Submitting/Presenting Author

Kyra McCarty, Children's Mercy HospitalFollow

Presenter Status

Resident/Psychology Intern

Abstract Type

Case report

Primary Mentor

Mukta Sharma, MD, MPH

Start Date

4-5-2022 11:30 AM

End Date

4-5-2022 1:30 PM

Presentation Type

Poster Presentation

Description

Background: Triosephosphate isomerase deficiency (TPID) is a glycolytic pathway enzymopathy causing hemolytic anemia and neurologic dysfunction. TPID is caused by mutations in the TPI1 gene. These patients experience severe hemolytic anemia in infancy followed by progressive neurodegeneration. Diagnosis of TPID is made by measuring decreased TPI enzyme activity elevated dihydroxyacetone phosphate (DHAP) levels in the blood. The diagnosis is confirmed by molecular genetic testing. Neurological involvement typically manifests between 6 and 24 months of age, causing progressive motor dysfunction. Chronic axonal neuropathy is often present on nerve biopsy, and peripheral neuropathy is evident on electrophysiologic studies. Splenectomy and blood transfusions may improve the hemolytic anemia, but no treatment is known for the progressive neurological impairment. Affected individuals typically die due to respiratory failure before 6 years of age.

Objectives/Goal: The objective of this case report is to document the use of BMT for treatment of TPID.

Methods/Design: The initial rationale for pursuing bone marrow transplant (BMT) arose from experience with treating TPID with blood transfusions to reverse the severe hemolytic anemia. The provision of permanent replacement of TPI enzyme by production within the bone marrow made hematopoietic stem cell transplant (HSCT) a promising treatment approach. In a mutant mouse model, HSCT reversed hemolytic anemia in mutant homozygotes and restored TPI enzyme activity to 100% of wild-type activity levels. Further, levels of the glycolytic metabolite DHAP returned to normal in mutant homozygotes after transplantation.

Results: A neonate with severe indirect hyperbilirubinemia was referred to Hematology. Red blood cell enzyme assay demonstrated decreased TPI activity level (6% of mean normal), consistent with TPID. At 1 year of age, genetic sequencing demonstrated Glu104Asp homozygous missense mutation confirming diagnosis of TPID. The family was referred for HSCT consultation in attempt to explore a potentially curative treatment. At 17 months of age, the child received allogenic unrelated HSCT. Seven weeks following transplant, TPI enzyme levels were within the normal reference range. The child developed waning chimerism concerning for graft failure, so underwent second allogenic unrelated HSCT at 21 months of age. The patient developed transfusion-dependent bone marrow aplasia, prompting rescue HSCT at 23 months of age. During hospitalization, the patient suffered respiratory failure and required tracheostomy. He developed truncal weakness and was unable to sit independently, crawl, or stand unsupported at discharge. At 6 years of age, he has slowly regained motor and developmental milestones via regular physical and occupational therapy. TPI enzyme levels have returned to normal reference range. In most recent follow-up, he can ambulate using a Gait trainer and kick a ball. He can speak using a PassyMuir valve, feed himself, use a pencil to write, and recently began toilet training.

Conclusions: This case demonstrates that HSCT can provide a permanent source of the TPI enzyme in the blood, reversing the hemolytic anemia and apparently halting further neurodegeneration. Routine pre- and post-transplant muscle biopsy would allow researchers to better understand the physiology associated with neurodegeneration. A multi-site clinical trial would provide the scale necessary to conclusively determine the degree to which enzyme replacement can salvage neurodevelopment.

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May 4th, 11:30 AM May 4th, 1:30 PM

A Novel Approach to Triosephosphate Isomerase Deficiency

Background: Triosephosphate isomerase deficiency (TPID) is a glycolytic pathway enzymopathy causing hemolytic anemia and neurologic dysfunction. TPID is caused by mutations in the TPI1 gene. These patients experience severe hemolytic anemia in infancy followed by progressive neurodegeneration. Diagnosis of TPID is made by measuring decreased TPI enzyme activity elevated dihydroxyacetone phosphate (DHAP) levels in the blood. The diagnosis is confirmed by molecular genetic testing. Neurological involvement typically manifests between 6 and 24 months of age, causing progressive motor dysfunction. Chronic axonal neuropathy is often present on nerve biopsy, and peripheral neuropathy is evident on electrophysiologic studies. Splenectomy and blood transfusions may improve the hemolytic anemia, but no treatment is known for the progressive neurological impairment. Affected individuals typically die due to respiratory failure before 6 years of age.

Objectives/Goal: The objective of this case report is to document the use of BMT for treatment of TPID.

Methods/Design: The initial rationale for pursuing bone marrow transplant (BMT) arose from experience with treating TPID with blood transfusions to reverse the severe hemolytic anemia. The provision of permanent replacement of TPI enzyme by production within the bone marrow made hematopoietic stem cell transplant (HSCT) a promising treatment approach. In a mutant mouse model, HSCT reversed hemolytic anemia in mutant homozygotes and restored TPI enzyme activity to 100% of wild-type activity levels. Further, levels of the glycolytic metabolite DHAP returned to normal in mutant homozygotes after transplantation.

Results: A neonate with severe indirect hyperbilirubinemia was referred to Hematology. Red blood cell enzyme assay demonstrated decreased TPI activity level (6% of mean normal), consistent with TPID. At 1 year of age, genetic sequencing demonstrated Glu104Asp homozygous missense mutation confirming diagnosis of TPID. The family was referred for HSCT consultation in attempt to explore a potentially curative treatment. At 17 months of age, the child received allogenic unrelated HSCT. Seven weeks following transplant, TPI enzyme levels were within the normal reference range. The child developed waning chimerism concerning for graft failure, so underwent second allogenic unrelated HSCT at 21 months of age. The patient developed transfusion-dependent bone marrow aplasia, prompting rescue HSCT at 23 months of age. During hospitalization, the patient suffered respiratory failure and required tracheostomy. He developed truncal weakness and was unable to sit independently, crawl, or stand unsupported at discharge. At 6 years of age, he has slowly regained motor and developmental milestones via regular physical and occupational therapy. TPI enzyme levels have returned to normal reference range. In most recent follow-up, he can ambulate using a Gait trainer and kick a ball. He can speak using a PassyMuir valve, feed himself, use a pencil to write, and recently began toilet training.

Conclusions: This case demonstrates that HSCT can provide a permanent source of the TPI enzyme in the blood, reversing the hemolytic anemia and apparently halting further neurodegeneration. Routine pre- and post-transplant muscle biopsy would allow researchers to better understand the physiology associated with neurodegeneration. A multi-site clinical trial would provide the scale necessary to conclusively determine the degree to which enzyme replacement can salvage neurodevelopment.

 

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