Leukodystrophy Patients Research Articles

Applicability of multiple quantitative magnetic resonance methods in genetic brain white matter disorders.

Magnetic resonance imaging (MRI) measures of tissue microstructure are important for monitoring brain white matter (WM) disorders like leukodystrophies and multiple sclerosis. They should be sensitive to underlying pathological changes. Three whole-brain isotropic quantitative methods were applied and compared within a cohort of controls and leukodystrophy patients: two novel myelin water imaging (MWI) techniques (multi-compartment relaxometry diffusion-informed MWI: MCR-DIMWI, and multi-echo T2 relaxation imaging with compressed sensing: METRICS) and neurite orientation dispersion and density imaging (NODDI). For 9 patients with different leukodystrophies (age range 0.4-62.4 years) and 15 control subjects (2.3-61.3 years), T1-weighted MRI, fluid-attenuated inversion recovery, multi-echo gradient echo with variable flip angles, METRICS, and multi-shell diffusion-weighted imaging were acquired on 3 Tesla. MCR-DIMWI, METRICS, NODDI, and quality control measures were extracted to evaluate differences between patients and controls in WM and deep gray matter (GM) regions of interest (ROIs). Pearson correlations, effect size calculations, and multi-level analyses were performed. MCR-DIMWI and METRICS-derived myelin water fractions (MWFs) were lower and relaxation times were higher in patients than in controls. Effect sizes of MWF values and relaxation times were large for both techniques. Differences between patients and controls were more pronounced in WM ROIs than in deep GM. MCR-DIMWI-MWFs were more homogeneous within ROIs and more bilaterally symmetrical than METRICS-MWFs. The neurite density index was more sensitive in detecting differences between patients and controls than fractional anisotropy. Most measures obtained from MCR-DIMWI, METRICS, NODDI, and diffusion tensor imaging correlated strongly with each other. This proof-of-concept study shows that MCR-DIMWI, METRICS, and NODDI are sensitive techniques to detect changes in tissue microstructure in WM disorders.

Nuclear import carrier Hikeshi cooperates with HSP70 to promote murine oligodendrocyte differentiation and CNS myelination.

Dysregulation of factors in nucleocytoplasmic transport is closely linked to neural developmental diseases. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of heat shock protein 70 family (HSP70s), leads to inherited leukodystrophy; however, the pathological mechanisms remain elusive. Here, we showed that Hikeshi is essential for central nervous system (CNS) myelination. Deficiency of Hikeshi, which is observed in inherited leukodystrophy patients, resulted in murine oligodendrocyte maturation arrest. Hikeshi is required for nuclear translocation of HSP70s upon differentiation. Nuclear-localized HSP70 promotes murine oligodendrocyte differentiation and remyelination after white matter injury. Mechanistically, HSP70s interacted with SOX10 in the nucleus and protected it from E3 ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following invivo demyelinating injury. Overall, these findings demonstrate that Hikeshi-mediated nuclear translocation of HSP70s is essential for myelinogenesis and provide insights into pathological mechanisms of Hikeshi-related leukodystrophy.

Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.

RANSIP newborn screening program: Working to bring early diagnostics, inclusion, and therapeutic access to metachromatic leukodystrophy patients

RANSIP newborn screening program: Working to bring early diagnostics, inclusion, and therapeutic access to metachromatic leukodystrophy patients

Novel disease-causing variants in a cohort of Iranian patients with metachromatic leukodystrophy and in silico analysis of their pathogenicity

ObjectiveMetachromatic leukodystrophy (MLD) is an autosomal recessive leukodystrophy caused by deficiency of aryl sulfatase A (ASA) activity affecting the nervous system. MLD and mutations in ARSA have not been widely studied in non-European cohorts. The genotype-phenotype spectrum of MLD patients was investigated in this study of a cohort of Iranian leukodystrophy patients. In silico analysis was performed to investigate the pathogenicity of the variants. MethodsGenetic analysis for 25 patients was performed with direct sequencing of the ARSA gene. The missense variants underwent in silico analysis to characterize the pathogenicity based on predicted structural and stability changes. Results19 patients had variants in ARSA genes, including 18 homozygotes and one compound heterozygote individual. In 6 individuals no mutations were found in ARSA gene, suggesting an alternative cause of their leukodystrophy. We found 5 novel disease causing variants: p.Phe64Ile, p.Ser292Alafs*34, p.Arg99Profs*35, p.Phe400Leu and p.Leu429Pro. 32 % of the patients had p.Gly311Ser substitution and resulted in juvenile MLD type. Different in silico analysis showed variable pathogenic effect for the variants. Conclusionc.931 G > A (p.Gly311Ser) and c.465 + 1 G > A variants are the most frequent alleles among Iranian MLD patients and five mutations appear to be confined to the Iranian patients. Population screening for these variants may be helpful to reduce the burden of the disease in this part of the world.

