Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.

A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).

Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 109/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.

Management of mucopolysaccharidosis type IH (Hurler's syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution's experience.

Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy.

BACKGROUND: Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown. DESIGN AND METHODS: We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. RESULTS: High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. CONCLUSIONS: We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.

Sustained response to intrathecal rituximab in EBV associated Post-transplant lymphoproliferative disease confined to the central nervous system following haematopoietic stem cell transplant.

Post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS) is a very rare complication of haematopoietic stem cell transplant (HSCT) and has a dismal prognosis. We report the successful treatment of this disorder with intrathecal rituximab therapy in two children who developed isolated CNS PTLD after HSCT. These children had failed to respond to standard chemotherapy, intravenous rituximab and EBV specific cellular therapy.

Pseudohyperkalaemia associated with leukaemic cell lysis during pneumatic tube transport of blood samples.

BACKGROUND: Pseudohyperkalaemia is relatively uncommon in children, but needs to be considered in cases where extreme hyperkalaemia is associated with normal renal function. CASE: A previously well 12 year-old boy presented with new onset T cell acute lymphoblastic leukaemia associated with a high peripheral blood white cell count. Plasma biochemistry tests on a blood sample sent to the laboratory using a pneumatic tube system showed a high plasma potassium level of 16.6 mmol/l, with otherwise normal electrolytes and renal function. A 12-lead electrocardiogram was normal, with no changes suggestive of hyperkalaemia. Pseudohyperkalaemia was suspected, and further samples transported to the laboratory by foot showed normal plasma potassium levels. It was subsequently demonstrated that the pseudohyperkalemia was due to the lysis of leukaemic white cells during the transport of blood samples from the ward to the laboratory within the pneumatic tube system. CONCLUSIONS: Paediatricians caring for children with haematological malignancies need to be aware of this cause of pseudohyperkalaemia so that unnecessary treatment, including the commencement of acute dialysis, is avoided. We recommend that blood samples collected from children with high white cell count malignancies are transported to the laboratory by foot rather than in pneumatic tube systems.

Hemophagocytosis by leukemic megakaryoblasts in acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13);RBM15-MKL1.

Acute megakaryoblastic leukemia is a rare variant of acute myeloid leukemia, whereby leukemic blasts display characteristic morphologic and phenotypic features indicating megakaryocytoid differentiation. A distinct entity characterized by the t(1;22)(p13;q13) translocation, resulting in the RBM15-MKL1 fusion oncogene, has been recently recognized. This is predominantly a disease afflicting infants and displays characteristic clinical features. We present a case of acute megakaryoblastic leukemia with t(1;22)(p13;q13) along with a discussion of the current understanding of the molecular biology of RBM15-MKL1. This case also displayed striking and unusual morphologic appearances including extensive hemophagocytosis by leukemic blasts, which has not been previously reported for this particular type of leukemia.

Successful allogeneic bone marrow transplant for Niemann-Pick disease type C2 is likely to be associated with a severe 'graft versus substrate' effect.

Niemann-Pick disease type C2 (NPC2) is caused by the inherited deficiency of a lysosomal cholesterol transport protein, NPC2 protein. Many cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. This disease is theoretically correctable by bone marrow transplantation (BMT), as the NPC2 protein is small and soluble and secreted and recaptured by the mannose-6-phosphate pathway. In this report we describe the first successful allogeneic bone marrow transplantation for this condition in a 16-month-old boy homozygous for the NPC2 p.E20X mutation, which has hitherto been reported to cause disease with a severe phenotype. During BMT there was an initial improvement of the established respiratory illness, with the immune suppression associated with transplant conditioning, but there was subsequent marked deterioration at the time of immune reconstitution and donor cell engraftment. This 'graft versus substrate' reaction was managed with intensive immune suppressant therapy, and it gradually resolved as the substrate was cleared by the engrafted donor macrophages. All immune suppression was withdrawn 18 months after transplantation, and his respiratory illness has resolved. He walked independently at 24 months and is continuing to reach development milestones after receiving his transplant. We conclude that the successful treatment of Niemann-Pick C2 therefore seems likely to be associated with a severe post-transplantation 'graft versus substrate' reaction that requires intense immune suppression before eventual resolution.