SNOMEDCT: 715437003; ORPHA: 2289; DO: 0081294;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.2 | Neuronal intranuclear inclusion disease | 603472 | Autosomal dominant | 3 | NOTCH2NLC | 618025 |
A number sign (#) is used with this entry because of evidence that neuronal intranuclear inclusion disease (NIID) is caused by a heterozygous repeat expansion (CGG) in the 5-prime untranslated region of the NOTCH2NLC gene (618025) on chromosome 1q21.
This heterozygous repeat expansion in the NOTCH2NLC gene can also cause the less severe neurologic disorder hereditary essential tremor-6 (ETM6; 618866), as well as oculopharyngodistal myopathy-3 (OPDM3; 619473), which shows some overlapping features.
Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant, slowly progressive neurodegenerative disorder characterized by a wide range of clinical manifestations, including pyramidal and extrapyramidal symptoms, cerebellar ataxia, cognitive decline and dementia, peripheral neuropathy, and autonomic dysfunction. The age at onset varies, but most individuals present as adults between about 30 and 70 years of age. Pathologic investigation shows eosinophilic intranuclear inclusions in almost all cell types, including neurons, skin cells, fibroblasts, and skeletal muscle. Brain imaging shows a characteristic leukoencephalopathy with high intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI), as well as white matter abnormalities in subcortical and brainstem regions. Skin biopsy combined with brain imaging is useful for diagnosis (summary by Sone et al., 2016).
The phenotype in some cases is suggestive of Parkinson disease (see 168600) and/or Alzheimer disease (see 104300), consistent with an evolving phenotypic spectrum of adult-onset NIID (summary by Tian et al., 2019).
Kimber et al. (1998) described female monozygotic twins who developed upper and lower limb neurogenic weakness in their thirties, followed by cerebellar ataxia, dysarthria, and death after an illness of about 20 years' duration. Autopsy revealed pathologic features typical of NIID and positive ubiquitin immunostaining of the inclusions. Two adult sons of one of the twins developed an identical illness.
Zannolli et al. (2002) reported a family in which 3 members in 2 generations had NIID characterized primarily by autonomic failure and cerebellar dysfunction. The mother and her 2 sons all had fecal and urinary incontinence, postural hypotension, and cerebellar atrophy, and the men had neurogenic erectile dysfunction. Other variable findings included gait and speech ataxia, ocular dysmetria, hyperreflexia, and limb hypotonia.
Sone et al. (2005) reported 2 large unrelated Japanese families in which several individuals spanning at least 2 generations had NIID. The patients presented between 16 and 30 years of age with a similar peripheral neuropathy characterized by gait impairment, severe muscle atrophy in the limbs, limb girdle, and face, distal sensory impairment as evidenced by electrophysiologic studies, and severe autonomic abnormalities, including gastrointestinal pseudoobstruction and bladder dysfunction. None of the patients had involuntary movements, ataxia, seizures, or dementia, suggesting the absence of central nervous system involvement; however, all except 1 patient were under the age of 60. Postmortem examination of 1 patient from each family showed intranuclear inclusions in both neural and glial cells in the central and peripheral nervous system and in nonneural tissues.
Sasaki et al. (2015) reported a 65-year-old Japanese man who presented with a 5-year history of slowly progressive gait disturbance and cognitive decline associated with a sensorimotor polyneuropathy and hyporeflexia in the lower limbs, constipation, and movement abnormalities consistent with parkinsonism. Brain imaging using T2-weighted and FLAIR imaging showed a diffuse leukoencephalopathy with high-intensity lesions in the cerebral white matter, corticomedullary junctions, corpus callosum, and cerebellar peduncles. The patient continued to develop new infarct-like lesions in the brain, although extensive workup excluded recurrent embolic events, cardiac abnormalities, vascular disease, and coagulation defects. Tissue biopsies showed eosinophilic intranuclear inclusions in various cells sampled, including adipocytes, muscle cells, Schwann cells, sweat gland cells, and vascular smooth muscle cells; these inclusions stained positively for ubiquitin (see, e.g., UBB, 191339) and p62 (SQSTM1; 601530). The clinical and pathologic findings were consistent with a diagnosis of NIID. The patient died several weeks later, and autopsy was not performed.
