Early Infantile Krabbe Disease Research Articles

Early Infantile Krabbe Disease Due To a Novel Compound Heterozygous Mutation in a Tunisian Family

Krabbe disease is a rare lysosomal storage illness caused by a mutation in the Galc gene. It characterized by severe neurological and metabolic disorders. The early infantile form is the most common. Regardless of the non-specific signs, diagnosis could be challenging. Over time, novel gene variants are uncovered.

Early transgene expression of GALC enzyme in a phase I/II safety, tolerability and efficacy study of PBKR03 in infants with early infantile Krabbe disease (EIKD) (GALax-C)

Early transgene expression of GALC enzyme in a phase I/II safety, tolerability and efficacy study of PBKR03 in infants with early infantile Krabbe disease (EIKD) (GALax-C)

A Roadmap for Potential Improvement of Newborn Screening for Inherited Metabolic Diseases Following Recent Developments and Successful Applications of Bivariate Normal Limits for Pre-Symptomatic Detection of MPS I, Pompe Disease, and Krabbe Disease.

The mucopolysaccharidoses (MPS), Pompe Disease (PD), and Krabbe disease (KD) are inherited conditions known as lysosomal storage disorders (LSDs) The resulting enzyme deficiencies give rise to progressive symptoms. The United States Department of Health and Human Services' Recommended Uniform Screening Panel (RUSP) suggests LSDs for inclusion in state universal newborn screening (NBS) programs and has identified screening deficiencies in MPS I, KD, and PD NBS programs. MPS I NBS programs utilize newborn dried blood spots and assay alpha L-iduronidase (IDUA) enzyme to screen for potential cases. Glycosaminoglycans (GAGs) offer potential as a confirmatory test. KD NBS programs utilize galactocerebrosidase (GaLC) as an initial test, with psychosine (PSY) activity increasingly used as a confirmatory test for predicting onset of Krabbe disease, though with an excessive false positive rate. PD is marked by a deficiency in acid α-glucosidase (GAA), causing increased glycogen, creatine (CRE), and other biomarkers. Bivariate normal limit (BVNL) methods have been applied to GaLC and PSY activity to produce a NBS tool for KD, and more recently, to IDUA and GAG activity to develop a NBS tool for MPS I. A BVNL tool based on GAA and CRE is in development for infantile PD diagnosis. Early infantile KD, MPS I, and PD cases were pre-symptomatically identified by BVNL-based NBS tools. This article reviews these developments, discusses how they address screening deficiencies identified by the RUSP and may improve NBS more generally.

Making Decisions About Krabbe Disease Newborn Screening.

Making Decisions About Krabbe Disease Newborn Screening.

A phase 1/2 open-label, multicenter, dose ranging and confirmatory study to assess the safety, tolerability and efficacy of PBKR03 administered to pediatric subjects with early infantile Krabbe disease (globoid cell leukodystrophy; GALax-C)

A phase 1/2 open-label, multicenter, dose ranging and confirmatory study to assess the safety, tolerability and efficacy of PBKR03 administered to pediatric subjects with early infantile Krabbe disease (globoid cell leukodystrophy; GALax-C)

Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease

ObjectiveTo provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD). MethodsKD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD. ResultsInfants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%. ConclusionThe KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.

Rare Saposin A deficiency: Novel variant and psychosine analysis

Saposin A is a post-translation product of the prosaposin (PSAP) gene that serves as an activator protein of the galactocerebrosidase (GALC) enzyme, and is necessary for the degradation of certain glycosphingolipids. Deficiency of saposin A leads to a clinical picture identical to that of early-infantile Krabbe disease caused by GALC enzyme deficiency. Galactosylsphingosine, also known as psychosine, is a substrate of the GALC enzyme that is known to be elevated in classic Krabbe disease. We present the case of an 18-month-old male with clinical and radiological findings concerning for Krabbe disease who had preserved GALC enzyme activity and negative GALC gene sequencing, but was found to have a homozygous variant, c.257 T > A (p.I86N), in the saposin A peptide of PSAP. Psychosine determination on dried blood spot at 18 months of age was elevated to 12 nmol/L (normal <3 nmol/L). We present this case to add to the literature on the rare diagnosis of atypical Krabbe disease due to saposin A deficiency, to report a novel presumed pathogenic variant within PSAP, and to suggest that individuals with saposin A deficiency may have elevated levels of psychosine, similar to children with classic Krabbe disease due to GALC deficiency.

