Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies

ObjectiveTo identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs).MethodsThe first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation.ResultsdHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family.ConclusionsThis study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.

Polyneuropathy

Typically polyneuropathy will cause the combination of distal limb muscle weakness, loss of tendon reflexes, and reduced distal limb sensation. There is variable involvement of the autonomic innervation, damage to which causes a dry, vasodilated foot or hand. Loss of tendon reflexes is a cardinal sign of polyneuropathy, often restricted to the ankle jerks in axonal degeneration, but involving more proximal reflexes in acquired demyelinating neuropathies which may involve more proximal segments or the nerve roots. Clinical features suggestive of demyelinating or conduction block polyneuropathy include: a relative lack of muscle wasting in relation to the degree of weakness because no denervation has occurred; weakness of proximal muscles as well as distal, because of nerve root involvement; and disproportionate loss of joint position and vibration sensations compared to relative preservation of pain and temperature sensations which are carried by unmyelinated fibres.

Motorneuron pools innervating muscles in vitamin A-induced proximal-distal duplicate limbs in the axolotl

Serially duplicated limbs containing two sets of proximal muscles were created in axolotls by vitamin A treatment. The innervation of three replicated proximal muscles was studied by using retrograde transport of horseradish peroxidase. These were the forelimb muscles biceps (seven cases) and anconeus (five cases) and the hindlimb muscle puboischiotibialis (five cases). In two cases (both of anconeus) innervation was from a correct motorneuron pool. In the other 15 cases the innervation was from an incorrect, distal limb muscle, motorneuron pool. These results are interpreted as evidence against long range signals between nerve and muscle controlling specific nerve regeneration. However, the data are compatible with models of axonal guidance that use local pathway cues.