Hampered Vitamin B12 Metabolism in Gaucher Disease?

Abstract

Untreated vitamin B₁₂ deficiency manifests clinically with hematological abnormalities and combined degeneration of the spinal cord and polyneuropathy and biochemically with elevated homocysteine (Hcy) and methylmalonic acid (MMA). Vitamin B₁₂ metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. Gaucher disease (GD) is characterized by dysfunctional lysosomal metabolism brought about by mutations in the enzyme beta-glucocerebrosidase (Online Mendelian Inheritance in Man (OMIM): 606463; Enzyme Commission (EC) 3.2.1.45, gene: GBA1). In this study, we collected and examined available literature on the associations between GD, the second most prevalent lysosomal storage disorder in humans, and hampered vitamin B₁₂ metabolism. Results from independent cohorts of patients show elevated circulating holotranscobalamin without changes in vitamin B₁₂ levels in serum. Gaucher disease patients under enzyme replacement therapy present normal levels of Hcy and MMA. Although within the normal range, a significant increase in Hcy and MMA with normal serum vitamin B₁₂ was documented in treated GD patients with polyneuropathy versus treated GD patients without polyneuropathy. Thus, a functional deficiency of vitamin B₁₂ caused by disrupted lysosomal metabolism in GD is a plausible mechanism, contributing to the neurological form of the disorder but this awaits confirmation. Observational studies suggest that an assessment of vitamin B₁₂ status prior to the initiation of enzyme replacement therapy may shed light on the role of vitamin B₁₂ in the pathogenesis and progression of GD.

Keywords
Gaucher disease; homocysteine; methylmalonic acid; lysosomal disease; vitamin B12; transcobalamin; lysosomal trafficking; polyneuropathy; cobalamin; enzyme replacement therapy

Introduction

Lysosomal storage disorders (LDs) are a broad group of more than 50 rare, life-threatening diseases characterized by abnormal degradation of glycans, carbohydrates, lipids and proteins, and lysosomal transporter and trafficking.¹

The concept of LDs or lysosomal disorders was developed in the early 1960s, after the discovery that Pompe disease was caused by a deficiency in the lysosomal enzyme α-glucosidase.² Lysosomal storage disorder may be caused not only by defective enzymes but also by enzyme activator proteins (eg, Prosaponin [PSAP] deficiency), membrane proteins (eg, Danon disease), transporters (eg, cystinosis), or enzyme signaling (eg, mucolipidosis type II). Lysosomal storage disorders are characterized by an abnormal storage of a variety of molecules, including triglycerides, sterols, sphingolipids, sulfatides, sphingomyelin, gangliosides, and lipofuscins.³ The buildup of substrates within lysosomes results in impaired function of the affected organs (eg, liver, spleen, bone, and nervous system), causing a wide and diverse range of clinical features. In addition, the release of lysosomal acid hydrolases into the cytoplasm will cause cellular damage, which may worsen disease progression. Also, dysregulation of apoptosis may cause disease manifestations in some LDs. Indeed, increased apoptosis has been noted in a number of the sphingolipidoses and in neuronal ceroid lipofuscinoses.⁴ Since different mechanisms related to apoptosis, cholesterol metabolism dysregulation, inflammation, and alteration in signal transduction are also related to the pathogenesis of these conditions, we prefer to use the term “lysosomal disorder” than “lysosomal storage disorder.”⁵ To date, more than 60 different proteins were identified as causing LDs.⁶ Individually, LDs are rare, inherited disorders with an estimated frequency from 1 in 25 000 to 1 in 250 000 live newborns, but the overall incidence of all LDs is estimated to be 1 in 7000 live newborns, which makes them a relevant public health issue. The frequency may be underestimated because nowadays more individuals with mild disease and/or adult-onset forms of the diseases are being identified.⁷

Gaucher disease (GD) is an autosomal recessive, multi-organ disorder caused by mutations in the lysosomal enzyme β-glucocerebrosidase (GCase, OMIM: 606463; EC 3.2.1.45, gene: GBA1), which catalyzes the conversion of the glycolipid glucosylceramide to ceramide and glucose.⁸ The GBA1 gene is located on chromosome 1q21, comprises 7.6 kb of genomic DNA, and it is divided into 11 exons.⁹ The GBA1 messenger RNA (mRNA) has approximately 2 kb and produces a mature protein of 497 amino acids with 56 kDa.^10,11 The expression levels of mRNA produced from GBA1 varies considerably between different cell types and has no direct correlation with GCase enzyme activity.¹⁰GBA1 has a pseudogene (GBAP) of approximately 5 kb, which is highly homologous (96%) with the functional gene. GBAP has an identical genomic organization and is located 16 kb downstream of GBA1.^9,10 The high degree of homology between the gene and the pseudogene must be taken into account in the investigation of mutations in patients with GD, since some of the mutations found in patients are also present in the GBAP sequence.^10-12

A dysfunctional or absent β-GCase protein leads to the buildup of glucosylceramide in the lysosome, in particular within macrophages of the reticuloendothelial system, and to a defective production of ceramide, the hydrophobic membrane anchor for all sphingolipids in the cell.¹³

This review covers clinical and molecular aspects of GD, the second most prevalent inborn error of LD, with an emphasis on lysosomal metabolism and the potential occurrence of abnormalities in vitamin B₁₂ status.

