Phenotypic Spectrum of Type 2–3 Gaucher Disease: A Case Study in the Balkan Genotype

Abstract

Patient: Male, 4-month-old

Final Diagnosis: Type 2–3 Gaucher disease, homozygosity for p.[His294Gln;Asp448His]

Symptoms: Hepatosplenomegaly • thrombocytopenia • anemia • elevated IgA • elevated IgM • low cholesterol • Gaucher cells • elevated chitotriosidase • elevated lyso-GB1 • oculomotor apraxia • dystonia • seizures • extrapyramidal syndrome • neck rigidity • trunk rigidity

Clinical Procedure: —

Specialty: Pediatrics and Neonatology

Objective: Unusual clinical course

Background

Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the glucosylceramidase beta 1 (GBA1) gene, with a wide range of clinical manifestations. Type 2 GD, the acute neuronopathic form, is the most severe and has historically been considered a distinct clinical entity. Emerging evidence suggests a broader phenotypic spectrum, including intermediate forms that do not fully align with the diagnostic criteria for either type 2 or type 3 GD. Here, we describe an Albanian patient with an unusual intermediate type 2–3 phenotype, homozygous for the rare GBA1 complex allele p.[His294Gln;Asp448His] that is frequently found in Balkan populations. Although this genotype is typically associated with early-onset type 2 GD and death within the first 2 years of life, our patient developed neurologic symptoms at 15 months and survived until age 5.

Case Report

A male Albanian infant presented at 4 months of age with hepatosplenomegaly and thrombocytopenia. Genetic testing revealed homozygosity for the rare GBA1 complex allele p.[His294Gln;Asp448His]. Enzyme replacement therapy, initiated at 7 months, led to temporary improvement of visceral and hematological symptoms. Neurologic manifestations – including oculomotor apraxia, dystonia, and seizures – emerged at 15 months. Despite continued enzyme replacement therapy and supportive care, the patient’s neurologic condition progressively worsened, and he died at age 5 due to disease progression and pulmonary complications.

Conclusions

This case reinforces the concept that type 2 GD exists on a phenotypic spectrum, rather than as a uniform clinical entity, and underscores the broad genotype–phenotype variability in GD.

Introduction

Gaucher disease (GD), a particularly common lysosomal storage disorder, is caused by deficiency of the enzyme glucocerebrosidase due to mutations in the glucosylceramidase beta 1 (GBA1) gene. This enzymatic defect leads to the accumulation of glucocerebroside in tissue macrophages, resulting in hematological, visceral, skeletal, and, in some cases, neurological involvement [1]. The clinical presentation of GD is highly variable, ranging from neonatal lethality to asymptomatic individuals in late adulthood [2].

GD is conventionally classified into 3 types based on the presence and progression of neurological symptoms [3–5]. Type 1 GD, the most common form, is characterized by the absence of early-onset neurological involvement. Type 2 GD, the acute neuronopathic form, manifests prenatally or in early infancy and typically results in death within the first 2 years of life. Type 3 GD, the subacute neuronopathic form, has a later onset and a more protracted neurological course, often beginning in childhood or adolescence [3,6,7]. Although this classification remains standard, phenotypic boundaries between types are increasingly considered fluid, reflecting a continuum rather than discrete entities [2,8]. Neurological features are rare but have occasionally been reported in type 1 GD; overlapping features are frequently observed between type 2 GD and type 3 GD [2,7,9]. Historically, type 2 GD was thought to present with a uniform phenotype. However, intermediate forms – characterized by delayed neurological onset (often beginning with oculomotor apraxia) and survival beyond infancy – have been described, blurring the distinction between type 2 GD and type 3 GD [7,10,11].

In this report, we describe a patient of Albanian origin with an intermediate type 2–3 GD phenotype, homozygous for the complex GBA1 allele p.[His294Gln;Asp448His], where both mutations occur in cis. This rare genotype has predominantly been reported in the Balkan population and is typically associated with severe, early-onset type 2 GD. We also review the relevant literature. This case report adheres to the CARE guidelines for the reporting of clinical cases.

