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Bone manifestations in neuronopathic Gaucher disease while receiving high-dose enzyme replacement therapy
Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Bone manifestations in neuronopathic Gaucher disease while receiving highdose enzyme replacement therapy Kunal C. Potnisa, Lauren B. Flueckingera, Christine I. Haa, Jariya Upadiaa, Donald P. Frushb, ⁎ Priya S. Kishnania, a b
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA Division of Pediatric Radiology, Department of Radiology, Duke University Medical Center, Durham, NC, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: Gaucher disease Avascular necrosis Osteonecrosis Bone manifestations Enzyme replacement therapy
Avascular necrosis (AVN), one type of bone infarction, is a major irreversible complication of Gaucher disease (GD). In this report, two pediatric patients with GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), developed AVN despite treatment on long-term, high-dose enzyme replacement therapy (ERT). ERT was initiated in both patients, who had intact spleens, shortly after diagnosis with an initial dramatic response. However, both patients exhibited AVN after 5.5 and 11 years on high-dose ERT, respectively, despite good compliance and normalized hematological findings and visceral symptoms. This report demonstrates the importance of careful, regular surveillance of the musculoskeletal system in addition to monitoring the neurological symptoms associated with neuronopathic GD. Additionally, it highlights the limitations of ERT in terms of targeting certain sanctuary sites such as bone marrow and suggests the need for new treatment modalities other than ERT monotherapy to address these limitations.
Abbreviations: GD Gaucher disease BMD bone mineral density AVN avascular necrosis ERT enzyme replacement therapy MRI magnetic resonance imaging DXA dual-energy X-ray absorptiometry ACE angiotensin-converting enzyme CHITO chitotriosidase TRAP tartrate-resistant acid phosphatase SRT substrate reduction therapy
1. Introduction Gaucher disease (GD) is an autosomal recessive, lysosomal storage disorder caused by β-glucocerebrosidase deficiency, resulting in accumulation of glucocerebroside in the lysosomes of reticuloendothelial cells [1]. Affected monocytes and macrophages, called Gaucher cells, preferentially accumulate in the bone marrow, liver, spleen, and lungs [2,3]. Individuals typically present with hepatosplenomegaly, pancytopenia, and skeletal abnormalities as well as neurological symptoms in
⁎
some cases [4]. The phenotypic manifestations of GD are highly variable and traditionally divided into three clinical subtypes based on neurological symptom presence and progression. Classically, neurological involvement is absent in GD type 1 (non-neuronopathic), severe in GD type 2 (acute neuronopathic, rapid progression), and mild to moderate in GD type 3 (chronic neuronopathic, attenuated progression). Among the neuronopathic forms of GD, a continuum of intermediate phenotypes has been reported, a testament to the heterogeneity of GD [5].
Corresponding author at: Duke University Medical Center, 905 S. LaSalle Street, GSRB1, 4th Floor, Box 103856, Durham, NC 27710, USA. E-mail address: [email protected] (P.S. Kishnani).
https://doi.org/10.1016/j.ymgme.2018.11.004 Received 28 June 2018; Received in revised form 7 November 2018; Accepted 8 November 2018 1096-7192/ © 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Potnis, K.C., Molecular Genetics and Metabolism, https://doi.org/10.1016/j.ymgme.2018.11.004
Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx
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Bone manifestations differ among clinical subtypes, including fractures, decreased bone mineral density (BMD), avascular necrosis (AVN), sclerosis, lytic and cystic lesions, joint collapse, undertubulation, chest deformities, lumbar lordosis, and kyphosis [6–9]. It remains unclear whether some orthopedic manifestations, particularly kyphosis, are a result of GD or a comorbidity. Bone crises and associated features are less common in GD today given the widespread uptake of early treatment and decrease in splenectomy prevalence, though these features were historically common in the pre-treatment era [10]. Enzyme replacement therapy (ERT) has served as the standard of care for treating somatic symptoms associated with GD types 1 and 3. For pediatric type 3 cases, Vellodi et al. recommend a minimum dose of 60 U/kg every two weeks with the possibility of increasing to 120 U/kg every two weeks to meet therapeutic goals as necessary [11]. ERT effectively improves hematological manifestations and significantly reduces hepatosplenomegaly [12,13]; however, the response of bone manifestations is slower and more variable [14]. Growing evidence suggests Gaucher cells in the bone marrow may be less effective at taking up exogenous β-glucocerebrosidase or may be impeded by fibrosis or modified vascularization; that is, the bone marrow may be a sanctuary site when treating GD with ERT [15]. There have been reports of AVN in patients with GD post-ERT initiation [16–19] and are typically correlated with late treatment initiation or splenectomy status [20–22]; however, AVN has also been documented despite high-dose ERT [15]. We present two additional cases of GD type 3, homozygous for the L483P (previously L444P) pathogenic variant, who developed AVN despite long-term treatment with high-dose ERT. Both patients were initiated on ERT shortly after diagnosis, have intact spleens, showed an initial dramatic response to ERT, and exhibited AVN after 5.5 and 11 years on high-dose ERT, respectively.
Fig. 1. Anteroposterior pelvic radiograph at 7 years of age (case 1) demonstrates AVN (arrows) characterized by sclerosis of the femoral head and neck with flattening of the proximal left femoral epiphysis and widening of the joint space compared to the normal right hip due to cartilage hypertrophy.