Gaucher Disease

Gaucher disease has been classified into 3 major types based on the absence (type 1) or presence (types 2 and 3) of neurological impairments.¹⁴ The prevalence of GD in the general population has been estimated to be about 1:60 000¹⁵; however, as seen in other autosomal recessive disorders, GD exhibits ethnical preference.

At the cellular level, GD is characterized by the presence of macrophages with an altered morphology due to abnormal lipid storage, also known as “Gaucher cells.” Gaucher cells are typically found in affected organs including spleen, liver, and bone marrow.¹⁶ In addition to exhibiting an abnormal morphology, macrophages from GD have a distinct pattern of expression of pro-inflammatory effectors.^17,18

At the subcellular level, GD features abnormalities in lysosomal pathways, which is accompanied by mitochondrial dysfunction and accumulation of α-synuclein in the mitochondrion.¹⁹ Lysosomal lipid storage in GD reduces the efficiency of lysosomes to fuse with autophagosomes, thereby impairing cellular clearance of unnecessary substrates, protein aggregates, and dysfunctional mitochondria.¹⁶ This triggers an inflammatory response that ultimately leads to cellular death.¹⁶ Interestingly, mitochondrial dysfunction and increased deposition of α-synuclein are 2 features of GD that are shared with other peripheral neuropathies such as Parkinson and Alzheimer diseases.²⁰

The molecular mechanism underlying GD pathogenesis remains elusive. A few metabolic hallmarks have been identified in GD, including increased chitotriosidase (EC 3.2.1.14), angiotensin-converting enzyme (EC 3.4.15.1), C-C Motif Chemokine Ligand 18 (CCL18) (P55774), tartrate-resistant acid phosphatase (EC 3.1.3.2), and serum ferritin (P02792 and P02794), and some of these continue to be utilized as diagnostic and prognostic tools in clinical practice.²¹ An interesting aspect of GD is the presumptive abnormality in vitamin B₁₂ status.^22-26 The earliest observations linking GD with vitamin B₁₂ metabolism were documented about 4 decades ago by Gilbert and Weinreb²⁶ and by Rachimilewitz and Rachimilewitz.²⁷ These studies demonstrated elevated levels of circulating holotranscobalamin (holo-TC) in GD patients, which was not associated with decreased serum levels of vitamin B₁₂ or any other vitamin B₁₂ binders.²⁶ The levels of holo-TC were directly proportional to the severity of GD.²⁶ Very few follow-up studies were conducted thereafter, and to this date, the associations between GD and vitamin B₁₂ metabolism are open for investigation, as also will be shown below.

Clinical Manifestations

Gaucher disease is classically divided into 3 clinical types based upon the severity and onset of neurological involvement; however, overlap is often seen among the phenotypes. Gaucher disease type 1 (OMIM 230800), the nonneuronopathic type, is the most common form of the disorder in the western hemisphere and the most prevalent type overall (90%-95% of the patients), with an incidence of 1 in 70 000 live newborns worldwide.²⁸ In Ashkenazi Jews, the incidence is 1 in 400 live newborns.²⁹ Type 1 is characterized by multi-organ involvement, especially hepatic, splenic, bone, hematologic, and pulmonary systems. The life expectancy depends on the time of diagnosis, severity of visceral involvement, and treatment. Patients with GD type 1 are treated with specific therapies such as enzyme replacement therapy (ERT) or substrate reduction therapy. Most treated patients usually have a normal life expectancy. The absence of early-onset primary central nervous system (CNS) is essential for the diagnosis of GD type 1.³⁰ During the last 2 decades, population studies have shown an association between GD and Parkinson disease. Carriers of GBA1 mutations are also at risk of developing parkinsonism.³¹ Also, GD type 1 patients are at an increased risk of developing cholelitiasis³² and hematological malignancies as multiple myeloma.³³

Gaucher disease type 2 (OMIM 230900), the acute neuronopathic type, is the less frequent phenotype, with an incidence of 1 in 100 000 live newborns and is characterized by cholestasis, hepatosplenomegaly, and early-onset and rapidly progressive CNS manifestations with bulbar involvement. Hydrops fetalis and collodion baby may be present in the most severe forms. The life expectancy varies from hours to a few months.³⁴ There is no specific treatment for patients with GD type 2.

