A number sign (#) is used with this entry because of evidence that axonal Charcot-Marie-Tooth disease type 2JJ (CMT2JJ) is caused by heterozygous mutation in the BAG3 gene (603883) on chromosome 10q26.

Heterozygous mutation in the BAG3 gene can also cause dilated cardiomyopathy-1HH (CMD1HH; 613881), distal hereditary motor neuropathy-15 (HMND15; 621094), and myofibrillar myopathy-6 (MFM6; 612954). These allelic disorders have overlapping features.

Charcot-Marie-Tooth disease type 2JJ (CMT2JJ) is an autosomal dominant axonal sensorimotor peripheral neuropathy characterized by adult onset of distal sensory impairment and distal muscle weakness and atrophy predominantly affecting the lower limbs. Some affected individuals have upper limb involvement. Electrophysiologic studies are consistent with a length-dependent axonal neuropathy (Fu et al., 2020).

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Shy et al. (2018) reported 2 large multigenerational families in which multiple individuals had adult-onset axonal sensorimotor peripheral neuropathy consistent with a diagnosis of CMT. Detailed clinical information was available for 4 patients from family WSU-75553 and 1 patient from family WSU-75767. The patients had adult onset (twenties to forties) of distal sensory impairment predominantly affecting the lower limbs; 3 patients had sensory defects in the distal upper limbs. Two patients had muscle weakness in the distal lower limb muscles, and 1 of the 2 also had mild muscle weakness in the distal upper limbs. Otherwise, most patients did not have notable muscle weakness, and none had proximal muscle weakness. Nerve conduction studies showed reduced motor and sensory responses, and EMG showed chronic denervation without myopathic findings. Sural nerve biopsy and muscle biopsy were not performed. Serum creatine kinase was normal or only mildly elevated. The patient from family WSU-75767 had cardiac palpitations and a family history of early cardiac death. Some individuals in family 75553 developed shortness of breath.

Fu et al. (2020) reported a Chinese woman (the proband) and her mother who presented at 26 and 50 years of age, respectively, with distal lower limb muscle weakness and atrophy resulting in walking difficulties as well as distal sensory impairment of the lower limbs. Muscle weakness progressed slowly to the proximal lower limbs, causing difficulty climbing stairs. Additional features included pes cavus, Achilles tendon contractures, and areflexia of all 4 limbs. MRI showed fatty infiltration of certain lower limb muscles (soleus, deep posterior compartment muscles). Serum creatine was normal. Electrophysiologic studies were consistent with an axonal sensorimotor neuropathy, and EMG demonstrated neurogenic features. Sural nerve biopsy of the proband showed a chronic axonal neuropathy with moderate loss of large-diameter myelinated fibers. There were no giant axons, axonal degeneration, or regeneration, and no onion bulb formations. Echocardiography and electrocardiogram were normal, and muscle biopsy was not performed.

The transmission pattern of CMT2JJ in the families reported by Shy et al. (2018) was consistent with autosomal dominant inheritance.

In 9 affected individuals from 2 large multigenerational families with CMT2JJ, Shy et al. (2018) identified a heterozygous P209S mutation in the BAG3 gene (603883.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The P209S variant occurs at a conserved residue in 1 of the 2 Ile-Pro-Val (IPV) motifs that mediates binding to HSPB8 (608014). Functional studies of the variant were not performed, but Shy et al. (2018) suggested that disruption of the IPV motif could interrupt BAG3-HSPB8 binding and fail to promote clearance of aggregate proteins in peripheral nerves, possibly resulting in damage to the nerves. The patients had no clinical evidence of a myopathy; neither muscle biopsy nor sural nerve biopsy were performed.

In a mother and daughter from a nonconsanguineous Chinese family with CMT2JJ, Fu et al. (2020) identified a heterozygous P209S mutation in the BAG3 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed.