Discussion

This systematic review synthesizes NCS findings in genetically confirmed 5q-SMA across 23 studies published between 1999 and 2025, comprising 395 patients spanning the clinical spectrum from SMA0 to SMA3. Three overarching observations emerge. First, despite the traditional view of 5q-SMA as a predominantly motor neuron disorder, peripheral nerve involvement is repeatedly described, particularly in severe infantile phenotypes. ^{Reference Anagnostou, Miller and Fehlings13,Reference Duman, Uysal, Skjei, Kizilay, Karauzum and Haspolat17,Reference Rudnik-Schöneborn, Goebel and Schlote34} Second, interpretation of the neurophysiological literature is substantially constrained by heterogeneous NCS methodology and incomplete reporting, with formal neuropathy classification feasible in only approximately half of the included studies. Third, longitudinal electrophysiological data – although limited and largely based on amplitude-only protocols – suggest that treated patients are more often reported as stable or improved, whereas deterioration is rarely documented and appears mainly in the small untreated sample. ^{Reference Axente, Sporea, Mirea, Burcea and Ion15,Reference Kariyawasam, D’Silva and Howells23,Reference Li, Sun and Xiang26,Reference Ros, Sleutjes and Goedee33}

A key finding of this review is that the available evidence is not methodologically uniform enough to support robust prevalence estimates of specific neuropathy subtypes across the full pooled cohort. While slightly more than half of studies reported complete motor and sensory NCS, only 12 of 23 studies provided sufficient detail to classify neuropathy type (axonal vs demyelinating; motor vs sensory vs sensorimotor). Conversely, nearly half relied on simplified amplitude-only protocols, particularly in treatment-focused or biomarker-oriented cohorts. ^{Reference Axente, Sporea, Mirea, Burcea and Ion15,Reference Boulay, Delmont, Audic, Chabrol and Attarian16,Reference Kariyawasam, D’Silva and Howells23,Reference Li, Sun and Xiang26,Reference Pant and Verma30} These designs are well suited for quantifying motor unit integrity and longitudinal change but intrinsically preclude mechanistic classification. As a result, apparent differences in reported neuropathy patterns across studies likely reflect differences in ascertainment and reporting rather than true biological divergence.

These methodological limitations are compounded by the overall low-to-moderate quality of the literature. Common sources of bias included incomplete reporting of patient selection, limited description of NCS acquisition parameters and lack of blinded outcome assessment, particularly in single-patient reports and small case series. ^{Reference Anagnostou, Miller and Fehlings13,Reference Fernández-Torre, Teja and Castellanos20,Reference Reid, Arends and Wirtz32} None of the included studies preregistered a protocol or reported sample-size calculations, further limiting inferential strength.

Across studies, two partially overlapping neurophysiological scenarios emerge that help reconcile seemingly contradictory findings.

Several case reports, small series and pathology-informed studies describe severe infantile SMA presenting with neurophysiological patterns resembling a peripheral sensorimotor axonal neuropathy or sensory neuronopathy, including reduced or absent SNAPs. ^{Reference Anagnostou, Miller and Fehlings13,Reference Duman, Uysal, Skjei, Kizilay, Karauzum and Haspolat17,Reference García-Cabezas, García-Alix and Martín21,Reference MacLeod, Taylor, Lunt, Mathew and Robb29,Reference Rudnik-Schöneborn, Goebel and Schlote34} In some cases, these findings led to initial misdiagnoses such as congenital neuropathy, Guillain–Barré syndrome or critical illness neuropathy. ^{Reference Pro, Tozzi and D’Amico12,Reference Fernández-Torre, Teja and Castellanos20} Collectively, these studies demonstrate that sensory abnormalities and mixed axonal patterns do not exclude SMA, particularly in severe infantile phenotypes.

In contrast, cohorts focusing on adolescents and adults, or on upper-limb sensory nerves, frequently report preserved SNAPs and a predominantly motor neurogenic profile. ^{Reference Farrar, Vucic and Lin18,Reference Li, Li, Wang and Wu27,Reference Ros, Sleutjes and Goedee33} In these studies, electrophysiology supports the concept of SMA as a “pure motor” disorder at the peripheral nerve level, despite marked motor neuron dysfunction. Importantly, this pattern does not negate sensory vulnerability in SMA but suggests that sensory involvement is phenotype-, age- and nerve-dependent.

This dual-scenario framework places negative findings (preserved SNAPs in older patients) and positive findings (sensory abnormalities in severe infantile phenotypes) on a biological continuum rather than treating them as contradictory observations.

Among the subset of studies with sufficient electrophysiological detail to classify neuropathy patterns, axonal involvement clearly predominates. Motor axonal neuropathy, sensory axonal neuropathy and sensorimotor axonal neuropathy were repeatedly reported across multiple studies. ^{Reference Duman, Uysal, Skjei, Kizilay, Karauzum and Haspolat17,Reference MacLeod, Taylor, Lunt, Mathew and Robb29,Reference Ravid, Topper and Eviatar31,Reference Rudnik-Schöneborn, Goebel and Schlote34} Sensorimotor axonal neuropathy was the most frequently reported mixed pattern, particularly in severe infantile SMA. ^{Reference Anagnostou, Miller and Fehlings13,Reference Fernández-Torre, Teja and Castellanos20,Reference Reid, Arends and Wirtz32} In contrast, demyelinating abnormalities were distinctly uncommon and never reported as isolated motor or isolated sensory demyelinating neuropathy.

