Successful Hematopoietic Stem Cell Transplantation for Niemann-Pick Disease Type B
http://www.100md.com
《小儿科》
Division of Research Immunology/Bone Marrow Transplantation
Department of Pediatrics, Keck School of Medicine
Saban Research Institute General Clinical Research Center, Childrens Hospital Los Angeles, Los Angeles, California
ABSTRACT
Histocompatible hematopoietic stem cell transplantation (HSCT) was conducted on a 4.5-year-old girl with Niemann-Pick disease type B. The donor was her unaffected brother. At the time of transplantation, she had severe pulmonary disease. After her first HSCT, she developed graft failure. Five years after her second HSCT, her sphingomyelinase levels are within normal levels, she has no pulmonary symptoms, and aside from persistent graft versus host disease, she is doing well.
Key Words: hematopoietic stem cell transplantation Niemann-Pick disease
Abbreviations: NPD, Niemann-Pick disease ASM, acid sphingomyelinase HSCT, hematopoietic stem cell transplantation CT, computed tomography ATG, antithymocyte globulin GVHD, graft-versus-host disease MMF, mycophenolate mofetil CSA, cyclosporin A
Niemann-Pick disease (NPD) type B is a lysosomal storage disorder characterized by a deficiency of acid sphingomyelinase (ASM) resulting in the accumulation of sphingomyelin in tissues such as the bone marrow, liver, spleen, and lungs.1 Unlike NPD type C, type B has little or no neurologic symptoms. We report a patient with NPD type B who was treated with hematopoietic stem cell transplantation (HSCT) with stable mixed chimerism 5 years post-HSCT.
CASE REPORT
A 15-month-old Hispanic female was diagnosed as having NPD after having an initial presentation of hepatosplenomegaly. The diagnostic work-up included a sphingomyelinase activity level of <20 pmol/minute per mg of protein (normal: 30–120 pmol/minute per mg of protein). The absence of any obvious neurologic impairment placed her in the type B category. Mutation analysis revealed a A452V/L476P mutation. She developed rapid pulmonary complications with diffuse interstitial lung disease, as shown on a computed tomography (CT) scan, and obstructive sleep apnea. Her obstructive sleep apnea improved with a tonsillectomy and adenoidectomy, but she remained hypoxemic during sleep because of her interstitial lung disease. At the time that she was referred for transplantation, her liver span was 15 cm in length and spleen span was 18 cm as measured by a CT scan.
The patient's mother delivered a healthy infant boy. At the age of 4.5 years, the patient received a histocompatible HSCT using the cord blood and additional bone marrow harvested from this brother. Before HSCT, the parents signed institutional review board–approved informed-consent forms for the transplant and the long-term evaluations for engraftment and late effects. Her conditioning regimen consisted of oral busulfan (16 mg/kg)/Cytoxan (200 mg/kg) and antithymocyte globulin (ATG). Her busulfan dose yielded a steady-state concentration of only 277 ng/mL (target level: 750–950 ng/mL). The busulfan dose was increased, and a repeat steady-state concentration was 472 ng/mL. Four additional doses of busulfan at a higher dose were given to compensate for the low levels. The patient received 1 dose of ATG with significant complications; however, additional doses could not be given because of hypoxia and pulmonary edema. These symptoms resolved after the ATG was discontinued. She received a total of 2.3 x 108 total nucleated bone marrow cells per kg and 1.3 x 107 total nucleated cord blood cells per kg. The total number of CD34+ cells infused was 8 x 106 cells per kg. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate 10 mg/m2 on days 3, 6, 11, and 18. Her transplant complications included veno-occlusive disease and mild to moderate respiratory distress. After an initial engraftment that showed mixed chimerism (85% donor/15% recipient), she began losing her graft. Additional immunosuppression was instituted with mycophenolate mofetil (MMF) and cyclosporin A (CSA). The graft improved for a short time, but as the immunosuppressive agents were tapered because of the adverse effects, she subsequently began to reject her graft, with peripheral blood chimerism studies showing 5% donor/95% recipient.
At the time of her graft failure, her liver and spleen sizes increased, and she became pancytopenic. Before initiating a second HSCT, she underwent a splenectomy. Her pancytopenia resolved, but her engraftment status remained at 95% recipient cells. Her pulmonary status at this time showed worsening interstitial lung disease by CT scan and moderate hypoxemia.
