Disease-Modifying Therapies in Spinal Muscular Atrophy: Neurodevelopmental and Behavioral Outcomes in the Treatment Era

Abstract

Spinal muscular atrophy (SMA) is a monogenic neuromuscular disorder caused by deficiency of the survival motor neuron (SMN) protein. Historically, SMA was regarded primarily as a disorder of lower motor neuron degeneration in which cognitive function was considered preserved. However, the advent of disease-modifying therapies (DMTs) has altered survival and motor outcomes, bringing cognitive, neurodevelopmental, and behavioral aspects of SMA into sharper clinical focus. This review re-examines cognitive and neurodevelopmental outcomes in SMA across historical and contemporary contexts, integrating pre-DMT clinical observations, mechanistic insights into SMN-dependent neurodevelopment, and emerging data from treated cohorts. Evidence from experimental models demonstrates that early SMN deficiency disrupts neural progenitor dynamics, synapse formation, circuit assembly, and neuron–glia interactions during critical developmental windows. These disturbances affect not only spinal motor circuits but also broader cortical and cerebellar networks, thereby conferring vulnerability to higher-order brain functions. Pre-DMT clinical studies reporting preserved cognition were shaped by survival bias, motor-dependent assessment tools, and limited evaluation of non-motor domains. In the DMT era, presymptomatic treatment has markedly improved developmental outcomes; nevertheless, cognitive, language, and behavioral phenotypes remain heterogeneous. Subtle vulnerabilities—particularly in expressive language, executive function, and social communication—are increasingly recognized, even among optimally treated individuals. These findings align with biological constraints imposed by developmental timing and limited plasticity of specific neural circuits. Assessment of neurodevelopmental outcomes in SMA is further complicated by motor confounding, reliance on proxy reports, and age- or severity-related limitations of existing tools, underscoring the need for motor-independent, domain-specific evaluation strategies. Collectively, current evidence supports reconceptualizing SMA in the DMT era as a neurodevelopmental condition characterized by persistent neurodevelopmental vulnerability, in which early intervention is necessary but not universally sufficient for complete normalization. Longitudinal follow-up, refined outcome measures, and trial designs incorporating non-motor endpoints are essential to capture the full impact of emerging therapies.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-026-03552-0.

Key Summary Points

Spinal muscular atrophy (SMA) should be reconceptualized in the disease-modifying therapy (DMT) era as a neurodevelopmental disorder in which early survival motor neuron (SMN) deficiency affects not only motor pathways but also higher-order brain functions.

Pre-DMT assumptions of preserved cognition were influenced by survival bias, motor-dependent assessment tools, and limited evaluation of non-motor domains.

Experimental and translational studies demonstrate that prenatal and early postnatal SMN deficiency disrupts cellular, synaptic, and circuit-level processes across multiple brain regions, conferring intrinsic neurodevelopmental vulnerability.

In the DMT era, neurodevelopmental outcomes are heterogeneous and appear to be associated, at a population level, with disease severity markers such as SMN2 copy number and treatment timing; however, improvement in motor function does not necessarily equate to normalization of cognitive or behavioral outcomes.

Early initiation of DMTs substantially improves survival and developmental trajectories but does not uniformly eliminate neurodevelopmental risk, underscoring the need for longitudinal, motor-independent assessment and continued neurodevelopmental follow-up.

Introduction

The identification of the survival motor neuron 1 (SMN1) gene as the causative gene for spinal muscular atrophy (SMA) marked a pivotal moment in neuromuscular research and established SMA as a prototypical monogenic neurodevelopmental disorder [1]. For decades, SMA was conceptualized primarily as a disorder of lower motor neuron degeneration, characterized by progressive muscle weakness, respiratory failure, and early mortality in its most severe forms. Within this framework, cognitive and behavioral development received relatively little attention, in part because survival was limited and clinical priorities focused on motor and respiratory outcomes.

The therapeutic landscape of SMA has changed dramatically with the advent of disease-modifying therapies (DMTs), including antisense oligonucleotides, gene replacement therapy, and small-molecule splicing modifiers. These interventions have transformed survival and motor trajectories, particularly when initiated presymptomatically, fundamentally altering the lived experience of individuals with SMA [2]. As increasing numbers of patients survive into childhood and adulthood, attention has shifted toward broader neurodevelopmental outcomes, including cognition, communication, behavior, and participation.

Historically, SMA has often been described as a condition in which cognition is preserved despite severe motor impairment. This assumption was supported by early clinical observations and small cohort studies conducted in the pre-DMT era [3]. However, more recent analyses suggest that this view may have been shaped by survival bias, motor-dependent assessment tools, and limited evaluation of higher-order cognitive domains [4, 5]. Emerging clinical, neuroimaging, and experimental data now indicate that SMN deficiency affects multiple aspects of nervous system development, raising questions about the completeness and durability of neurodevelopmental rescue achieved by current therapies.

