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).