Clinical phenotypes of neuromuscular diseases caused byDYNC1H1 mutation
A total of 105 patients with neuromuscular diseases were reported
carrying DYNC1H1 mutations, among which 103 (43 males, 27 females
and 33 genders not mentioned) harbored one heterozygous variant inDYNC1H1 . In comparison, the other two patients (a young male and
his mother) had two variants. Of 66 patients with exact ages provided,
the average age was 21.8±19.7 years old (range, 1.0 -82.0; median,
15.5). The onset age of the patients with DYNC1H1 mutations was
relatively young, with 34/90 (37.8%) at birth, 27/90 (30.0%) in
infancy (<1 year), 14/90 (15.6%) in early childhood (1-3
years), 7/90 (7.8%) in childhood (3-12 years), 1/90 (1.1%) at juvenile
(12-18 years) and 7/90 (7.8%) in adulthood (>18 years)
(Fig.4A). Muscle weakness of lower limbs was the most common clinical
phenotype of these patients (98/102 patients, 96.1%). The distribution
of lower limb weakness was different among patients, with 44/68 (64.7%)
presented with proximal-dominant weakness, 16/68 (23.5%) had
distal-dominant weakness, and 10/68 (14.7%) showed similar severity of
muscle weakness between proximal and distal lower limbs. Although the
incidence of weakness was high, most patients remained ambulant (89/102,
87.3%), and Gower’s sign was not common in patients (9/54, 16.7%),
suggesting the relatively mild degree of lower limb and trunk muscle
impairment. Muscle wasting of lower limbs was also a predominant
clinical phenotype with 83/98 (84.7%) patients involved, among which
more patients (34/55, 61.8%) showed distal-dominant atrophy compared to
proximal-dominant atrophy (11/55, 20.0%). A small part of patients
(18/97, 18.6%) also had upper limb involvement. However, the
involvement of trunk muscles was rare, which was observed in 5/97
(5.2%) patients. Delayed motor milestones were usually the earliest
clinical manifestation of patients with SMA-LED or CMT2O and were
reported in 54/90 (60%) patients. The sensory system was usually
exempted from the diseases, with 10/84 (11.9%) presented with sensory
abnormalities. Most patients (91/101, 90.1%) showed deformities that
predominantly involving the musculoskeletal system. Of these
abnormalities, joint contracture or deformities occurred in 36/91
(39.6%) patients. Pes cavus occurred in 37/91 (40.7%) patients
and pes planus was observed in 6/91 (6.6%) patients. In
addition, 26/91 (28.6%) patients had other kinds of feet deformities.
There were 3/91 (3.3%) patients and 25/91 (27.5%) patients presenting
with hand and spine deformities, respectively. Other kinds of
abnormalities involving other body parts were also found in 20/91
(22.0%) patients, including scapular winging, high-arch palate,
exotropia, retinoblastoma, strabismus, bilateral congenital cataract,
aortic root dilation, accessory spleen and facial dysmorphia, etc. The
involvement of the central nervous system (CNS) was relatively less
common. Seizure episode occurred in 11/101 (10.9%) patients. About a
third patients (31/94, 33.0%) had abnormal intelligence or delayed
intelligence development and 13/94 (13.8%) were diagnosed as attention
deficit hyperactivity disorder (ADHD). The impairment of intelligence
was mostly mild (17/21, 81.0%), followed by severe (3/21, 14.3%) and
moderate (1/21, 4.8%) level. The percentage of some clinical phenotypes
were shown in Fig.4B.
The most notable clinical phenotype on physical examination was abnormal
tendon reflex in lower limbs, which was observed in 75/90 (83.3%)
patients. Most of these patients (73/75, 97.3%) showed decreased or
absent tendon reflex, while increased tendon reflex was also found
(2/75, 2.7%). Serum creatine kinase (CK) level only increased in 3/24
(12.5%) patients. The nerve conduction velocity (NCV) test usually
showed normal results, with only 10/57 (17.5%) exceptions. In addition,
abnormal brain MRI was detected in 18/30 (60.0%) patients. The detailed
information of clinical phenotypes of patients with neuromuscular
diseases caused by DYNC1H1 mutations was listed in table S2.