A number sign (#) is used with this entry because of evidence that autosomal dominant distal hereditary motor neuronopathy-15 (HMND15) is caused by heterozygous mutation in the BAG3 gene (603883) on chromosome 10q26. One such family has been reported.

Heterozygous mutation in the BAG3 gene can also cause myofibrillar myopathy-6 (MFM6; 612954), dilated cardiomyopathy-1HH (CMD1HH; 613881), and Charcot-Marie-Tooth disease-2JJ (CMT2JJ; 621095). These allelic disorders have overlapping features.

Autosomal dominant distal hereditary motor neuronopathy-15 (HMND15) is characterized by adult onset of slowly progressive distal weakness and atrophy of the lower limbs associated with absent reflexes. Sensory deficits are not present. Neurophysiologic studies are consistent with a distal motor neuronopathy (de Fuenmayor-Fernandez de la Hoz et al., 2024).

For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).

De Fuenmayor-Fernandez de la Hoz et al. (2024) reported a large Spanish family in which 8 individuals spanning 2 generations developed slowly progressive muscle weakness and atrophy affecting the distal lower limbs in their forties and fifties. Achilles reflexes were absent. The upper limbs and proximal lower limbs were not affected. The disorder was slowly progressive, but all remained ambulant, some with a cane. None had sensory abnormalities, except for PII-2, who reported sensory deficits at age 80. Of note, this patient also had MGUS (monoclonal gammopathy of undetermined significance), which may have contributed to the sensory loss. MRI studies in 5 patients showed fatty replacement of lower limb muscles in a distal to proximal gradient. EMG showed neuropathic changes consistent with chronic and ongoing axonal loss, and electrophysiologic studies showed decreased compound action motor potentials (CMAP) with normal nerve conduction velocities (NCV). Sensory conduction values were normal. Sural nerve biopsy was not performed; muscle biopsy in 3 patients showed denervation and renervation, but was otherwise normal. In particular, there were no signs of myofibrillar myopathy or rimmed vacuoles. Serum creatine kinase was normal or mildly increased. One 57-year-old female mutation carrier had only muscle cramps in her calves, without muscle weakness. Family history was notable for a deceased female obligate carrier who had no neuropathy symptoms when she died of gastric cancer at age 73.

The transmission pattern of HMND15 in the family reported by de Fuenmayor-Fernandez de la Hoz et al. (2024) was consistent with autosomal dominant inheritance with some evidence of incomplete penetrance in females.

In 8 affected members of a Spanish family with HMND15, de Fuenmayor-Fernandez de la Hoz et al. (2024) identified a heterozygous frameshift in the BAG3 gene (Val505GlyfsTer6; 603883.0013), thus eliminating the LEAD sequence, a functional caspase recognition and cleavage site. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. Western blot analysis of muscle tissue from 2 patients showed presence of a truncated BAG3 protein. Functional studies of the variant were not performed, but the authors noted that mutant caspase-resistant BAG3 cells are able to resist apoptosis in vitro. They suggested that the frameshift mutation in this family, eliminating the LEAD sequence, would decrease apoptosis and result in increased expression of mutant BAG3, possibly causing increased binding to HSPB8 (608014), the formation of intracellular aggregates, and disrupted autophagy in lower motor neurons. The patients had no sensory abnormalities. Sural nerve biopsy was not performed; muscle biopsy showed neurogenic changes, but was otherwise normal.