Gaucher disease type 3 (OMIM 231000), the subacute or chronic neuronopathic type, is particularly prevalent in Asian and Arab countries.¹⁴ Gaucher disease type 3 is characterized by an intermediate phenotype with visceral manifestations as GD type 1 and CNS manifestations are less severe than GD type 2. Patients may have severe bone involvement, with kyphoscoliosis, ataxia, myoclonic epilepsy, strabismus, horizontal gaze palsy, and dementia. Some patients may present corneal clouding and cardiac valvular calcifications. Enzyme replacement therapy is indicated to treat the visceral signs and symptoms of GD, but it fails to alleviate CNS manifestations. The life expectancy is 20 to 30 years.³⁵

Diagnosis

Clinical manifestations, such as hepatosplenomegaly, bone lesions, hematologic changes, and/or CNS involvement, are important signs that would suggest the presence of GD.^23,36 However, the diagnosis of GD should not be based exclusively on the clinical evaluation of the patient. There are other LDs that may present with symptoms similar to GD, which may complicate the establishment of a precise diagnosis.

The standard diagnostic method for GD is the evaluation of β-GCase (acid β-glucosidase) activity in dried blood spots, peripheral blood leukocytes, cultured skin fibroblasts, or other nucleated cells. Molecular analysis of GBA1, which encodes GCase, and the identification of 2 disease-causing mutations may assist the patient’s clinical classification into a determined subtype or at least make it possible to distinguish between neuronopathic and nonneuronopathic forms.³⁷ Genetic testing enables the confirmation and a better characterization of the patient’s condition and is considered an essential tool for GD diagnosis.³⁸ Up to date, more than 400 different disease-causing mutations have been described in the GBA1 gene (www.hgmd.cf.ac.uk ^37,39). GBA1 mutations may alter GCase stability and/or impair its catalytic function.^37,38

The identification of disease-causing mutations in GBA1 may be challenging due to the GBAP. The most accurate method for mutation analysis in GD is full-gene sequencing of GBA1.³⁹ In order to describe a recombinant allele, a combination of direct sequencing along with an additional method, such as Southern blot or qPCR, is strongly recommended.^40,41 The occurrence of deletion and/or duplication of any region of GBA1 can be specifically addressed by multiplex ligation-dependent probe amplification.^40,41

Vitamin B₁₂ Metabolism

Vitamin B₁₂ is an essential micronutrient synthesized only by a select group of bacteria and archaea. Humans completely rely on a dietary intake of minimally 2 to 3 μg of vitamin B₁₂ per day,⁴² which is indispensable to support the activities of cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Dietary vitamin B₁₂ is absorbed in the lower portions of the ileum after sequential relay by the dedicated transporters haptocorrin, intrinsic factor, and transcobalamin.^43,44 Vitamin B₁₂ bound to transcobalamin, that is, holo-TC is distributed via systemic circulation to all cells in the body. Cells take up holo-TC via receptor-mediated endocytosis, aided by the transcobalamin receptor (CD320),^45,46 which shuttles vitamin B₁₂ into lysosomes. The protein binder TC undergoes degradation in the lysosome, liberating vitamin B₁₂ that is subsequently exported out of this compartment using the transporters LMBR1 Domain Containing 1 (LMBRD1)^47,48 and ATP Binding Cassette Subfamily D Member 4 (ABCD4).^49,50 Once in the cytosol, newly internalized vitamin B₁₂ undergoes processing and trafficking by proteins, CblC^51-57 and CblD,^58-63 respectively, to finally reach acceptor proteins, MS in the cytosol and MCM in the mitochondrion.

Insufficient intake and certain inborn errors of metabolism impairing the cellular transport, trafficking, and utilization of vitamin B₁₂ manifest as functional cobalamin deficiency, with either isolated or combined homocystinuria and methylmalonic aciduria. Untreated vitamin B₁₂ deficiency causes hematological abnormalities, subacute combined degeneration of the spinal cord, and polyneuropathy.⁶⁴ However, its precise role in the progression of neurological diseases (measured as the onset of dementia in only 1 large study⁶⁵) has been debated.⁶⁵ It is possible that sufficiency of vitamin B₁₂ is important for preventing nerve deterioration. Vitamin B₁₂ administration only partially reverses clinically established nerve degeneration and neuropathies.