8 months. Patient underwent an open reduction internal fixation surgery of the right femur and an additional repair surgery at 7 years and 10 months. Upon follow-up, improper healing was noted; workup for anti-imiglucerase antibodies was negative. Alteration of the ERT schedule to 60 U/kg weekly occurred in an attempt to better impact bone health. Gaucher biomarkers, including angiotensin-converting enzyme (ACE), chitotriosidase (CHITO), and tartrate-resistant acid phosphatase (TRAP), exhibited a downward trend following this dose alteration; however, all remained elevated (200–250 IU/L, 4500–5700 nmol/h/ mL, and 30–44 IU/L, respectively). By 9 years, patient regained full mobility and was ambulatory without assistive devices. MRI at 10 years revealed stable AVN of the left femoral head with flattening and irregularity (Fig. 2). At 12 years, postural changes with kyphosis and lumbar lordosis were noted. At 13 years, routine MRI revealed worsening AVN on the left femoral head and new involvement of the right femoral head (Fig. 3) without clinically appreciable symptoms. DXA scans of the lumbar spine and right
2. Case 1 A Hispanic male presented at the Duke Metabolic Clinic at age 14 months with frequent epistaxis, hepatosplenomegaly, interstitial lung disease, and failure to thrive with height, weight, and head circumference at the < 3rd, 10th, and 7th percentiles, respectively. Family history was positive for two deceased siblings with reported Gaucher-like symptoms without a formal diagnosis. Consanguinity was denied. Clinical presentation, bone marrow biopsy, and low enzyme activity of 1.9 nmol/h/mg protein (lower limit of normal: 12.5 nmol/h/ mg protein) confirmed a diagnosis of GD. Genetic testing in an experienced lab revealed homozygous L483P pathogenic variants. At 17 months, ERT was initiated with imiglucerase 60 U/kg every two weeks. Interstitial lung disease and hepatosplenomegaly persisted, and the dose was increased to 120 U/kg every two weeks at 24 months. At 4 years, patient exhibited bilateral sixth cranial nerve palsy requiring surgery and abnormal central conduction bilaterally on brainstem auditory evoked response (BAER). Hearing loss continued and required bilateral hearing aids at 12 years, at which time formal assessment documented the patient to be at least 1 year developmentally delayed relative to age-matched peers. Bone health was routinely monitored during childhood via magnetic resonance imaging (MRI), radiography, and dual-energy X-ray absorptiometry (DXA). BMD was consistently below average for age and weight, though skeletal films were normal. At 7 years, the patient reported pain and began limping. DXA scans of the lumbar spine and right hip at this time noted Z-scores of −1.58 and −1.3, respectively. Radiographs noted AVN of the left femoral head (Fig. 1). Additionally, patient experienced a vitamin D deficiency (< 10 ng/mL), which responded to supplementation (54 ng/mL; normal range: 24–86 ng/mL). An episode of bone crisis occurred that same year and was treated with IV fluids and pain medications in a hospital setting. Subsequent radiographs noted stabilization of the left femoral head but revealed a new fracture in the right femoral neck at 7 years and
Fig. 2. Coronal view from a T2-weighted pelvic MRI at 10.5 years of age (case 1) demonstrates heterogeneous signal intensity (arrow) in the proximal left femur due to AVN. The abnormal appearance of the right femur (*) was felt to be due to artifact from the orthopedic hardware. 2
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Fig. 3. Coronal T1-weighted (a) and T2-weighted (b) pelvic MRI at 13 years of age (case 1). Note reconstitution of the articular surface on the left although the femur is slightly laterally subluxed with loss of femoral head sphericity. There is low signal seen in the right femoral head in both (a) and (b) (arrows) due to AVN that could be secondary to the orthopedic hardware; artifact from the hardware indicated (*). This was greater on the prior MRI, but the technique was different, and it is unclear if AVN developed in the 26-month interval between the two scans or was present prior to the previous MRI. Slight transition to more normal fatty marrow in (a) (arrowhead) in the left femur is probably due to changes of necrosis in this region previously as well as altered mechanics from the bilateral femoral abnormalities over the years.
Fig. 4. Coronal T1-weighted (a) and T2-weighted (b) pelvic MRI at 17 years of age (case 2). There is a new focal signal abnormality revealed in (a) in the anteromedial left femoral head measuring 10 × 12 × 12 mm (arrow). This area is T1 bright with a T1 dark serpiginous rim in (a) and predominantly T2 bright in (b) with some internal areas of low T2 signal (arrow). The appearance is consistent with infarct (AVN).
hip exhibited Z-scores of −1.88 and −2.44, respectively. Patient was fitted for a thoracolumbosacral orthosis brace at 15 years for worsening kyphosis. Anti-imiglucerase antibodies remained negative. At publication, patient's visceral symptoms are stable at 17 years. His liver and spleen are normal in size and appearance. ACE, CHITO and TRAP have been stable but remain elevated at 170 IU/L, 3898 nmol/h/mL, and 23.1 IU/L, respectively. Pelvic MRI revealed no new AVN or worsening articular collapse. His height and weight track at the < 3rd percentile and the 10th–25th percentiles, respectively.