In parallel, systematic reviews have highlighted substantial heterogeneity in reported cognitive and communicative outcomes across SMA subtypes and treatment eras, underscoring the need for a more nuanced and developmentally informed framework [4]. These observations challenge a purely motor-centric model of SMA and support reconceptualization of the disease as a neurodevelopmental condition with potential non-motor manifestations.

In this review, we examine cognitive, neurodevelopmental, and behavioral outcomes in SMA across historical and contemporary contexts. By integrating pre-DMT clinical observations, mechanistic insights into SMN-dependent neurodevelopment, and emerging data from treated cohorts, we aim to clarify how early SMN deficiency and therapeutic timing confer persistent neurodevelopmental vulnerability in the DMT era.

Literature Search Strategy

This article is a narrative review based on a comprehensive literature search rather than a systematic or scoping review. The literature was identified primarily through searches of PubMed conducted in December 2025, which yielded approximately 1774 records. The search strategy combined terms related to SMA with terms related to neurodevelopmental, cognitive, and behavioral outcomes.

Studies were selected based on their relevance to neurodevelopmental, cognitive, and behavioral aspects of SMA across both the pre-treatment and treatment eras. Additional relevant publications were identified through manual screening of reference lists and citation tracking of key articles. Detailed search terms are provided in the Supplementary Material S1.

As this article is a narrative review based on previously published studies, ethical approval was not required.

Cognitive Function in SMA Before the DMT Era

Before the advent of DMTs, SMA was widely regarded as a condition in which cognitive function is preserved despite severe motor impairment. This view was supported by multiple clinical studies reporting average or even above-average intellectual performance in children and adolescents with SMA, particularly in type II and III phenotypes [3, 6, 7]. Observations of precocious language development further reinforced the perception that cognitive development in SMA was not only spared but potentially enhanced in certain domains [8].

However, these conclusions were shaped by the clinical and methodological context of the pre-DMT era. Survival bias likely played an important role, as children with the most severe phenotypes often did not survive long enough to undergo formal cognitive assessment. As a result, early studies disproportionately represented individuals with milder disease courses, limiting generalizability across the full SMA spectrum [3, 9]. In addition, sample sizes were typically small, and longitudinal follow-up was rarely feasible, further constraining interpretation.

Assessment-related limitations also contributed substantially to the prevailing narrative. Many cognitive tests used in earlier studies relied heavily on motor responses, speech production, or sustained physical engagement, introducing systematic bias in individuals with significant motor impairment. Subsequent investigations demonstrated that performance on specific cognitive tasks, such as visuospatial matching or executive function measures, correlated inversely with motor ability, suggesting that apparent cognitive strengths or weaknesses could reflect task demands rather than true cognitive capacity [10, 11]. These findings underscore the difficulty of disentangling cognition from motor function using conventional assessment tools.

More recent syntheses of the pre-DMT literature have highlighted considerable heterogeneity in reported cognitive outcomes. Systematic and scoping reviews reveal variability across age groups, SMA subtypes, and cognitive domains, with inconsistent evidence for both preserved and impaired function [4, 5, 12]. Importantly, adult studies conducted before widespread DMT availability identified measurable cognitive impairment in a subset of patients, particularly in executive and attentional domains, challenging the notion of universal cognitive preservation [11, 13].

Taken together, the historical view of preserved cognition in SMA reflects a convergence of survival bias, assessment constraints, and the clinical realities of the pre-DMT era. While early reports provided valuable insights, their conclusions cannot be directly extrapolated to contemporary treated cohorts. Revisiting these foundations is essential for interpreting neurodevelopmental outcomes in the DMT era and for framing SMA as a disorder with potential neurodevelopmental involvement beyond motor neuron pathology, as explored in subsequent sections.

Neurodevelopmental Consequences of SMN Protein Deficiency: Insights from Basic and Translational Research

This section provides the biological rationale underlying the heterogeneity of neurodevelopmental and behavioral outcomes observed in the disease-modifying therapy era.

Figure 1 summarizes the proposed framework in which prenatal and early postnatal SMN deficiency affects multiple neural populations during critical developmental windows, leading to persistent neurodevelopmental vulnerability despite partial rescue by disease-modifying therapies.

Fig. 1.