Lysosomal Disorders of Vitamin B₁₂

The lysosome is an essential compartment in cellular vitamin B₁₂ metabolism by connecting uptake and downstream utilization of the micronutrient. Two genetic disorders affecting lysosomal proteins LMBRD1 (cblF)^47,48 and ABCD4 (cblJ)^49,50,66 have been described, leading to trapping of vitamin B₁₂ inside the lysosome and the concomitant onset of functional cobalamin deficiency by inactivation of the B₁₂ acceptors MS and MCM. LMBRD1 and ABCD4 mediate the export of vitamin B₁₂ from the lysosome.^47-50,66

Apart from these canonical defects of lysosomal vitamin B₁₂ transporters, 2 other reports documented abnormal vitamin B₁₂ metabolism caused by genetic mutations that impair the endocytic and lysosomal pathways independent of vitamin B₁₂ metabolism. These include the occurrence of abnormal lysosome acidification in a patient with Alzheimer disease⁶⁷ and impaired endocytosis in a patient with mutations in the rabenosyn-5 gene.^67,68 In both cases, cellular vitamin B₁₂ deficiency was documented.⁶⁸

Table 1
Demographics, Treatment, Vitamin B₁₂ Status, and Clinical Manifestations of Adult GD Type 1 in a Cohort of European Patients.a,b,c

		Polyneuropathy (n = 17)	No Polyneuropathy (n = 86)	P Value
Demographics
	Age in years, median (range)	61 (41-75)	39 (18-67)	<.001
	Gender, male/female, n (%)	11 (64.7)/6 (35.3)	38 (44.2)/48 (55.8)	NS
Enzyme replacement therapy
	Receiving ERT, n (%)	15 (88.2)	74 (86.0)	NS
	Duration in years, median (range)	3.0 (0.2-10.9)	2.| (0.0-|3.6)	NS
	Dosage in IU/kg/m, median (range)	30.0 (11.1-112.2)	58.2 (|2.3-|56.3)	.013
Vitamin B12 status
	Vitamin B|2 (pmol/L), median (range)	208 (88-593)	237 (86-886)	NS
	Homocysteine (μmol/L), median (range)	||.4 (7.5-30.4)	9.7 (4.6-26.5)	.013
	Methylmalonic acid (μmol/L), median (range)	0.|8 (0.09-0.98)	0.|2 (0.03-0.54)	.001
Systemic GD type | manifestations, n (%)
	Splenomegaly	16 (94.1)	77 (89.5)	NS
	Hepatomegaly	16 (94.1)	64 (74.4)	NS
	Thrombocytopenia	|0 (58.8)	66 (76.7)	NS
	Bleeding tendencies	9 (52.9)	38 (44.2)	NS
	Anemia	9 (52.9)	34 (39.5)	NS
	Bone/joint pain	9 (52.9)	24 (27.9)	NS
	Bone crisis	6 (35.3)	25 (29.|)	NS

• Abbreviations: ERT, enzyme replacement therapy; GD, Gaucher disease; NS, not statistically significant.
• ^a
  N=103.
• ^b
  Table Modified from Biegstraaten et al.⁸²
• ^c
  Normal ranges: methylmalonic acid, <30 μmol/L; homocysteine, pre-menopausal females, 6 to 15 μmol/L, males, and postmenopausal females, 8to 18 μmol/L.

Vitamin B₁₂ Status in GD

The overlap of clinical manifestations of GD and vitamin B₁₂ deficiency concerning neurological impairments suggests shared mechanisms of pathogenesis. One hypothesis is that lysosomal dysfunction in GD leads to functional deficiency of vitamin B₁₂ by disrupting the uptake, intralysosomal degradation of transcobalamin, or the export of free vitamin B₁₂ from the organelle into the cytoplasm, thereby compromising the downstream reactions of MS and MCM. Further, it is unknown whether the abnormal accumulation of glycosphingolipids, in particular N-acyl-sphingosyl-1-O-β-d-glucoside, may affect vitamin B₁₂ transit in and out of the lysosome.

The earliest assessment of vitamin B₁₂ status in GD reported abnormally high levels of circulating TC,^26,29 which did not correlate with serum levels of vitamin B₁₂ or any other B₁₂-transport protein levels. It was suggested that increased TC levels in GD resulted from a general status of inflammation. Unfortunately, no other biomarkers of vitamin B₁₂ status were measured.⁶⁹ Indeed, although holo-TC represents the bioactive fraction of vitamin B₁₂ that is available for cellular uptake,^70-73 this has limitations as a stand-alone marker of vitamin B₁₂ status in that the majority of circulating vitamin B₁₂ is bound to haptocorrin (80%), and thus, fluctuations in the serum level of holo-TC (representing 6%-20% of total serum vitamin B₁₂^70-73) may not be accurate marker of vitamin B₁₂ sufficiency (reviewed by Djaldetti et al⁷⁴). For instance, low levels of holo-TC have been determined in patients with several disorders not featuring vitamin B₁₂ deficiency.^75-78 At present time, it is unknown whether and how holo-TC levels vary in various disease states, and thus, the diagnostic and prognostic value of holo-TC as a first-line test awaits further investigation.