Case Report

We present the case of a child born to non-consanguineous Albanian parents who was diagnosed with an uncommon phenotype of GD. The pregnancy and delivery were normal; birth weight was 2.9 kg. The child was breastfed for more than 6 months. At 4 months of age, he was referred to our hospital for evaluation of liver and spleen enlargement. No neurological signs were observed at the first visit. Laboratory findings on admission were as follows: hemoglobin 8.6 g/dL, red blood cell count 3.8×10⁶/mm³, platelet count 8.1×10³/mm³, prothrombin time 43.2%, alanine transaminase and aspartate aminotransferase within normal ranges, cholesterol 126 mg/dL (normal range: 140–200 mg/dL), and elevated IgA (100 mg/dL, normal range: 5–34 mg/dL) and IgM (289 mg/dL, normal range: 17–66 mg/dL). Abdominal computed tomography showed hepatosplenomegaly, with a spleen length of 11.8 cm and a liver length of 8.5 cm. Bone marrow aspiration was performed to exclude hematological diseases, leishmaniasis, and other conditions; it confirmed the presence of Gaucher cells. At 5 months of age, the child underwent confirmatory testing for GD in Italy. Laboratory findings indicated low glucocerebrosidase activity (<1.5 μmol/L/h, normal range: ≥4.6 μmol/L/h) and an elevated glucosylsphingosine level (329 nmol/L, normal range: <12 nmol/L). Both tests were performed on peripheral blood. Genetic testing revealed homozygosity for the complex GBA1 allele p.[His294Gln;Asp448His]. These findings definitively confirmed the diagnosis of GD.

Enzyme replacement therapy (ERT) with imiglucerase was initiated at 7 months of age, using a dose of 50 IU/kg body weight every 2 weeks. At a follow-up visit (age 14 months), the child was active, playing with objects, sitting unsupported, and walking while holding his mother’s hand. However, oculomotor apraxia was observed for the first time. Laboratory findings were hemoglobin 9.8 g/dL, platelet count 7.2×10⁴/mm³, alanine transaminase 23 U/L, and aspartate aminotransferase 84 U/L. Neurological signs gradually became more pronounced. At subsequent follow-up visits, the child exhibited dysphagia, laryngospasm, oculomotor apraxia, extrapyramidal syndrome, incoordination, gait disturbances, and seizures. Head magnetic resonance imaging at 15 months of age showed an enlarged cisterna magna. Electroencephalography demonstrated paroxysmal abnormalities in the right parieto-temporal region. Baclofen was added to the treatment regimen, along with imiglucerase. At age 15 months (after 7 months of ERT), imiglucerase was replaced with velaglucerase alfa, another form of ERT, for non-medical reasons (lack of drug availability).

Subsequently, the child continued treatment with velaglucerase alfa. While receiving ERT, he showed clinically significant improvement in visceral and hematological findings, with reductions in liver and spleen size and increases in platelet count (1.72×10⁵/mm³) and hemoglobin level (10.5 g/dL) (Figure 1A, 1B). The levels of biomarkers chitotriosidase and glucosylsphingosine remained elevated, despite brief periods of mild decrease (Figure 1C, 1D). At age 3, head computed tomography revealed pronounced hydrocephalus (Figure 2); ventriculostomy was performed, followed by the placement of a ventriculoperitoneal shunt. Percutaneous gastrostomy was performed due to feeding difficulties. During this period, an attempt was made to treat the child with the chaperone ambroxol, administered at a starting dose of 3 mg/kg and increased by 3 mg/kg each month for approximately 8 months. A reduction in laryngospasm episodes was observed.

Figure 1.

Laboratory findings. (A) Platelet count. (B) Hemoglobin concentration. (C) Chitotriosidase activity. (D) Glucosylsphingosine level.

Figure 2.

Computed tomography scan of the head showing pronounced hydrocephalus.

The last 2 years were characterized by progressive neurological deterioration, neck and trunk rigidity, dysphagia, feeding difficulties, laryngospasm, strabismus, extrapyramidal syndrome, incoordination, gait disturbances, seizures, and failure to thrive. At age 5, the child died of respiratory failure due to frequent lung infections and aspiration pneumonia.

Discussion

This report describes a distinct neuronopathic phenotype of GD associated with an extremely rare pathogenic variant in the GBA1 gene, thereby broadening the clinical understanding of the disorder. Historically, neuronopathic GD has been classified into 2 forms: type 2 (acute) and type 3 (subacute), which together encompass a wide clinical spectrum that ranges from mild type 3 GD (eg, isolated oculomotor apraxia) to the severe pre- and perinatal presentations characteristic of type 2 GD [1,6,12,13]. The mechanisms underlying this phenotypic variability remain unclear but are thought to involve promoter mutations, modifier genes, and epigenetic and environmental factors [1,4,14,15].

Similar to types 1 and 3 GD, type 2 GD lies on a phenotypic continuum, with overlapping clinical features and limited genotype–phenotype correlation [12]. Patients who survive beyond their second year of life and exhibit a clinical course between types 2 and 3 are considered to have an intermediate phenotype [6,7]. For example, Goker-Alpan et al [7] described 9 children with this intermediate type 2–3 phenotype, characterized by delayed onset at a mean age of 12.6 months, in contrast to the typical onset at 3.5 months for classic type 2 GD [16]. All patients in that series survived beyond age 2, with the oldest reaching 6 years; however, all patients also experienced rapid neurological deterioration.

