dSMA

• dHMN I:  +/- UMN

  • HSPB1 - AD

  • HSPB8 - Junveile onset

  • GARS - Distal LE

  • DYNC1H1

  • 7q34

• dHMN IIB:  +/- UMN

  • HSPB1 - AD

• dHMN IIA: +/- UMN

  • HSPB8: Distal LE

• dHMN II:  BSCL1

• dHMN IIC: HSBP3: AR

• dHMN III: 11q13: AR, childhood onset, distal predominant

• dHMN IV: PLEKHG5: AR, childhood onset, distal predominant, diaphgragmatic paralysis, scapular winging.

• dHMN VA:  GARS:  AD, onset in hands, +/- UMN

• dHMN VB: BSCL2:  AD onset in hands,  ventilatory distress

• dHMN VI: IGHMBP2: infantile, vocal cord paralysis

• dHMN VIIB: 

  • DCTN1: AD distal LE

  • TRPV4

• dHMN VII A: 2q14: UMN

• fALS4: SETX:  AD distal LE

• ATP7A: X-linked distal LE

• 9p21.1: AR distal LE: Abnormal cervical spine imaging. 

Benign focal amyotrophy

Scapuloperoneal

• PMP22

• TRPV4

Distal hereditary motor neuropathies are a group of disorders characterized by the almost exclusive involvement of the lower motor neuron without sensory involvement. Some hereditary motor neuropathies are termed distal spinal muscular atrophy (SMA), distinguished from classic or proximal SMA by the clinically distal-predominant weakness. The leading theory is that distal hereditary motor neuropathies do not localize to the anterior horn cell but to the motor nerve axon. Nomenclature trends favor a more gene-focused terminology. Responsible genes encode proteins with a wide variety of functions, with gene variants leading to abnormal protein synthesis, mitochondrial dysfunction, impaired chaperone function, altered apoptotic mechanisms, impaired axonal trafficking, impaired ion channel function, and abnormal signaling at the synapse. The inheritance pattern can be autosomal dominant, autosomal recessive, or X-linked. 

Clinically, these disorders present with slowly progressive length-dependent weakness and atrophy with reduced or absent reflexes and relatively preserved sensation.While most hereditary motor neuropathies start with lower extremity weakness of the feet and ankles, some have an upper extremity predominance. Onset is typically within the first two decades of life. The hereditary motor neuropathies or neuronopathies that exhibit upper motor neuron involvement overlap clinically with juvenile amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegias.

Respiratory and bulbar symptoms in hereditary motor neuropathies are rare, with a few exceptions. SMA with respiratory distress type 1 due to autosomal recessive variations in IGHMBP2 presents with respiratory failure from bilateral or unilateral diaphragmatic paralysis in the first year of life. Gene replacement therapy for IGHMBP2-related disease is in early clinical trials. Distal hereditary motor neuropathies type VII, caused by autosomal dominant variations in SLC5A7 (type 7A) or DCTN1 (type 7B), is characterized by vocal cord paralysis with hand weakness and atrophy initially presenting in childhood or early adulthood. Vocal cord paralysis is also described in neuropathy syndromes related to TRPV4 (type 8), including a scapuloperoneal distal motor neuropathy phenotype.

Electrophysiology is particularly helpful in distinguishing hereditary motor neuropathies from other differential diagnoses. Hereditary motor neuropathies will have low-amplitude compound muscle action potentials and preserved sensory responses on nerve conduction studies,with chronic neurogenic findings on needle EMG. Compared with motor neuron disorders such as SMA or ALS, the chronic neurogenic findings in hereditary motor neuropathies are primarily seen in distal muscles. Distal myopathies can clinically mimic hereditary motor neuropathies and can be differentiated by EMG. Some genes associated with hereditary motor neuropathies also have a CMT2 phenotype. Examples include neuropathies associated with SORD, TRPV4, GARS1, HSPB1, and HSPB8.