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

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.

Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease

“…The identical DWI subcortical high intensity was thought to be a specific sign for NIID30 31; however, it was less common in the muscle weakness and movement disorder types, making it difficult to be associated with NIID. Furthermore, it was also reported in other CGG repeat expansion diseases, including fragile X-associated tremor/ataxia syndrome (FXTAS) and oculopharyngeal myopathy with leukoencephalopathy 14 32 33. In addition, we reported diffuse DWI high signal in the white matter of patients with NIID 34.…”

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

“…These aggregates are present in both neurons and glial cells in the central and peripheral nervous systems, as well as in various other tissues, including the skin, which observation can be determinant to confirm diagnosis of this multifaced syndrome (Patel et al, 1985;Kimber et al, 1998;Pountney et al, 2003;Liu et al, 2008;Sone et al, 2011;Mori et al, 2012;Chen H. et al, 2020;Zhang et al, 2021). Importantly, these intranuclear inclusions are virtually identical and indistinguishable to those observed in FXTAS (Gelpi et al, 2017;Lim et al, 2020;Toko et al, 2021). Similarly, brain MRI of individuals with NIID reveal abnormalities reminiscent of FXTAS with mild brain atrophy and white matter lesions, including T2-weighted hyperintensities in the middle cerebellar peduncle and high-intensity signals in the corticomedullary junction (Gelpi et al, 2017;Sugiyama et al, 2017;Ng et al, 2020b).…”

Clinical and mechanism advances of neuronal intranuclear inclusion disease

“…Because FXTAS and NIID are both autosomal-dominant GGC trinucleotide repeat expansion diseases in different genes (FMR1 gene and NOTCH2NLC gene, respectively) ( Padilha et al, 2018 ; Toko et al, 2021 ), FXTAS is an important disease to differentiate from NIID. More importantly, FXTAS has similar clinical symptoms and radiological features to late-onset NIID, such as ataxia, tremor, Parkinsonism, cognitive decline, and bilateral high-signal abnormalities along the corticomedullary junction in DWI sequences ( Leehey, 2009 ; Padilha et al, 2018 ).…”