Discussion
SMA-LED and CMT2O are related to DYNC1H1 mutations and are
characterized by predominant wasting and weakness of lower limbs,
delayed motor milestones, and abnormalities on electromyography (EMG)
examination. In this study, we reported two CMT2O cases with
heterozygous DYNC1H1 mutations c.1792C>T/p.R598C and
c.790C>G/p.R264G, respectively. The former mutation of
DYNC1H1 is, to our knowledge, the first one reported in East Asia that
causes CMT 2O, and the latter is a novel dominant mutation reported for
the first time worldwide. In addition, we analyzed the clinical
phenotypes of neuromuscular diseases caused by DYNC1H1 mutations
and relevant genotype-phenotype correlation in previous publications. We
compared the clinical characteristics between the two disease entities.
We found that all CMT2O patients were presented with distal-dominant
wasting, while proximal-dominant lower limb wasting can be observed in
some cases of SMA-LEDs. We also found that patients with mutations in
the DYN1 region may have more severe phenotype than those mutated in the
DHC_N1 region.
Our results showed that weakness and wasting of lower limbs were the
most common clinical phenotype of DYNC1H1- related neuromuscular
diseases. Delayed motor milestones were also observed in a large
percentage of patients. The most common phenotype on physical
examination was decreased or absent tendon reflex. This was in
accordance with previous animal experiments that the Swlheterozygous mutation of Dync1h1 led to absent H reflex in mice,
even if the motor nerve function was normal (Chen et al., 2007).
The most common clinical features of SMA-LED and CMT2O, including
delayed motor milestones and lower limb-predominant wasting and
weakness, are often not specific, especially in the early stage of the
diseases. Typically, SMA-LED and CMT2O are diagnosed and differentiated
according to EMG results. On EMG examination, SMA-LED is characterized
by motor axonal or motor neuron loss, which is in the form of active
denervation, compensatory reinnervation and enlargement of the motor
unit action potential (Arnold, Kassar, & Kissel, 2015). CMT2O usually
presents a typical pattern of axonal neuropathy affecting both motor and
sensory modalities on EMG, similar to other CMT type2 diseases (Pakhrin
et al., 2018). Our study also suggested the NCV test as another
applicable electrophysiological approach to differentiate these disease
entities, as abnormal NCV result may be more commonly seen in SMA-LED
than that in CMT2O. However, in the early stage of these diseases,
electrophysiological abnormalities may not be typical enough to make an
accurate diagnosis. Therefore, considering the common variants of gene
that may lead to SMA-LED and CMT2O, clinical phenotypes may be an
essential characterization in the early diagnosis and differentiation of
these two disease entities. In our study, it was found that all CMT2O
patients were presented with distal-dominant wasting, while
proximal-dominant lower limb wasting can be observed in some cases of
SMA-LEDs. Besides, SMA-LED patients had a higher percentage of
proximal-dominant weakness of lower limbs, while CMT2O patients more
frequently presented distal-dominant weakness. This may suggest that
although lower limb involvement is a common feature of both diseases,
they may have different distribution pattern of muscle impairment, which
may provide some insights for clinicians when making an early diagnosis.
In addition, abnormal sensation was more common in CMT2O patients,
consistent with earlier reports that SMA-LED patients are usually exempt
from sensory impairment (Arnold et al., 2015). Therefore, the
involvement of the sensory system may be a relatively strong indicator
of CMT2O in patients with DYNC1H1 mutation presenting relevant
clinical manifestations.
DYNC1H1 mutations involved in our study were located either in the
DHC_N1 region or in the DYN1 region. Not only did patients with
mutations in DYN1 present with more severe atrophy and weakness of lower
limbs, but they may also show clinical phenotypes more complicated and
difficult to make a right diagnosis. Besides, manifestations of CNS
impairment, such as epilepsy, cognitive impairment, ADHD and abnormal
brain MRI was more common in patients with mutations in the DYN1 region.
This is in accordance with earlier finding that mutations in the tail
domain (close to the N-terminal) usually lead to pure motor neuron
deficits hardly with any signs of brain abnormalities (Harms et al.,
2012); (Rossor et al., 2012), while mutations in the motor domain (close
to the C-terminal) often cause malformation of cortical development
(MCD) and epilepsy (Poirier et al., 2013). Interestingly, no DYNC1H1
mutation related to motor neuron diseases has been observed located in
the C-terminal (Dynein_C region). This suggests a highly clinical
heterogeneity of DYNC1H1 variants, the mechanism of which
warrants further investigation, such as epigenetic modification,
environmental exposure, etc. In addition, as precision medicine is
becoming more and more advocated, this genotype-phenotype correlation ofDYNC1H1 mutation may serve as a reference for accurate diagnosis
and personalized treatment.
Our study also suggested that some mutation sites of DYNC1H1 had
a higher recurrence rate than other sites, of which exon 8 seemed to be
the mutational hot region and c.1792C>T/p.R598C was the
most frequent point mutation. However, no c.1792C>T/p.R598C
mutation has been found in the East Asian population at present,
although some other recurrent DYNC1H1 mutations have been
detected in East Asia. On one hand, this discrepancy may reflect
differences on genetic level among different races; on the other hand,
this result may be due to the relatively limited amount of cases in this
area. Considering the large population basis in East Asia, more
different kinds of DYNC1H1 mutations may be gradually detected,
as our team recently identified a teenage patient with CMT2O caused by
c.1792C>T/p.R598C heterozygous mutation in DYNC1H1 .
Up to now, no specific treatment for SMA-LED and CMT2O has been put
forward yet, thus symptomatic treatment and orthopedic surgery remain
important in order to decrease the risk of complications of these
diseases as early as possible. Therefore, genetic testing is of
necessity in early diagnosis and prompt treatment. Besides, gene
treatment, such as genome editing, provides new insight into treating
diseases caused by pathogenic gene mutations, especially those with high
recurrent rate. In this regard, early genetic testing for clinically
suspected SMA-LED or CMT2O patients will be illustrating for applying
appropriate therapeutics and trying new therapeutic techniques.
The conclusions of this study shouldn’t be assessed without the
consideration of several limitations. Firstly, not all patients have a
well-recorded phenotype, though the literature were systematically
reviewed. Thus, the study did not present a complete mutation spectrum
since patients without any detailed description of clinical features are
not studied. Secondly, the reporting bias of included articles cannot be
ignored because cases with recurrent variants and classical phenotypes
were less likely to be reported. Thirdly, all these comparisons are
based on cases in the literature and online database. Therefore, the
genotype-phenotype correlations should be validated in an independent
cohort. Despite the limitations above, our study provided a
comprehensive summary of the DYNC1H1 mutations spectrum by
selecting SMA-LED and CMT2O diseases and unrevealed the hidden
correlation between genotype and phenotype.