Elevated Leukodystrophy Incidence Predicted From Genomics Databases

BackgroundLeukodystrophies are genetic diseases affecting the white matter and leading to early death. Our objective was to determine leukodystrophy incidence, using genomics sequencing databases allele frequencies of disease-causing variants. MethodsFrom 49 genes, representing the standardly defined group of leukodystrophies, we identified potential disease-causing variants from publications in the Human Genetic Mutation Database and from predictions in the Genome Aggregation Database. Allele frequencies were estimated from Genome Aggregation Database. Allele frequencies for each gene were summed to generate a super allele frequency and we used the Hardy-Weinberg equation to calculate overall expected live birth incidence associated with the gene in question. ResultsWe identified 4564 pathogenic variants for 25 discrete leukodystrophies. The largest effect was from GALC variants (Krabbe disease), which had a predicted incidence of one in 12,080 live births, 8.3 times higher than published estimates. The second most frequently predicted leukodystrophy was the RNA polymerase III–related disorders, which had an incidence of 1:26,160. Overall, we found a leukodystrophy incidence of 1 in 4733 live births, significantly higher than previous estimates. ConclusionsOur data are consistent with a significant underdiagnosis of leukodystrophy patients. An intriguing additional consideration is that there may be genetic modifiers that lead to weaker, absent, or adult-onset disease phenotypes.

Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction.

ObjectiveIn metachromatic leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted metachromatic leukodystrophy patients.MethodsAutopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) metachromatic leukodystrophy patients, and two age‐matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t‐test, linear regression or the nonparametric Mann–Whitney U‐test was performed to evaluate differences between the transplanted, nontransplanted, and control group.ResultsIn brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti‐inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in metachromatic leukodystrophy, we detected no enzymatic cross‐correction to resident astrocytes and oligodendrocytes.InterpretationIn conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross‐correction of oligo‐ and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.

Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency

To explore the candidate pathogenic gene in a premature ovarian insufficiency (POI) proband from a consanguineous marriage and detect the potential effects of mutation on cellular energy metabolism. Genetic and functional studies. Reproductive medicine center. A patient with POI, from a consanguineous family, and her family members were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University. Whole exome sequencing (WES) was performed for the proband. Variation revealed by WES sequencing was validated by Sanger sequencing in her family. Sequencing data were combined with those of other sporadic cases listed in public databases to identify the causative gene. Rare homozygous nonsynonymous variants were identified and included in subsequent analysis. Metabolic analyzes were performed using Seahorse XFe96 analyzers to measure oxygen consumption and then obtain further results of ATP production and extracellular acidification rate. The differences in energy metabolism measurements between wild type and mutation were analyzed and compared. A novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation (NM_020745: exon2: c.337G>C: p. G113R) was identified in the aminoacylation region using WES. The mutation was highly conserved among species and predicted to be disease causing. AARS2 encodes mitochondrial alanyl-tRNA synthetase, which attaches alanine onto tRNA-ala. AARS2 mutations were previously reported in female leukodystrophy patients with POI. In mitochondrial stress tests, the ATP productions of the mutation group (3.58 ± 0.46fmol/min/cell) was significantly lower than that of the wild type group (6.96 ± 1.56fmol/min/cell). This is the first report of a homozygous pathogenic AARS2 mutation in POI. This mutation may lead to incorrect aminoacylation of tRNA, affect mitochondrial translation, and cause oxidative phosphorylation defects, which may be responsible for POI.