A study performed within an Ashkenazi Jewish cohort of 85 untreated GD patients and 122 neighbor controls showed a high incidence of low-serum vitamin B₁₂, elevated plasma homocysteine (Hcy), and methylmalonic acid (MMA); however, these findings were not statistically significant with respect to controls, due to an overall low vitamin B₁₂ status among healthy Ashkenazi individuals.²³ The generally low vitamin B₁₂ status in this Ashkenazi Jewish population has been suggested to arise from frequent blood donation that would exhaust blood and liver storages of vitamin B₁₂ as well as to ethnical differences.^79,80 A questionnaire-based study identified a high incidence of neurological complaints in patients with nonneuronopathic forms of GD, with concomitant vitamin B₁₂ deficiency and gammopathies.⁸¹ Unfortunately, no laboratory measurements of marker metabolites Hcy and MMA were performed in these studies, which makes it difficult to ascertain the role of vitamin B₁₂ status in this cohort of GD patients.⁸¹

A 2-year prospective, longitudinal, observational cohort study involving 8 centers across 7 countries in Europe examined vitamin B₁₂ status in adult patients with GD type 1 with (n = 17) and without (n = 86) polyneuropathy.⁸² The study found statistically significant elevation of serum Hcy and MMA in patients with polyneuropathy compared to those without neuropathic impairment, with low–normal values of serum vitamin B₁₂ in both groups.⁸² However, both groups of patients displayed metabolite levels still within the normal range (MMA, <0.4 μmol/L; Hcy, premenopausal females, 6-15 μmol/L, males, and postmenopausal females, 8-18 μmol/L).⁸² Importantly, both groups of patients had received ERT for at last 2 to 3 years. Table 1 summarizes the data that represent the largest examination of vitamin B₁₂ status in GD to date. Patients with polyneuropathy had received a lower dose of ERT compared to patients without polyneuropathy.⁸² In the absence of vitamin B₁₂ biomarker (Hcy and MMA) values before ERT, it is difficult to state whether the reported values represent a partially corrected vitamin B₁₂ metabolism. In sum, a disturbed vitamin B₁₂ metabolism in GD is plausible, but the available data beg for additional investigation.

Outlook

Lysosomal storage disorders and GD in particular are complex diseases affecting various facets of metabolism. The occurrence of vitamin B₁₂ deficiency as a general manifestation of GD awaits further confirmation, but available studies point to disturbances in vitamin B₁₂ metabolism that may originate from abnormal lysosomal metabolism or a general status of inflammation as it has been reported in 2 other human disorders,^73,74 not intrinsically related to vitamin B₁₂ metabolism. It has been suggested that aging leads to increased impairments in lysosomal metabolism, and that this could explain the concomitant disturbances of vitamin B₁₂ pathways often found in association with diseases featuring peripheral neuropathies, such as Alzheimer and Parkinson disorders.^83,84 This further supports the need for vitamin B₁₂ supplementation in the aging population, beyond the known limitations in gastric absorption of the micronutrient, which also becomes less efficient with aging. Our revision of the available literature points to the importance of assessing vitamin B₁₂ status prior to the initiation of ERT in GD patients, in order to establish involvement of this micronutrient on the onset of symptoms and possibly in its associated peripheral neuropathies.

Acknowledgments

L.H. wishes to acknowledge intramural support from the Department of Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

