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.