3. Case 2 An 18-month old Caucasian male presented with anemia, hepatosplenomegaly, and failure to thrive to an outside institution. Low enzyme activity of 4 nmol/h/mg protein (lower limit of normal: 12.5 nmol/h/mg protein) was noted, and genetic testing revealed homozygosity for the L483P pathogenic variant. There was no known family history of GD, and consanguinity was denied. ERT was initiated at 35 U/kg every two weeks at age 22 months, and presenting 3
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between development of AVN and factors such as ERT dose and duration, similar to the two GD type 3 cases reported here. These two cases highlight the importance of addressing the remaining limitations of current therapies in GD, particularly in preventing bone complications. Other reports have described the use of combination ERT and SRT as well as stand-alone SRT in the treatment of GD. In a recent report by Amato et al., combination ERT and SRT treatment in a patient with type 1 disease resulted in a significant reduction of bone pain [23]. In a study by Giraldo and colleagues, no new cases of bone crisis, AVN, or pathologic fractures were reported after two years of SRT in patients with GD type 1 previously on ERT [24]. Additionally, in a pooled analysis of prospective studies by Pastores et al., patients with GD type 1 previously on ERT who transitioned to SRT were found to have significant increases in BMD and decreases in bone pain over two years [25]. For case 2 in our report, SRT may have helped stabilize the patient's BMD. The literature suggests SRT products distribute more extensively throughout tissue, which could potentially contribute to the osseous therapeutic benefit observed in these studies [26,27]. However, future studies that examine bone disease in patients with GD on SRT over more than two years are necessary to better assess the long-term benefits and side effects of SRT in managing bone manifestations. It is noteworthy that both patients presented here were homozygous for the L483P variant, suggesting that there may be additional osseous genotype-phenotype correlations that should be investigated in this group. L483P homozygosity is one of the most common genotypes for GD type 3, which is the most prevalent form of GD in some regions of the world, including Northern Sweden, Poland, Egypt, and Japan [9,28]. Mistry and colleagues describe a characteristic “disabling ‘gibbus’ spinal deformity” exhibited by some groups of L483P homozygotes around the world, thought to exacerbate progressive neurological and pulmonary disease associated with GD type 3 [29]. In a study by Andrade-Campos et al., two Spanish patients homozygous for the L483P variant manifested Norrbottnian-like thoracic deformations during childhood prior to diagnosis [30]. Suwannarat et al. reported a similar phenotype in a Thai patient with L483P homozygosity during childhood [31]. With regard to the cases presented in this report, while as complete a workup as possible was completed, whole exome sequencing was not performed; thus, other, possibly ethnicity-related genetic factors related to bone manifestations cannot be ruled out and represent an area for future inquiry.
symptoms resolved. At 4 years, the patient established care at the Duke Metabolic Clinic, at which time he was growing and developing normally without any observable features of GD. ERT continued every two weeks at 35 U/kg. ERT dosing was increased to 60 U/kg every two weeks at 6 years after consulting with Gaucher experts given the association between type 3 disease and the L483P disease-causing variant. Bone health remained normal with routine monitoring until DXA scans at 11 years noted slightly below average BMD of the lumbar spine and right hip (Z-scores of −1.1 and −1.0, respectively). Liver MRI displayed increased volume relative to growth. Height and weight measured 139.7 cm (20th percentile) and 30.3 kg (10th percentile), respectively. Chest asymmetry with right-sided prominence developed at 14 years without presence of scoliosis or kyphosis. At 16 years, DXA scan revealed osteopenia in the lumbar spine and right hip with Zscores of −1.2 and 2.0, respectively. At 17 years, mild kyphosis and lumbar lordosis persisted. Radiographs and pelvic MRI revealed a focal signal in the left femoral head consistent with AVN (Fig. 4) as well as several benign-appearing lesions in the anterior cortex of the proximal femurs bilaterally at 17 years. Patient denied bone pain. CHITO and TRAP were elevated at 1017 nmol/h/mL and 132 IU/L, respectively, and ACE was in the normal range at 112 IU/L. DXA scans revealed below average BMD of the lumbar spine and right hip with Z-scores of −2.30 and −2.10, respectively. No surgical intervention was recommended at this time. Patient transitioned treatment modalities from intravenous ERT to oral substrate reduction therapy (SRT) with eliglustat 84 mg twice a day at 18 years. At 20 years, DXA scans documented no change in BMD relative to previous scans at 17 years. At publication, patient is clinically stable with SRT without evidence of bone crisis. His bone health via imaging is stable, and patient does not report pain. 4. Discussion We present two cases of GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), who developed AVN despite treatment on high-dose ERT for 5.5 and 11 years, respectively. Risk factors for AVN including splenectomy, poor ERT compliance, antibodies to imiglucerase, low ERT dose, anemia, trauma, corticosteroid use, poor nutrition, and late initiation of ERT were absent [15,20–22]. While case 1 was noted to have vitamin D deficiency at 7 years, a risk factor for AVN, this was improved through supplementation. In spite of good compliance and the absence of