• ¹ O.K. G-T, T. B . Lysosomal Storage Disorders. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. http://www.ncbi.nlm.nih.gov/books/NBK6177/ Published 2013. Accessed February, 2017.
  » http://www.ncbi.nlm.nih.gov/books/NBK6177/
• ² Hers, HG . Inborn lysosomal diseases. Gastroenterology. 1965;48:625–633.
• ³ Ciechanover, A. Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Neurodegener Dis. 2012;10(1-4):7–22.
• ⁴ Levine, B, Kroemer, G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.
• ⁵ Gieselmann, V . Cellular pathophysiology of lysosomal storage diseases. In: Mehta, A., Beck, M., Sunder-Plassmann, G., eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, United Kingdom: Oxford PharmaGenesis; 2006.
• ⁶ Samie, MA., Xu, H. Lysosomal exocytosis and lipid storage disorders. J Lipid Res. 2014;55(6):995–1009.
• ⁷ Wang, RY., Bodamer, OA., Watson, MS., Wilcox, WR. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011;13(5):457–484.
• ⁸ Beutler, E . Gaucher disease: new molecular approaches to diagnosis and treatment. Science. 1992;256(5058):794–799.
• ⁹ Horowitz, M, Wilder, S, Horowitz, Z, Reiner, O, Gelbart, T, Beutler, E. The human glucocerebrosidase gene and pseudogene: structure and evolution. Genomics. 1989;4(1):87–96.
• ¹⁰ Hruska, KS, LaMarca, ME, Scott, CR, Sidransky, E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008;29(5):567–583.
• ¹¹ Grabowski, GA, Petsko, GA, Kolodny, EH. Gaucher disease. In: David, Valle M, Beaudet, Arthur L., Vogelstein, Bert, Kinzler, Kenneth W., Antonarakis, Stylianos E., Ballabio, Andrea, Gibson, K. Michael, Mitchell, Grant, eds. OMMBID—The Online Metabolic and Molecular Bases of Inherited Disease. New York, USA: McGraw-Hill; 2013.
• ¹² Sidransky, E. Gaucher disease: insights from a rare Mendelian disorder. Discov Med. 2012;14(77):273–281.
• ¹³ van Echten-Deckert, G., Herget, T. Sphingolipid metabolism in neural cells. Biochim Biophys Acta. 2006;1758(12):1978–1994.
• ¹⁴ Zimran, A. How I treat Gaucher disease. Blood. 2011;118(6):1463–1471.
• ¹⁵ Dandana, A, Ben Khelifa, S, Chahed, H, Miled, A, Ferchichi, S. Gaucher disease: clinical, biological and therapeutic aspects. Pathobiology. 2016;83(1):13–23.
• ¹⁶ Coutinho, MF, Alves, S. From rare to common and back again: 60 years of lysosomal dysfunction. Mol Genet Metab. 2016;117(2):53–65.
• ¹⁷ Boven, LA, van Meurs, M, Boot, RG. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am J Clin Pathol. 2004;122(3):359–369.
• ¹⁸ Pandey, MK, Grabowski, GA. Immunological cells and functions in Gaucher disease. Crit Rev Oncog. 2013;18(3):197–220.
• ¹⁹ Gegg, ME, Schapira, AH. Mitochondrial dysfunction associated with glucocerebrosidase deficiency. Neurobiol Dis. 2016;90:43–50.
• ²⁰ Migdalska-Richards, A, Schapira, AH. The relationship between glucocerebrosidase mutations and Parkinson disease. J Neurochem. 2016;139(suppl 1):177–190.
• ²¹ Koppe, T, Doneda, D, Siebert, M. The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease. Genet Mol Biol. 2016;39(1):30–34.
• ²² D’Amico, A, Bertini, E. Metabolic neuropathies and myopathies. Handb Clin Neurol. 2013;113:1437–1455.
• ²³ Gielchinsky, Y, Elstein, D, Green, R. High prevalence of low serum vitamin B12 in a multi-ethnic Israeli population. Br J Haematol. 2001;115(3):707–709.
• ²⁴ Vital, A, Lepreux, S, Vital, C. Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum. J Peripher Nerv Syst. 2014;19(4):333–342.
• ²⁵ Zeb Jan, A, Zahid, B, Ahmad, S, Gul, Z. Pancytopenia in children: a 6-year spectrum of patients admitted to Pediatric Department of Rehman Medical Institute, Peshawar. Pak J Med Sci. 2013;29(5):1153–1157.
• ²⁶ Gilbert, HS, Weinreb, N. Increased circulating levels of transcobalamin ii in Gaucher’s disease. N Engl J Med. 1976;295(20):1096–1101.
• ²⁷ Rachimilewitz, B, Rachimilewitz, M. Serum transcobalamin II concentration. N Engl J Med. 1977;296(20):1174.
• ²⁸ Weinreb, NJ, Kaplan, P. The history and accomplishments of the ICGG Gaucher registry. Am J Hematol. 2015;90(suppl 1):S2–S5.
• ²⁹ Zimran, A, Gelbart, T, Westwood, B, Grabowski, GA, Beutler, E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991;49(4):855–859.
• ³⁰ Weinreb, NJ, Goldblatt, J, Villalobos, J. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis. 2013;36(3):543–553.