Conceptual framework linking early survival motor neuron (SMN) deficiency to persistent neurodevelopmental vulnerability in spinal muscular atrophy (SMA). Prenatal and early postnatal deficiency of SMN protein affects multiple levels of nervous system development beyond motor neurons. Reduced SMN availability disrupts cellular and synaptic processes across diverse neuronal and glial populations, leading to impaired maturation of higher-order neural circuits. Disease-modifying therapies may partially and in a timing-dependent manner modulate these cellular and synaptic processes; however, network-level vulnerabilities may persist and contribute to heterogeneous neurodevelopmental outcomes, including language, executive function, and social communication. The figure illustrates the hierarchical and temporal relationships between early molecular deficits, circuit-level disruption, and long-term neurodevelopmental manifestations in SMA

To understand how SMN deficiency gives rise to neurodevelopmental and behavioral consequences, it is essential to consider the fundamental biological functions of the SMN protein. Although SMA has historically been viewed through the lens of motor neuron vulnerability, SMN is a ubiquitously expressed protein with essential roles in RNA metabolism and cellular homeostasis across multiple tissues and developmental stages. Accordingly, this chapter first outlines the core molecular functions of SMN and then expands to its broader intracellular roles, cell type-specific effects, and impact on neural development and circuit formation.

SMN Protein: Core Biological Functions

The SMN protein is a ubiquitously expressed, evolutionarily conserved factor essential for RNA metabolism. Early cell biological studies showed that SMN localizes to both the cytoplasm and distinct nuclear structures termed “gems,” closely associated with Cajal bodies and spliceosomal components, linking SMN to pre-mRNA processing [14].

The canonical function of SMN is its role in the assembly of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. SMN forms a multiprotein complex with Gemins and associated factors that mediates the ordered assembly of Sm proteins onto uridine-rich small nuclear RNAs, a process that becomes inefficient or error-prone in the absence of SMN [15, 16]. Structural studies identified the SMN Tudor domain as a critical interface for binding symmetrically dimethylated arginine residues on Sm proteins, providing a molecular basis for specificity in snRNP biogenesis [16].

Loss or reduction of SMN disrupts snRNP assembly fidelity, leading to widespread but subtle alterations in pre-mRNA splicing rather than uniform global failure of gene expression [17]. Because SMA results from reduced rather than absent SMN, and disease severity correlates with residual SMN abundance across tissues [18], cells operate near a functional threshold, rendering dynamic developmental processes particularly vulnerable to SMN deficiency. These molecular roles form the foundation for downstream cell type-specific and neurodevelopmental abnormalities.

SMN Protein Functions Beyond Motor Neurons: Non–Neuron-Specific Intracellular Roles

Although motor neurons are the most clinically vulnerable cell type in SMA, SMN is ubiquitously expressed and performs fundamental intracellular functions across tissues and developmental stages. Beyond its canonical role in spliceosomal snRNP assembly, SMN acts as a molecular chaperone for ribonucleoprotein (RNP) biogenesis, influencing multiple RNA processing pathways across cell types [19, 20].

The SMN–SIP1 (Gemin2) complex is essential for the assembly of Sm proteins onto uridine-rich snRNAs, a process required across proliferating and differentiating cells [15, 19]. Structural and biochemical studies demonstrated that the Tudor domain of SMN mediates interactions with symmetrically dimethylated Sm proteins, underscoring a conserved mechanism of RNP assembly [16, 21]. Partial reduction of SMN does not abolish snRNP biogenesis globally but compromises its fidelity and efficiency, resulting in selective vulnerability of downstream RNA pathways [17].

In addition to spliceosomal snRNPs, SMN is required for the biogenesis of specialized RNPs such as U7 small nuclear ribonucleoprotein (U7 snRNP), which is essential for the 3′-end processing of replication-dependent histone mRNAs [22]. Disruption of this pathway links SMN deficiency to impaired cell cycle regulation and chromatin dynamics, underscoring effects on fundamental cellular homeostasis beyond motor neuron–specific functions.

More recently, SMN has been shown to act as a molecular chaperone for messenger RNP (mRNP) assembly, facilitating interactions between RNA-binding proteins and their target transcripts [23]. This extends SMN function to cytoplasmic RNA localization and local translation, processes critical for neuronal polarity, migration, and synaptic maturation, but also operative in glial and progenitor populations.

Collectively, these non-neuron-specific intracellular roles explain why SMN deficiency results in widespread developmental perturbations rather than a phenotype restricted to motor neurons, establishing a foundation for understanding how early global disruptions of RNA metabolism manifest as later circuit-level and neurodevelopmental abnormalities.

Distribution of SMN Protein in the Central Nervous System During Development

The spatial and temporal distribution of SMN protein within the developing central nervous system provides insight into the selective vulnerability of specific neural circuits in SMA. Although SMN is ubiquitously expressed, its levels and subcellular localization vary across brain regions, cell types, and developmental stages, indicating that developmental context shapes disease susceptibility.