A second HSCT from her sibling was performed 19 months after the first transplant. She received a conditioning regimen of CamPath 1H (92 mg/m2) and total body irradiation of 200 cGy as a single fraction. GVHD prophylaxis consisted of CSA and MMF. The second transplant was complicated by enteroviral meningitis, acute pancreatitis, a Mallory Weiss esophageal tear resulting from the MMF, and renal tubular acidosis resulting from the CSA. Both the MMF and CSA were stopped, and tacrolimus was begun for GVHD prophylaxis.
At the time of this writing, she is 10 years old and it is 5.5 years after her second HSCT. She developed significant chronic GVHD of her skin only and has required ongoing therapy with tacrolimus, Rapamune, and daclizumab.
Engraftment
Since her second HSCT, she has remained stable with 95% donor cell engraftment and 5% recipient cells.
Her sphingomyelinase level 5 years post-HSCT is 76 pmol/minute per mg of protein (normal: 30–120 pmol/minute per mg of protein).
Pulmonary
A pre-HSCT CT scan of the patient's chest is shown in Fig 1A, and a CT scan performed 4 years post-HSCT is shown for comparison in Fig 1B. Her initial CT scan showed significant interstitial lung disease. Four years post-HSCT, her CT scan showed no evidence of interstitial lung disease. Her pulmonary-function testing revealed very mild restrictive lung disease, which was felt to be caused by low lung volumes from her hepatomegaly. She no longer needs oxygen and is not on any pulmonary medications.
Cardiac
The patient developed a mitral regurgitation and a mild mitral valve prolapse that was revealed on echocardiogram. She clinically does not have any cardiac symptoms at this time. Five years post-HSCT, the patient had a lipid profile that showed a triglyceride level of 305 mg/dL (normal: 35–135 mg/dL), total cholesterol of 690 mg/dL (normal: 65–175 mg/dL), high-density lipoprotein of 45 mg/dL (normal: 35–70 mg/dL), and low-density lipoprotein of 584 mg/dL (normal: 60–115 mg/dL). There were no pretransplant lipid panels performed to determine if these values have increased or decreased. Therefore, we do not know whether the HSCTs had an effect on her lipid profile.
Hepatic
The patient's most recent CT scan shows that her liver span is now 9 cm (her spleen was removed previously). Her transaminase levels remain elevated, with an aspartate aminotransferase level of 283 U/L (normal: 15–46 U/L) and alanine aminotransferase level of 305 U/L (normal: 3–35 U/L). The transaminase levels have remained stable for the past 3 years, with no significant change in values.
Neurologic
Long-term follow-up studies reveal that although she had a decline in her neurocognitive function 3 years post-HSCT, she has improved by 5 years post-transplant. She now remains stable to improved in all areas of neurocognitive function except in the areas of visual motor development and memory (Fig 2). Tests for expressive vocabulary and memory tests could not be performed pretransplant because of her young age. Her ophthalmologic evaluation is normal, with no evidence of cherry-red spots.
Endocrine
Endocrine evaluations revealed that she is below the 5th percentile for height and weight and 50th percentile for a 5-year-old. Glucagon stimulation testing shows normal growth-hormone levels despite not growing. Her bone age is 2 standard deviations below her chronological age. Her thyroid function remains normal. Her pubertal development is delayed, and she has prepubertal gonadotropic hormone levels. She remains Tanner stage 1 for both breast development and genitalia.
DISCUSSION
NPD type B is a lysosomal-storage disorder resulting from the loss of ASM activity. There is marked hepatosplenomegaly and the presence of foam cells in the bone marrow; however, there is minimal to no neurologic impairment. Children who present with NPD type B have a pronounced hepatic impairment, often leading to death in those patients who present early. There are several patients with NPD type B who have a phenotype that includes neurodegeneration.2,3 This disorder is autosomal recessive and panethnic. The natural history of these patients includes worsening hematologic, lipid, pulmonary, and hepatic symptoms over time. The majority of patients have an atherogenic lipid profile (low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, and high triglycerides), restrictive lung disease with abnormal diffusion lung capacity, and hepatic dysfunction, with some patients developing liver failure.4 Long-term follow-up studies on patients with NPD type B have shown that these patients have short stature, delayed bone age, and low insulin-like growth factor I levels.5 It is unclear at this time whether an HSCT would reverse these underlying problems.
