Distal hereditary motor neuronopathy type IID is an autosomal dominant neurologic disorder characterized by onset of slowly progressive distal lower limb weakness and atrophy between the second and fourth decades of life. Weakness usually begins in the calf ... Distal hereditary motor neuronopathy type IID is an autosomal dominant neurologic disorder characterized by onset of slowly progressive distal lower limb weakness and atrophy between the second and fourth decades of life. Weakness usually begins in the calf muscles and later involves more proximal muscles. The severity is variable, and some patients have difficulty walking or running. Most also have upper limb involvement, particularly of the triceps and intrinsic hand muscles. Some patients may lose independent ambulation later in the disease course. Sensory impairment is typically not present, and cognition and bulbar function are normal (summary by Sumner et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN (dHMN), see HMN type I (HMN1; 182960).
Boylan et al. (1995) reported a large multigenerational family of English and German descent in which 9 living individuals and 1 deceased individual were diagnosed with distal spinal muscular atrophy. Affected individuals developed distal leg weakness, often associated ... Boylan et al. (1995) reported a large multigenerational family of English and German descent in which 9 living individuals and 1 deceased individual were diagnosed with distal spinal muscular atrophy. Affected individuals developed distal leg weakness, often associated with exertional limb pain and cramps, between the second and fourth decades. Features included calf muscle atrophy, ankle weakness with inability to toe-walk or stand on toes, and loss of ankle reflexes. Seven patients also developed proximal lower limb weakness. Four patients had pes cavus and 1 had pes planus. All remained ambulatory, but older patients required a cane or foot orthoses. Most patients had upper extremity weakness, particularly of the triceps and intrinsic hand muscles. There were no cognitive, bulbar, bowel, or bladder symptoms. Sensory symptoms were mostly absent, except in the oldest patient who was found to have vitamin B12 deficiency. EMG studies were consistent with a neurogenic process; fibrillations and fasciculations were also observed in some patients. Muscle biopsies showed neurogenic atrophy and a reduction in the number of intramuscular nerve axons. Sumner et al. (2013) reported follow-up of the family described by Boylan et al. (1995) and also reported a father and son from an unrelated family with the same disorder. Overall, the age at onset ranged between 17 and 48 years, although 1 patient had onset at age 13 years. Some patients had difficulty running and walking, and 3 patients had lost independent ambulation at ages 82, 45, and 48 years, respectively, but the severity was variable.
In 2 unrelated families with autosomal dominant distal hereditary motor neuronopathy type IID, Sumner et al. (2013) identified a heterozygous missense mutation in the FBXO38 gene (C206R; 608533.0001). The mutation was found in the first family (Boylan et ... In 2 unrelated families with autosomal dominant distal hereditary motor neuronopathy type IID, Sumner et al. (2013) identified a heterozygous missense mutation in the FBXO38 gene (C206R; 608533.0001). The mutation was found in the first family (Boylan et al., 1995) by exome sequencing. Sanger and whole-exome sequencing of 192 additional subjects with dHMN identified the same heterozygous C206R mutation in the second family. In vitro studies showed that the mutant protein was unable to promote activation of KLF7 (604865) target genes, including CDKN1A (116899) and L1CAM (308840). Primary motor neurons transfected with the mutant FBXO38 gene showed suppression of primary neurite outgrowth compared to wildtype, although the number of neurites was similar to wildtype. The findings suggested that this transcriptional pathway has a role in axonal development and neuronal maintenance. Sumner et al. (2013) stated that further studies would be needed to determine whether the mutation caused haploinsufficiency, a dominant-negative effect, or a toxic gain of function.