Elexacaftor/Tezacaftor/Ivacaftor Therapy in a Child With Cystic Fibrosis and Type 1 Spinal Muscular Atrophy

We present the case of a 7-year and 6-month-old girl affected with Cystic Fibrosis (CF) and pancreatic insufficiency [1] diagnosed at a few months of age through neonatal screening with CFTR genotype F508del/4016insT. From the fifth month of life, the patient presented a severe neurological and respiratory condition characterized by hypotonia, absence of osteotendinous reflexes, tongue fasciculations, delayed motor development, and recurrent respiratory infections. At 12 months of age, a diagnosis of Spinal Muscular Atrophy type 1 (SMA1) [2] was made based on clinical suspicion and subsequent molecular analysis, which revealed the homozygous deletion of exons 7 and 8 in the SMN1 gene and the presence of two copies of the SMN2 gene. Furthermore, the presence of chronic Pseudomonas aeruginosa infection and the absence of cough reflex contributed to the worsening of respiratory function [3]. At 12 months, when SMA1 was genetically confirmed, the subject began treatment with Nusinersen at the SMA Reference Center, continuing follow-up with the CF Reference Center [4-6]. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was used to assess motor function [7], with an initial score of 22/64 (at the age of 12 months) and an improvement to 52/64 at 2 years old. Then CHOP INTEND decreased to 49/64 at 3 years of age, remaining stable for the next 2 years. Due to lung function decline, increased respiratory exacerbations and severe muscolar hypotrophy, the subject began treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for compassionate use at 5 years and 6 months of age. Clinical, laboratory, and radiological parameters, as well as respiratory function, including the lung clearance index (LCI 2.5) and the number of respiratory exacerbations requiring intravenous antibiotic treatment were recorded during the 2 following years. A significant clinical response was observed after starting ETI therapy (Table S1): a weight gain (T0: 12 kg; T6: 15 kg), although dystrophy persisted, an improvement in respiratory function, measured by a reduction in LCI 2.5 (T0:9; T6:6); reduction of sweat chloride (SwCl) test value (SwCl T0: 83; SwCl T6: 38); a reduction in the number of respiratory exacerbations per years, requiring intravenous antibiotic therapy, (T0: 3; T12: 1; T24: 2); an improvement in nocturnal polygraphy during non-invasive ventilation, in particular for the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) (T0: AHI 5.7 and ODI 4.7; T6: AHI 1.9 and ODI 0.8). CHOP INTEND Score (T0: 49, T12: 50, T24:52), suggesting a slight improvement in motor function (See Figure S1 and Table S1). Cultures from deep pharyngeal aspirations showed occasional Pseudomonas aeruginosa, but colonization was not observed during follow-up. The study was approved by the Ethical committee of the CF regional Centre of Campania (Ethics Committee number 77/2021) and was conducted in accordance with the Declaration of Helsinki. CF and SMA1 are two severe genetic diseases that rarely coexist in the same subject. Their combination creates an especially challenging clinical picture, because each condition aggravates the limitations and complications of the other. CF is caused by variants in the CFTR gene, producing dysfunctional chloride transport across epithelial cells. This results in thick, dehydrated secretions in the airways, persistent respiratory infections, progressive lung damage, and multi-organ involvement. SMA1 is an autosomal recessive neurodegenerative disorder linked to deletions or variants in the SMN1 gene. The absence of the survival motor neuron protein impairs motor neuron viability and leads to profound hypotonia, muscle weakness, poor motor development, and severe respiratory compromise within the first months of life. Together, these conditions compound respiratory fragility, since CF requires effective coughing and airway clearance while SMA1 reduces muscle strength and ventilatory capacity. Historically, the prognosis for children with each of these conditions has been poor. Most subjects with SMA1 died within the first years of life, and those with CF often experienced progressive loss of lung function and shortened life expectancy [1, 2]. Over the last decade, however, new treatments have revolutionized their clinical landscape. Nusinersen, an antisense oligonucleotide designed to enhance production of the SMN protein through SMN2 gene modulation, was the first disease-modifying therapy for SMA1 and has demonstrated improved survival and motor development [4]. In parallel, the introduction of CFTR modulators such as ETI has dramatically improved pulmonary function, reduced exacerbations, and extended the lifespan of people with CF [2]. To our knowledge, no data about children with CF and SMA1 treated with ETI and Nusinersen have been previously reported and no information exists on how the two therapies may interact in subjects suffering from both diseases. The case presented involves a girl with CF and SMA1, diagnosed early through neonatal screening and symptom, respectively. Nusinersen therapy started at 12 months initially improved her motor abilities, but over time her neurological function plateaued while her respiratory status worsened. Recurrent infections, weight loss, and increasing ventilatory dependence reflected the cumulative burden of both diseases. Compassionate initiation of ETI at age 5 and a half marked a turning point. Over the subsequent 2 years, the child exhibited improved growth, fewer pulmonary exacerbations, lower SwClvalues, and stabilization or slight improvement in her motor function scores. The implications of these findings extend beyond simple symptom control. Improved lung function and oxygenation may indirectly protect motor neurons by reducing systemic inflammation and oxidative stress, thereby easing muscular fatigue. Weight gain contributes to better muscle trophism, potentially reinforcing neuromuscular performance. Such potential cross-system benefits suggest that therapies developed for one genetic disease could have unexpected positive consequences when applied in complex comorbid conditions. The combined treatment with Nusinersen and ETI resulted in a significant improvement in both respiratory and neurological parameters in a young girl with CF and SMA1. This case emphasizes the importance of an integrated therapeutic approach in managing complex and rarely coexisting genetic diseases and highlights the need for continuous monitoring of the efficacy and safety of such combined treatments. A. Castaldo: conceptualization, investigation, formal analysis. A. Tosco: conceptualization, investigation. I. Bitetti: methodology, validation, data curation. A. Varone: conceptualization, methodology. C. Cimbalo: writing – review and editing, writing – original draft, investigation, formal analysis. R. Cerchione: investigation, writing – original draft, writing – review and editing, formal analysis. M. Borrelli: investigation, formal analysis. A. Corcione: writing – original draft, writing – review and editing. P. Buonpensiero: formal analysis, visualization, resources. A. Di Pasqua: investigation, validation. A. Sepe: conceptualization, investigation, methodology. The authors received no specific funding for this work. Subject's parents gave written informed consent for data publication. The authors declare no conflicts of interest. Data are available on request to corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.