Sone et al. (2016) reported the clinicopathologic features of 57 cases of adult-onset NIID, including 19 patients from 6 families with the disorder and 38 patients with sporadic disease. The average age at symptom onset was 39.6 years (range, 16-68) in familial cases and 63.6 (range, 51-76) in sporadic cases. Skin biopsy and postmortem neuropathologic studies showed eosinophilic intranuclear inclusions that were ubiquitin- and p62-positive. Clinical features included abnormal behavior and dementia as well as autonomic impairment, such as miosis and bladder dysfunction. Muscle weakness and sensory impairment were more common among familial cases (72-94%) than sporadic cases (about 28%), and ataxia was more common among sporadic cases (53%) compared to familial cases (6%). Less common features included disturbances of consciousness and generalized convulsions. A subset (21%) of patients with sporadic disease presented with subacute encephalitic episodes, often with fever, headache, vomiting, cerebral edema, and elevated CSF protein. Nerve conduction studies showed distal sensory impairment. Based on this study, Sone et al. (2016) suggested that there are 2 main clinical subgroups: a 'limb weakness' type, usually familial NIID patients with onset of symptoms before 40 years of age, and a 'dementia dominant' type, usually patients with sporadic disease who present between 51 and 76 years of age. However, both groups eventually developed similar symptoms, consistent with a single disease entity. Sone et al. (2016) noted some similarities to FXTAS (300623), but genetic evaluation excluded abnormalities in the FMR1 gene (309550).
Takumida et al. (2017) and Morimoto et al. (2017) independently reported unrelated Japanese patients, a 78-year-old woman and a 71-year-old man, respectively, with onset of a similar neurodegenerative disorder in their mid-sixties. Features included cognitive impairment with executive dysfunction and a sensorimotor peripheral neuropathy; urinary dysfunction, tremor, and athetosis were noted in 1 of the patients. Brain imaging in both showed a subcortical leukoencephalopathy with T2-weighted hyperintensities also in the brainstem, middle cerebellar peduncles, and U-fibers. Skin, muscle, and sural nerve biopsies showed widespread eosinophilic intranuclear inclusions in various cell types, including epithelial cells, smooth and skeletal muscle cells, and fat cells. Retrospective studies of a stomach biopsy from the male patient showed that similar inclusions were present 16 years earlier.
Yamaguchi et al. (2018) reported postmortem findings of a 79-year-old Japanese woman with NIID who had a positive family history of the disorder. She first developed postural hand tremor at age 66, followed by progressive memory disturbances, apathy, urinary incontinence, ataxia, hyporeflexia, and distal muscle atrophy over the following decade. Brain imaging showed characteristic diffuse high-intensity T2-weighted lesions in the white matter and U fibers, and skin biopsy showed eosinophilic ubiquitin-positive intranuclear inclusions in multiple cell types. She died of aspiration pneumonia at age 79. Neuropathologic examination showed frontal-dominant cortical atrophy and cerebellar atrophy, as well as spongiosis of the white matter adjacent to the cerebral cortex. Swollen astrocytes and neurons had eosinophilic p62- and UBB-positive intranuclear inclusions. Sural nerve showed a reduction in myelinated fibers and Schwann cell inclusions. The inclusions were also found in the heart, liver, kidney, and parathyroid tissues, indicating a systemic disorder. Family history revealed that 9 family members spanning 4 generations had variable yet similar symptoms, including 2 patients with MRI-confirmed leukoencephalopathy.
Similar detailed case reports of individual Japanese patients older than 70 years of age with NIID were provided by Kitagawa et al. (2014), Araki et al. (2016), Yamada et al. (2017), and Mitsutake et al. (2019). The patient reported by Mitsutake et al. (2019) had intracranial hemorrhages.
