Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy

Abstract

Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical phenotypes caused by the intronic repeat expansion of NOTCH2NLC. 1,2 An acute encephalopathic episode can manifest in some patients with NIID. 3,4 Herein, we report an NIID patient harboring a de novo {(GGA) n (GGC) n } n repeat expansion in NOTCH2NLC, who developed abrupt mitochondrial encephalomyopathy, lactic acidosis, and stroke-like (MELAS)-like episode in the 15-year course clinical diagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Case report A 31-year-old woman developed slowly progressing muscle weakness and paresthesia in all extremities. Neurologic examination at 33 years of age revealed distal dominant muscle weakness with areflexia and abnormal deep sensations in all extremities without obvious cranial nerve involvement. A nerve-conduction study revealed sensorimotor polyneuropathy in all extremities (table e-1, links.lww.com/NXG/A335). Although clinical and electrophysiologic features met the diagnostic criteria for CIDP, 5 she showed limited response to immunotherapy. At 45 years, she abruptly started experiencing headaches, nausea, and eventually, loss of consciousness. Neurologic examination revealed left conjugate eye deviation, neck stiffness, and left hemiparesis. Blood analysis revealed an elevated blood lactate/pyruvate molar ratio (lactate: 2.1 mmol/L, pyruvate: 0.022 mmol/L, molar ratio: 91, normal range <25.8). Brain MRI showed abnormal hyperintensities in the right hemisphere on diffusion-weighted images (DWIs) (figure, A) and T2weighted images (figure, B), with gadolinium enhancement not corresponding to the vascular distribution. Hyperperfusion on arterial spin labelling (figure, C), dilation of the right cerebral artery (figure, D), and elevated lactate peak on magnetic resonance spectroscopy (MRS) (figure, E) in the involved areas were also identified. She was diagnosed with MELAS and was administered IV levetiracetam, edaravone, and oral taurine. She gradually improved without residual cognitive disturbances. Neither histopathologic studies nor whole mitochondrial genome sequence analysis on muscle biopsy showed any specific findings for mitochondrial disease. At 47 years of age, a follow-up neurologic examination revealed bilateral miosis with sluggish response to light. Brain MRI revealed both gray and white matter hyperintensities on T2-weighted images corresponding to acute encephalopathic lesions (figure, F and G). However, there was no abnormal corticomedullary hyperintensity on DWI. Abdominal skin biopsy performed at 47 years of age and re-examination of the sural nerve sample at 35 years resulted in NIID diagnosis, demonstrating eosinophilic intranuclear inclusions surrounded by a halo and antiubiquitin and p62-immunoreactive intranuclear inclusions in fibroblasts, sweat gland cells (figure, H),

A Case Report of Neuronal Intranuclear Inclusion Disease Presenting With Recurrent Migraine-Like Attacks and Cerebral Edema: A Mimicker of MELAS

“…Additionally, DWI high signals on the corpus callosum and symmetrical T2 high signals of the cerebral white matter are also useful diagnostic clues. Cerebral edema not corresponding to the vascular distribution has only been reported in a few cases of NIID ( 5 , 7 , 8 , 10 ). This could be easily misdiagnosed as MELAS when there was no abnormal corticomedullary hyperintensity on DWI ( 8 , 10 ).…”

“…Cerebral edema not corresponding to the vascular distribution has only been reported in a few cases of NIID ( 5 , 7 , 8 , 10 ). This could be easily misdiagnosed as MELAS when there was no abnormal corticomedullary hyperintensity on DWI ( 8 , 10 ). Actually, our patient had been initially considered as MELAS and NIID was suspected as faint DWI high-intensity signals in the corticomedullary junction was retrospectively recognized.…”

Father-to-offspring transmission of extremely long NOTCH2NLC repeat expansions with contractions: genetic and epigenetic profiling with long-read sequencing

“…II-1 in Family F2 (Patient 11 in a previous report) had leukoencephalopathy [ 10 ]. II-2 in Family F3 was diagnosed as NIID with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) in her clinical course of polyneuropathy [ 9 ]. II-2 in Family F4 is an affected twin with oculopharyngodistal myopathy (OPDM) (patient 7 in a previous report) [ 8 ].…”

Clinical and mechanism advances of neuronal intranuclear inclusion disease

“…In addition, the reflexes in some patients with NIID were hyporeflexia ( Hirose et al, 2018 ). A recent study reported a case of NIID with mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS)-like episodes in chronic polyneuropathy, and this patient developed slowly progressing muscle weakness and paraesthesia in all extremities ( Ishihara et al, 2020 ).…”

“…Although progressive symptoms, such as cognitive impairment and parkinsonism, are key features of NIID as a neurodegenerative disease, episodic attacks are also found in some patients with NIID, such as encephalitis-like, vestibular migraine-like attacks, or MELAS-like or epileptic episodes ( Xiao et al, 2018 ; Yamanaka et al, 2019 ; Ishihara et al, 2020 ; Li et al, 2020b ; Ataka et al, 2021 ; Zhao et al, 2021 ).…”