There have been very few therapeutic options available to patients with NPD type B. To date there have been 2 reported cases of successful transplantation of this disorder. One patient had resolution of her pulmonary symptoms; however, neurologic symptoms occurred with the presence of cherry-red spots. Her neurologic symptoms led to a respiratory arrest. This patient is now 16 years post-HSCT but has severe physical and mental disabilities.6,7 The second patient has not been described in any publications but is reportedly stable (Morris Kletzel, MD, Northwestern University, personal communication, 2005.
The mutations in our patient, A452V/L476P, are private mutations and have not been well characterized phenotypically. Therefore, we do not know the severity of the symptoms that patients with this mutation might expect. Because of the severe hepatic and pulmonary impairment that this child had, one would expect that this type of mutation would result in patients with severe symptoms. Over the past 5 years posttransplant, our patient has had resolution of her pulmonary symptoms. Although her liver has decreased in size clinically, it remains enlarged with elevated transaminase levels. She continues to have elevated triglyceride and low-density lipoprotein cholesterol levels. There has not been any long-term neurologic impairment to date in our patient. It is concerning that her neurocognitive studies show a deterioration in her visual motor development and her memory scores. It has been shown that long-term effects of HSCT can result in deficits of visual motor development and memory.8,9 It is unclear whether these are manifestations of her underlying disease, her transplant, or complications from having GVHD.
Gene therapy has been used in murine models with partial correction of NPD. Miranda et al10 have performed stem cell gene therapy in ASM-knockout mice. The results of these studies showed high levels of ASM (fivefold over normal), and engrafted animals had increased life spans from 5 to 9 months. ASM activities were increased, and sphingomyelin storage was reduced in the spleen, liver, and lungs of the treated mice. However, all transplanted animals developed ataxia and died earlier than normal mice.
CONCLUSIONS
This case represents a successful HSCT for NPD type B, which has improved the patient's pulmonary symptoms. However, the complications of her transplant are still present (GVHD, renal tubular dysfunction). Early diagnosis of this disease is imperative for this and other metabolic disorders for HSCT to offer a curative potential. Transplantation should be considered for those with severe disease, especially those with pulmonary symptoms. Unfortunately, the likelihood of finding an unaffected HLA-matched sibling donor is small. For those who do not have a sibling donor, an unrelated transplant is a possible option. Future directions should be directed toward enzyme-replacement or gene therapy, which would solve the problem of not finding a suitable donor and reduce the complications of transplant.
ACKNOWLEDGMENTS
This work was supported in part by National Institute of Health NCRR General Clinical Research Center (GCRC) grant MO1 RR00043 and was performed at the GCRC at Childrens Hospital Los Angeles. Computational assistance was provided by National institutes of Health NCRR GCRC grant MO1 RR00043, CDMAS Project, and performed at the GCRC at Childrens Hospital Los Angeles.
FOOTNOTES
Accepted May 20, 2005.
No conflict of interest declared.
REFERENCES
Schuchman EH, Desnick RJ. Niemann Pick disease type A and B: acid sphyngomyelinase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001
Elleder M, Cihula J. Niemann-Pick disease (variation in the sphingomyelinase deficient group). Neurovisceral phenotype (A) with an abnormally protracted clinical course and variable expression of neurological symptomatology in three siblings. Eur J Pediatr. 1983;140 :323 –328
Elleder M, Nevoral J, Spicakova V, et al. A new variant of sphingomyelinase deficiency (Niemann-Pick): visceromegaly, minimal neurological lesions and low in vivo degradation rate of sphingomyelin. J Inherit Metab Dis. 1986;9 :357 –366
Wasserstein MP, Larkin AE, Glass RB, Schuchman EH, Desnick RJ, McGovern MM. Growth restriction in children with type B Niemann-Pick disease. J Pediatr. 2003;142 :424 –428
Vellodi A, Hobbs JR, O'Donnell NM, Coulter BS, Hugh-Jones K. Treatment of Niemann-Pick disease type B by allogeneic bone marrow transplantation. Br Med J (Clin Res Ed). 1987;295 :1375 –1376
Victor S, Coulter JBS, Besley GTN, et al. Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. J Inherit Metab Dis. 2003;26 :775 –785
Cool VA. Long-term neuropsychological risks in pediatric bone marrow transplant: what do we know Bone Marrow Transplant. 1986;18 (suppl 3):S45–S49
Smedler AC, Ringden K, Bergman H, Bolme P. Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation. Acta Paediatr Scand. 1990;79 :613 –621
Miranda SR, Erlich S, Friedrich VL, Gatt S, Schuchman EH. Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease. Gene Ther. 2000;7 :1768 –1776(Ami J. Shah, MD, Neena Ka)
Department of Pediatrics, Keck School of Medicine
Saban Research Institute General Clinical Research Center, Childrens Hospital Los Angeles, Los Angeles, California
ABSTRACT
Histocompatible hematopoietic stem cell transplantation (HSCT) was conducted on a 4.5-year-old girl with Niemann-Pick disease type B. The donor was her unaffected brother. At the time of transplantation, she had severe pulmonary disease. After her first HSCT, she developed graft failure. Five years after her second HSCT, her sphingomyelinase levels are within normal levels, she has no pulmonary symptoms, and aside from persistent graft versus host disease, she is doing well.
