Nelson and Amick (1966) reported a family in which 6 members had insidious onset and gradual progression of symmetrical distal atrophy and weakness of the extremities associated with hyporeflexia. Age at onset ranged from 20 to 40 years ... Nelson and Amick (1966) reported a family in which 6 members had insidious onset and gradual progression of symmetrical distal atrophy and weakness of the extremities associated with hyporeflexia. Age at onset ranged from 20 to 40 years and the inheritance appeared to be autosomal dominant. The lack of sensory changes and normal motor nerve conduction velocities distinguished the disorder from peroneal muscular atrophy. Progression was slow, so that affected persons survived until at least middle life. D'Alessandro et al. (1982) described a 59-year-old father and 20-year-old son with a distal form of spinal muscular atrophy. EMG and muscle biopsy confirmed motor neuron disease in both. Muscle cramps were the only symptom. The disorder was associated with hypertrophy of the calves. The father-to-son transmission excluded Kennedy disease (313200), an X-linked disorder, unless the mother was a heterozygous carrier. No comment on consanguinity was made. Groen et al. (1993) described a family in which a 26-year-old man had typical signs of distal spinal muscular atrophy accompanied by atrophic muscles of the lower leg, whereas the father and sister had the picture of benign spinal muscular atrophy with hypertrophy of the calves as described by D'Alessandro et al. (1982). Timmerman et al. (1992) described a kindred in which many members in 6 generations were affected with what the authors labeled autosomal dominant distal hereditary motor neuropathy type II. Age at onset, determined for 11 patients, ranged from 14 to 35 years with a mean age at onset of 21.6 +/- 6.0 years. The first clinical symptoms appeared with a weakness of the extensor hallux longus muscle. Over the next 10 years, the disease progressed to complete paralysis and atrophy of all distal leg muscles with some weakness of the thigh muscles. The distal arm muscles were also affected but weakness was less pronounced. In a few elderly patients, vibratory sense was impaired but no other sensory losses were noted. Deep tendon reflexes were preserved but were sometimes diminished or even absent in the legs. Some of the older patients needed walking-aids or were wheelchair-bound. Motor and sensory nerve conduction velocities were normal. Chronic neurogenic alterations were demonstrated by electromyography. Linkage studies with markers on 1q, 5q, 17p, and 19q, excluded Charcot-Marie-Tooth disease type I (118220; 118200) and autosomal recessive SMA. Jansen et al. (1986) reported an autosomal dominant scapulohumeral form of SMA beginning between the end of the fourth and the sixth decade and showing rapid progression without evidence of corticospinal tract dysfunction. Death from respiratory failure occurred within 2 years of onset. Jansen et al. (1986) thought that this entity was separate from amyotrophic lateral sclerosis (ALS; 105400).
In affected members of 4 families with dHMN2, Irobi et al. (2004) identified heterozygous mutations in the same codon of the HSPB8 gene (608014.0001-608014.0002). One of the families had previously been reported by Timmerman et al. (1992). ... In affected members of 4 families with dHMN2, Irobi et al. (2004) identified heterozygous mutations in the same codon of the HSPB8 gene (608014.0001-608014.0002). One of the families had previously been reported by Timmerman et al. (1992). Irobi et al. (2010) compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N (608014.0001) and K141E (608014.0002) mutations resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Expression of the K141E, and to a lesser extent the K141N, mutation also induced spheroids in the neurites. There were no signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons and glial cells. - Reviews Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies.