Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

Abstract

Background Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of diseases characterized by exclusive degeneration of peripheral motor nerves, while only 20.0–47.8% of dHMN patients are genetically identified. Recently, GGC expansion in the 5’UTR of NOTCH2NLC has been associated with dHMN. Accordingly, short tandem repeat (STR) should be further explored in genetically unsolved patients with dHMN. Methods A total of 128 patients from 90 unrelated families were clinically diagnosed as dHMN, and underwent a comprehensively genetic screening. Skin biopsies were conducted with routine protocols. Results Most patients showed chronic distal weakness of lower limbs (121/128), while 20 patients initially had asymmetrical involvements, 14 had subclinical sensory abnormalities, 11 had pyramidal impairments, five had cerebellar disturbance, and four had hyperCKmia. The rate of genetic detection was achieved in 36.7% (33/90), and the rate increased to 46.7% (42/90) if patients with variants uncertain significance were included. The most common causative genes included chaperone‐related genes (8/33, 24.2%), tRNA synthetase genes (4/33, 12.1%), and cytoskeleton‐related genes (4/33, 12.1%). Additionally, two dominant inherited families were attributed to abnormal expansion of GGC repeats in the 5‘UTR of NOTCH2NLC; and a patient with dHMN and cerebellar symptoms had CAG repeat expansion in the ATXN2 gene. Skin biopsy from patients with GGC expansion in NOTCH2NLC revealed typical intranuclear inclusions on histological and ultrastructural examinations. Interpretations This study further extends the genetic heterogeneity of dHMN. Given some dHMN patients may be associated with nucleotides repeat expansion, STR screening is necessary to perform in genetically unsolved patients.

Subclinical peripheral neuropathy is common in neuronal intranuclear inclusion disease with dominant encephalopathy

“…More recently, the expansion accounted for 10.6% (seven of 66) of molecularly unsolved CMT2 cases in a Taiwanese Charcot–Marie–Tooth disease (CMT) cohort, and most affected individuals presented as mild axonal sensorimotor polyneuropathy [16]. In addition, distal hereditary motor neuropathy was identified in some patients with CGG expansion in NOTCH2NLC [17]. Collectively, pure or dominant peripheral neuropathy mimicking CMT can be one phenotype of NIID.…”

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

“…Therefore it was necessary to measure the CGG repeat number to determine its pathogenicity in the genetic diagnosis of NIID patients. The repeat expansion in NOTCH2NLC also showed some rare clinical phenotypes, such as neurodegenerative dementia ( Jiao et al, 2020 ), non-vascular leukoencephalopathy ( Liu et al, 2022 ), motor neuron disease ( Yuan et al, 2020 ), sensorimotor with autonomic neuropathy ( Wang et al, 2021 ), distal motor neuropathy ( Wu et al, 2022 ), as well as oculopharyngeal distal myopathy (OPDM) ( Yu et al, 2021 ). Because of the small number of these cases, the relationship between the clinical phenotype and the number of CGG repeat had not been established, but distal motor neuropathy and OPDM were generally considered to have more repeats.…”

The polyG diseases: a new disease entity

“…Nevertheless, several studies have indicated that carriers with more than 300 repeats of expanded CGG show a mild or asymptomatic phenotype [ 20 , 127 ]. Beyond NIID, expanded CGG repeats in NOTCH2NLC are occasionally related to a small proportion of Parkinson's disease (PD) [ 65 , 97 , 110 ], multiple system atrophy (MSA) [ 29 ], essential tremor (ET) [ 105 ], degenerative dementia [ 4 , 101 ], ALS [ 46 , 130 ], inherited peripheral neuropathy [ 118 ], distal motor neuropathy [ 122 , 128 ], mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) [ 57 , 123 ], and oculopharyngodistal myopathy (OPDM) [ 127 ]. Intriguingly, CGG expansion in NOTCH2NLC was rarely detected in NIID cases reported in people of Caucasian descent, suggesting that NIID is likely to be genetically heterogeneous among different ethnic groups [ 15 ].…”