• ³¹ Sidransky, E, Samaddar, T, Tayebi, N. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology. 2009;73(17):1424–1425, author reply 1425-1426.
• ³² Taddei, TH, Dziura, J, Chen, S. High incidence of cholesterol gallstone disease in type 1 Gaucher disease: characterizing the biliary phenotype of type 1 Gaucher disease. J Inherit Metab Dis. 2010;33(3):291–300.
• ³³ Mistry, PK, Taddei, T, vom Dahl, S, Rosenbloom, BE. Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog. 2013;18(3):235–246.
• ³⁴ Grabowski, GA, Zimran, A, Ida, H. Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. Am J Hematol. 2015;90(suppl 1):S12–S18.
• ³⁵ Tylki-Szymanska, A, Czartoryska, B. Enzyme replacement therapy in type III Gaucher disease. J Inherit Metab Dis. 1999;22(2):203–204.
• ³⁶ Elstein, D, Steinberg, A, Abrahamov, A, Zimran, A. Ethical guidelines for enzyme therapy in neuronopathic Gaucher disease. Am J Hum Genet. 1997;61(4):A354.
• ³⁷ Elstein, D, Zimran, A. IV epoprostenol in Gaucher’s disease. Chest. 2000;117(6):1821.
• ³⁸ Goitein, O, Elstein, D, Abrahamov, A. Lung involvement and enzyme replacement therapy in Gaucher’s disease. QJM. 2001;94(8):407–415.
• ³⁹ Charrow, J., Andersson, HC., Kaplan, P. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med. 2000;160(18):2835–2843.
• ⁴⁰ Basgalupp, SP, Siebert, M, Vairo, FPe. Use of a multiplex ligation-dependent probe amplification method for the detection of deletions/duplications in the GBA1 gene in Gaucher disease patients [Published online October 20, 2016]. Blood Cell Mol Dis. pii: S1079-9796(16)30217-0.
• ⁴¹ Amico, G, Grossi, S, Vijzelaar, R. MLPA-based approach for initial and simultaneous detection of GBA deletions and recombinant alleles in patients affected by Gaucher Disease. Mol Genet Metab. 2016;119(4):329–337.
• ⁴² Dietary Reference Intakes: Thiamin R, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Institute of Medicine. Food and Nutrition Board. Washington, DC: National Academy Press; 1998.
• ⁴³ Zimran, A, Elstein, D. Management of Gaucher disease: enzyme replacement therapy. Pediatr Endocrinol Rev. 2014;12(suppl 1):82–87.
• ⁴⁴ Alcalay, RN, Dinur, T, Quinn, T. Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. JAMA Neurol. 2014;71(6):752–757.
• ⁴⁵ Quadros, EV, Nakayama, Y, Sequeira, JM. The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. Blood. 2009;113(1):186–192.
• ⁴⁶ Alam, A, Woo, JS, Schmitz, J. Structural basis of transcobalamin recognition by human CD320 receptor. Nat Commun. 2016;7:12100.
• ⁴⁷ Gailus, S, Suormala, T, Malerczyk-Aktas, AG. A novel mutation in LMBRD1 causes the cblF defect of vitamin B(12) metabolism in a Turkish patient. J Inherit Metab Dis. 2010;33(1):17–24.
• ⁴⁸ Rutsch, F, Gailus, S, Suormala, T, Fowler, B. LMBRD1: the gene for the cblF defect of vitamin B(1)(2) metabolism. J Inherit Metab Dis. 2011;34(1):121–126.
• ⁴⁹ Coelho, D., Kim, JC., Miousse, IR. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet. 2012;44(10):1152–1155.
• ⁵⁰ Takeichi, T, Hsu, CK, Yang, HS. Progressive hyperpigmentation in a Taiwanese child due to an inborn error of vitamin B12 metabolism (cblJ). Br J Dermatol. 2015;172(4):1111–1115.
• ⁵¹ Kim, J., Gherasim, C., Banerjee, R. Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci U S A. 2008;105(38):14551–14554.
• ⁵² Hannibal, L, DiBello, PM, Jacobsen, DW. Proteomics of vitamin B12 processing. Clin Chem Lab Med. 2013;51(3):477–488.
• ⁵³ Kim, J, Hannibal, L, Gherasim, C, Jacobsen, DW, Banerjee, R. A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins. J Biol Chem. 2009;284(48):33418–33424.
• ⁵⁴ Hannibal, L, Kim, J, Brasch, NE. Processing of alkylcobalamins in mammalian cells: arole for the MMACHC (cblC) gene product. Mol Genet Metab. 2009;97(4):260–266.
• ⁵⁵ Froese, DS, Zhang, J, Healy, S, Gravel, RA. Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab. 2009;98(4):338–343.
• ⁵⁶ Morel, CF, Lerner-Ellis, JP, Rosenblatt, DS. Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab. 2006;88(4):315–321.
• ⁵⁷ Lerner-Ellis, JP, Tirone, JC, Pawelek, PD. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet. 2006;38(1):93–100.
• ⁵⁸ Jusufi, J., Suormala, T., Burda, P., Fowler, B., Froese, DS., Baumgartner, MR. Characterization of functional domains of the cblD (MMADHC) gene product. J Inherit Metab Dis. 2014;37(5):841–849.