Early studies of human fetal tissue demonstrated high SMN expression during prenatal development, with prominent nuclear and cytoplasmic localization in neurons of the spinal cord and brain [24, 25]. SMN shows enriched expression in motor neurons but is also robustly present in interneurons, cortical neurons, cerebellar neurons, and glial precursors, supporting a broad role in neural development rather than a motor neuron-exclusive function [24, 26]. Regional differences were observed, with high SMN levels in the spinal cord, brainstem, cerebellum, and cerebral cortex during critical periods of neuronal differentiation and circuit formation [25].

Developmental regulation of SMN expression is supported by experimental studies in animal models. Quantitative analyses in mice revealed that SMN protein levels are highest during embryonic and early postnatal stages, followed by a decline during the perinatal period [27]. This decline occurs across multiple CNS regions, with tissue-specific differences in timing and magnitude, suggesting region-specific thresholds for SMN sufficiency. Human postmortem data corroborate these findings, demonstrating a marked decrease in SMN protein levels after birth [28].

These spatial and temporal expression patterns have pathogenic implications. Brain regions and neural circuits that undergo prolonged maturation—such as corticospinal, cerebellar, and associative networks—may be disproportionately affected by early SMN deficiency, even when motor neuron survival is partially preserved. The perinatal decline in SMN expression further highlights a critical developmental window during which SMN deficiency may irreversibly perturb circuit assembly, synaptic refinement, and connectivity.

Together, these observations support a model in which SMA represents a disorder of neurodevelopmental vulnerability shaped by the interaction between SMN expression dynamics and region-specific developmental demands, providing a biological rationale for the heterogeneity of central nervous system involvement across SMA phenotypes and underscoring the importance of early therapeutic intervention.

SMN-Dependent Cellular Mechanisms Underlying Neural Development and Circuit Assembly

Experimental evidence indicates that SMN deficiency disrupts neural development through cell-autonomous and non-cell-autonomous mechanisms extending beyond motor neuron survival. At the cellular level, SMN plays essential roles in neural progenitor specification, neuronal maturation, synapse formation, and interactions with glial cells, linking molecular dysfunction to circuit-level abnormalities.

Early studies showed that reduced SMN levels impair axonal growth and growth cone dynamics, partly through altered localization of β-actin mRNA and cytoskeletal regulation, leading to defects in neuronal polarity and connectivity [29]. Subsequent work showed that SMN deficiency interferes with activity-dependent processes required for synapse maturation, including calcium channel clustering and presynaptic organization at axon terminals [30]. These abnormalities are associated with altered excitability and impaired neurotransmission within developing motor circuits.

Beyond motor neurons, SMN-dependent mechanisms affect the assembly and refinement of sensory–motor networks. Defective synaptic input from sensory afferents and impaired maturation of central synapses occur early in disease models, preceding overt neurodegeneration [31, 32]. Functional studies show early disruption of sensory–motor connectivity and reduced excitatory drive onto motor neurons, indicating that circuit dysfunction emerges during critical developmental windows rather than as a late consequence of neuronal loss [33, 34].

At the molecular level, impaired RNA processing and local mRNA regulation link SMN deficiency to abnormal neuronal differentiation and synaptic stability. SMN-dependent U12 intron splicing events are essential for motor circuit function [35], while interactions between SMN and RNA-binding proteins such as HuD contribute to post-transcriptional regulation required for normal motor neuron development and function [36].

Non-neuronal cells also contribute to circuit-level consequences of SMN deficiency. Recent studies identified abnormal microglia-dependent synaptic remodeling mediated by the classical complement pathway, indicating that altered neuron–glia interactions shape maladaptive circuit refinement during development [37]. Emerging evidence further indicates that cerebellar pathology contributes to broader neurodevelopmental deficits in SMA, reinforcing that SMN-dependent mechanisms extend beyond spinal motor circuits [38].

Collectively, these SMN-dependent cellular mechanisms provide an intermediate framework linking molecular dysfunction to higher-order circuit abnormalities, helping explain why neurodevelopmental vulnerability in SMA may persist despite improved motor neuron survival and setting the stage for interpreting functional and cognitive outcomes discussed in subsequent sections.

Impact of SMN Deficiency on Brain Development and Neural Circuit Formation

Disruption of SMN-dependent cellular processes has consequences at the systems level, shaping brain development and neural circuit formation across multiple regions. Experimental and human studies support the view that SMN deficiency affects not only spinal motor circuits but also broader networks involved in cortical, cerebellar, and sensorimotor integration.

Early studies in severe SMA mouse models showed that reduced SMN levels cause regionally selective abnormalities in brain development, including impaired hippocampal growth and altered cortical architecture [39]. These changes coincide with reduced cell proliferation and neurogenesis during perinatal development, suggesting that SMN deficiency perturbs brain maturation before overt motor neuron degeneration. Complementary findings from invertebrate models established a developmental role for SMN in regulating stem cell division, proliferation, and differentiation, highlighting conserved mechanisms influencing neural tissue growth and patterning [40].

