Introduction
Dynein cytoplasmic 1 heavy chain 1 (DYNC1H1), located on 14q32.31, is
the core structure of cytoplasmic dynein, which is a large
(~1.5 MDa) motor protein complex responsible for
retrograde axonal transport in all eukaryotic cells (Pfister et al.,
2006). DYNC1H1 plays an essential role in ATPase-dependent movement
along the microtubule and recruitment of other dynein subunits (Pfister
et al., 2006). Mutations in DYNC1H1 can lead to various
developmental and degenerative diseases of the nervous system, which are
referred to as ”dyneinopathy” characterized by locomotor and motor
system deficits, sensory system defects, and (or) brain morphology and
function abnormalities (Marzo et al., 2019).
Spinal muscular atrophy lower limb-dominant (SMA-LED, OMIM #158600) and
Charcot-Marie-Tooth type 2O (CMT2O, OMIM #614228) have both been
reported as hereditary neuromuscular diseases caused by DYNC1H1variants (Harms et al., 2012); (Tsurusaki et al., 2012); (Weedon et al.,
2011). Spinal muscular atrophy (SMA) is caused by the impairment of
motor neurons in the spinal cord. SMA-LED is an autosomal dominant
hereditary type of SMA characterized by muscle weakness and wasting
predominantly affecting the lower limbs (Harms et al., 2010).
Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and
sensory neuropathies (HMSN), is a genetically heterogeneous disease,
clinically characterized by progressive distal muscle weakness and
wasting, sometimes accompanied by sensory abnormalities. CMT2O was
firstly reported by Weedon et al. in a large four-generation
family and the patients presented with delayed motor milestones,
abnormal gait and slowly progressive distal lower limb atrophy and
weakness accompanied with pes cavus deformity (Weedon et al.,
2011), as we proposed the human mutation counterpart through mapping theSwl allele in a dync1h1 mutation animal model (Chen et
al., 2007).
SMA-LED and CMT2O share many common clinical phenotypes and will
sometimes be misdiagnosed. Although numerous cases have been reported
worldwide, the analysis on their manifestation difference and
genotype-phenotype correlation is still limited. In this study, we first
reported DYNC1H1 gene c.1792C>T/p.R598C and
c.790C>G/p.R264G pathogenic mutations in two CMT 2O cases,
respectively. Next, we reviewed previous publications and described the
phenotypic and genetic characteristics of neuromuscular diseases caused
by DYNC1H1 mutations and compared the clinical phenotypes between
SMA-LED and CMT2O. Furthermore, we focused on the genotype-phenotype
correlation of DYNC1H1 variants to provide references for making
personalized clinical decisions in clinical practice.