other typical AVN risk factors, case 1 continued to exhibit low growth percentiles and case 2's osteopenia did not normalize, further demonstrating that bone marrow is a sanctuary site and that ERT treatment response is not completely robust. At the time of AVN development, while case 1 was symptomatic, case 2 appeared to be asymptomatic. Furthermore, the development of AVN and worsening of BMD occurred despite stabilization of the visceral and hematological manifestations of GD. Overall, our cases demonstrate the necessity of continued monitoring of patients with neuronopathic GD, especially as it pertains to MRI of the pelvis, radiographs of the pelvis and long bones, and bone density scans. AVN is an irreversible complication and, therefore, all attempts to prevent its development should be taken [19]. Should an AVN develop, early identification can lead to more positive outcomes for the patient. The dose recommendations from Vellodi et al. were considered in the treatment plans for both cases presented, although the global medical community has not completely embraced this increased dose above the package insert as standard of care [11]. The treating clinical team initiated a higher therapy dose in the hopes that these patients would demonstrate a lower likelihood of developing bone symptoms; however, the long-term, high-dose therapy did not prevent AVN formation. This outcome is in concordance with previous studies in which increases in ERT dose failed to prevent AVN formation in some patients with type 1 disease [15,19]. In these studies, there was no relationship
5. Conclusions We present two non-splenectomized patients with GD type 3 (L483P homozygotes) who began treatment on high-dose ERT shortly after diagnosis during infancy. Despite stabilization of their hematological and visceral symptoms, both patients ultimately developed AVN. This report demonstrates the importance of careful, regular surveillance of the musculoskeletal system in patients with GD and the potential for differential osseous risk between GD subtypes. Additionally, it highlights the limitations of ERT in terms of targeting certain sanctuary sites such as bone marrow and suggests the need for new treatment modalities to address these limitations. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosures Priya S. Kishnani has received research/grant support and honoraria from Sanofi Genzyme and Shire Therapeutics. Priya S. Kishnani is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation. Lauren B. Flueckinger has received honoraria 4
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from Sanofi Genzyme and Shire Therapeutics.
enzyme replacement therapy, Haematologia 93 (7) (2008) 1119–1120. [16] H. Ida, O.M. Rennert, K. Iwasawa, M. Kobayashi, Y. Eto, Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation, Hum. Genet. 105 (1–2) (1999) 120–126. [17] O. Goker-Alpan, Therapeutic approaches to bone pathology in Gaucher disease: past, present and future, Mol. Genet. Metab. 104 (4) (2011) 438–447. [18] G.M. Pastores, S. Wallenstein, R.J. Desnick, M.M. Luckey, Bone density in Type 1 Gaucher disease, J. Bone Miner. Res. 11 (11) (1996) 1801–1807. [19] P.B. Deegan, E. Pavlova, J. Tindall, P.E. Stein, P. Bearcroft, T.M. Cox, Osseous Manifestations of Adult Gaucher Disease in the Era of Enzyme Replacement Therapy, Medicine 90 (1) (2011) 52–60. [20] P.K. Mistry, P. Deegan, A. Vellodi, A. Cole, M. Yeh, N.J. Weinreb, Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis, Br. J. Haematol. 147 (4) (2009) 561–570. [21] D. Elstein, I. Hadas-Halpern, M. Itzchaki, A. Lahad, A. Abrahamov, Effect of lowdose enzyme replacement therapy on bones in Gaucher disease patients with severe skeletal involvement, Blood Cell Mol. Dis. 22 (2) (1996) 104–111. [22] S.W. Rodrigue, D.I. Rosenthal, N.W. Barton, D. Zurakowski, H.J. Mankin, Risk factors for osteonecrosis in patients with type 1 Gaucher's disease, Clin. Orthop. Relat. Res. 362 (May 1999) (1999) 201–207. [23] D. Amato, M.A. Patterson, Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports, J. Med. Case Rep. 12 (19) (2018) 1–6. [24] P. Giraldo, P. Alfonso, K. Atutxa, M.A. Fernandez-Galan, A. Barez, M. Pocovi, Realworld clinical experience with long-term miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project, Haematologica 94 (12) (2009) 1771–1775. [25] G.M. Pastores, D. Elstein, M. Hrebicek, A. Zimran, Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies, Clin. Ther. 29 (8) (2007) 1645–1654. [26] N. Belmatoug, M. Di Rocco, C. Fraga, P. Giraldo, D. Hughes, T.M. Cox, Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe, Eur. J. Internal Med. 37 (2017) 25–32. [27] L.L. Bennett, K. Turcotte, Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease, Drug Des. Devel. Ther. 9 (2015) 4639–4647. [28] G. Drelichman, N. Fernandez Escobar, N. Basack, L. Aversa, M.S. Larroude, ... J.L. Saavedra, Skeletal involvement in Gaucher disease: an observational multicenter study of prognostic factors in the Argentine Gaucher disease patients, Am. J. Hematol. 91 (10) (2016) E448–E453. [29] P.K. Mistry, G. Lopez, R. Schiffmann, N.W. Barton, N.J. Weinreb, E. Sidransky, Gaucher disease: Progress and ongoing challenges, Mol. Genet. Metab. 120 (1–2) (2017) 8–21. [30] M. Andrade-Campos, P. Alfonso, P. Irun, J. Armstrong, C. Calvo, ... P. Giraldo, Diagnosis features of pediatric Gaucher disease patients in the era of enzymatic therapy, a national-base study from the Spanish Registry of Gaucher Disease, Orphanet J. Rare Dis. 12 (1) (2017) 84. [31] P. Suwannarat, S. Keeratichamroen, D. Wattanasirichaigoon, L. Ngiwsara, J.R.K. Cairns, S. Pangkanon, Molecular characterization of type 3 (neuronopathic) Gaucher disease in Thai patients, Blood Cell Mol. Dis. 39 (3) (2007) 348–352.