More recent human-based approaches have strengthened the translational relevance of these findings. Studies using isogenic patient-derived induced pluripotent stem cell organoids revealed early defects in neural progenitor specification and lineage commitment, showing that SMN deficiency biases neurodevelopmental trajectories at early stages of human neural development [41]. These abnormalities were only partially rescued by genetic correction, suggesting that early developmental disruptions may have lasting consequences for circuit formation even when SMN levels are later restored.

At the functional level, clinical and neurophysiological data indicate that altered circuit development contributes to atypical motor and sensorimotor organization in individuals with SMA. Analyses of locomotor muscle synergies in patients with milder phenotypes revealed patterns suggestive of immature or developmentally altered corticospinal and sensory contributions, indicating that disrupted activity-dependent refinement shapes circuit-level outcomes [42]. These findings align with neuropathological reports implicating cortical and cerebellar involvement and extend the impact of SMN deficiency beyond the spinal cord.

Collectively, these studies support a model in which SMN deficiency interferes with brain development and neural circuit assembly through combined effects on progenitor dynamics, regional maturation, and activity-dependent refinement. Such systems-level alterations provide a framework for understanding persistent neurodevelopmental vulnerability in SMA, even with improved survival and motor outcomes in the treatment era.

Vulnerability of Higher-Order Brain Functions Under SMN Deficiency

Higher-order brain functions, including cognition, social communication, and executive processes, are selectively vulnerable to early SMN deficiency. This vulnerability likely reflects their prolonged developmental trajectories and complex network architectures, rendering them particularly sensitive to subtle disruptions during critical periods of brain maturation.

Neuroanatomical and neuroimaging studies implicate long-range connectivity and associative networks in SMA. Diffusion-based imaging in children with type II and III SMA reveals reduced white matter integrity and disrupted structural brain networks extending beyond primary motor pathways, indicating altered maturation of distributed cortical circuits supporting higher-order processing [43]. These findings suggest that SMN deficiency interferes with activity-dependent refinement of long-range connections that continue to develop into childhood and adolescence.

The cerebellum represents a key node within these vulnerable networks. Recent pathological and experimental evidence indicates that cerebellar involvement contributes to neurodevelopmental deficits in SMA, potentially through disrupted cerebellar–cortical interactions essential for cognitive and executive functions [38]. These interactions rely on precise temporal coordination and synaptic plasticity, features particularly susceptible to early molecular and cellular perturbations.

At the cellular level, prenatal SMN-dependent defects in translational regulation affect primary cilia and associated signaling pathways across the central nervous system, providing a mechanistic link between early developmental disruption and later-emerging higher-order functional vulnerabilities [44]. These observations suggest that higher-order brain functions are not secondarily affected by motor disability alone but reflect intrinsic neurodevelopmental vulnerability under conditions of SMN deficiency.

Implications for the DMT Era: Timing, Plasticity, and Residual Neurodevelopmental Risk

The advent of DMTs has fundamentally transformed the clinical course of SMA; however, evidence indicates that early SMN restoration does not uniformly normalize neurodevelopmental outcomes. This discrepancy can be understood through the lens of developmental timing, neural plasticity, and circuit-level constraints.

Experimental and clinical studies show that SMN expression is highest during prenatal and early postnatal development and declines thereafter, defining a narrow window during which SMN-dependent processes are most critical [28]. In severe SMA models, impaired motor axon development and circuit formation are evident prenatally, necessitating therapeutic intervention before or immediately after birth to achieve maximal rescue [45]. Animal studies further show that delayed SMN restoration improves survival but fails to fully correct neuromuscular junction pathology and circuit maturation, establishing the concept of a critical therapeutic window [46, 47].

Clinical data from the DMT era support these experimental insights. Presymptomatic treatment initiated through newborn screening results in superior motor outcomes compared with treatment after symptom onset, particularly in infants with fewer SMN2 copies [2, 48]. Nevertheless, even among presymptomatically treated individuals, heterogeneity in motor and neurodevelopmental trajectories persists, suggesting that some aspects of circuit development may be only partially reversible once early developmental processes are disrupted.

Neural plasticity appears to be region- and process-specific. While certain motor functions demonstrate substantial postnatal recovery, higher-order circuits that rely on early-established connectivity and prolonged refinement may retain residual vulnerability. Thus, the DMT era reveals a dual reality: early SMN restoration is transformative yet constrained by developmental timing, leaving a persistent neurodevelopmental vulnerability that must be carefully interpreted in long-term outcome studies. These concepts are summarized schematically in Fig. 1.