Sone et al. (2019) reported 9 families segregating with NIID and 40 patients with sporadic NIID. Two of the families (families 1 and 2), in which patients presented mainly with a severe sensorimotor neuropathy, were previously reported by Sone et al. (2005); family 3 was previously reported by Sone et al. (2016). Some of the patients with sporadic disease had been reported by Kitagawa et al. (2014), Araki et al. (2016), and Yamada et al. (2017). Most of the patients had dementia and leukoencephalopathy. The patients had brain imaging and pathologic findings consistent with the diagnosis.
Ishiura et al. (2019) reported patients from 12 families with NIID, 14 unrelated patients with sporadic NIID, and 2 patients with NIID and unavailable family history. The diagnosis was made on the basis of characteristic brain MRI findings, including high-intensity signals in the corticomedullary junction and the T2-weighted hyperintensities in the middle cerebellar peduncles, and/or intranuclear inclusions in skin or brain tissue. Several of the families and patients had previously been reported by Sasaki et al. (2015), Morimoto et al. (2017), Takumida et al. (2017), Yamaguchi et al. (2018), and Mitsutake et al. (2019).
Tian et al. (2019) reported 20 patients from 4 unrelated Chinese families with NIID and 5 additional Chinese patients with sporadic occurrence of NIID. The diagnosis in the probands was made through skin biopsy, sometimes accompanied by brain imaging. The largest family (family 1) was a 5-generation family containing 12 affected individuals spanning 3 generations. Clinical manifestations of all patients were variable and evolved over time, but the authors were able to identify 2 main phenotypic subgroups among these familial cases: a 'muscle weakness-predominant type' (families 1 and 2) with a relatively earlier average age of onset, usually in the thirties (range, 30-54 years), and a 'dementia-predominant type' (families 3 and 4), with a relatively later average age of onset, usually after age 40 (range, 31-71 years). Core features in the muscle weakness group included muscle weakness affecting the limbs but also later including bulbar muscles, muscle atrophy, tremor, ataxia, distal sensory impairment, and slowed nerve conduction velocities consistent with a peripheral neuropathy. Some patients had bladder dysfunction. Dementia was not present, but a few patients had disturbances of consciousness or abnormal behavior. Brain imaging, performed only in some of these patients, tended to be normal. Core features in the dementia-dominant group included cognitive decline, abnormal behavior, autonomic dysfunction, bladder dysfunction, disturbance of consciousness, tremor, rigidity, and limb muscle weakness; sensory disturbances were also seen. Leukoencephalopathy was found in those patients studied. The 5 patients with sporadic disease fell into the dementia group, with features such as abnormal behavior, stroke-like episodes, and disturbances of consciousness. All had severe leukoencephalopathy with high signals in the U-fibers on DWI. Bladder dysfunction and abnormalities in nerve conduction velocities were also found. After identification of the genetic cause of NIID in these families and patients, Tian et al. (2019) subsequently identified 5 additional families through direct genetic analysis. Three of the families (families 5, 6, and 7) were ascertained from a cohort of 205 families with a diagnosis of Parkinson disease, and 2 families (families 8 and 9) were ascertained from a cohort of 140 families with a diagnosis of Alzheimer disease. Clinical manifestations in the entire group of patients in the study included bladder dysfunction (56.4%), tremor (47.5%), muscle weakness (46.2%), abnormal behavior (37.5%), sensory disturbance/peripheral neuropathy (35.1%), dementia (35.0%), rigidity (30.0%), bradykinesia (30.0%), ataxia (17.5%), disturbed consciousness (17.5%), miosis (17.2%), stroke-like episodes (10.0%), and encephalitic episodes (5.0%). Although only about 37.5% of affected individuals in the familial cases had classic NIID radiologic findings on brain imaging, all had positive skin biopsies. The severity of symptoms varied widely, even between sibs with similar repeat sizes. Of note, frank dementia was not observed in either the muscle weakness or parkinsonism groups. These overall findings suggested that GGC repeat expansions in the NOTCH2NLC gene may contribute to more common neurodegenerative disorders. The authors suggested the term 'NIID-related disorders' to cover the phenotypic spectrum of adult-onset NIID.
