Clinical phenotypic and genetic analysis of two CMT2O cases
Case 1 is a 14-year-old female patient who complained of difficulty standing upright from a squatting position for over one year and came to Huashan Hospital, Fudan University for further examination. Her mother declared that the patient learned to walk at 14 months of age and ran slower than her peers since childhood. On physical examination, the patient presented with pes cavus and muscle wasting of distal lower limbs. Muscle strength was normal except for 4/5 weaknesses of distal upper limbs and 4/5 bilateral lower limbs weaknesses. Tendon reflexes were attenuated in all limbs, and Babinski’s sign was negative. The sensory system was normal on examination. The patient also showed an unaffected intelligence level. Her parents presented normal, and there was no related family history (Fig.1A).
Case 2 is a 15-year-old male patient who came to Huashan Hospital, Fudan University, due to the noticeable thinning of lower limbs for two years. His father complained that the patient could walk at 19 months of age and had been prone to fall since childhood. Physical examination showed mild lordosis and muscle wasting of both lower limbs. Muscle strength was normal except for 4/5 weakness of bilateral distal lower limbs. Tendon reflexes were attenuated. Babinski’s sign was absent. The patient’s sensory examination was normal with an unaffected intelligent level. His parents were both normal, and no related family history was declared (Fig.1B).
Laboratory examinations revealed normal (181 U/L) and elevated (294 U/L) level of serum creatine kinase in the two patients, respectively. In case 1, electromyogram (EMG) suggested anterior spinal horn deterioration, and the involvement of motor nerve axons could not be excluded as well. And in case 2, EMG showed chronic neurogenic damage with consideration of impairment of anterior horn motor neurons or anterior spinal root. The nerve conduction velocity (NCV) test, motor nerve F wave latency, H reflex latency and repetitive nerve stimulation (RNS) revealed normal results in both patients. In the second patient, MR scan of the femur showed a partial fat signal suggesting muscle atrophy of the right thigh muscle group and a small amount of effusion in the right hip joint cavity. Biopsy of the left sural nerve revealed that the pathological changes were consistent with pathological characteristics of chronic axonal peripheral neuropathy.
Whole-exome sequencing discovered DYNC1H1 c.1792C>T/p.R598C and DYNC1H1 c.790C>G/p.R264G heterozygous mutations in the two patients, respectively, the latter of which is a novel mutation site that has not been reported before. Sanger sequencing revealed that the parents of both patients did not carry these point mutations (Fig.1A, B), indicating these mutations de novo. Bioinformatics software (Polyphen2, SIFT, Mutation Taster) and ACMG guidelines predicted both mutations as ”pathogenic” (Fig.1C).