P.071 Clinical and demographic predictors of stress in parents of children with genetically determined leukoencephalopathies

Background: Genetically-determined leukoencephalopathies comprise a rare group of inherited white matter disorders. The vast majority are associated with a progressive disease course and early death. This study seeks to determine the clinical and demographic correlates of stress in parents of leukodystrophy patients, for future clinical guidance. Methods: A cross-sectional study including 36 families was performed. Children aged 1 month to 12 years with a diagnosed leukodystrophy or genetically-determined leukoencephalopathy were included. 31 mothers and 24 fathers completed the Parental Stress Index, 4th edition (PSI-4). One demographic questionnaire was completed per family. Clinical data was gathered within 6 months of the questionnaires. Statistical analysis was performed with total stress (TS) scores as the primary outcome. Results: Mothers and fathers had comparable TS scores. No clinical or demographic factors predicted the father’s TS score. Greater ambulatory impairment, using the GMFCS scale, correlated to lower TS scores in the mother. Conclusions: The progressive nature of these conditions makes it such that anticipating a child’s inability to walk may cause more stress for mothers than a child’s actual inability to ambulate. The inability of all other variables to predict total stress highlights a need for individualized approaches when addressing stress in these families.

Bone marrow harvesting from paediatric patients undergoing haematopoietic stem cell gene therapy

Collection of an adequate amount of autologous haematopoietic stem progenitor cells (HSPC) is required for ex vivo manipulation and successful engraftment for certain inherited disorders. Fifty-seven paediatric patients (age 0.5–11.4 years) underwent a bone marrow harvest for the purpose of HSPC gene therapy (GT), including adenosine deaminase-severe combined immunodeficiency (ADA-SCID), Wiskott–Aldrich syndrome (WAS) and metachromatic leukodystrophy (MLD) patients. Total nucleated cells and the percentage and absolute counts of CD34+ cells were calculated at defined steps of the procedure (harvest, CD34+ cell purification, transduction with the gene transfer vector and infusion of the medicinal product). A minimum CD34+ cell dose for infusion was 2 × 106/kg, with an optimal target at 5–10 × 106/kg. Median volume of bone marrow harvested was 34.2 ml/kg (range 14.2–56.6). The number of CD34+ cells collected correlated inversely with weight and age in all patients and particularly in the MLD children group. All patients reached the minimum target dose for infusion: median dose of CD34+ cells/kg infused was 10.3 × 106/kg (3.7–25.9), with no difference among the three groups. Bone marrow harvest of volumes > 30 ml/kg in infants and children with ADA-SCID, WAS and MLD is well tolerated and allows obtaining an adequate dose of a medicinal product for HSPC-GT.

Cell Replacement Therapy Improves Pathological Hallmarks in a Mouse Model of Leukodystrophy Vanishing White Matter.

SummaryStem cell therapy has great prospects for brain white matter disorders, including the genetically determined disorders called leukodystrophies. We focus on the devastating leukodystrophy vanishing white matter (VWM). Patients with VWM show severe disability and early death, and treatment options are lacking. Previous studies showed successful cell replacement therapy in rodent models for myelin defects. However, proof-of-concept studies of allogeneic cell replacement in models representative of human leukodystrophies are lacking. We tested cell replacement in a mouse model representative of VWM. We transplanted different murine glial progenitor cell populations and showed improved pathological hallmarks and motor function. Improved mice showed a higher percentage of transplanted cells that differentiated into GFAP+ astrocytes, suggesting best therapeutic prospects for replacement of astroglial lineage cells. This is a proof-of-concept study for cell transplantation in VWM and suggests that glial cell replacement therapy is a promising therapeutic strategy for leukodystrophy patients.

Scope and Burden of Non-Standard of Care Hematopoietic Stem Cell Transplantation in Pediatric Leukodystrophy Patients.

Inherited leukodystrophies are a group of diseases affecting central nervous system myelin that lead to death or significant health problems. Although for most leukodystrophies there are no curative treatments, for a handful of diseases hematopoietic stem cell transplantation (HSCT; bone marrow transplant) can stop disease progression, and if initiated in a timely fashion, prevent many or all neurologic and other systems involvement. However, HSCT is a complex procedure with significant morbidity and mortality risks. The study goal was to determine whether HSCT was being more widely used outside of those leukodystrophies for which HSCT is typically employed. The authors conducted a 2-year retrospective review of HSCT performed across the United States in 51 children's hospitals that are part of the Pediatric Health Information System. The authors screened for 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes for leukodystrophies in which HSCT is "nonstandard," including sphingolipidoses, Fabry disease, Gaucher disease, and Niemann-Pick disease, and excluded patients who had ICD-10 codes for leukodystrophies that are HSCT candidates, specifically X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, and Hurler disease. The authors identified 91 patients (from a total cohort of 937) with one of the nonstandard leukodystrophies who had HSCT. HSCT was performed at 20 of the hospitals, with the majority performed at only 6 hospitals. Average costs ($786 846) per patient were more than 6 times higher than patients who did not have HSCT. The data show that an unexpectedly large number of leukodystrophy patients are receiving transplants for conditions in which HSCT is not typically used, and which are associated with high medical costs.