References [1] G.A. Grabowski, S. Gatt, M. Horowitz, Acid beta-glucosidase: enzymology and molecular biology of Gaucher disease, Crit. Rev. Biochem. Mol. Biol. 25 (6) (1990) 385–414. [2] R.J. Wenstrup, M. Roca-Espiau, N.J. Weinreb, B. Bembi, Skeletal aspects of Gaucher disease: a review, Br. J. Radiol. 75 (S1) (2002) A2–A12. [3] H. Andersson, P. Kaplan, K. Kacena, J. Yee, Eight-year clinical outcomes of longterm enzyme replacement therapy for 884 children with Gaucher disease type 1, Pediatrics 122 (6) (2008) 1182–1190. [4] F. Ceravolo, M. Grisolia, S. Sestito, F. Falvo, M.T. Moricca, D. Concolino, Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report, J. Med. Case Rep. 11 (19) (2017) 1–5. [5] O. Goker-Alpan, R. Schiffmann, J.K. Park, B.K. Stubblefield, N. Tayebi, E. Sidransky, Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3, J. Pediatr. 143 (2) (2003) 273–276. [6] J. Charrow, R. Scott, Long-term treatment outcomes in Gaucher disease, Am. J. Hepatol. 90 (S1) (2015) S19–S24. [7] G.M. Pastores, D.A. Hughes, Gaucher Disease, GeneReviews, 2000 updated 2015. (Internet). [8] A. Tylki-Szymanska, B. Czartoryska, Enzyme replacement therapy in type III Gaucher disease, J. Inherit. Metab. Dis. 22 (2) (1999) 203–204. [9] A. Tylki-Szymanska, A. Vellodi, A. El-Beshlawy, J.A. Cole, E. Kolodny, Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry, J. Inherit. Metab. Dis. 33 (4) (2010) 339–346. [10] P.K. Mistry, J.L. Batista, H.C. Andersson, M. Balwani, T.A. Burrow, J. Charrow, P. Kaplan, A. Khan, P.S. Kishnani, E.H. Kolodny, B. Rosenbloom, C.R. Scott, N. Weinreb, Transformation in pretreatment manifestations of Gaucher disease type 1 during two decades of alglucerase/imiglucerase enzyme replacement therapy in the International Collaborative Gaucher Group (ICGG) Gaucher Registry, Am. J. Hematol. 92 (9) (2017) 929–939. [11] A. Vellodi, A. Tylki-Szymanska, E.H. Davies, E. Kolodny, B. Bembi, R. Schiffmann, Management of neuronopathic Gaucher disease: revised recommendations, J. Inherit. Metab. Dis. 32 (5) (2009) 660–664. [12] A. Zimran, D. Elstein, Management of Gaucher disease: enzyme replacement therapy, Pediatr. Endocrinol. Rev. 12 (S1) (2014) 82–87. [13] N.W. Barton, R.O. Brady, J.M. Dambrosia, A.M. Di Bisceglie, S.H. Doppelt, K. Yu, Replacement therapy for inherited enzyme deficiency—macrophage-targeted glucocerebrosidase for Gaucher's disease, N. Engl. J. Med. 324 (21) (1991) 1464–1470. [14] N.J. Weinreb, J. Charrow, H.C. Andersson, P. Kaplan, E.H. Kolodny, A. Zimran, Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry, Am. J. Med. 113 (2) (2002) 112–119. [15] M. de Fost, C.J.M. van Noesel, J.M.F.G. Aerts, M. Maas, R.G. Pöll, C.E.M. Hollak, Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of
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Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Bone manifestations in neuronopathic Gaucher disease while receiving highdose enzyme replacement therapy Kunal C. Potnisa, Lauren B. Flueckingera, Christine I. Haa, Jariya Upadiaa, Donald P. Frushb, ⁎ Priya S. Kishnania, a b
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA Division of Pediatric Radiology, Department of Radiology, Duke University Medical Center, Durham, NC, USA
A R T I C LE I N FO
A B S T R A C T
Keywords: Gaucher disease Avascular necrosis Osteonecrosis Bone manifestations Enzyme replacement therapy
Avascular necrosis (AVN), one type of bone infarction, is a major irreversible complication of Gaucher disease (GD). In this report, two pediatric patients with GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), developed AVN despite treatment on long-term, high-dose enzyme replacement therapy (ERT). ERT was initiated in both patients, who had intact spleens, shortly after diagnosis with an initial dramatic response. However, both patients exhibited AVN after 5.5 and 11 years on high-dose ERT, respectively, despite good compliance and normalized hematological findings and visceral symptoms. This report demonstrates the importance of careful, regular surveillance of the musculoskeletal system in addition to monitoring the neurological symptoms associated with neuronopathic GD. Additionally, it highlights the limitations of ERT in terms of targeting certain sanctuary sites such as bone marrow and suggests the need for new treatment modalities other than ERT monotherapy to address these limitations.
