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Infantile Tay-Sachs disease: a case report
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Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
(N=70, any EMG data), suggesting the need for guidelines on standard procedures for diagnosing CTS in MPS I, including referrals to hand surgeons. (Supported by Sanofi Genzyme.) doi:10.1016/j.ymgme.2016.11.133
125 Early initiation of prophylactic immune tolerance induction and enzyme replacement therapy in prenatally diagnosed infantile onset Pompe disease with a CRIM-negative mutation Punita Guptaa, Brian Shayotaa, Alejandra Gomeza, Lorien Tambini-Kinga, Zoheb Kazib, Priya S. Kishnanib, aSt. Joseph's Regional Medical Center, Paterson, NJ, United States, bDuke University Medical Center, Durham, NC, United States Pompe disease is an autosomal recessive glycogen storage disorder caused by a deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA). The diagnosis of infantie onset Pompe disease (IOPD) is often delayed with median age being 4.7 months. Without ERT, death is imminent, usually within the first 2 years of life secondary to cardiorespiratory insufficiency. Early treatment with ERT has resulted in significantly improved outcomes with CRIM status being one of the important prognostic factors. The management of CRIM negative IOPD has evolved significantly in recent years with the advent of ITI, which helps reduce the immune response to ERT. Our patient was diagnosed prenatally through amniocentesis which confirmed a homozygous (c.2560CNT/c.2560CNT) GAA gene mutation. This is a nonsense mutation previously reported to be associated with severe IOPD and predictive of CRIM negative status. Fetal echocardiogram at 32 weeks showed the presence of biventricular hypertrophy. The patient was born via cesarean section at 38 weeks gestation. Prophylactic ITI was started on day 2 of life with methotrexate, rituximab, and IVIG. ERT with alglucosidase alfa was then started on day 3 of life. Echocardiogram on day 6 of life revealed severe biventricular cardiac hypertrophy with mild ejection fraction compromise requiring a short course of inotropic therapy, with complete recovery of cardiac function by week 5. The patient has otherwise been healthy, with normal neurological development and cardiac function at 13 months of age and is managed on an out-patient basis. To our knowledge, no prior reports have been made examining the clinical course and disease progression in CRIM negative IOPD patients treated with prophylactic ITI and ERT at such an early neonatal period. This case exemplifies the integration of prenatal genetic diagnosis to the coordination of complex multidisciplinary care in the treatment of a rare, previously fatal genetic condition. doi:10.1016/j.ymgme.2016.11.134
126 Infantile Tay-Sachs disease: a case report Punita Gupta, Alejandra Gomez, St. Joseph's Regional Medical Center, Paterson, NJ, United States Tay-Sachs disease belongs to a group of neurodegenerative disorders caused by intralysosomal storage of GM2 ganglioside resulting from hexosaminidase A deficiency. It is inherited in an autosomal recessive manner and has been reported in children of virtually all ethnic, racial, and religious groups. As the result of extensive genetic counseling of carriers identified through carrier screening programs and monitoring of at-risk pregnancies, the incidence of TSD in the Ashkenazi Jewish population of North
America has been reduced by greater than 90%. Certain populations that are relatively isolated genetically have been found to carry HEXA mutations with frequencies comparable to or even greater than those observed in Ashkenazi Jews. Our patient presented to the genetics clinic at 16 months of age for evaluation of hypotonia and developmental regression. Prenatal history was significant for oligohydramnios and IUGR. Postnatally she met all motor and social milestones till 6 months of age, by which time she was sitting independently and beginning to crawl. Thereafter she gradually started to regress with eventual loss of head control by 12 months of age. Her exam at 16 months of age revealed hypotonia, head lag, drooling, inability to fixate and exaggerated startle response. Ophthalmology evaluation revealed cherry red spot. Biochemical testing for Hexosaminidase A activity in serum was below 10% and most suggestive of Tay-Sachs disease. Molecular testing is underway. The mother underwent prenatal carrier screening and was screen normal for TSD. It tested for 9 common variants in the HEXA gene with a detection rate of 23% in the Hispanic population. Parents are of Dominican descent and consanguinity was denied. This brings up the question of whether biochemical testing should supplement prenatal carrier screening in order to provide the opportunity to discuss future options for this yet untreatable fatal condition. doi:10.1016/j.ymgme.2016.11.135