Update on Leukodystrophies: A Historical Perspective and Adapted Definition.

Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

P.004 Endocrine and growth abnormalities in 4H leukodystrophy patients with a molecular diagnosis

Background: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder characterized by hypomyelination, hypodontia and hypogonadotropic hypogonadism caused by mutations in POLR3A, POLR3B and POLR1C. The endocrine abnormalities have never been systematically studied. Methods: A cross sectional international multicenter study was performed and the following variables were assessed: weight, height, head circumference, pubertal history, hormone levels and neurological and non-neurological features. Data was analyzed to determine whether there was a correlation between the presence of endocrine abnormalities and mutations in a specific gene and/or the presence of specific symptoms such as other non-neurological symptoms. Results: Data was collected on 156 patients. Endocrine data were available for 144 patients. The most common endocrine abnormalities seen in this cohort were short stature (54/90 patients (60%)) and delayed puberty (53/70 patients (76%)). 13 of the 58 patients tested (22%) had abnormal thyroid function. Patients with POLR3A mutations were more likely to have endocrine abnormalities. Conclusions: Our results confirm that the most common endocrine features in 4H leukodystrophy are short stature and pubertal abnormalities. However, the other potential endocrine abnormalities are typically under-investigated in this patient population. A prospective study is required to investigate the extent and severity of the endocrine abnormalities in 4H leukodystrophy.

Targeted leukodystrophy diagnosis based on charges and yields for testing.

Inherited leukodystrophies are a group of neurological disorders with significant morbidity and mortality. Children and their families can experience lengthy diagnostic odysseys; however, there is no data on the charges related to testing for diagnosis in leukodystrophy patients, compared to approaches using next-generation sequencing (NGS). Our objective was to determine charges related to the determination of diagnosis, and overall yield of diagnostic testing, for leukodystrophy patients. We determined and quantified all inpatient and outpatient lab testing, including brain MRIs, obtained for the purpose of diagnosis, in a retrospective population cohort of children with inherited leukodystrophies. Each patient had average charges of $8,231 (range $543-26,437) for diagnostic testing. Overall charges related to diagnosis for the entire cohort was $526,794. A final etiological diagnosis was determined in 34% of patients. In those in whom a specific diagnosis was determined, average time to diagnosis was 1.4 years. If NGS on the entire cohort had been performed instead, charges would have been ∼$359,600 (at $5,800/patient). Alternatively, a two-tier approach consisting of first, biochemical testing (serum very-long chain fatty acids and leukocyte lysosomal enzyme testing), and then with NGS for remaining undiagnosed patients, would have resulted in total cohort charges of $361,309. We have determined the charges directly associated with diagnostic testing in a population cohort of children with leukodystrophy. We conclude that appropriately incorporating NGS into diagnostic algorithms could lower charges; reduce time to diagnosis; and reduce amount of testing.

Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation.

The accuracy of mitochondrial protein synthesis is dependent on the coordinated action of nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mtARSs) and the mitochondrial DNA-encoded tRNAs. The recent advances in whole-exome sequencing have revealed the importance of the mtARS proteins for mitochondrial pathophysiology since nearly every nuclear gene for mtARS (out of 19) is now recognized as a disease gene for mitochondrial disease. Typically, defects in each mtARS have been identified in one tissue-specific disease, most commonly affecting the brain, or in one syndrome. However, mutations in the AARS2 gene for mitochondrial alanyl-tRNA synthetase (mtAlaRS) have been reported both in patients with infantile-onset cardiomyopathy and in patients with childhood to adulthood-onset leukoencephalopathy. We present here an investigation of the effects of the described mutations on the structure of the synthetase, in an effort to understand the tissue-specific outcomes of the different mutations. The mtAlaRS differs from the other mtARSs because in addition to the aminoacylation domain, it has a conserved editing domain for deacylating tRNAs that have been mischarged with incorrect amino acids. We show that the cardiomyopathy phenotype results from a single allele, causing an amino acid change R592W in the editing domain of AARS2, whereas the leukodystrophy mutations are located in other domains of the synthetase. Nevertheless, our structural analysis predicts that all mutations reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation. According to our model, the cardiomyopathy mutations severely compromise aminoacylation whereas partial activity is retained by the mutation combinations found in the leukodystrophy patients. These predictions provide a hypothesis for the molecular basis of the distinct tissue-specific phenotypic outcomes.