Cognitive and Neurodevelopmental Outcomes in the DMT Era

The introduction of DMTs has fundamentally altered the natural history of SMA, enabling survival and motor milestone acquisition that were previously unattainable. As survival has improved, increasing attention has been directed toward cognitive, neurodevelopmental, and behavioral outcomes. Against the background of persistent neurodevelopmental vulnerability established by early SMN deficiency, emerging evidence indicates that these outcomes are heterogeneous and closely related to treatment timing, disease severity, and the duration of early SMN deficiency. At present, comparative data on neurodevelopmental and behavioral outcomes across different DMT modalities remain limited. Consequently, this review focuses on shared developmental principles and outcome patterns in the treatment era rather than modality-specific comparisons. Key representative clinical studies evaluating neurodevelopmental, cognitive, and behavioral outcomes in SMA across treatment eras are summarized in Table 1.

Table 1.

Key clinical studies evaluating neurodevelopmental, cognitive, and behavioral outcomes in spinal muscular atrophy

Study	Population	Treatment context	Age at assessment	Domains assessed	Key findings
Cooper et al., 2024 [48] (systematic review)	NBS-identified infants	Presymptomatic DMT	~ 2–5 years	Primarily motor; limited non-motor outcomes	Motor outcomes substantially improved; limited systematic non-motor data
Buchignani et al., 2024 [53]	Infants (type I and presymptomatic)	Early DMT (pre-/early symptomatic)	8–36 months	Language, communication	Comprehension preserved; expressive language often delayed
Kölbel et al., 2024 [52]	NBS-identified children	Early DMT after screening	~ 2–3 years	Global development	Cognitive scores below average in ~ 20–35% of children
Steffens et al., 2024 [56]	Children (2–3 SMN2 copies)	DMT in first year of life	2–5 years	Cognition, communication	~ 50% demonstrated suboptimal performance in at least one cognitive domain
Brusa et al., 2025 [54]	Children with type I	Post-symptomatic DMT	2–9 years	Language, social communication	Persistent language delay; social communication difficulties in a subset
Buchignani et al., 2025 [57]	Children (type I and presymptomatic)	DMT	2–10 years	Behaviour, ASD, cognition	ASD diagnosed in ~ 10%; highlights need for motor-adapted assessment
Mix et al., 2021 [11]	Adults	Mostly untreated or pre-DMT era	~ 20–65 years	Cognition, executive function	Overall cognition preserved; executive dysfunction associated with disease severity

Studies are ordered according to developmental stage and treatment timing rather than publication year

ASD autism spectrum disorder, DMT disease-modifying therapy, NBS newborn screening, SMN2 survival motor neuron 2

Although currently available disease-modifying therapies differ substantially in their mechanisms of action and biodistribution, robust comparative data regarding neurodevelopmental outcomes across treatment modalities remain limited. While theoretical considerations suggest that differences in central nervous system exposure or systemic distribution could influence neurodevelopmental trajectories, existing clinical evidence is insufficient to support definitive modality-specific conclusions.

Accordingly, in this review we do not interpret residual neurodevelopmental vulnerabilities as evidence of treatment failure, nor do we attribute them to specific therapeutic approaches. Rather, these findings are best understood as reflecting intrinsic neurodevelopmental constraints imposed by early SMN deficiency, developmental timing, and limited plasticity of certain neural circuits. Clarifying whether and how differences in DMT mechanisms influence long-term cognitive and behavioral outcomes remains an important priority for future longitudinal studies.

From a mechanistic perspective, differences in biodistribution among available disease-modifying therapies provide important theoretical context for interpreting potential neurodevelopmental effects, although current clinical evidence does not permit modality-specific conclusions. Intrathecally administered antisense oligonucleotides, such as nusinersen, are primarily distributed within the cerebrospinal fluid compartment, with prominent exposure in the spinal cord and measurable distribution across central nervous system tissues in translational models [49]. In contrast, systemically administered gene replacement therapy using an AAV9 vector demonstrates broad systemic biodistribution, characterized by prominent hepatic transduction and the capacity for central nervous system transduction rather than CNS-restricted exposure [50]. Small-molecule splicing modifiers such as risdiplam are orally administered and exhibit broad systemic distribution with demonstrated penetration of the blood–brain barrier, enabling simultaneous SMN upregulation in both central and peripheral tissues [51].

Several recent cohort studies of children identified through newborn screening have reported generally favorable global developmental profiles, particularly among those treated presymptomatically. However, even within these cohorts, subtle neurodevelopmental vulnerabilities are frequently observed. A population-based study evaluating children 2 years after newborn screening demonstrated that, while many children achieve age-appropriate global development, approximately 20-35% of presymptomatically treated infants exhibit delays in at least one non-motor developmental domain, most commonly language or adaptive skills [48, 52]. These findings suggest that early treatment mitigates, but does not uniformly eliminate, neurodevelopmental risk.

