Unrelated Donor BMT for Treatment of Patients With PGK Deficiency
Condition: Phosphoglycerate Kinase (PGK) Deficiency
Study type: Interventional

Summary: 
      Phosphoglycerate kinase (PGK) deficiency is a rare x-linked disorder characterized by
      hemolytic anemia, seizures, muscle fatigue, and progressive neurological dysfunction. The
      disease is caused by the deficiency of PGK, an enzyme required for ATP formation through the
      glycolytic pathway. PGK is an enzyme that is ubiquitous to all cells of the human body, but
      red blood cells, muscles, and nerve cells are most severely affected by the absence of PGK
      due to their reliance upon the glycolytic pathway. Mutations of the PGK gene are highly
      variable and result in diverse phenotypes, ranging from mild hemolytic anemia only to severe
      mental retardation and early death in childhood. The more severe phenotypes show progressive
      neurologic deterioration between infancy and adolescence.

      This is a 2 patient study aimed at studying the role of stem cell transplant in PGK
      deficiency. Because the disease is so rare, the study will be limited to the 2 sibling
      patients followed by our group, though it would be open to other participants who would meet
      inclusion/exclusion criteria if such presented to us. The objective of this study is to
      evaluate the feasibility and efficacy of stem cell transplants to treat patients with PGK
      deficiency, Amiens subtype.
    

Detailed description: 
      Phosphoglycerate kinase (PGK) deficiency is a rare x-linked disorder characterized by
      hemolytic anemia, seizures, muscle fatigue, and progressive neurological dysfunction. The
      disease is caused by the deficiency of PGK, an enzyme required for ATP formation through the
      glycolytic pathway. PGK is an enzyme that is ubiquitous to all cells of the human body, but
      red blood cells, muscles, and nerve cells are most severely affected by the absence of PGK
      due to their reliance upon the glycolytic pathway. Mutations of the PGK gene are highly
      variable and result in diverse phenotypes, ranging from mild hemolytic anemia only1 to severe
      mental retardation and early death in childhood.2-5 The more severe phenotypes show
      progressive neurologic deterioration between infancy and adolescence.2,3,5 PGK-Amiens refers
      to a particular mutation that is an A to T transversion, which predicts an amino acid change
      of aspartate (Asp: GAT) to valine (Val: GTT) at the 164th position from the NH2-terminal
      methionine residue. This D164V mutation has been identified previously as PGK-Amiens or
      PGK-New York in a French and in a Chinese family respectively.3,6 This particular mutation
      results in the most severe phenotype. All 6 of the boys described in the literature with this
      mutation have had progressive neurologic decline, seizures, episodes of hemiplegia, aphasia,
      emotional lability, and severe hemolytic crises. Two of the boys died in childhood, 2 are
      institutionalized with no ability to communicate or provide self-care, and 2 are moderately
      mentally retarded with seizures and hemolytic anemia. The two brothers cared for at this
      institution have the Amiens variant of PGK deficiency.

      Allogeneic bone marrow transplantation (BMT) became feasible in the 1960s after elucidation
      of the Human Leukocyte Antigen (HLA) complex. Since then, the therapy has evolved into an
      effective therapy for many hematologic disorders(7). Otherwise incurable malignancies are
      frequently cured by this approach, with the likelihood of cure ranging from 10% to 85%,
      depending on the disease and disease-status. The treatment strategy incorporates very large
      doses of chemotherapy and often radiation to eliminate malignant cells and to immunosuppress
      the recipient enough to allow engraftment of donor cells. Donor cells give rise to
      hematopoiesis within two to three weeks, rescuing the patient from the effects of high dose
      therapy. In the ideal circumstance, immune recovery and recipient-specific tolerance occurs
      over the following 6-18 months, and the patient is cured of his or her underlying hematologic
      disorder, off of immunosuppression, with a functionally intact donor-derived immune system.
      However, complications of the process are common and include potentially permanent or fatal
      organ damage from the effects of high dose chemotherapy, infection, hemorrhage, and, in
      particular, graft-versus-host-disease. A realistic estimate of transplant-related mortality,
      including deaths due to acute and chronic graft-versus-host diseases, in the standard
      HLA-matched sibling setting is as high as 25%. The risk of treatment related mortality thus
      limits the success of the approach even in younger patients and certainly precludes its use
      in older patients. Thus, particularly for older patients, new strategies in transplantation
      are needed.