Horizontal gaze palsy was the first neurological sign noted in the work by Goker-Alpan et al [7]; similarly, it was the earliest neurologic manifestation in our patient, appearing at 15 months of age. Before this manifestation, the patient exhibited hepatosplenomegaly and thrombocytopenia between 4 and 5 months of age. After initial improvement with ERT – during which the child became more active, engaged with objects, and was able to sit unsupported and walk with assistance – neurological symptoms progressed. These included neck and trunk rigidity (opisthotonos), dysphagia, laryngospasm, strabismus, extrapyramidal signs, incoordination, gait disturbance, seizures, and failure to thrive. Thoracic kyphosis, a non-neurological feature typically associated with type 3 GD [3], was also observed.

The report by Goker-Alpan et al [7] also described genotypic heterogeneity among patients with the intermediate phenotype; the p.(Leu483Pro) variant was the most frequent pathogenic mutation. Notably, 2 patients exhibited homozygosity for this variant, which is typically associated with type 3 GD [3,12]. Another genotype linked to the intermediate type 2–3 phenotype is the complex allele p.[Asp448His;Leu422Profs*4], observed by Darling et al in a patient who presented with Parkinsonian features [10].

Genetic testing in our patient revealed homozygosity for the GBA1 complex allele p.[His294Gln;Asp448His]. This allelic combination, in which both pathogenic variants occur in cis on the same allele and are inherited from each parent, has been documented [17]. This complex allele has been consistently associated with early-onset, rapidly progressive type 2 GD [18,19]. It is a rare genotype, predominantly found in patients from Albania and neighboring regions [20–23]. Internal data from our center – the only specialized GD center in Albania – indicate that this double pathogenic allele is highly prevalent, found in more than 50% of our patients (based on 57 patients in total), and associated with substantial phenotypic variability. In addition to the present case, 2 other patients in our center have shown homozygosity for this allele and displayed the classic type 2 GD phenotype (unpublished data), consistent with previous reports [18,19,23,24].

In a study by Dimitriou et al involving 141 patients with GD, this complex allele was identified in 15% of Greek-origin patients and in 36% of Albanian-origin patients living in Greece. All 5 patients with homozygosity for this allele exhibited type 2 GD [22]. To our knowledge, the patient in the present case is the second reported individual with this genotype to exhibit an intermediate phenotype – the first was an infant of Albanian origin described by Filocamo et al [11].

Due to the heterogeneous clinical presentation of GD, treatment strategies must be individualized. The primary therapeutic approaches include ERT and substrate reduction therapy [13]; however, neither has demonstrated efficacy in treating neurological manifestations. ERT remains the standard of care for patients with type 3 GD because it greatly improves visceral and hematological symptoms, enhances quality of life, and extends survival [12]. However, the role of ERT in type 2 GD remains controversial. Although some clinicians argue that ERT offers little benefit in acute neuronopathic forms, it has nonetheless been administered to many patients in recent years [10,12,21,25]. In the present case, ERT was initiated at 7 months of age and led to improvements in visceral and hematological parameters; as expected, it had no effect on neurological progression.

Recently, pharmacological chaperone therapy has emerged as a promising therapeutic strategy for lysosomal storage disorders, particularly those with neurological involvement, because certain chaperones are capable of crossing the blood–brain barrier [25–27]. In GD, mutant glucocerebrosidase is often misfolded and targeted for degradation despite retention of potential residual activity. Pharmacological chaperones selectively bind to the misfolded enzyme in the endoplasmic reticulum, stabilize its structure, and facilitate correct folding and trafficking to lysosomes, thereby restoring enzymatic activity [28]. In 2009, ambroxol – an over-the-counter mucolytic – was reported to act as a pharmacological chaperone for mutant glucocerebrosidase when administered at high doses [29]. Initially, high-dose ambroxol was used in type 3 GD, where it led to substantial neurological improvement [28]. More recently, several studies have demonstrated positive outcomes in patients with acute neuronopathic GD who received high-dose ambroxol [25,26,29,30]. However, consensus regarding its routine use in this context has not yet been established.

We administered ambroxol to our patient and observed a reduction in the frequency and severity of laryngospasm. Nonetheless, due to the short treatment duration (8 months, from 25 to 33 months of age), no definitive conclusions can be drawn regarding its efficacy. Supportive management remains a critical aspect of care; it includes nutritional support, nasogastric feeding, infection prevention, and seizure control. Although current therapies may not alter the neurological course of the disease, they can influence prognosis, prolong survival, and improve quality of life [12]. Treating infants with neuronopathic GD remains a considerable challenge. Early involvement of the multidisciplinary medical team, the patient’s family, and a support network is essential to establish treatment goals and help families cope with the severity of the diagnosis [27].

Conclusions

This case reinforces the concept that type 2 GD exists on a phenotypic spectrum, rather than as a uniform clinical entity, and underscores the broad genotype–phenotype variability in GD.