Abbreviations: GD Gaucher disease BMD bone mineral density AVN avascular necrosis ERT enzyme replacement therapy MRI magnetic resonance imaging DXA dual-energy X-ray absorptiometry ACE angiotensin-converting enzyme CHITO chitotriosidase TRAP tartrate-resistant acid phosphatase SRT substrate reduction therapy
1. Introduction Gaucher disease (GD) is an autosomal recessive, lysosomal storage disorder caused by β-glucocerebrosidase deficiency, resulting in accumulation of glucocerebroside in the lysosomes of reticuloendothelial cells [1]. Affected monocytes and macrophages, called Gaucher cells, preferentially accumulate in the bone marrow, liver, spleen, and lungs [2,3]. Individuals typically present with hepatosplenomegaly, pancytopenia, and skeletal abnormalities as well as neurological symptoms in
⁎
some cases [4]. The phenotypic manifestations of GD are highly variable and traditionally divided into three clinical subtypes based on neurological symptom presence and progression. Classically, neurological involvement is absent in GD type 1 (non-neuronopathic), severe in GD type 2 (acute neuronopathic, rapid progression), and mild to moderate in GD type 3 (chronic neuronopathic, attenuated progression). Among the neuronopathic forms of GD, a continuum of intermediate phenotypes has been reported, a testament to the heterogeneity of GD [5].
Corresponding author at: Duke University Medical Center, 905 S. LaSalle Street, GSRB1, 4th Floor, Box 103856, Durham, NC 27710, USA. E-mail address: [email protected] (P.S. Kishnani).
https://doi.org/10.1016/j.ymgme.2018.11.004 Received 28 June 2018; Received in revised form 7 November 2018; Accepted 8 November 2018 1096-7192/ © 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Potnis, K.C., Molecular Genetics and Metabolism, https://doi.org/10.1016/j.ymgme.2018.11.004
Molecular Genetics and Metabolism xxx (xxxx) xxx–xxx
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Bone manifestations differ among clinical subtypes, including fractures, decreased bone mineral density (BMD), avascular necrosis (AVN), sclerosis, lytic and cystic lesions, joint collapse, undertubulation, chest deformities, lumbar lordosis, and kyphosis [6–9]. It remains unclear whether some orthopedic manifestations, particularly kyphosis, are a result of GD or a comorbidity. Bone crises and associated features are less common in GD today given the widespread uptake of early treatment and decrease in splenectomy prevalence, though these features were historically common in the pre-treatment era [10]. Enzyme replacement therapy (ERT) has served as the standard of care for treating somatic symptoms associated with GD types 1 and 3. For pediatric type 3 cases, Vellodi et al. recommend a minimum dose of 60 U/kg every two weeks with the possibility of increasing to 120 U/kg every two weeks to meet therapeutic goals as necessary [11]. ERT effectively improves hematological manifestations and significantly reduces hepatosplenomegaly [12,13]; however, the response of bone manifestations is slower and more variable [14]. Growing evidence suggests Gaucher cells in the bone marrow may be less effective at taking up exogenous β-glucocerebrosidase or may be impeded by fibrosis or modified vascularization; that is, the bone marrow may be a sanctuary site when treating GD with ERT [15]. There have been reports of AVN in patients with GD post-ERT initiation [16–19] and are typically correlated with late treatment initiation or splenectomy status [20–22]; however, AVN has also been documented despite high-dose ERT [15]. We present two additional cases of GD type 3, homozygous for the L483P (previously L444P) pathogenic variant, who developed AVN despite long-term treatment with high-dose ERT. Both patients were initiated on ERT shortly after diagnosis, have intact spleens, showed an initial dramatic response to ERT, and exhibited AVN after 5.5 and 11 years on high-dose ERT, respectively.
Fig. 1. Anteroposterior pelvic radiograph at 7 years of age (case 1) demonstrates AVN (arrows) characterized by sclerosis of the femoral head and neck with flattening of the proximal left femoral epiphysis and widening of the joint space compared to the normal right hip due to cartilage hypertrophy.
8 months. Patient underwent an open reduction internal fixation surgery of the right femur and an additional repair surgery at 7 years and 10 months. Upon follow-up, improper healing was noted; workup for anti-imiglucerase antibodies was negative. Alteration of the ERT schedule to 60 U/kg weekly occurred in an attempt to better impact bone health. Gaucher biomarkers, including angiotensin-converting enzyme (ACE), chitotriosidase (CHITO), and tartrate-resistant acid phosphatase (TRAP), exhibited a downward trend following this dose alteration; however, all remained elevated (200–250 IU/L, 4500–5700 nmol/h/ mL, and 30–44 IU/L, respectively). By 9 years, patient regained full mobility and was ambulatory without assistive devices. MRI at 10 years revealed stable AVN of the left femoral head with flattening and irregularity (Fig. 2). At 12 years, postural changes with kyphosis and lumbar lordosis were noted. At 13 years, routine MRI revealed worsening AVN on the left femoral head and new involvement of the right femoral head (Fig. 3) without clinically appreciable symptoms. DXA scans of the lumbar spine and right
2. Case 1 A Hispanic male presented at the Duke Metabolic Clinic at age 14 months with frequent epistaxis, hepatosplenomegaly, interstitial lung disease, and failure to thrive with height, weight, and head circumference at the < 3rd, 10th, and 7th percentiles, respectively. Family history was positive for two deceased siblings with reported Gaucher-like symptoms without a formal diagnosis. Consanguinity was denied. Clinical presentation, bone marrow biopsy, and low enzyme activity of 1.9 nmol/h/mg protein (lower limit of normal: 12.5 nmol/h/ mg protein) confirmed a diagnosis of GD. Genetic testing in an experienced lab revealed homozygous L483P pathogenic variants. At 17 months, ERT was initiated with imiglucerase 60 U/kg every two weeks. Interstitial lung disease and hepatosplenomegaly persisted, and the dose was increased to 120 U/kg every two weeks at 24 months. At 4 years, patient exhibited bilateral sixth cranial nerve palsy requiring surgery and abnormal central conduction bilaterally on brainstem auditory evoked response (BAER). Hearing loss continued and