HINT1 neuropathy: Expanding the genotype and phenotype spectrum

Abstract

Inherited peripheral neuropathy (IPN) is a heterogeneous group of disorders due to pathogenic variation in more than 100 genes. In 2012, the first cases of IPN associated with HINT1 pathogenic variations were described in 33 families sharing the same phenotype characterized by an axonal neuropathy with neuromyotonia and autosomal recessive inheritance (NMAN: OMIM #137200). Histidine Triad Nucleotide Binding Protein 1 regulates transcription, cell-cycle control, and is possibly involved in neuropsychiatric pathophysiology. Herein, we report seven French patients with NMAN identified by Next Generation Sequencing. We conducted a literature review and compared phenotypic and genotypic features with our cohort.We identified a new HINT1 pathogenic variation involved in NMAN: c.310G>C p. (Gly104Arg). This cohort is comparable with literature data regarding age of onset (7,4yo), neuronal involvement (sensorimotor 3/7 and motor pure 4/7), and skeletal abnormalities (scoliosis 3/7, feet anomalies 6/7). We expand the phenotypic spectrum of HINT1-related neuropathy by describing neurodevelopmental or psychiatric features in six out of seven individuals such as generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), mood disorder and attention deficit hyperactivity disorder (ADHD). However, only 3/128 previously described patients had neuropsychiatric symptomatology or neurodevelopmental disorder. These features could be part of HINT1-related disease, and we should further study the clinical phenotype of the patients.

The HINT1 Gene rs2526303 Polymorphism and Its Association with Personality Traits in Cigarette Smokers

“…It is one of three HINT proteins (HINT1, HINT2, and HINT3) in the human genome. HINT1 regulates transcriptional and cell cycles [12]. Although HINT1 is expressed widely in the liver, kidney, and brain, including the mesocortical and mesostriatal regions [13], its physiological function must be better understood.…”

Association of the rs3864283 Polymorphism Located in the HINT1 Gene with Cigarette Use and Personality Traits

“…It is one of three HINT proteins (HINT1, HINT2, and HINT3) in the human genome. HINT1 is involved in transcriptional and cell cycle regulation [ 25 ]. Little is known about the physiological function of HINT1 protein, although it is widely expressed in the liver, kidney, and brain, including mesocortical and mesostriatal regions [ 26 ].…”