Unusual electrophysiological findings in a Chinese ALS 4 family with SETX-L389S mutation: a three-year follow-up.

Amyotrophic lateral sclerosis type 4 (ALS4) is a familial form of ALS caused by mutations in the SETX gene. To date, there are seven unrelated ALS4 families with four missense mutations (L389S, T31I, R2136H, and M386T) in SETX. ALS4 is characterized by early onset, distal muscle weakness and atrophy, pyramidal signs, and the absence of sensory deficits. Motor conduction studies often present normality or reduced amplitudes of compound muscle action potential (CMAP). The conduction blocks (CBs) are rare and only observed in one male of an Italian ALS4 family. Our study showed that seven symptomatic patients presented the classical ALS4 phenotype with two asymptomatic females in a Chinese family spanning three generations. Sequencing analysis revealed a heterozygous c.1166T > C/p.L389S mutation in SETX that co-segregated with disease phenotype in the family. The same mutation has been identified previously in three ALS4 families from the United States and Italy, respectively. Specifically, three young males presented multiple CBs and abnormal temporal dispersions (TD) in the median, ulnar and tibial nerves over the three-year follow-up period. Moreover, for the first time, we found that senataxin was also expressed in the myelin sheath of peripheral nerves besides axons. The study indicates that CBs and abnormal TD are the characteristics in the ALS4 family, providing pivotal familial evidence of CBs and TD of motor nerves in ALS4. The unusual electrophysiological features may be associated with the expression of senataxin in peripheral nerves.

Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain.

Limb-girdle muscular dystrophies (LGMD) are a group of clinically and genetically heterogeneous diseases characterized by weakness and wasting of the pelvic and shoulder girdle muscles. Twenty-four recessive LGMD (types R1-R24) and five dominant LGMD (types D1-D5) have been identified with characterization of mutations in various genes. To date, LGMD D3 (previously known as LGMD1G) has been characterized in only two families with Brazilian or Uruguayan origin. Each was caused by a distinct mutation at codon 378 in the prion-like domain of HNRNPDL encoding heterogeneous nuclear ribonucleoprotein D like (HNRNPDL), an RNA processing protein. Our study characterized eight patients suffering from LGMD D3 in a Chinese family spanning three generations. Muscle biopsy specimens from two patients showed a myopathy with rimmed vacuoles. Sequencing analysis revealed a heterozygous c.1132G > A (p.D378N) mutation in HNRNPDL that co-segregated with disease phenotype in the family. The same mutation has been identified previously in the Brazilian family with LGMD D3. However, most patients in the current family showed distal as well as proximal limb weakness rather than weakness of toe and finger flexor muscles that were typical features in the other two LGMD D3 families reported previously. The present study indicates that the same mutation in HNRNPDL results in various phenotypes of LGMD D3. That all mutations in three unrelated families with different ethnic background occur at the same position in codon 378 of HNRNPDL gene suggests a mutation hotspot. Acceleration of intrinsic self-aggregation of HNRNPDL caused by mutation of the prior-like domain may contribute to the pathogenesis of the disease.