required bilateral hearing aids at 12 years, at which time formal assessment documented the patient to be at least 1 year developmentally delayed relative to age-matched peers. Bone health was routinely monitored during childhood via magnetic resonance imaging (MRI), radiography, and dual-energy X-ray absorptiometry (DXA). BMD was consistently below average for age and weight, though skeletal films were normal. At 7 years, the patient reported pain and began limping. DXA scans of the lumbar spine and right hip at this time noted Z-scores of −1.58 and −1.3, respectively. Radiographs noted AVN of the left femoral head (Fig. 1). Additionally, patient experienced a vitamin D deficiency (< 10 ng/mL), which responded to supplementation (54 ng/mL; normal range: 24–86 ng/mL). An episode of bone crisis occurred that same year and was treated with IV fluids and pain medications in a hospital setting. Subsequent radiographs noted stabilization of the left femoral head but revealed a new fracture in the right femoral neck at 7 years and
Fig. 2. Coronal view from a T2-weighted pelvic MRI at 10.5 years of age (case 1) demonstrates heterogeneous signal intensity (arrow) in the proximal left femur due to AVN. The abnormal appearance of the right femur (*) was felt to be due to artifact from the orthopedic hardware. 2
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Fig. 3. Coronal T1-weighted (a) and T2-weighted (b) pelvic MRI at 13 years of age (case 1). Note reconstitution of the articular surface on the left although the femur is slightly laterally subluxed with loss of femoral head sphericity. There is low signal seen in the right femoral head in both (a) and (b) (arrows) due to AVN that could be secondary to the orthopedic hardware; artifact from the hardware indicated (*). This was greater on the prior MRI, but the technique was different, and it is unclear if AVN developed in the 26-month interval between the two scans or was present prior to the previous MRI. Slight transition to more normal fatty marrow in (a) (arrowhead) in the left femur is probably due to changes of necrosis in this region previously as well as altered mechanics from the bilateral femoral abnormalities over the years.
Fig. 4. Coronal T1-weighted (a) and T2-weighted (b) pelvic MRI at 17 years of age (case 2). There is a new focal signal abnormality revealed in (a) in the anteromedial left femoral head measuring 10 × 12 × 12 mm (arrow). This area is T1 bright with a T1 dark serpiginous rim in (a) and predominantly T2 bright in (b) with some internal areas of low T2 signal (arrow). The appearance is consistent with infarct (AVN).
hip exhibited Z-scores of −1.88 and −2.44, respectively. Patient was fitted for a thoracolumbosacral orthosis brace at 15 years for worsening kyphosis. Anti-imiglucerase antibodies remained negative. At publication, patient's visceral symptoms are stable at 17 years. His liver and spleen are normal in size and appearance. ACE, CHITO and TRAP have been stable but remain elevated at 170 IU/L, 3898 nmol/h/mL, and 23.1 IU/L, respectively. Pelvic MRI revealed no new AVN or worsening articular collapse. His height and weight track at the < 3rd percentile and the 10th–25th percentiles, respectively.
3. Case 2 An 18-month old Caucasian male presented with anemia, hepatosplenomegaly, and failure to thrive to an outside institution. Low enzyme activity of 4 nmol/h/mg protein (lower limit of normal: 12.5 nmol/h/mg protein) was noted, and genetic testing revealed homozygosity for the L483P pathogenic variant. There was no known family history of GD, and consanguinity was denied. ERT was initiated at 35 U/kg every two weeks at age 22 months, and presenting 3
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between development of AVN and factors such as ERT dose and duration, similar to the two GD type 3 cases reported here. These two cases highlight the importance of addressing the remaining limitations of current therapies in GD, particularly in preventing bone complications. Other reports have described the use of combination ERT and SRT as well as stand-alone SRT in the treatment of GD. In a recent report by Amato et al., combination ERT and SRT treatment in a patient with type 1 disease resulted in a significant reduction of bone pain [23]. In a study by Giraldo and colleagues, no new cases of bone crisis, AVN, or pathologic fractures were reported after two years of SRT in patients with GD type 1 previously on ERT [24]. Additionally, in a pooled analysis of prospective studies by Pastores et al., patients with GD type 1 previously on ERT who transitioned to SRT were found to have significant increases in BMD and decreases in bone pain over two years [25]. For case 2 in our report, SRT may have helped stabilize the patient's BMD. The literature suggests SRT products distribute more extensively throughout tissue, which could potentially contribute to the osseous therapeutic benefit observed in these studies [26,27]. However, future studies that examine bone disease in patients with GD on SRT over more than two years are necessary to better assess the long-term benefits and side effects of SRT in managing bone manifestations. It is noteworthy that both patients presented here were homozygous for the L483P variant, suggesting that there may be additional osseous genotype-phenotype correlations that should be investigated in this group. L483P homozygosity is one of the most common genotypes for GD type 3, which is the most prevalent form of GD in some regions of the world, including Northern Sweden, Poland, Egypt, and Japan [9,28]. Mistry and colleagues describe a characteristic “disabling ‘gibbus’ spinal deformity” exhibited by some groups of L483P homozygotes around the world, thought to exacerbate progressive neurological and pulmonary disease associated with GD type 3 [29]. In a study by Andrade-Campos et al., two Spanish patients homozygous for the L483P variant manifested Norrbottnian-like thoracic deformations during childhood prior to diagnosis [30]. Suwannarat et al. reported a similar phenotype in a Thai patient with L483P homozygosity during childhood [31]. With regard to the cases presented in this report, while as complete a workup as possible was completed, whole exome sequencing was not performed; thus, other, possibly ethnicity-related genetic factors related to bone manifestations cannot be ruled out and represent an area for future inquiry.