Language and communication have emerged as particularly sensitive domains. Across recent cohort studies, expressive language delay has been reported in approximately 30-50% of infants and young children with SMA, including those treated presymptomatically, whereas receptive language skills are often relatively preserved [53, 54]. Longitudinal observational studies further demonstrate that expressive language improves following treatment initiation, but often remains below population norms, paralleling patterns observed in motor development [55, 56]. Recent focused analyses of expressive language and social communication similarly report delayed verbal output and subtle social communication difficulties in a subset of children with SMA type I, underscoring the need for continued developmental surveillance beyond infancy [54].

Cognitive outcomes assessed using standardized neuropsychological instruments also reveal marked interindividual variability. Studies evaluating children treated during the first year of life generally report preserved overall cognitive function at the group level. Nevertheless, approximately 15–25% of patients demonstrate suboptimal performance in specific cognitive domains, particularly processing speed, attention or executive function [11, 56]. Clinical factors associated with less favorable cognitive outcomes include greater disease severity, reliance on ventilatory or nutritional support, and lower motor function, highlighting the close interdependence of motor and cognitive development in SMA [55]. In contrast, adult patients with later-onset SMA who did not receive DMTs during childhood show measurable cognitive impairment in some cohorts, illustrating the long-term consequences of chronic SMN deficiency and providing an important comparator for outcomes observed in the treatment era [13].

Behavioral and neuropsychiatric features are increasingly recognized as part of the SMA neurodevelopmental spectrum. Recent cohort studies incorporating structured developmental screening tools have reported that, although most treated children do not meet criteria for autism spectrum disorder, structured screening nonetheless identifies behavioral or emotional concerns in approximately 10–20% of children, including attentional problems, sensory sensitivities, or repetitive behaviors [57]. These features are typically subclinical and heterogeneous, and do not constitute a distinct neuropsychiatric phenotype. These observations are consistent with emerging mechanistic and pathological data implicating cerebellar and long-range network involvement in SMA and support a broader conceptualization of SMN-associated neurodevelopmental vulnerability [38].

Importantly, these findings should not be interpreted as evidence of treatment failure, but rather as reflecting the intrinsic neurodevelopmental vulnerability associated with early SMN deficiency.

Across studies, heterogeneity remains a defining feature. Differences in SMN2 copy number, age at treatment initiation, treatment modality, and baseline clinical status contribute to variable neurodevelopmental trajectories. Moreover, methodological challenges—including motor confounding of cognitive assessments and reliance on parent-reported measures in early childhood—complicate interpretation and cross-study comparison. A recent scoping review emphasizes the need for motor-independent, longitudinal, and domain-specific assessment strategies to more accurately characterize cognitive and behavioral outcomes in the DMT era [5].

Taken together, emerging evidence from the DMT era supports a shift in how neurodevelopmental outcomes in SMA are interpreted. While early initiation of therapy markedly improves survival and motor milestone acquisition, neurodevelopmental outcomes remain heterogeneous. At a population level, less favorable cognitive and language outcomes tend to be observed in individuals with greater disease severity, including those with fewer SMN2 copies or more severe early motor involvement. However, this association is probabilistic rather than deterministic and is characterized by substantial interindividual variability.

Importantly, motor and cognitive outcomes are not interchangeable. Several studies demonstrate that children who achieve major motor milestones following early treatment may nonetheless exhibit vulnerabilities in specific neurodevelopmental domains, particularly expressive language, executive function, or social communication. These observations suggest that motor improvement alone cannot be assumed to reflect complete neurodevelopmental normalization.

From a biological perspective, this dissociation is consistent with experimental data indicating that higher-order neural circuits have prolonged and tightly regulated developmental trajectories, and may be particularly sensitive to early SMN deficiency. In this context, it is plausible that the developing brain requires a higher or more sustained threshold of SMN expression than motor neurons to support normal circuit assembly and refinement. Early SMN restoration may therefore be necessary but not universally sufficient to fully normalize neurodevelopmental outcomes.

Assessment of Cognitive, Neurodevelopmental, and Behavioral Outcomes in SMA

Accurate assessment of cognitive, neurodevelopmental, and behavioral outcomes in SMA remains challenging. These challenges stem from profound motor impairment, age- and severity-dependent limitations of available tools, and frequent reliance on proxy reporting. Addressing these methodological issues is essential for reliable outcome interpretation in clinical practice and research settings.

