Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GCase catalyzes the hydrolysis of glucosylceramide (GluCer) to ceramide and glucose. Its deficiency results in the accumulation of GluCer within lysosomes, especially in macrophages (Gaucher cells) (1–3).

GD presents with a wide phenotypic spectrum, ranging from non-neuronopathic forms (GD1) to acute (GD2) or chronic (GD3) neuronopathic forms. GD3 can manifest with visceral involvement characterized by hepatosplenomegaly, cytopenia, bone marrow infiltration, and skeletal involvement, as well as slowly progressive neurological deterioration of variable onset and severity. Neurological manifestations may include supranuclear horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia, spasticity, and developmental delay (4–6).

Enzyme replacement therapy (ERT) is effective in treating non-neurological manifestations of GD3. While some evidence suggests initiating therapy for symptomatic patients (7), other studies indicate that specific treatment with ERT should be considered for all GD3 patients (8, 9). This recommendation extends to presymptomatic siblings of GD3 patients, particularly those with specific genotypes such as homozygous or compound heterozygous p.Leu483Pro and p.Asp448His variants (10).

Pulmonary involvement in GD can range from clinically asymptomatic with normal or mild radiographic changes to severe respiratory symptoms with significant radiographic findings (11). Infiltrative lung involvement, including interstitial lung diseases and rapidly progressive lung consolidation, is caused by Gaucher cells infiltrating the perivascular, peribronchial, septal regions, and alveolar air spaces.

Chest X-rays may show diffuse interstitial and nodular infiltrates, with honeycombing. However, the diagnostic gold standard is high-resolution computed tomography (HRCT), which typically reveals ground-glass opacities, sometimes superimposed with interlobular and intralobular septal thickening.

Despite the availability of enzyme replacement therapy (ERT), the course of the lung disease is associated with high morbidity and mortality. Patients frequently require long-term oxygen therapy and sometimes artificial ventilation (12).

In these cases, a deeper understanding of the pathogenesis of the damage and the use of personalized therapies is necessary. We describe the case of a patient with GD3 identified through neonatal screening, who suffered from severe interstitial lung disease poorly responsive to early ERT. The patient was successfully treated with anti-inflammatory and immunomodulatory therapy.

The patient is the third child born to non-consanguineous parents; the father is of Balkan origin, and the mother is Italian. At birth, extended neonatal screening, active in Northeast Italy for lysosomal diseases since 2015 (13, 14), showed reduced GCase activity (0.84 µmol/L/h, normal value >2.5) and elevated Lyso-Gb1 values (1,436 nmol/L, normal value 5.64–33.31) on dried blood spot (DBS), suggesting GD.

The diagnosis was confirmed by reduced GCase activity in lymphocytes (0.08 µmol/h/mg protein, normal value 0–1.93 µmol/h/mg protein) and elevated Lyso-Gb1 levels in plasma (182 µmol/L, normal value <1.93 µmol/L). Molecular testing of the GBA1 gene, become available when the child was 2 months old, revealed compound heterozygosity for the allele c.882T > G + c.1342G > C (p.His294Gln + p.Asp448His) and the allele c.1448T > C (p.Leu483Pro). Both alleles have been associated with acute and chronic neurovisceral phenotypes of Gaucher disease (15, 16) (for methods, see Supplementary Materials).

We describe the case of a patient with GD3, diagnosed through neonatal screening and early treated with ERT and chaperone therapy. Despite this, the patient developed severe lung disease with respiratory distress, requiring oxygen therapy.

Pulmonary involvement is more frequent in GD2 and GD3 patients (1, 22, 23), especially in those carrying the p.Leu483Pro variant, as our patient. Consistent with our case, primary lung disease is likely to occur at early ages, even in subjects with no overt neurological disease. It is related to a higher disease severity (11, 22, 24).

While improvements in pulmonary function tests and some clinical parameters have been reported in individuals receiving high-dose ERT, the general experience is that pulmonary manifestations are slow to respond to enzyme treatment, and some damage may not be reversed (12, 25, 26). Several cases of neuronopathic GD with progressive respiratory symptoms despite ERT have been described, necessitating tracheotomy and artificial ventilation (27). Few cases of lung transplantation have also been reported (26).

The inadequate response to ERT is likely attributable to poor accessibility of the infused enzyme to the lungs, as confirmed by post-mortem examinations. Burrow et al. reported on a 12.5-year-old GD type 3 patient who had received 11 years of ERT. The autopsy revealed clusters of macrophages and very elevated glucosylceramide (GluCer) and glucosylsphingosine (GluS) levels in the lungs and lymph nodes, while the liver and spleen were clear of storage cells and had nearly normal GluCer and GluS levels. The pathological features of the lungs were essentially identical to those of untreated GD3 patients, suggesting that ERT may not effectively penetrate (28). This highlights the need for additional therapeutic approaches and strategies based on a better understanding of lung damage pathogenesis.

It is known that in GD, chronic constitutive macrophage activation may lead to persistent immune system stimulation and systemic inflammation (29, 30). In a previous study, we demonstrated that TNF-alpha levels and P-p38 are sensitive markers of inflammation and cellular stress in Gaucher disease, showing alterations even in the presymptomatic phase (20). Other Authors have reported elevated plasma levels of TNF-alpha and other cytokines in GD patients, with highest concentrations in those with neuronopathic forms (31). Our patient also showed increased TNF-alpha levels without concomitant infections.

TNF-alpha is a pleiotropic cytokine that regulates several pathways, including the MAPK pathway (32). We investigated the activation of the proinflammatory kinase p38 in our patient, which was strongly elevated compared to the control before steroid therapy. Previous in vivo studies have demonstrated p38 activation in GD mice, showing increased P-p38 levels in brain tissues of neuronopathic mice and other affected organs such as liver and lung across all types of GD (33). Overactive p38 contributes to the generation of various inflammatory mediators, amplifying the inflammatory milieu (34).

The effect of steroids in other inflammatory lung diseases has been already reported, including their effects on cytokine production and MAPK pathways. It has been demonstrated that the extent of TNF-induced p38 MAPK phosphorylation is reduced in cells treated with dexamethasone. Indeed, the MAPK deactivator—mitogen-activated protein kinase phosphatase 1 (MKP-1)—is a corticosteroid-inducible gene (35–37). Consistently, our patient showed a reduction in TNF-alpha levels and P38 activation after steroid therapy. In particular, TNF-alpha levels were notably reduced after the first month of therapy, coinciding with clinical improvement. However, they subsequently increased during the tapering phase, concurrent with a return to baseline clinical conditions.

Due to the transient clinical benefit with corticosteroids, we used hydroxychloroquine for long-term treatment. Indeed, it is generally well-tolerated with relatively few side effects.

Interestingly, hydroxychloroquine appears to have an unfavorable effect on lysosomal function, inhibiting lysosomal acidification and preventing autophagosome degradation (38). Nevertheless, it proved effective in our patient. This observation, coupled with the further improvement in inflammation and cellular stress markers, leads us to hypothesize that the mechanism of action is primarily related to the immunomodulatory effect of the drug. The exact mechanism of action for its immunomodulatory effect is not fully understood, but it seems to include decreased macrophage-mediated cytokine production, especially IL-1 and IL-6 (19, 39).

Our patient showed an optimal clinical response after 2 months of therapy, with normal ventilatory pattern on polysomnography and further improvement in inflammatory biomarkers.

In conclusion, pulmonary involvement is crucial in determining the prognosis in neuronopathic Gaucher disease and can greatly influence the patient's quality of life. Although controlling respiratory symptoms is important, it is extremely challenging to achieve with currently available therapies. Our case underscores the potential role of inflammation in the pathogenesis of lung damage and the possible benefits of targeting the inflammatory pathways involved. The positive response to steroid therapy and hydroxychloroquine opens avenues for further research into these treatment modalities.