symptoms resolved. At 4 years, the patient established care at the Duke Metabolic Clinic, at which time he was growing and developing normally without any observable features of GD. ERT continued every two weeks at 35 U/kg. ERT dosing was increased to 60 U/kg every two weeks at 6 years after consulting with Gaucher experts given the association between type 3 disease and the L483P disease-causing variant. Bone health remained normal with routine monitoring until DXA scans at 11 years noted slightly below average BMD of the lumbar spine and right hip (Z-scores of −1.1 and −1.0, respectively). Liver MRI displayed increased volume relative to growth. Height and weight measured 139.7 cm (20th percentile) and 30.3 kg (10th percentile), respectively. Chest asymmetry with right-sided prominence developed at 14 years without presence of scoliosis or kyphosis. At 16 years, DXA scan revealed osteopenia in the lumbar spine and right hip with Zscores of −1.2 and 2.0, respectively. At 17 years, mild kyphosis and lumbar lordosis persisted. Radiographs and pelvic MRI revealed a focal signal in the left femoral head consistent with AVN (Fig. 4) as well as several benign-appearing lesions in the anterior cortex of the proximal femurs bilaterally at 17 years. Patient denied bone pain. CHITO and TRAP were elevated at 1017 nmol/h/mL and 132 IU/L, respectively, and ACE was in the normal range at 112 IU/L. DXA scans revealed below average BMD of the lumbar spine and right hip with Z-scores of −2.30 and −2.10, respectively. No surgical intervention was recommended at this time. Patient transitioned treatment modalities from intravenous ERT to oral substrate reduction therapy (SRT) with eliglustat 84 mg twice a day at 18 years. At 20 years, DXA scans documented no change in BMD relative to previous scans at 17 years. At publication, patient is clinically stable with SRT without evidence of bone crisis. His bone health via imaging is stable, and patient does not report pain. 4. Discussion We present two cases of GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), who developed AVN despite treatment on high-dose ERT for 5.5 and 11 years, respectively. Risk factors for AVN including splenectomy, poor ERT compliance, antibodies to imiglucerase, low ERT dose, anemia, trauma, corticosteroid use, poor nutrition, and late initiation of ERT were absent [15,20–22]. While case 1 was noted to have vitamin D deficiency at 7 years, a risk factor for AVN, this was improved through supplementation. In spite of good compliance and the absence of other typical AVN risk factors, case 1 continued to exhibit low growth percentiles and case 2's osteopenia did not normalize, further demonstrating that bone marrow is a sanctuary site and that ERT treatment response is not completely robust. At the time of AVN development, while case 1 was symptomatic, case 2 appeared to be asymptomatic. Furthermore, the development of AVN and worsening of BMD occurred despite stabilization of the visceral and hematological manifestations of GD. Overall, our cases demonstrate the necessity of continued monitoring of patients with neuronopathic GD, especially as it pertains to MRI of the pelvis, radiographs of the pelvis and long bones, and bone density scans. AVN is an irreversible complication and, therefore, all attempts to prevent its development should be taken [19]. Should an AVN develop, early identification can lead to more positive outcomes for the patient. The dose recommendations from Vellodi et al. were considered in the treatment plans for both cases presented, although the global medical community has not completely embraced this increased dose above the package insert as standard of care [11]. The treating clinical team initiated a higher therapy dose in the hopes that these patients would demonstrate a lower likelihood of developing bone symptoms; however, the long-term, high-dose therapy did not prevent AVN formation. This outcome is in concordance with previous studies in which increases in ERT dose failed to prevent AVN formation in some patients with type 1 disease [15,19]. In these studies, there was no relationship
5. Conclusions We present two non-splenectomized patients with GD type 3 (L483P homozygotes) who began treatment on high-dose ERT shortly after diagnosis during infancy. Despite stabilization of their hematological and visceral symptoms, both patients ultimately developed AVN. This report demonstrates the importance of careful, regular surveillance of the musculoskeletal system in patients with GD and the potential for differential osseous risk between GD subtypes. Additionally, it highlights the limitations of ERT in terms of targeting certain sanctuary sites such as bone marrow and suggests the need for new treatment modalities to address these limitations. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Disclosures Priya S. Kishnani has received research/grant support and honoraria from Sanofi Genzyme and Shire Therapeutics. Priya S. Kishnani is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation. Lauren B. Flueckinger has received honoraria 4
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from Sanofi Genzyme and Shire Therapeutics.
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