heterogeneous disease entity because the clinical pictures of previously described cases were highly variable. In the present review, reported NIHID cases have been categorized into three clinical subgroups according to onset and disease duration, and the clinical phenotype of each subgroup is discussed. Neuronal intranuclear inclusions (NII) in NIHID are ubiquitinated and their prevalence is inversely correlated with neuronal loss, suggesting that NII formation is a protective mechanism involving the ubiquitin–proteasome‐dependent proteolytic pathway. In several polyglutamine diseases, disease‐related proteins containing abnormally expanded polyglutamine tracts aggregate in neuronal nuclei, resulting in NII formation. The similarity between NII in NIHID and polyglutamine diseases suggests that they are formed during a common proteolysis‐related process that takes place in the nucleus. Although the pathogenetic mechanism underlying NIHID remains unknown, the data reviewed here suggest that it might be related to accumulation of as yet unidentified abnormal proteins or dysfunction of the intranuclear ubiquitin–proteasome pathway.     

Neuronal intranuclear hyaline inclusion disease with polyglutamine-immunoreactive inclusions

Neuronal intranuclear hyaline inclusion disease (NIHID) is a group of neurodegenerative disorders characterized by the presence of intranuclear inclusions in neurons (NIs). We report here clinicopathological findings of a 25-year-old female patient who died after 13 years of a clinical course characterized by progressive gait disturbance and movement disorders. Histological examination revealed widespread NIs with neuronal loss in restricted regions; neuronal loss was severe in the subthalamic nucleus, internal pallidum, substantia nigra, Edinger-Westphal nucleus and Purkinje cell layer. Quantification of the NIs combined with a graded evaluation of neuronal loss revealed an overall tendency for more severe neuronal loss to be accompanied by a lower frequency of NIs. A morphological similarity to the nuclear inclusions recently identified in several CAG repeat diseases prompted us to examine the immunolocalization of ubiquitin and expanded polyglutamine stretches, which demonstrated the presence of ubiquitin at the periphery of most NIs. An expanded polyglutamine stretch was seen in the center of limited number of NIs. These findings indicate that abnormal fragments such as expanded polyglutamine regions are incorporated into the inclusion, aggregated in its center, and thereby metabolized by a ubiquitin-dependent proteolytic pathway. Although it remains to be elucidated how the formation of NIs is related to neuronal degeneration, our findings suggest that NIs are formed in the process of sequestering or degrading abnormal protein fragments and formation of NIs may not be immediately toxic to neurons. Received: 22 June 1999 / Revised, accepted: 20 August 1999     

Brain neurotransmitter abnormalities in neuronal intranuclear inclusion body disorder

Biochemical markers for the major neurotransmitter systems were measured in the brain of a patient who died with neuronal intranuclear inclusion disease. A severe nigrostriatal dopamine deficiency constitutes the basis for the parkinsonian features in the patient. A marked loss of brain norepinephrine and serotonin was found in the basal ganglia and hypothalamus. Brain amino acid (gamma-aminobutyric acid and glutamate) and cholinergic (choline acetyltransferase activity) systems were either normal or less severely affected.     

Adult-onset neuronal intranuclear inclusion disease mimicking Fragile X-associated tremor-ataxia syndrome in ethnic Chinese patients

Two ethnic Chinese men with clinico-radiologic features of Fragile X-associated tremor-ataxia syndrome (FXTAS) were found on genetic testing to have neuronal intranuclear inclusion disease (NIID), highlighting that NIID should be considered in the differential diagnosis of FXTAS. NIID may also be much more common than FXTAS in certain Asian populations.     

Neuronal intranuclear inclusion disease in identical twins

A pair of female identical twins exhibited slurred speech, nystagmus, and oculogyral spasms starting at age 11. The patients then had episodic rage, extrapyramidal and lower motor neuron abnormalities, and grand mal seizures, but retained largely normal intelligence, until death at age 21. Severe loss of nigral and craniospinal motor neurons was noted postmortem. Round, eosinophilic, autofluorescent inclusion bodies, 3 to 10 microns in diameter, were observed in the nuclei of most nerve cell types of the central and peripheral nervous systems and retina. Ultrastructurally the inclusions appeared as masses of filaments without a limiting membrane, the constituent filaments having a diameter of 8.5 to 9.5 nm. Histochemical results suggested the presence of proteins with a high content of tryptophan. Four similar cases have been reported previously under various designations. We propose the name neuronal intranuclear inclusion disease for the disorder.