Table 1.
Demographics, clinical presentation and pathological findings of cases of neuronal intranuclear inclusion disease (NIID) examined, with resulting analysis for HRNR variants
| ID | Age of onset | Age at death | Sex | Family history | Country of origin | Clinical Diagnosis/Presentation pre-biopsy | Main pathological findings and site of pathology | HRNR variant | Estimated number of GGC repeats in NOTCH2NLC | |
|---|---|---|---|---|---|---|---|---|---|---|
| Allele 1 | Allele 2 | |||||||||
| 1 | 17 | 24 | M | Yes | UK | Young-onset parkinsonism and dysautonomia | Widespread neuronal hyaline intranuclear inclusions immunoreactive for ubiquitin and p62 (brain) | No variants detected | 21 | - |
| 2 | 33 | 46 | M | Yes | Australia | Slowly progressive motor and sensory neuronopathy with ataxia | Eosinophilic neuronal intranuclear inclusions (brain) | No variants detected | 22 | 28 |
| 3 | 60 s | 67 | F | No | Australia | Unknown presentation | Eosinophilic intranuclear inclusions in pyramidal cells (brain) | c.3236 G > A, p.(Glu1054Lys), synonymous c.3346 C > T | 15 | 20 |
| 4 | 52 | 72 | F | No | Australia | Slowly progressive primary lateral sclerosis | Cortical neuronal and astrocytic intranuclear inclusions (brain) | No variants detected | 15 | 23 |
| 5 | 11 | 21 | F | Yes (monozygotic twin) | Finland | Ataxia, seizures, and extrapyramidal symptoms | Inclusion bodies in most nerve cell types of central and peripheral nervous systems, as well as in occasional astrocytes | c.3023 G > C, p.(Ser1008Thr) – confirmation of variant found in the same individual by Park et al.[1] | 19 | 22 |
| 6 | 49 | 62 | F | Yes | Spain | Ataxia | Intranuclear hyaline inclusions in neurons and glia in widespread areas of the brain immunoreactive for ubiquitin (brain) | No variants detected | 15 | 25 |
| 7 | 82 | 84 | F | Yes | Spain | Dementia | Intranuclear hyaline inclusions in neurons and glia in widespread areas of the brain immunoreactive for ubiquitin (brain) | No variants detected | 16 | 23 |
| 8 | 26 | - | F | No | USA | Unknown presentation | Pathological changes in keeping with NIID (brain) | No variants detected | 17 | 23 |
| 9 | 84 | - | M | No | USA | Alzheimer’s disease, ataxia | Intranuclear hyaline inclusions in neurons and glia in widespread areas of the brain (brain) | c.3236 G > A, p.(Glu1054Lys), synonymous c.3346 C > T | 15 | 19 |
| 10 | 69 | - | M | No | USA | Diagnosed clinically with NIID | Neuronal intranuclear inclusions (brain) | No variants detected | 14 | 27 |
| 11 | 80 | - | M | No | USA | Unknown presentation | Neuronal intranuclear inclusions (brain) | c.3236 G > A, p.(Glu1054Lys), synonymous c.3346 C > T | 19 | - |
| 12 | 51 | N/A | F | No | Ukraine | Recurrent encephalopathy and migraines | NOTCH2NLC repeat expansion positive NIID: Antemortem biopsy contains p62 positive intranuclear inclusions (skin) | No variants detected | 19 | 92–106 |
All cases were previously investigated for the NOTCH2NLC GGC repeat expansion with sizing of the repeat sequence through repeat-primed PCR [7]. NIID cases 1 to 11 were not associated with repeat expansion in NOTCH2NLC. Case 12 was the only case found to have a GGC repeat expansion in NOTCH2NLC to be associated with NIID, with repeat sizing from Oxford Nanopore Technologies long-read sequencing. Case 5 is the case investigated by Park and colleagues [1, 8]