127 Outside the fiber: interstitial pathology of skeletal muscle in infantile Pompe disease Christine I. Ha, Ankit K. Desai, Justin Waterfield, Zoheb B. Kazi, Stephanie L. Austin, Edward H. Bossen, Priya S. Kishnani, Anne F. Buckley, Duke University Medical Center, Durham, NC, United States The outcome of infantile Pompe disease (IPD) has improved dramatically since the introduction of alglucosidase alfa enzyme replacement therapy (ERT). However, long-term survivors on ERT – even those treated from early infancy – demonstrate muscle weakness, dysphagia, motor speech deficits, and ptosis, indicating that current therapy is insufficient to prevent disease progression in skeletal muscle. We hypothesize that traversing the interstitium of skeletal muscle tissue is a key factor in the delivery of ERT to myocytes and that interstitial pathology contributes to the skeletal muscle symptoms of long-term survivors of IPD. The goal of this study is to characterize pathologic interstitial changes in IPD skeletal muscle that could affect ERT efficacy and muscle function. Clinical muscle biopsies from IPD patients, taken before and during ERT, were reviewed via electron microscopy (EM) and via light microscopy using special stains and immunohistochemistry. Tissue findings were correlated with clinical status at the time of biopsy. We found that skeletal muscle biopsies from IPD patients frequently demonstrated expansion of the interstitial space, both before and during ERT. CD31 immunostaining showed that even in skeletal muscle with markedly increased stroma, capillary architecture was not qualitatively different from that of less-affected muscle; at the ultrastructural level, capillary structures appeared unaltered. CD3 immunostaining showed only minimal inflammation. Trichrome staining, reticulin staining, and type IV collagen immunostaining revealed that fibrosis was only one component of the stromal expansion. PAS/D staining demonstrated that some of the stromal expansion was due to glycogen deposition; on EM studies, much of the deposited stromal material structurally resembled glycogen. These newly-described skeletal muscle interstitial findings challenge some of our assumptions regarding the pathophysiology of IPD. Stromal changes could contribute to the limited efficacy of ERT in
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
(N=70, any EMG data), suggesting the need for guidelines on standard procedures for diagnosing CTS in MPS I, including referrals to hand surgeons. (Supported by Sanofi Genzyme.) doi:10.1016/j.ymgme.2016.11.133
125 Early initiation of prophylactic immune tolerance induction and enzyme replacement therapy in prenatally diagnosed infantile onset Pompe disease with a CRIM-negative mutation Punita Guptaa, Brian Shayotaa, Alejandra Gomeza, Lorien Tambini-Kinga, Zoheb Kazib, Priya S. Kishnanib, aSt. Joseph's Regional Medical Center, Paterson, NJ, United States, bDuke University Medical Center, Durham, NC, United States Pompe disease is an autosomal recessive glycogen storage disorder caused by a deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA). The diagnosis of infantie onset Pompe disease (IOPD) is often delayed with median age being 4.7 months. Without ERT, death is imminent, usually within the first 2 years of life secondary to cardiorespiratory insufficiency. Early treatment with ERT has resulted in significantly improved outcomes with CRIM status being one of the important prognostic factors. The management of CRIM negative IOPD has evolved significantly in recent years with the advent of ITI, which helps reduce the immune response to ERT. Our patient was diagnosed prenatally through amniocentesis which confirmed a homozygous (c.2560CNT/c.2560CNT) GAA gene mutation. This is a nonsense mutation previously reported to be associated with severe IOPD and predictive of CRIM negative status. Fetal echocardiogram at 32 weeks showed the presence of biventricular hypertrophy. The patient was born via cesarean section at 38 weeks gestation. Prophylactic ITI was started on day 2 of life with methotrexate, rituximab, and IVIG. ERT with alglucosidase alfa was then started on day 3 of life. Echocardiogram on day 6 of life revealed severe biventricular cardiac hypertrophy with mild ejection fraction compromise requiring a short course of inotropic therapy, with complete recovery of cardiac function by week 5. The patient has otherwise been healthy, with normal neurological development and cardiac function at 13 months of age and is managed on an out-patient basis. To our knowledge, no prior reports have been made examining the clinical course and disease progression in CRIM negative IOPD patients treated with prophylactic ITI and ERT at such an early neonatal period. This case exemplifies the integration of prenatal genetic diagnosis to the coordination of complex multidisciplinary care in the treatment of a rare, previously fatal genetic condition. doi:10.1016/j.ymgme.2016.11.134