Deng et al. (2019) retrospectively studied 15 Chinese patients from 12 unrelated families with NIID initially diagnosed through skin biopsies. The age of onset ranged from 52 to 69 years, although 1 patient (P3) had onset at age 36 years and another (P6) had onset at age 16 years. Features included cognitive impairment (93.3%), episodic encephalopathy (66.7%), bladder dysfunction (60.0%), abnormal behavior (53.3%), convulsions (53.3%), muscle weakness (53.3%), visual abnormalities (53.3%), sensory disturbances (46.7%), dysarthria (46.7%), miosis (40.0%), tremor (40.0%), rigidity (40.0%) and ataxia (33.3%). Among the patients with bladder dysfunction, 7 needed permanent cystostomy. Brain imaging showed diffuse high signals on T2-weighted images and DWI signals along the corticomedullary junction.
Okubo et al. (2019) reported 12 unrelated Japanese patients with genetically-confirmed NIID who were identified from a cohort of 101 patients with unexplained leukoencephalopathy. Most patients had onset of symptoms between 48 and 70 years, although 1 (patient 6) had onset of paranoid delusions at age 27; she was diagnosed clinically with schizophrenia. Presenting symptoms were highly variable and included dementia, abnormal behavior, repetitive vomiting, tremor, bladder dysfunction, and dizziness. All but 1 eventually developed dementia and hyperintensities on DWI: patient 9, who did not have dementia or DWI findings, manifested transient motor freezing. Clinical details were limited, but most had decreased tendon reflexes and neuropathy confirmed by nerve conduction studies, and enlarged ventricles on brain imaging. Less common features included muscle weakness, sensory disturbances, tremor, and encephalitic episodes. Some patients did not have DWI abnormalities at presentation, but developed them later, particularly coinciding with encephalitic episodes. The pathogenic repeat expansions in NOTCH2NLC ranged from 89 (in patient 9) to 149. Studies of the variants were not performed. Okubo et al. (2019) concluded that NIID is a major genetic cause of adult leukoencephalopathy among Japanese individuals.
Chen et al. (2020) recruited 12 patients with NIID initially ascertained based on characteristic MRI findings and subsequently confirmed by genetic analysis. Ten patients were Chinese and 2 brothers were of Malaysian origin. The patients, who had onset of symptoms between 50 and 69 years of age, presented with various symptoms, including dementia, urinary dysfunction, gait ataxia, and syncope. All eventually developed urinary dysfunction that frequently required catheterization. Although dementia was common, 4 patients did not have dementia. Other variable features included tremor, parkinsonism, constipation, neuropathy, and syncope. Five of 6 patients studied had increased CSF protein levels compared to controls, and the plasma neurofilament level was increased in 7 patients who had blood drawn, suggesting neuroaxonal pathology. The authors concluded that characteristic MRI findings may be a better predictor of NIID than clinical features, since these patients had a diverse range of presentations.
Clinical Variability
Chen et al. (2020) reported a 3-generation family, presumably of Chinese origin, with essential tremor. The proband was a 67-year-old man with a 4-year history of tremor in the head and both hands. Brain imaging at the onset of symptoms showed no obvious white matter abnormalities, but brain imaging at age 67 showed abnormal diffusion-weighted imaging (DWI) at the corticomedullary junction. Esophageal polyp biopsy showed p62 (SQSTM1; 601530)-positive cells, consistent with intranuclear inclusions. Molecular studies identified an expanded GGC repeat in the NOTCH2NLC gene in the proband (over 200 repeats), as well as in 15 additional family members, although the size of the repeat expansions in family members was not provided. Of the 16 mutation carriers, 10 had essential tremor with a mean onset of 53.5 years. Four of these patients developed cognitive dysfunction; other clinical details were limited. One affected family member had DWI abnormalities on brain imaging, whereas another affected family member had no leukoencephalopathy, but did have p62-positive cells on skin biopsy. Considering the family history, tremor, dementia, MRI findings, and pathologic immunostaining, the family was diagnosed with NIID. Chen et al. (2020) suggested that NIID is a heterogeneous disorder and that patients may present with essential tremor before the onset of other symptoms. The report suggested that there is a phenotypic spectrum associated with repeat expansions in the NOTCH2NLC gene.