Motor confounding is a central obstacle. Many standardized cognitive assessments require fine motor responses, speech production, or sustained postural control, all of which may be compromised in SMA. Studies across neuromuscular disorders show that apparent cognitive deficits may reflect task demands rather than true impairment [58]. In SMA, performance on cognitive subtests correlates with motor function, particularly in processing speed and executive domains, underscoring the risk of underestimating cognitive abilities when motor demands are not adequately controlled [59].

To mitigate these limitations, several adaptations and alternative approaches have been explored. Modified versions of early developmental tools, such as the Bayley Scales with reduced motor and visual demands, show improved feasibility and validity in children with motor impairments [60, 61]. In severely affected infants and children with limited verbal output, eye-tracking paradigms allow assessment of visual attention, matching, and learning without motor responses, supporting motor-independent cognitive evaluation [10]. However, such approaches remain heterogeneous and are not yet standardized for widespread clinical use.

Reliance on proxy-reported measures is a further limitation. Parent- and caregiver-reported questionnaires are indispensable in early childhood and in individuals with severe disability, yet may be influenced by caregiver expectations, disease burden, or psychosocial stress. While proxy reports provide valuable information on everyday functioning and quality of life, they should be complemented by objective, performance-based assessments whenever feasible [4, 12].

Age and disease severity constrain assessment strategies. Tools suitable for infants may lack sensitivity in older children, whereas instruments designed for school-aged populations often remain inaccessible to non-sitters or non-speakers. Behavioral and contextual factors—including fatigue, sleep disturbance, and emotional well-being—can also influence test performance and are increasingly recognized as modifiers of cognitive outcomes in SMA [62].

In the DMT era, these methodological considerations have direct implications for clinical trials and long-term follow-up. As survival improves and developmental expectations evolve, outcome measures must extend beyond motor function to capture meaningful cognitive and behavioral domains. Motor-independent, developmentally appropriate, and longitudinal assessment frameworks are needed to accommodate the broad phenotypic spectrum of SMA. Such approaches are essential for accurately characterizing neurodevelopmental trajectories and for identifying manifestations of persistent neurodevelopmental vulnerability, thereby informing targeted supportive interventions alongside DMTs.

Conclusions and Future Perspectives

In the disease-modifying therapy era, spinal muscular atrophy should no longer be viewed solely as a disorder of motor neuron degeneration. Accumulating clinical and experimental evidence indicates that SMA is a neurodevelopmental condition in which prenatal and early postnatal SMN deficiency affects multiple levels of nervous system development, including higher-order brain circuits [28, 45, 63].

Early initiation of disease-modifying therapies has transformed survival and motor outcomes and represents a major therapeutic success [2, 48]. Nevertheless, neurodevelopmental outcomes remain heterogeneous, and improvement in motor function does not uniformly translate into complete normalization of cognitive, language, or behavioral domains [4]. Population-level associations with disease severity markers, such as SMN2 copy number and treatment timing, further support the presence of intrinsic neurodevelopmental vulnerability [48, 63].

These findings should not be interpreted as limitations of current therapies, but rather as reflections of biological constraints related to developmental timing and neural plasticity [28, 64]. The key unmet neurodevelopmental challenges in the DMT era, together with their implications for long-term clinical follow-up and future research priorities, are summarized schematically in Fig. 2.

Fig. 2.

Unmet neurodevelopmental challenges and future directions in spinal muscular atrophy (SMA). Despite substantial overall improvement in motor development following the introduction of disease-modifying therapies (DMTs), several neurodevelopmental challenges remain. These include the prenatal onset of survival motor neuron (SMN) deficiency, incomplete rescue of neural circuit development, and late-emerging neurodevelopmental vulnerabilities. Consequently, outcomes across neurodevelopmental domains remain heterogeneous and may not fully normalize, even in the DMT era. This framework highlights the need for longitudinal neurodevelopmental follow-up, motor-independent assessment strategies, early supportive interventions beyond motor function, and research and clinical trials incorporating non-motor endpoints to more comprehensively address long-term outcomes and quality of life in individuals with SMA

Accordingly, longitudinal, motor-independent assessment strategies and continued neurodevelopmental follow-up are essential, even in optimally treated individuals. Future clinical trials and observational studies should incorporate non-motor outcomes to more comprehensively capture the full impact of emerging therapies and to better inform long-term care in SMA.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Kentaro Okamoto was responsible for the conception and design of the review, literature analysis and interpretation, and drafting of the manuscript.

Funding

No funding was received for this study or publication of this article.

Data Availability

No new data were generated or analysed in this study. Data sharing is not applicable to this article.

Declarations

Conflict of Interest

Kentaro Okamoto has received honoraria for invited lectures from Biogen Japan (2021) and Chugai Pharmaceutical Co., Ltd. (a member of the Roche Group) (2022). The author declares no other conflicts of interest.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.