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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Kentaro Okamoto

摘要

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.