Hematopoietic Stem Cell Transplantation in the Leukodystrophies: A Systematic Review of the Literature

The objective of this study is to systematically review the literature on worldwide numbers of leukodystrophy patients undergoing hematopoietic stem cell transplantation (HSCT) as well as the safety and efficacy of the procedure in this patient population. A PubMed and EMBASE search up to June 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. The effect estimates of HSCT upon survival in early-stage disease versus late-stage disease were compared. One hundred and fifty-two studies qualified for inclusion and reported on a total of 689 patients. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Meta-analysis in a subset of larger studies indicates that transplantation in earlier stages of disease fairs better than in the late stages. Beyond survival, little longitudinal data on functional outcome is reported and neurological outcome is sparse. Further studies are needed to determine the neurological outcome following HSCT in the leukodystrophies. HSCT in the early stages of cerebral disease is still recommended for select leukodystrophies.

Quantification of sulfatides in dried blood and urine spots from metachromatic leukodystrophy patients by liquid chromatography/electrospray tandem mass spectrometry

BackgroundTreatments are being developed for metachromatic leukodystrophy (MLD), suggesting the need for eventual newborn screening. Previous studies have shown that sulfatide molecular species are increased in the urine of MLD patients compared to samples from non-MLD individuals, but there is no data using dried blood spots (DBS), the most common sample available for newborn screening laboratories. MethodsWe used ultra-high performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) to quantify sulfatides in DBS and dried urine spots from 14 MLD patients and 50 non-MLD individuals. ResultsSeveral sulfatide molecular species were increased in dried urine samples from all MLD samples compared to non-MLD samples. Sulfatides, especially low molecular species, were increased in DBS from MLD patients, but the sulfatide levels were relatively low. There was good separation in sulfatide levels between MLD and non-MLD samples when dried urine spots were used, but not with DBS, because DBS from non-MLD individuals have measurable levels of sulfatides. ConclusionSulfatide accumulation studies in urine, but not in DBS, emerges as the method of choice if newborn screening is to be proposed for MLD.

Outcomes Of Allogeneic Cord Blood Transplantation For Leukodystrophies; A Joint Study of Eurocord and “Inborn Errors WP-EBMT”