The characteristic findings on MRI-based diffusion weighted imaging (DWI) is a powerful and accurate noninvasive method of diagnosis of NIID. Most patients, particularly those with dementia, have high signals at the corticomedullary junction, as well as diffuse leukoencephalopathy affecting subcortical and cortical regions. The diagnosis can be confirmed pathologically through skin biopsy (summary by Sone et al., 2019 and Tian et al., 2019).
Differential Diagnosis
Ng et al. (2020) reported a man of East Asian descent who presented with cognitive impairment at age 64. He had no family history of a similar disorder, and there were no motor signs. Brain imaging showed a DWI signal at the gray-white matter junction, characteristic of NIID, as well as the MCP sign, a T2-weighted abnormality in the middle cerebral peduncles. He was predicted to have NIID, but genetic analysis was negative for the pathogenic repeat expansion. As suggested by Sone et al. (2016) the authors tested the FMR1 (309550) gene and identified an abnormal repeat expansion (110 CGG repeats), confirming the diagnosis of FXTAS (300623). The authors emphasized the need for genetic studies including both NOTCH2NLC and FMR1 for patients in whom MRI is used as a screening tool for neurodegenerative disorders.
The transmission pattern of NIID in the families reported by Ishiura et al. (2019) and Sone et al. (2019) was consistent with autosomal dominant inheritance.
The transmission pattern of NIID in the families reported by Tian et al. (2019) was consistent with autosomal dominant inheritance; there was some evidence of genetic anticipation.
Reported cases of central nervous system NIID are usually sporadic, but the disorder was described in identical twins by Haltia et al. (1984).
Kimber et al. (1998) and Zannolli et al. (2002) suggested that NIID is an autosomal dominant disorder.
In affected members of 9 unrelated Japanese families with NIID and in 40 Japanese patients with sporadic NIID, Sone et al. (2019) identified a heterozygous trinucleotide repeat expansion (GGC) in the 5-prime untranslated region of the NOTCH2NLC gene (618025.0001). The mutation, which was found by a combination of linkage analysis, long-read whole-genome sequencing, and a specific protocol to detect tandem repeats, segregated with the disorder in all families. The repeat number in a total of 63 patients ranged from 71 to 183, and the repeat number among 225 controls ranged from 6 to 30, although 1 control had 61 repeats and may have been a presymptomatic carrier. RNA analysis of NOTCH2NLC in fibroblasts derived from 2 patients from 1 family showed normal expression levels, but abnormal antisense transcripts and evidence of differentially expressed genes. However, there was no difference in methylation of a CpG island immediately downstream of the repeat. Many of the families and patients had previously been reported.
Independently and simultaneously, Ishiura et al. (2019) identified a heterozygous expanded CGG repeat in the 5-prime untranslated sequence of the NOTCH2NLC gene in 12 probands from unrelated Japanese families with NIID and in 14 Japanese patients with sporadic NIID. The abnormal expansions segregated with the disorders in 3 families who were studied in detail. The repeat expansion was also identified in 2 Malaysian males of Chinese descent with the disorder. The number of CGG repeat units among patients ranged from 90 to 180, whereas the number of repeat units in over 1,000 controls ranged from 7 to 43. The authors observed intergenerational instability of expanded repeats in 2 parent-offspring pairs, although genetic anticipation could not be confirmed. Noting the phenotypic overlap with other expanded trinucleotide repeat disorders, mainly FXTAS (300623), Ishiura et al. (2019) hypothesized that NIID is also caused by an expanded trinucleotide repeat. The authors used whole-genome sequencing data from the NIID patients and applied a software program to analyze short reads for abnormal tandem repeats. The identified tandem repeat expansions in the NOTCH2NLC gene were confirmed by RP-PCR, Southern blot, and long-read sequence analyses. Examination of the expanded sequence from 1 patient suggested that the expanded CGG repeat was hypermethylated; however, there was no difference between RNA transcript levels of 3 patients compared to 8 controls. Many of the families and patients had previously been reported. (Ishiura et al. (2019) indicated that the NOTCH2NLC and NBPF19 (614006) genes are identical, but Scott (2019) stated that the genes are distinct and that the repeat occurs in the NOTCH2NLC gene.)