• ⁵⁹ Mah, W, Deme, JC, Watkins, D. Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism. Mol Genet Metab. 2013;108(2):112–118.
• ⁶⁰ Gherasim, C, Hannibal, L, Rajagopalan, D, Jacobsen, DW, Banerjee, R. The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning. Biochimie. 2013;95(5):1023–1032.
• ⁶¹ Stucki, M, Coelho, D, Suormala, T, Burda, P, Fowler, B, Baumgartner, MR. Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. Hum Mol Genet. 2012;21(6):1410–1418.
• ⁶² Miousse, IR, Watkins, D, Coelho, D. Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. J Pediatr. 2009;154(4):551–556.
• ⁶³ Coelho, D, Suormala, T, Stucki, M. Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med. 2008;358(14):1454–1464.
• ⁶⁴ Hemmer, B, Glocker, FX, Schumacher, M, Deuschl, G, Lucking, CH. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. 1998;65(6):822–827.
• ⁶⁵ Health Quality, O. Vitamin B12 and cognitive function: an evidence-based analysis. Ont Health Technol Assess Ser. 2013;13(23):1–45.
• ⁶⁶ Kim, JC, Lee, NC, Hwu, PW. Late onset of symptoms in an atypical patient with the cblJ inborn error of vitamin B12 metabolism: diagnosis and novel mutation revealed by exome sequencing. Mol Genet Metab. 2012;107(4):664–668.
• ⁶⁷ Zhao, H, Li, H, Ruberu, K, Garner, B. Impaired lysosomal cobalamin transport in Alzheimer’s disease. J Alzheimers Dis. 2015;43(3):1017–1030.
• ⁶⁸ Stockler, S, Corvera, S, Lambright, D. Single point mutation in rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking. Orphanet J Rare Dis. 2014;9:141.
• ⁶⁹ Gillis, S, Hyam, E, Abrahamov, A, Elstein, D, Zimran, A. Platelet function abnormalities in Gaucher disease patients. Am J Hematol. 1999;61(2):103–106.
• ⁷⁰ Elstein, D, Abrahamov, A, Altarescu, G, Zimran, A. Evolving features in type 3 Gaucher disease on long-term enzyme replacement therapy. Blood Cell Mol Dis. 2013;50(2):140.
• ⁷¹ Zimran, A, Pastores, GM, Tylki-Szymanska, A. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. Am J Hematol. 2013;88(3):172–178.
• ⁷² Yetley, EA, Pfeiffer, CM, Phinney, KW. Biomarkers of vitamin B-12 status in NHANES: a roundtable summary. Am J Clin Nutr. 2011;94(1):313S–321S.
• ⁷³ Zimran, A, Altarescu, G, Elstein, D. Nonprecipitous changes upon withdrawal from imiglucerase for Gaucher disease because of a shortage in supply. Blood Cell Mol Dis. 2011;46(1):111–114.
• ⁷⁴ Djaldetti, M, Straussberg, R, Bessler, H, Zimran, A, Cohen, AM. Spontaneous decrease of spleen size in a patient with type 1 Gaucher’s disease. Haematologica. 1998;83(8):766–767.
• ⁷⁵ Pastores, GM, Elstein, D, Hrebicek, M, Zimran, A. Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies. Clin Ther. 2007;29(8):1645–1654.
• ⁷⁶ Zimran, A, Elstein, D. No justification for very high-dose enzyme therapy for patients with type III Gaucher disease. J Inherit Metab Dis. 2007;30(6):843–844.
• ⁷⁷ Zuckerman, S, Lahad, A, Shmueli, A. Carrier screening for Gaucher disease: lessons for low-penetrance, treatable diseases. JAMA. 2007;298(11):1281–1290.
• ⁷⁸ Elstein, D, Dweck, A, Attias, D. Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood. 2007;110(7):2296–2301.
• ⁷⁹ Elstein, D, Klutstein, MW, Lahad, A, Abrahamov, A, Hadas-Halpern, I, Zimran, A. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet. 1998;351(9115):1544–1546.
• ⁸⁰ Veinot, JP, Elstein, D, Hanania, D, Abrahamov, A, Srivatsa, S, Zimran, A. Gaucher’s disease with valve calcification: possible role of Gaucher cells, bone matrix proteins and integrins. Can J Cardiol. 1999;15(2):211–216.
• ⁸¹ Elstein, D., Abrahamov, A., Hadas-Halpern, I., Meyer, A., Zimran, A. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM. 1998;91(7):483–488.
• ⁸² Biegstraaten, M, Mengel, E, Marodi, L. Peripheral neuropathy in adult type 1 Gaucher disease: a 2-year prospective observational study. Brain. 2010;133(10):2909–2919.
• ⁸³ Zhao, H., Brunk, UT., Garner, B. Age-related lysosomal dysfunction: an unrecognized roadblock for cobalamin trafficking? Cell Mol Life Sci. 2011;68(24):3963–3969.
• ⁸⁴ Reynolds, E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949–960.

Publication Dates

• Publication in this collection
  16 May 2019
• Date of issue
  2017

History

• Received
  09 Aug 2016
• Reviewed
  27 Dec 2016
• Accepted
  28 Dec 2016