BackgroundThis study aims to describe transplant outcomes and disease-specific clinical outcomes of allogeneic cord blood transplantation (CBT) in leukodystrophies. Leukodystrophies are rare inborn errors of metabolism (IEM) in which the development and maintenance of brain myelin is primarily affected. They are characterized by rapid neurological deterioration. Hematopoietic stem cell transplantation (HSCT) has been shown to halt disease progression for selected leukodystrophies, including adrenoleukodystrophy (ALD), Krabbe disease (globoid cell leukodystrophy) and metachromatic leukodystrophy (MLD). The fast availability of unrelated cord blood (UCB) makes HSCT feasible in leukodystrophy patients who lack an HLA-matched sibling. Patients and methodsAll patients transplanted for leukodystrophies with related and unrelated umbilical cord blood in EBMT centers between 1996 and 2012 were included. HSCT data were collected from the EUROCORD database. An additional questionnaire on disease-specific clinical outcomes was sent to participating centers. Included in the questionnaire were enzyme- and (for ALD) fatty acid levels, general disease status, performance score, MRI/MRS status, peripheral neuropathy, school attendance and performance, mental development testing, adrenal insufficiency (for ALD only), vision and hearing. Kaplan-Meier estimates were used to calculate overall survival (OS) and cumulative incidence methods for secondary outcomes, including neutrophil and platelet engraftment, incidence of graft-versus-host disease (GvHD), donor chimerism and disease-specific characteristics at most recent follow-up. The two-sided log-rank test was used for univariate comparisons. ResultsSeventy patients (31 ALD, 5 Krabbe, 34 MLD) were available for analysis, with a median age at transplant of 6.5 years (range 0-43 years). Median follow-up for survivors was 46 months. Overall survival at 4 years was 60% (±6%). Cumulative incidences of neutrophil and platelet engraftment were 88% (±4%) at day 60, and 73% (±6%) at day 180, respectively. Ten patients experienced graft failure and 5 had autologous recovery; 4 received a 2nd HSCT (2 CBT, 1 Haplo, 1 BM) and of those 3 were alive in a median of 60 months after HSCT. Acute-GvHD (grade II-IV) occurred in 16 patients (22% ±5%) at day 100 and chronic GvHD in 9 patients (13% ±5%). Out of the 24 patients who died, 18 (67%) died of transplant-related causes and 6 (33%) died of disease progression. Higher survival was seen in patients who had no or 1 HLA mismatch (OS 81%), compared to patients who received UCBT with 2 HLA mismatches (OS 47%, p 0.02).On 37 patients (53%), information on disease-specific characteristics was available. OS among these patients was 68% (±8), which was not significantly different from patients without disease-specific information (p=0,307). Of the 37 patients, 19 (51%) were asymptomatic at transplant, 14 (38%) had mild disease and 4 (11%) were severely affected. Overall survival was dramatically worse in patients with severe disease at transplant; all 4 severely affected patients died, while 79% of patients with mild disease and 76% of asymptomatic patients survived. At most recent follow-up, disease status was stable in 15 (57.7%), had improved in 2 (7.7%) and worsened in 9 (34.6%) surviving patients. The majority of patients showed abnormalities on MRI-scanning pre-HSCT (n=25, 68%). In patients with normal MRI-scans pre-transplant OS was 69%; in patients with abnormal MRI-scans 75%. At most recent follow-up, MRI-scans were stable in 12 (43.9%), improved in 5 (17.8%) and worsened in 11 (39.3%) patients. Eighteen patients (50%) showed peripheral neuropathy pre-HSCT, of which 13 were mildly affected and 5 severely affected. Of patients who had no signs of peripheral neuropathy pre-HSCT, 70% survived, versus 77% of patients who were mildly affected and 40% of those severely affected. At most recent follow-up, peripheral neuropathy was stable in 14 (56%), had improved in 3 (12%) and worsened in 8 (32%) patients. ConclusionWe found an overall survival of 60% at 4 years after CBT for leukodystrophies, with relatively low rates of GvHD. Use of a mismatched donor (>1 HLA mismatch) negatively impacts survival. Data on clinical characteristics suggest that overall survival is strongly influenced by disease status at transplant. Disclosures:No relevant conflicts of interest to declare.

National Variation in Costs and Mortality for Leukodystrophy Patients in US Children's Hospitals

Inherited leukodystrophies are progressive, debilitating neurological disorders with few treatment options and high mortality rates. Our objective was to determine national variation in the costs for leukodystrophy patients and to evaluate differences in their care. We developed an algorithm to identify inherited leukodystrophy patients in deidentified data sets using a recursive tree model based on International Classification of Disease, 9th Edition, Clinical Modification, diagnosis and procedure charge codes. Validation of the algorithm was performed independently at two institutions, and with data from the Pediatric Health Information System (PHIS) of 43 US children's hospitals, for a 7-year period between 2004 and2010. A recursive algorithm was developed and validated, based on six International Classification of Disease, 9th Edition, Clinical Modification, codes and one procedure code that had a sensitivity up to 90% (range 61-90%) and a specificity up to 99% (range 53-99%) for identifying inherited leukodystrophy patients. Inherited leukodystrophy patients comprise 0.4% of admissions to children's hospitals and 0.7% of costs. During 7 years, these patients required $411 million of hospital care, or $131,000/patient. Hospital costs for leukodystrophy patients varied at different institutions, ranging from two to 15 times more than the average pediatric patient. There was a statistically significant correlation between higher volume and increased cost efficiency. Increased mortality rates had an inverse relationship with increased patient volume that was not statistically significant. We developed and validated a code-based algorithm for identifying leukodystrophy patients in deidentified national datasets. Leukodystrophy patients account for $59 million of costs yearly at children's hospitals. Our data highlight potential to reduce unwarranted variability and improve patient care.