      Stem cells for allogeneic transplant are traditionally obtained from one of three sources:
      bone marrow (1), peripheral blood stem cells mobilized by provision of the growth factor GCSF
      (2), or umbilical cord blood (3). Each source has specific advantages and disadvantages. The
      desired source of stem cells for allogeneic transplant is a matched sibling donor. However,
      if that is not feasible, a matched unrelated donor can be sought through the National Marrow
      Donor Program (NMDP). The National Marrow Donor Program (NMDP) in Minneapolis, Minnesota, was
      established in 1986 to facilitate the search for, and procurement of, HLA-matched marrow from
      volunteer, unrelated marrow donors for patients with life-threatening diseases curable by SCT
      (7). The NMDP network consists of 99 donor centers, 108 collection centers, 150 transplant
      centers and a Coordinating Center in Minneapolis. As of June 29, 2003, the NMDP had a
      registry of 5,032,382 volunteer marrow donors and 28,574 cord blood units stored, and had
      facilitated 13,213 unrelated marrow transplants (marrow, PBSC and cord blood) worldwide. Over
      600,000 donors in the NMDP Registry are contributed by European registries, which are
      affiliated with the NMDP. In addition, approximately 1 million donors are available by
      searching NMDP International Cooperative Registries in Europe, South America, and Asia. On
      average, searching patients have a 75% chance of finding a match within the NMDP, with a
      median time from search to transplant of less than 6 months. Vanderbilt University Medical
      Center is a NMDP approved aphaeresis center, collection center and transplant center and
      adheres to the policies and procedures of the NMDP as outlined in The 18th Edition of the
      NMDP Standards (effective since September 13th, 2002, implemented February 10th, 2003).

      Stem cell transplantation (SCT) has been performed in children with various metabolic
      diseases, including mucopolysaccharide disorders (MPS), leukodystrophies, and glycoprotein
      metabolic disorders.8 The prototypical metabolic disorder for SCT is Hurler syndrome, or MPS
      IH. Hurler syndrome results from the lack of a lysosomal enzyme needed to degrade
      glycosaminoglycans, which then build up and cause progressive intellectual decline,
      hepatosplenomegaly, cardiac valvular disease, airway abnormalities, and skeletal
      abnormalities. SCT performed early in the disease process leads to enzyme replacement and
      stops progression of disease.9 SCT has helped other MPS disorders including severe
      Maroteaux-Lamy syndrome and Sly syndrome, but unfortunately, and for reasons not well
      understood, SCT has not helped in several other MPS disorders, such as Hunter, Sanfilippo,
      and Morquio syndromes.8 X-linked adrenoleukodystrophy is a disease that affects boys with
      variable degrees of severity. When boys show early MRI changes and undergo SCT, outcome is
      very good, with preservation of neurological and neurocognitive function.10,11 Other
      leukodystrophies that respond to early SCT include Krabbe disease and metachromatic
      leukodystrophy.8,12 Glycoprotein metabolic disorders are exceedingly rare and thus there is
      limited experience with SCT in patients with these disorders. There have been successful
      outcomes in preservation of cognitive function in α-mannosidosis,13 fucosidosis,14 Batten
      disease,15 and Gaucher disease Type I.16 SCT has not been able to salvage children with Fabry
      disease, Tay Sachs disease, Pompe disease, and Sandhoff disease.8 Again, it is poorly
      understood why SCT is able to stop neurologic decline in some metabolic disorders and not
      others.

      Definitive therapy for PGK deficiency necessarily involves production of the PGK enzyme. The
      hemolytic anemia that is part of this disease could be cured by allogeneic stem cell
      transplant, as replacing the hematopoietic system would ensure production of the enzyme in
      the red blood cells. However, the neurologic complications of the disease would require that
      the enzyme can find its way into the neurons themselves. Because of the rarity of PGK
      deficiency, there has been as yet no controlled study to define the most efficacious
      approach. In fact, there is no mention of any therapy in the literature. There is currently
      no enzyme replacement therapy and no major research effort underway to do so. To our
      knowledge, stem cell transplant in this disease has not been performed except for in one 7
      month old child with PGK-Amiens in Australia, who is currently being prepared for SCT. The
      stem cell source will be determined by the donor availability. The donor registry allows the
      donor the option of donating either peripheral blood or bone marrow.

      (Please note all reference numbers refer to the Reference list of the study protocol, pages 9
      and 10.)
    

Intervention name(s): Unrelated Donor BMT
Intervention type(s): Procedure
Intervention description(s): Unrelated donor bone marrow transplantation has not been performed with these patients in the past
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment