Changing clinical manifestations of Gaucher disease in Taiwan

This was a retrospective cohort study of GD patients followed in two main tertiary hospitals in Taiwan (National Taiwan University [NTUH] and China Medical University Hospital [CMUH]), accounting for the care of 64% of the Taiwanese GD population. Patients with confirmed Gaucher disease visiting the hospital between 1998, and April 2022, were reviewed. Some of the patients had been reported [25, 26]. Medical records were retrospectively reviewed, and demographic data (age, date of birth, and sex), information pertaining to diagnosis (sonographic measurements of the liver and spleen, hemograms, age at diagnosis, molecular diagnosis, phenotype categorization, as well as presenting symptoms including skeletal manifestations, oculomotor dysfunction, poor feeding, and ichthyosis), treatment data (medical management, initial age at intervention), and data regarding evolvement under treatment (hemograms and survival status) were collected. In general, physical examination and neurological examination were done at time of diagnosis, and every 6–12 months thereafter until 2 years of age. After that, annual check would be done for registry evaluation and drug application. Patients with neurological involvement, such as gaze palsy, slow or absent saccades, intellectual disability, seizure, or intellectual impairment, were classified as having neuropathic GD following assessment by neurological examination, which evaluated mental status, posture, cranial nerves, motor systems including muscle atrophy, tone and power, sensory system, coordination, and gait, with or without electroencephalography and intelligence test via the Wechsler Intelligence Scales for Adults (WAIS) or for Children (WISC). GD2 was classified if the patient had neonatal ichthyosis or neurological symptoms before 6 months of age. Although gaze palsy is considered the required criterion for neuropathic GD [9], sometimes it is not readily perceived, especially in young patients [27]. Therefore, patients with various degrees of neurological involvement with/without oculomotor apraxia, lymphadenopathies or kyphosis were classified as having GD3.

Liver and spleen parameters included liver and spleen measurements that were converted to multiples of the age-specific uppermost limits of normal, as recommended by Konuş et al., given the substantial variations in the sizes of the liver and spleen among individuals of different ages [28].

Statistical analyses were conducted using IBM SPSS Statistics, versions 28.0.1.1 and 27.0.1.0, Prism 9 for macOS, versions 9.3.1 and 9.5.1, and Microsoft Excel for Mac, version 16.60. Sex, molecular diagnosis, age at diagnosis, age at symptom onset, initial presentations, age at treatment, treatment interventions, and current age/age of death were tabulated. The p values of the survival curve were determined by the log-rank test. All other p values were calculated with the Mann–Whitney test. Results with a p value less than 0.05 were considered statistically significant.

Between 1999, and April 2022, 27 patients, including 4 patients who died, were under the care of either NTUH or CMUH, as shown in Table 1. Among them, 9 patients (33%) were categorized as having GD1, 3 (11%) as having GD2, and 14 (52%) as having GD3. One case (4%) was unclassified due to the accidental death of the patient at 1 year old without other symptoms following diagnosis by newborn screening during the neonatal period. Although not statistically significant (p = 0.542), the incidence of GD2 increased from 5 to 33% with NBS by juxtaposing patients who were clinically diagnosed with patients who were diagnosed by NBS (Table 2).

Consistent with the corresponding disease severity, the median ages at diagnosis after clinical suspicion were the earliest for patients with GD2 (0.92 years) and the latest for patients with GD1 (24.41 years, IQR [3.72–35.65]). With further stratification by the year ERT became available (in 1998), the age of diagnosis during the pre-ERT era was 24.41 years [5.22–33.52] as opposed to 1.18 years [0.15–2.83] during the post-ERT era (Additional file 1: Table S1). In contrast, individuals diagnosed following NBS had a median age at diagnosis of 0.08 years [0.05–0.28] a median age at symptom onset of 0.50 years [0.05–1.37]. As shown in Fig. 1, the ages at diagnosis have remained in the neonatal period since the introduction of NBS for GD in 2015, the post-NBS era.

Hepatosplenomegaly, anemia, and thrombocytopenia were the main presentations of GD patients (Fig. 2). The degree of splenomegaly was more prominent than that of hepatomegaly prior to treatment (Additional file 2: Figure S1). With stratification by diagnostic method (Table 2), patients diagnosed following NBS were mostly asymptomatic upon diagnosis with statistical significance (p < 0.001) observed in analyses of hepatosplenomegaly, anemia, and thrombocytopenia (Additional file 3: Figure S2).

ERT was warranted in all patients who were clinically diagnosed (regardless of the timing of diagnosis), except for GD2 patients (Fig. 3). One GD1 patient (11%) was identified as having received ERT and substrate reduction therapy (SRT). The client’s treatment was shifted from ERT, which was complicated by fortnightly intravenous infusions requiring frequent absences from work, to SRT, which involved a once-daily oral regimen on the grounds of the client’s concern about the school-to-work transition in 2021. In addition to this GD1 patient, six GD3 patients (43%) received accompanying SRT owing to protracted neurological manifestations (miglustat only) and/or imaging-proven lymphadenopathies (either miglustat or eliglustat) despite receiving ERT. Ambroxol was used in five GD3 patients (36%) due to the progression of neurological manifestations, including intractable seizures and progressing cognitive decline, as well as one GD1 patient (9%) owing to evolving Parkinson’s disease. Splenectomy was only performed in patients diagnosed during the pre-ERT era (Additional file 4: Figure S3). One NBS-diagnosed patient who underwent ERT in addition to hematopoietic stem cell transplantation (HSCT) was eventually classified as having GD2 (Additional file 5: Figure S4).

In addition to the findings regarding splenectomy, serial changes in the hemoglobin and platelet levels of the GD1 (n = 9) and GD3 (n = 14) patients (Fig. 4) also substantiated the effect of ERT in reversing disease progression, given that anemia and thrombocytopenia have been shown to be indicators of symptom onset. Moreover, the longitudinal transformations revealed that the effect may have been more conspicuous in individuals who were diagnosed by NBS, i.e., after 2015, than in those who were diagnosed clinically, as the NBS-diagnosed individuals convalesced from anemia and thrombocytopenia within a couple of years of treatment, while some of the clinically diagnosed individuals required longer durations. Fifty percent of patients diagnosed during the pre-ERT exhibited various degrees of skeletal manifestations at the time of diagnosis, which was often delayed. In patients diagnosed during the post-ERT era, almost all patients were diagnosed before overt skeletal symptoms appeared (Table S1). The latest assessment age was 19 years [8.3–41.46] (designated by the age of death if the patient was deceased). The duration of follow-up was 14.85 years [4.8–26.88]. While the 5-year survival rates were 0% for GD2 patients and 100% for GD1 and GD3 patients, one GD1 patient died of internal bleeding from a traffic accident at the age of 53 years in late April of 2022 with a follow-up duration of 27 years. The Kaplan–Meier survival curves of the GD1 and GD3 patients both exhibited significant differences (p < 0.0001) from that of the GD2 patients (Fig. 5). Of note, one patient who expired by accidental death prior to the onset of any symptom such that subtyping could not be performed, as mentioned in the “Distribution of GD types” section, was excluded from the Kaplan–Meier survival analysis by subtype. Twenty-nine percent (4 of 14) of the GD3 patients had seizures (Table 3). In addition, lymphadenopathies were observed in 50% (7 of 14) of the GD3 patients receiving regular ERT (Additional file 6: Figure S5).

This study is the first cohort study to provide a comparison of the GD population diagnosed during the pre-NBS and post-NBS eras in Taiwan. It is of crucial importance to understand the epidemiology as well as the clinical characteristics when designing a treatment strategy for a rare disease such as GD. In 2006, Wan et al. first reported on the GD cohort in Taiwan via their extensive study of GD disease mutations a year after NBS became available for GD [7]. With sixteen years of cumulation, GD patients diagnosed during the post-NBS era were juxtaposed with those diagnosed during the pre-NBS era. Our cohort encompassed 64% of the Gaucher population in Taiwan, of which 1/7 were diagnosed during the post-NBS era. This study showed that the distribution of subtypes in Taiwan varies greatly from that worldwide. Moreover, the most prevalent genotype worldwide was p.Asp409Ser/p.Asp409Ser (44.2% [374/847]) as opposed to p.Leu483Pro/p.Leu483Pro (41% [11/27]) in our cohort, which coincides with the mutation analysis by Wan et al.; the worldwide prevalence of p.Leu483Pro/p.Leu483Pro was 2.2% (19/847) worldwide based on the Gaucher Outcome Survey analysis by Zimran et al. [7, 29]. However, as only patients visiting NTUH or CMUH between 1998 and 2021 were included, patients who were cared for in other medical institutes or those who died before 1998 were not included in this study.

GD patients have been able to receive regular treatment since 1998 under the coverage of the health care system in Taiwan. With the introduction of NBS for GD in 2015, a distinctive representation of the pre-ERT era, post-ERT clinical era, and post-ERT NBS era (or simply the post-NBS era) is apparent in the Gaucher population. From our data, nearly 90% of the patients in this cohort had either the GD1 (33%) or GD3 (52%) subtype, as opposed to approximately 90% of the patients with the GD1 subtype reported worldwide, highlighting the phenotypic uniqueness of our cohort [10]. While neuro-ophthalmologic study was not performed, patients were assessed at intervals by the treating physicians, who made records of notable interval changes. Records of abnormal eye movements were detailed in medical charts of patients with oculomotor apraxia, and electroencephalographic studies were traceable for patients with clinical suspicion of seizures. Since the introduction of NBS for GD in Taiwan, a redistribution in subtypes has been noted, with an increase in individuals with GD2. To be exact, the diagnoses can be made within the neonatal period, curtailing the symptom-to-treatment interval, which enables these patients to receive early intervention. In contrast with the worldwide distribution of 5% reported for the GD3 subtype [8], it was the most common subtype in our cohort, with a prevalence of 52%. Moreover, patients with GD in Taiwan are entitled to treatment without having to cope with economic hardships.

Hepatosplenomegaly, anemia, and thrombocytopenia were the main presentations in clinically diagnosed GD patients across the eras. ERT is approved for the treatment of both GD1 and GD3 patients in Taiwan. For GD2 patients, ERT is sometimes administered for palliative measures to relieve visceral manifestations or is given until the diagnosis of GD3 is disproved [30]. With the use of ERT, patients are exempt from splenectomy, which was the treatment of choice for Gaucher disease before the advent of ERT [31], indicating the effect of ERT in relieving the disease burden. Moreover, most patients display thrombocytopenia and anemia in their initial presentations, with less severity in the GD1 group. Under regular ERT, patients with GD1 and GD3 are able to reinstate hematological stabilizations to impede anemic and thrombocytopenic events, which agrees with the current use of ERT [32]. Although skeletal manifestations affect approximately 50% of patients diagnosed during the pre-ERT era, they were nonexistent in those diagnosed in the post-ERT era. However, while Charrow et al. showed that some skeletal improvement could be attained by ERT, it seemed to be difficult to exercise such an effect for the majority of subjects exhibiting skeletal symptoms [12]. As the recuperation of already established bone disease is difficult or even impossible with ERT, possibly due to altered vascularization, fibrosis, or differing ability of the subpopulations of Gaucher cells in the bone marrow to take up the exogenous enzyme [6, 33, 34], the difference in skeletal manifestations between individuals diagnosed during the pre- and the post-ERT eras reiterates the importance of early diagnosis, which allows early treatment to improve outcomes.

With NBS, the GD community exhibits a greater proportion of GD2 than previously anticipated. This could be attributed to the rarity of the disease, the phenotypes of which are likely to be unrecognized, let alone precisely diagnosed before disease progression. In our cohort, all except one patient diagnosed by NBS were asymptomatic, which concurs with a previous pilot study on NBS for LSDs [35]. The only symptomatic GD2 patient at the time of diagnosis by NBS initially presented with hepatosplenomegaly, anemia, thrombocytopenia, oculomotor apraxia, and ichthyosis and expired at 3 months of age. NBS helped in rapid diagnostic confirmation. The only GD2 patient who underwent treatment was asymptomatic when diagnosed by NBS with confirmation of the compound heterozygous p.Leu483Pro/RecNciI genotype at 2.5 months old. Due to the emergence of hepatosplenomegaly at 5 months of age in addition to squinting, HSCT and ERT were provided promptly in the hope that the patient had the GD3 subtype. While studies comparing the safety and efficacy of HSCT to ERT and SRT are scarce, treatment options with HSCT have been proposed in the context of neuronopathic GD, though the effectiveness is limited [36]. However, as the deterioration progressed, the diagnosis of GD2 was justified, and the patient died at 1 year 11 months of age. Considering the difference in the subtype distributions during the pre-NBS era and post-NBS era, GD patients with severe symptoms were likely to be underdiagnosed during the pre-NBS era.

Patients with GD3 exhibit neurological presentations in addition to visceral, hematological, and skeletal involvement. While the majority of symptoms are amenable to ERT, neurological presentations progress owing to the inability of ERT to cross the blood–brain barrier. As demonstrated by Narita et al. and Aries et al., chaperone therapy with ambroxol has the potential to provide neurological efficacy for both GD3 and GD2 given its ability to cross the blood‒brain barrier as a small molecule [37, 38]. In our cohort, almost half of the GD3 (5 of 12) patients were prescribed ambroxol due to the progression of neurological manifestations. One patient was noted to exhibit improvement of cognitive function [39]. Another patient showed improved development delay and seizure. Another patient who presented with seizure attacks that became refractory after being relatively well controlled with antiepileptic drugs for 7 years was put on ambroxol in addition to 4 antiepileptic medications. Improvement was not noted until after the addition of lacosamide a year later, and mild diffuse brain atrophy was evident under magnetic resonance study. However, another patient exhibited aggravation of neurological symptoms after undergoing spine surgery while receiving ambroxol. The remaining patient was stationary for neurological progression with the addition of ambroxol with a follow-up period of 3.5 years. In addition, severe lymphadenopathies were encountered in GD3 patients, especially those with the homozygous p.Leu483Pro genotype, indicating resistance to soft tissue involvement in GD3 patients receiving ERT [32]. Although eliglustat benefited lymphadenopathies in GD3 patients, it did not have effects on their neurological symptoms [26]. Managing GD3 patients with these neurological presentations remains an unmet need, which accordingly calls for new treatments.

Although their prognoses vary greatly, the symptomatology of GD2 and GD3 patients may not always be discernible initially, especially for those diagnosed by NBS. The genotype p.Leu483Pro/RecNciI was shared by one GD2 patient and one GD3 patient (patient 14 of Table 3). They were both asymptomatic when diagnosed with GD by NBS with low glucocerebrosidase activities of 0.53 μmol/hr/L and 0.47 μmol/hr/L, respectively. ERT was applied in the GD2 patient after abnormal eye movement was observed at the age of 6 months. The neurological progression of the GD2 patient deteriorated despite management with ERT alongside HSCT and he expired after 20 and a half weeks of treatment. On the other hand, ERT was implemented early in the GD3 patient with low platelet count, elevation of lyso-Gb1, and borderline splenomegaly at the age of 5 weeks [39]. Ambroxol was later added for neurological features of mild horizontal gaze palsy and trunk rigidity emerged at 6 months of age. Delayed milestone in gross motor without regression or seizure was noted at 18-months-old. Under active management with ERT and ambroxol, she celebrated her fifth birthday with a stabilized neurological progression. At 4 years 3 months, the WISC result for Full-scale IQ (FIQ) was 71 with a Verbal Comprehension Index (VCI) of 93. She was able to walk independently, run, and jump with ataxia, hypertonicity and gaze palsy. As per her current presentation, the clinical classification was GD3 although the genotype is p.Leu483Pro/RecNciI. The wide spectrum of the same genotype recapitulates not only the importance of early diagnosis to allow timely intervention but also the significance of not withholding ERT and/or ambroxol on patients with genotypes of unfavorable outcome forecast.