Tian et al. (2019) identified a heterozygous GGC repeat expansion in the NOTCH2NLC gene in affected members of 4 unrelated Chinese NIID families and in 5 patients with sporadic NIID. The variant in the first family, which was a 5-generation family, was found by a combination of linkage analysis and long-read genome sequencing and confirmed by PCR analysis. The expanded repeat segregated with the disorder in the families. Subsequently, 3 additional families with a diagnosis of Parkinson disease and 2 additional families with a diagnosis of Alzheimer disease were identified by long-read sequencing, bringing the total to 9 unrelated families. The repeat size among 211 healthy controls ranged from 5 to 38, with nodes at 11 and 16 repeats, whereas all familial and patients with sporadic disease had repeats larger than 66 (range 66 to 517). The number of GGC repeats in the muscle weakness-predominant phenotypic subtype ranged from 118 to 517; the repeat size in the parkinsonism-dominant subgroup ranged from 66 to 102; and the repeat size in the dementia-dominant subtype ranged from 91 to 268 GGC repeats. There was no significant difference in methylation pattern or expression of NOTCH2NLC between controls and patients, suggesting that the expanded repeat may be pathogenic at the RNA level. Tian et al. (2019) noted that NOTCH2NLC is a human-specific gene whose expression in the human brain increases significantly with age, which may explain the later onset of features in most patients.
In 15 Chinese patients from 12 unrelated families with NIID, Deng et al. (2019) identified a heterozygous pathogenic trinucleotide GGC repeat expansion in the 5-prime region of the NOTCH2NLC gene. Initial whole-genome sequencing failed to identify a potential causative abnormality; the mutation was found by long-read sequencing of the short tandem repeat expansion of this gene based on the report of Sone et al. (2019). The findings were confirmed by RP-PCR and the expansion segregated with the disorder in the families. Functional studies were not performed, and the authors noted that a limitation of their study was that precise numbers of GGC repeats were not calculated. However, Deng et al. (2019) noted that the unaffected mother of patient 6 (P6, who had onset at age 16), had an expansion that did not reach a pathogenic level, suggesting possible genetic anticipation.
Among 12 unrelated patients with NIID, Chen et al. (2020) identified a pathogenic repeat expansion in the NOTCH2NLC gene. There were 10 unrelated Chinese patients and 2 Malaysian brothers. The median length of the repeat in patients was 107 units (range 92 to 138) compared to a median length of 24 unit (range 14 to 39) in 50 controls. Of note, the 2 Malaysian sibs had expanded repeats on both alleles (106/58 and 128/62). Five of 10 patients studied had GGA or AGC interruptions within the GGC expansion, which was associated with an earlier age at onset and higher frequency of dementia.
At the time of the report of Yau et al. (2020), pathogenic repeat expansions in the NOTCH2NLC gene associated with neurologic disease had been identified only in individuals of East Asian descent. Yau et al. (2020) did not identify a pathogenic repeat expansion in the NOTCH2NLC gene among 52 European patients with adult-onset leukoencephalopathy. The estimated repeat size found in this cohort ranged from 12 to 26. The authors suggested that there may be a founder effect in the East Asian population. However, Doi et al. (2020) responded that their studies had not identified a founder effect among Japanese NIID cases.
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