Key Words: hematopoietic stem cell transplantation Niemann-Pick disease
Abbreviations: NPD, Niemann-Pick disease ASM, acid sphingomyelinase HSCT, hematopoietic stem cell transplantation CT, computed tomography ATG, antithymocyte globulin GVHD, graft-versus-host disease MMF, mycophenolate mofetil CSA, cyclosporin A
Niemann-Pick disease (NPD) type B is a lysosomal storage disorder characterized by a deficiency of acid sphingomyelinase (ASM) resulting in the accumulation of sphingomyelin in tissues such as the bone marrow, liver, spleen, and lungs.1 Unlike NPD type C, type B has little or no neurologic symptoms. We report a patient with NPD type B who was treated with hematopoietic stem cell transplantation (HSCT) with stable mixed chimerism 5 years post-HSCT.
CASE REPORT
A 15-month-old Hispanic female was diagnosed as having NPD after having an initial presentation of hepatosplenomegaly. The diagnostic work-up included a sphingomyelinase activity level of <20 pmol/minute per mg of protein (normal: 30–120 pmol/minute per mg of protein). The absence of any obvious neurologic impairment placed her in the type B category. Mutation analysis revealed a A452V/L476P mutation. She developed rapid pulmonary complications with diffuse interstitial lung disease, as shown on a computed tomography (CT) scan, and obstructive sleep apnea. Her obstructive sleep apnea improved with a tonsillectomy and adenoidectomy, but she remained hypoxemic during sleep because of her interstitial lung disease. At the time that she was referred for transplantation, her liver span was 15 cm in length and spleen span was 18 cm as measured by a CT scan.
The patient's mother delivered a healthy infant boy. At the age of 4.5 years, the patient received a histocompatible HSCT using the cord blood and additional bone marrow harvested from this brother. Before HSCT, the parents signed institutional review board–approved informed-consent forms for the transplant and the long-term evaluations for engraftment and late effects. Her conditioning regimen consisted of oral busulfan (16 mg/kg)/Cytoxan (200 mg/kg) and antithymocyte globulin (ATG). Her busulfan dose yielded a steady-state concentration of only 277 ng/mL (target level: 750–950 ng/mL). The busulfan dose was increased, and a repeat steady-state concentration was 472 ng/mL. Four additional doses of busulfan at a higher dose were given to compensate for the low levels. The patient received 1 dose of ATG with significant complications; however, additional doses could not be given because of hypoxia and pulmonary edema. These symptoms resolved after the ATG was discontinued. She received a total of 2.3 x 108 total nucleated bone marrow cells per kg and 1.3 x 107 total nucleated cord blood cells per kg. The total number of CD34+ cells infused was 8 x 106 cells per kg. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate 10 mg/m2 on days 3, 6, 11, and 18. Her transplant complications included veno-occlusive disease and mild to moderate respiratory distress. After an initial engraftment that showed mixed chimerism (85% donor/15% recipient), she began losing her graft. Additional immunosuppression was instituted with mycophenolate mofetil (MMF) and cyclosporin A (CSA). The graft improved for a short time, but as the immunosuppressive agents were tapered because of the adverse effects, she subsequently began to reject her graft, with peripheral blood chimerism studies showing 5% donor/95% recipient.
At the time of her graft failure, her liver and spleen sizes increased, and she became pancytopenic. Before initiating a second HSCT, she underwent a splenectomy. Her pancytopenia resolved, but her engraftment status remained at 95% recipient cells. Her pulmonary status at this time showed worsening interstitial lung disease by CT scan and moderate hypoxemia.