Demyelinating features were reported in only a small number of patients and always in a sensorimotor distribution. ^{Reference Pro, Tozzi and D’Amico12,Reference Duman, Uysal, Skjei, Kizilay, Karauzum and Haspolat17,Reference Fernández, Peciña, Muñoz-Cabello, Antínolo and Borrego19,Reference Rudnik-Schöneborn, Barisić and Eggermann35} Importantly, several of these cases had plausible alternative explanations. Fernández et al. ^{Reference Fernández, Peciña, Muñoz-Cabello, Antínolo and Borrego19} described a patient with SMA II and a PMP22 duplication consistent with Charcot-Marie-Tooth disease type 1A, while Rudnik-Schöneborn et al. ^{Reference Rudnik-Schöneborn, Barisić and Eggermann35} reported compound genetic findings including variants in SH3TC2, a gene associated with hereditary demyelinating neuropathy. These cases highlight the importance of considering coexisting hereditary neuropathies or genetic modifiers when demyelinating features are observed. Taken together, the available clinical and neurophysiological evidence does not support primary demyelination as a characteristic or defining feature of 5q-SMA.

Experimental data provide biological plausibility for myelin involvement in SMA: Hunter et al. ^{Reference Hunter, Aghamaleky Sarvestany, Roche, Symes and Gillingwater36} demonstrated intrinsic Schwann cell defects in SMA mouse models, including reduced SMN expression and impaired myelin protein production reversible by SMN restoration. However, the rarity of demyelinating patterns in the clinical literature suggests that, while possible, demyelination is not a common or defining feature of 5q-SMA.

Sensory involvement represents a central and nuanced finding in this review. Developmental studies have shown that SMN expression, while highest in anterior horn motor neurons, is also present at lower levels in posterior horn neurons and DRG from fetal life into adulthood. ^{Reference Tizzano, Cabot and Baiget37} This distribution provides a plausible biological substrate for sensory involvement in SMA.

Clinically, sensory abnormalities were reported both as isolated sensory axonal neuropathy and as part of a broader sensorimotor axonal pattern. ^{Reference Duman, Uysal, Skjei, Kizilay, Karauzum and Haspolat17,Reference Ravid, Topper and Eviatar31,Reference Rudnik-Schöneborn, Goebel and Schlote34} Pathology-based studies further support genuine sensory neuron involvement in severe infantile SMA. ^{Reference MacLeod, Taylor, Lunt, Mathew and Robb29,Reference Rudnik-Schöneborn, Goebel and Schlote34} In contrast, large cohorts of adolescents and adults demonstrated preserved median SNAPs in the vast majority of patients, with abnormalities more often attributable to age or comorbidities such as diabetes or chemotherapy exposure. ^{Reference Ros, Sleutjes and Goedee33} These observations suggest that sensory involvement in SMA is phenotype-dependent, nerve-dependent, and modulated by disease severity and systemic factors.

Longitudinal NCS data were available only in a subset of studies and were predominantly based on amplitude-only protocols. In nusinersen-treated cohorts, CMAP/SNAP amplitudes were reported as stable or improved in most patients, with no reported deterioration. ^{Reference Axente, Sporea, Mirea, Burcea and Ion15,Reference Kariyawasam, D’Silva and Howells23,Reference Li, Sun and Xiang26} Patients treated with risdiplam showed uniformly stable electrophysiological trajectories in available reports, ^{Reference Ros, Sleutjes and Goedee33} while all patients assessed after onasemnogene abeparvovec showed improvement. ^{Reference Pant and Verma30} In contrast, deterioration was observed only in the small untreated sample. ^{Reference Pro, Tozzi and D’Amico12}

These findings should be interpreted cautiously: follow-up intervals, baseline severity and electrophysiological endpoints varied widely across studies, limiting direct comparability. In this context, reported longitudinal “improvements” in CMAP or SNAP amplitudes should be interpreted as stabilization or relative improvement within substantial methodological constraints, rather than as unequivocal evidence of axonal regeneration or true neurophysiological recovery; such changes may reflect developmental maturation, improved survival of motor units, technical variability or disease stabilization under treatment. Nonetheless, the overall pattern is consistent with stabilization or improvement of peripheral motor unit measures in treated patients.

Taken together, the findings of this review indicate that peripheral nerve involvement is a relevant but heterogeneous component of the 5q-SMA spectrum. Axonal abnormalities predominate when neuropathy patterns can be classified, sensory involvement is biologically plausible and most evident in severe infantile phenotypes, and demyelinating features are rare and frequently confounded by alternative explanations. From a diagnostic standpoint, the presence of sensory abnormalities on NCSs should therefore not exclude 5q-SMA from the differential diagnosis, particularly in infants and neonates with severe phenotypes, in whom mixed axonal or sensory neuronopathic patterns have been repeatedly reported. ^{Reference Anagnostou, Miller and Fehlings13,Reference Duman, Uysal, Skjei, Kizilay, Karauzum and Haspolat17,Reference García-Cabezas, García-Alix and Martín21,Reference MacLeod, Taylor, Lunt, Mathew and Robb29,Reference Rudnik-Schöneborn, Goebel and Schlote34} Instead, such findings should prompt careful molecular evaluation for SMN1-related SMA, alongside systematic exclusion of coexisting hereditary neuropathies or genetic modifiers, especially when demyelinating features are observed. ^{Reference Fernández, Peciña, Muñoz-Cabello, Antínolo and Borrego19,Reference Hunter, Aghamaleky Sarvestany, Roche, Symes and Gillingwater36}

Future studies would benefit from standardized NCS reporting, including both motor and sensory studies with distal latencies and conduction velocities, assessment of both upper- and lower-limb nerves, and explicit documentation of comorbidities and coexisting genetic neuropathies. Such standardization is essential to clarify the true frequency, mechanisms and clinical relevance of peripheral neuropathy in 5q-SMA, particularly in the era of disease-modifying therapies.