Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease

Abstract

Background and Aims

Differentiating hereditary axonal polyneuropathies caused by distinct gene variants remains a clinical challenge. This comparative case study of DNAJB2- and HINT1-related neuropathies aimed to broaden the phenotypic spectrum associated with these genes and to explore non-motor symptoms and quality of life (QoL) in affected individuals.

Methods

Six patients carrying two novel DNAJB2 variants and six age-matched patients with HINT1 variants underwent detailed clinical and electrophysiological characterization. Motor function was assessed longitudinally using the Medical Research Council (MRC) scale. Non-motor symptoms (neuropathic pain, autonomic dysfunction, depression, fatigue, restless legs syndrome) and QoL were evaluated with patient-reported outcomes and compared to four healthy controls (HC).

Results

Both patient groups exhibited a CMT2 phenotype. Nerve conduction studies revealed a length-dependent axonal predominantly motor but not pure motor neuropathy in most of the patients. Disease onset tended to occur later in patients with DNAJB2 variants, who yet developed more severe neuropathy. The spectrum of additional clinical features differed between the two groups. All patients with DNAJB2 variants fulfilled criteria for depression, compared with one with a HINT1 variant. Significant fatigue was present in the majority of both groups, while restless legs syndrome was observed in four patients with a DNAJB2 variant but in none with a HINT1. QoL was significantly reduced in DNAJB2 versus HC, with no difference in QoL between patients with DNAJB2 and HINT1 variants.

Interpretation

This study expands the clinical spectrum of DNAJB2- and HINT1-related neuropathies, highlighting distinct non-motor features and their impact on QoL, and providing the first direct comparison of these two rare axonal disorders.