A second HSCT from her sibling was performed 19 months after the first transplant. She received a conditioning regimen of CamPath 1H (92 mg/m2) and total body irradiation of 200 cGy as a single fraction. GVHD prophylaxis consisted of CSA and MMF. The second transplant was complicated by enteroviral meningitis, acute pancreatitis, a Mallory Weiss esophageal tear resulting from the MMF, and renal tubular acidosis resulting from the CSA. Both the MMF and CSA were stopped, and tacrolimus was begun for GVHD prophylaxis.
At the time of this writing, she is 10 years old and it is 5.5 years after her second HSCT. She developed significant chronic GVHD of her skin only and has required ongoing therapy with tacrolimus, Rapamune, and daclizumab.
Engraftment
Since her second HSCT, she has remained stable with 95% donor cell engraftment and 5% recipient cells.
Her sphingomyelinase level 5 years post-HSCT is 76 pmol/minute per mg of protein (normal: 30–120 pmol/minute per mg of protein).
Pulmonary
A pre-HSCT CT scan of the patient's chest is shown in Fig 1A, and a CT scan performed 4 years post-HSCT is shown for comparison in Fig 1B. Her initial CT scan showed significant interstitial lung disease. Four years post-HSCT, her CT scan showed no evidence of interstitial lung disease. Her pulmonary-function testing revealed very mild restrictive lung disease, which was felt to be caused by low lung volumes from her hepatomegaly. She no longer needs oxygen and is not on any pulmonary medications.
Cardiac
The patient developed a mitral regurgitation and a mild mitral valve prolapse that was revealed on echocardiogram. She clinically does not have any cardiac symptoms at this time. Five years post-HSCT, the patient had a lipid profile that showed a triglyceride level of 305 mg/dL (normal: 35–135 mg/dL), total cholesterol of 690 mg/dL (normal: 65–175 mg/dL), high-density lipoprotein of 45 mg/dL (normal: 35–70 mg/dL), and low-density lipoprotein of 584 mg/dL (normal: 60–115 mg/dL). There were no pretransplant lipid panels performed to determine if these values have increased or decreased. Therefore, we do not know whether the HSCTs had an effect on her lipid profile.
Hepatic
The patient's most recent CT scan shows that her liver span is now 9 cm (her spleen was removed previously). Her transaminase levels remain elevated, with an aspartate aminotransferase level of 283 U/L (normal: 15–46 U/L) and alanine aminotransferase level of 305 U/L (normal: 3–35 U/L). The transaminase levels have remained stable for the past 3 years, with no significant change in values.
Neurologic
Long-term follow-up studies reveal that although she had a decline in her neurocognitive function 3 years post-HSCT, she has improved by 5 years post-transplant. She now remains stable to improved in all areas of neurocognitive function except in the areas of visual motor development and memory (Fig 2). Tests for expressive vocabulary and memory tests could not be performed pretransplant because of her young age. Her ophthalmologic evaluation is normal, with no evidence of cherry-red spots.
Endocrine
Endocrine evaluations revealed that she is below the 5th percentile for height and weight and 50th percentile for a 5-year-old. Glucagon stimulation testing shows normal growth-hormone levels despite not growing. Her bone age is 2 standard deviations below her chronological age. Her thyroid function remains normal. Her pubertal development is delayed, and she has prepubertal gonadotropic hormone levels. She remains Tanner stage 1 for both breast development and genitalia.
DISCUSSION
NPD type B is a lysosomal-storage disorder resulting from the loss of ASM activity. There is marked hepatosplenomegaly and the presence of foam cells in the bone marrow; however, there is minimal to no neurologic impairment. Children who present with NPD type B have a pronounced hepatic impairment, often leading to death in those patients who present early. There are several patients with NPD type B who have a phenotype that includes neurodegeneration.2,3 This disorder is autosomal recessive and panethnic. The natural history of these patients includes worsening hematologic, lipid, pulmonary, and hepatic symptoms over time. The majority of patients have an atherogenic lipid profile (low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, and high triglycerides), restrictive lung disease with abnormal diffusion lung capacity, and hepatic dysfunction, with some patients developing liver failure.4 Long-term follow-up studies on patients with NPD type B have shown that these patients have short stature, delayed bone age, and low insulin-like growth factor I levels.5 It is unclear at this time whether an HSCT would reverse these underlying problems.
There have been very few therapeutic options available to patients with NPD type B. To date there have been 2 reported cases of successful transplantation of this disorder. One patient had resolution of her pulmonary symptoms; however, neurologic symptoms occurred with the presence of cherry-red spots. Her neurologic symptoms led to a respiratory arrest. This patient is now 16 years post-HSCT but has severe physical and mental disabilities.6,7 The second patient has not been described in any publications but is reportedly stable (Morris Kletzel, MD, Northwestern University, personal communication, 2005.
