Non-5q SMAs are genetically heterogeneous, clinically diverse and rare compared to 5q SMA [41]. Phenotypic classification may be based on distribution of weakness (distal, proximal or bulbar) and mode of inheritance (Table 16.2) [42, 43]. This classification system, however, does not include all non-5q motor axonopathies or neuronopathies, excludes SMA plus syndromes, and in particular excludes conditions with uncertain nosology or those with no gene/locus information [41].

Distal SMAs present with predominantly distal weakness. They exhibit significant phenotypic overlap with distal hereditary motor neuropathies or neuronopathies (dHMN).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by mutations in the gene IGHMBP2, which encodes the immunoglobulin μ-binding protein. Most patients with SMARD1 have low birth weight and present within the first 3 to 6 months of life with diaphragmatic paralysis, hypotonia, distal more than proximal weakness, and sensory and autonomic involvement, followed by ventilator dependency [44, 45]. Life expectancy is usually limited primarily due to the severe respiratory weakness [45]. Respiratory failure between 6 weeks and 6 months combined with the presence of diaphragmatic eventration or preterm birth is a good predictor of the presence of IGHMBP2 mutations [44]. Patients with SMARD1 usually have normal serum CK levels and no primary cardiomyopathy, but severe autonomic dysfunction can lead to secondary cardiovascular collapse [45, 46]. In a series of 141 patients with respiratory distress and diaphragmatic and intercostal weakness, three distinct phenotypes were noted: (1) SMARD-congenital: arthrogryposis multiplex congenita with associated respiratory failure at birth, (2) SMARD1-like: respiratory distress with onset between 6 weeks to 6 months along with hip flexion weakness with minimal or no movements of the distal muscle groups, and (3) SMARD-late: respiratory distress after age 6 months without multiple congenital contractures; however, the phenotype can be more variable [44, 47].

EMG in SMARD1 shows marked reduction of or complete absence of CMAPs and markedly slow conduction velocities, more predominantly in the lower extremities. Similar but milder findings may be seen in sensory studies [48, 49]. Needle EMG initially shows a denervation pattern only in distal muscles, but diffuse changes can be seen later. EMG of the diaphragm, if performed, may show denervation changes [45, 48, 49].

HMN5A and Charcot-Marie-Tooth type 2D (CMT2D) are allelic conditions caused by mutations in GARS [50, 51]. The clinical distinction between HMN5A and CMT2D is usually based on whether sensory abnormalities are present [50]. Patients with GARS mutations usually present in their twenties with predominantly upper-limb weakness, most notably including selective atrophy of the thenar eminence and first dorsal interosseous (FDI) muscles. The hypothenar eminence is usually spared until later in the course of the disease. Peroneal weakness and atrophy and reduced vibration sensation are usually present in all patients with CMT2D and about half of the patients with HMN5A [52]. EMG shows a motor axonopathy with typical features of absent or markedly reduced CMAPs recording abductor pollicis brevis (APB) and preserved CMAPs recording abductor digiti minimi (ADM). CMAP amplitudes from peroneal muscles are typically below 2 mV and below 1 mV when leg atrophy is clinically evident. SNAP amplitudes and conduction velocities are usually normal, although sural SNAP amplitude can be reduced. Even in presymptomatic mutation-carrying individuals, large long-duration motor unit potentials with reduced recruitment pattern can be seen in the thenar muscles. Similarly, chronic partial denervation can be seen in the ADM and extensor muscles of the legs even in the absence of apparent muscle atrophy [50, 51].

Mutations in BSCL2 gene result in allelic phenotypes including spastic paraplegia with amyotrophy of hands and feet (Silver syndrome/SPG17), congenital generalized lipodystrophy, type 2, distal SMA with early hand involvement (dHMNV), and dHMN beginning in the legs (dHMNII) [53, 54]. Phenotypes can be variable, but common features include hand muscle weakness and wasting, gait abnormalities, stiffness in the lower limbs, and foot deformities. Ambulation is usually preserved [53]. EMG shows reduced CMAPs, predominantly in the lower extremities, with occasional temporal dispersion and partial conduction block, and slowing of conduction velocity in the demyelinating range, suggesting that demyelination compounds a presentation that is otherwise predominantly axonal. In the upper extremities, median nerve CMAPs and conduction velocities are typically more affected than the ulnar nerve. EMG shows chronic denervation with large motor unit potentials with or without polyphasia, and without any abnormal spontaneous activity [53].

SMA with lower extremity predominance (SMA-LED) is caused by dominant mutations in the dynein gene (DYNC1H1) encoding a microtubule motor protein in the dynein-dynactin complex and mutations in BICD2, which encodes a dynein adaptor protein. Features of SMA-LED with DYNC1H1 mutations include congenital or very early onset, severe weakness in the proximal legs, specifically quadriceps, and a static or minimally progressive course [43, 55]. In BICD2 mutations, onset may be in utero, at birth, or in early childhood. The typical presentation consists of delayed motor milestones, along with predominantly lower limb non-length-dependent weakness, with a variable amount of wasting and contractures. Contractures are most commonly found in the ankle. Of note, arthrogryposis or contractures are uncommon in DYNC1H1mutations. In some patients, scapular winging is present. A subset of patients can have upper motor neuron signs, but all patients usually have stable or only slowly progressive lower motor neuron disease, and most remain ambulatory throughout their lives [56]. In contrast to DYNC1H1 mutations, abnormal cortical development and epilepsy are not typical features of BICD2 mutations [56, 57].

Nerve conduction studies in DYNC1H1-associated SMA-LED may be normal. In older patients, mild CMAP amplitude reductions in the lower extremities may occur. EMG usually shows chronic denervation in both proximal and distal leg muscles [43]. Similar findings may be seen in BICD2-associated SMA-LED. CMAP amplitudes are occasionally reduced, especially in the common peroneal nerve. Nerve conduction velocities and SNAPs are usually normal or borderline reduced. Needle examination shows chronic denervation and large motor units with or without polyphasia [56].

TRPV4-related disorders are another example of diverse phenotypes: (1) congenital distal SMA with arthrogryposis and asymmetric atrophy and weakness, in the lower extremities, (2) scapuloperoneal SMA with scapular winging, laryngeal distribution of weakness, distal muscle wasting and weakness with absent deep tendon reflexes, and (3) CMT2C associated with vocal cord and phrenic nerve paralysis. EMG usually shows normal conduction velocities with reduced CMAP amplitudes and some polyphasic or giant motor units with evidence of a predominantly motor axonal neuropathy [58–62].

Brown-Vialetto-van Laere syndrome (BVVLS) and Fazio-Londe disease are clinically overlapping motor neuron diseases involving primarily lower cranial nerves; they present with ponto-bulbar palsy, sensorineural deafness in BVVLS, and respiratory failure. BVVLS and Fazio-Londe disease have been linked to mutations in the RFT2 (C200RF54) gene with defective riboflavin transport; riboflavin supplementation has been reported to be helpful in some cases [63, 64]. Early in the course, electrophysiological testing may be normal, but repeat examinations at later time points may detect motor neuron disease with greater sensitivity [64–66].