126 Infantile Tay-Sachs disease: a case report Punita Gupta, Alejandra Gomez, St. Joseph's Regional Medical Center, Paterson, NJ, United States Tay-Sachs disease belongs to a group of neurodegenerative disorders caused by intralysosomal storage of GM2 ganglioside resulting from hexosaminidase A deficiency. It is inherited in an autosomal recessive manner and has been reported in children of virtually all ethnic, racial, and religious groups. As the result of extensive genetic counseling of carriers identified through carrier screening programs and monitoring of at-risk pregnancies, the incidence of TSD in the Ashkenazi Jewish population of North
America has been reduced by greater than 90%. Certain populations that are relatively isolated genetically have been found to carry HEXA mutations with frequencies comparable to or even greater than those observed in Ashkenazi Jews. Our patient presented to the genetics clinic at 16 months of age for evaluation of hypotonia and developmental regression. Prenatal history was significant for oligohydramnios and IUGR. Postnatally she met all motor and social milestones till 6 months of age, by which time she was sitting independently and beginning to crawl. Thereafter she gradually started to regress with eventual loss of head control by 12 months of age. Her exam at 16 months of age revealed hypotonia, head lag, drooling, inability to fixate and exaggerated startle response. Ophthalmology evaluation revealed cherry red spot. Biochemical testing for Hexosaminidase A activity in serum was below 10% and most suggestive of Tay-Sachs disease. Molecular testing is underway. The mother underwent prenatal carrier screening and was screen normal for TSD. It tested for 9 common variants in the HEXA gene with a detection rate of 23% in the Hispanic population. Parents are of Dominican descent and consanguinity was denied. This brings up the question of whether biochemical testing should supplement prenatal carrier screening in order to provide the opportunity to discuss future options for this yet untreatable fatal condition. doi:10.1016/j.ymgme.2016.11.135
127 Outside the fiber: interstitial pathology of skeletal muscle in infantile Pompe disease Christine I. Ha, Ankit K. Desai, Justin Waterfield, Zoheb B. Kazi, Stephanie L. Austin, Edward H. Bossen, Priya S. Kishnani, Anne F. Buckley, Duke University Medical Center, Durham, NC, United States The outcome of infantile Pompe disease (IPD) has improved dramatically since the introduction of alglucosidase alfa enzyme replacement therapy (ERT). However, long-term survivors on ERT – even those treated from early infancy – demonstrate muscle weakness, dysphagia, motor speech deficits, and ptosis, indicating that current therapy is insufficient to prevent disease progression in skeletal muscle. We hypothesize that traversing the interstitium of skeletal muscle tissue is a key factor in the delivery of ERT to myocytes and that interstitial pathology contributes to the skeletal muscle symptoms of long-term survivors of IPD. The goal of this study is to characterize pathologic interstitial changes in IPD skeletal muscle that could affect ERT efficacy and muscle function. Clinical muscle biopsies from IPD patients, taken before and during ERT, were reviewed via electron microscopy (EM) and via light microscopy using special stains and immunohistochemistry. Tissue findings were correlated with clinical status at the time of biopsy. We found that skeletal muscle biopsies from IPD patients frequently demonstrated expansion of the interstitial space, both before and during ERT. CD31 immunostaining showed that even in skeletal muscle with markedly increased stroma, capillary architecture was not qualitatively different from that of less-affected muscle; at the ultrastructural level, capillary structures appeared unaltered. CD3 immunostaining showed only minimal inflammation. Trichrome staining, reticulin staining, and type IV collagen immunostaining revealed that fibrosis was only one component of the stromal expansion. PAS/D staining demonstrated that some of the stromal expansion was due to glycogen deposition; on EM studies, much of the deposited stromal material structurally resembled glycogen. These newly-described skeletal muscle interstitial findings challenge some of our assumptions regarding the pathophysiology of IPD. Stromal changes could contribute to the limited efficacy of ERT in