The mutations in our patient, A452V/L476P, are private mutations and have not been well characterized phenotypically. Therefore, we do not know the severity of the symptoms that patients with this mutation might expect. Because of the severe hepatic and pulmonary impairment that this child had, one would expect that this type of mutation would result in patients with severe symptoms. Over the past 5 years posttransplant, our patient has had resolution of her pulmonary symptoms. Although her liver has decreased in size clinically, it remains enlarged with elevated transaminase levels. She continues to have elevated triglyceride and low-density lipoprotein cholesterol levels. There has not been any long-term neurologic impairment to date in our patient. It is concerning that her neurocognitive studies show a deterioration in her visual motor development and her memory scores. It has been shown that long-term effects of HSCT can result in deficits of visual motor development and memory.8,9 It is unclear whether these are manifestations of her underlying disease, her transplant, or complications from having GVHD.
Gene therapy has been used in murine models with partial correction of NPD. Miranda et al10 have performed stem cell gene therapy in ASM-knockout mice. The results of these studies showed high levels of ASM (fivefold over normal), and engrafted animals had increased life spans from 5 to 9 months. ASM activities were increased, and sphingomyelin storage was reduced in the spleen, liver, and lungs of the treated mice. However, all transplanted animals developed ataxia and died earlier than normal mice.
CONCLUSIONS
This case represents a successful HSCT for NPD type B, which has improved the patient's pulmonary symptoms. However, the complications of her transplant are still present (GVHD, renal tubular dysfunction). Early diagnosis of this disease is imperative for this and other metabolic disorders for HSCT to offer a curative potential. Transplantation should be considered for those with severe disease, especially those with pulmonary symptoms. Unfortunately, the likelihood of finding an unaffected HLA-matched sibling donor is small. For those who do not have a sibling donor, an unrelated transplant is a possible option. Future directions should be directed toward enzyme-replacement or gene therapy, which would solve the problem of not finding a suitable donor and reduce the complications of transplant.
ACKNOWLEDGMENTS
This work was supported in part by National Institute of Health NCRR General Clinical Research Center (GCRC) grant MO1 RR00043 and was performed at the GCRC at Childrens Hospital Los Angeles. Computational assistance was provided by National institutes of Health NCRR GCRC grant MO1 RR00043, CDMAS Project, and performed at the GCRC at Childrens Hospital Los Angeles.
FOOTNOTES
Accepted May 20, 2005.
No conflict of interest declared.
REFERENCES
Schuchman EH, Desnick RJ. Niemann Pick disease type A and B: acid sphyngomyelinase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001
Elleder M, Cihula J. Niemann-Pick disease (variation in the sphingomyelinase deficient group). Neurovisceral phenotype (A) with an abnormally protracted clinical course and variable expression of neurological symptomatology in three siblings. Eur J Pediatr. 1983;140 :323 –328
Elleder M, Nevoral J, Spicakova V, et al. A new variant of sphingomyelinase deficiency (Niemann-Pick): visceromegaly, minimal neurological lesions and low in vivo degradation rate of sphingomyelin. J Inherit Metab Dis. 1986;9 :357 –366
Wasserstein MP, Larkin AE, Glass RB, Schuchman EH, Desnick RJ, McGovern MM. Growth restriction in children with type B Niemann-Pick disease. J Pediatr. 2003;142 :424 –428
Vellodi A, Hobbs JR, O'Donnell NM, Coulter BS, Hugh-Jones K. Treatment of Niemann-Pick disease type B by allogeneic bone marrow transplantation. Br Med J (Clin Res Ed). 1987;295 :1375 –1376
Victor S, Coulter JBS, Besley GTN, et al. Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant. J Inherit Metab Dis. 2003;26 :775 –785
Cool VA. Long-term neuropsychological risks in pediatric bone marrow transplant: what do we know Bone Marrow Transplant. 1986;18 (suppl 3):S45–S49
Smedler AC, Ringden K, Bergman H, Bolme P. Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation. Acta Paediatr Scand. 1990;79 :613 –621
Miranda SR, Erlich S, Friedrich VL, Gatt S, Schuchman EH. Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease. Gene Ther. 2000;7 :1768 –1776(Ami J. Shah, MD, Neena Ka)