Ethical issues with testing and treatment for Krabbe disease.

Early-infantile Krabbe disease (EIKD) is an autosomal recessive, progressive, neurodegenerative disorder that usually leads to death in infancy. A study published in 2005 indicated that hematopoietic stem-cell transplantation (HSCT) was effective in the treatment for EIKD when used before the onset of symptoms. This finding suggested that newborn screening for EIKD, which would allow earlier diagnosis, might lead to earlier treatment and better outcomes. In 2006, New York was the first state to implement newborn screening for Krabbe disease; however, the results were not as good as proponents had hoped. In this paper, we present the history of efforts to diagnose and treat EIKD. Based on our findings, we question the efficacy of newborn screening for Krabbe disease. We present two arguments. First, testing itself is too imprecise. Even with the most rigorous testing standards, such as those used in New York, many of the children who are identified as being 'at risk' for EIKD remain asymptomatic. It is unclear if they will remain asymptomatic forever and, thus, whether the tests should be considered 'false positives', or whether they will eventually develop the disease. Second, we question the efficacy of early HSCT. We recommend placing a moratorium on mandatory newborn screening for EIKD. WHAT THIS PAPER ADDS: Current tests to identify which children are likely to develop Krabbe diseased are inadequate. Many children identified as being 'at risk' for early infantile Krabbe disease remain asymptomatic. Psychosine appears to be more specific than low galactosylceramidase levels for diagnosing early infantile Krabbe disease.

Diffuse Cranial Nerve Involvement in a Patient With Early Infantile Krabbe Disease

Diffuse Cranial Nerve Involvement in a Patient With Early Infantile Krabbe Disease

Long-Term Functional Outcomes after Hematopoietic Stem Cell Transplant for Early Infantile Krabbe Disease

Allogeneic hematopoietic stem cell transplantation (HSCT) can retard the progression of early infantile Krabbe disease (EIKD). Superior outcomes are achieved if HSCT is performed before the onset of symptoms; however, little information is available about the long-term outcomes in surviving patients. We now describe functional outcomes in presymptomatic infants who underwent HSCT for EIKD at ≤ 2 months of age. Records of the 19 patients who underwent HSCT for EIKD at ≤ 2 months of age from 1996 to 2010 were reviewed. Long-term functional outcomes were compared between those transplanted at < 30 days and ≥ 30 days of life. Median age at transplant was 27 days (range, 19 to 61). Median follow-up of the cohort was 12.6 years. Overall survival at 5 and 10 years post-transplant was 84.2% (95% confidence interval, 58.7% to 94.6%) and 78.6% (95% confidence interval, 52.5% to 91.4%), respectively. More favorable outcomes were seen in patients who underwent HSCT at < 30 days of age, particularly in domains of mobility (P = .01), communication (P = .02), and feeding (P = .008). Improved functional outcomes were observed when HSCT was performed in the first month of life, defining a critical period for intervention. These results support the implementation of newborn screening to enable rapid diagnosis and early treatment of infants with EIKD.

A comparison of three proposed methods of newborn screening for early infantile Krabbe disease

Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features.37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa.Median liver stiffness was 4.6 [3–15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis.Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.

Developmental outcomes of cord blood transplantation for Krabbe disease: A 15-year study.

To describe long-term outcomes of children with early-infantile Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) in the first 7 weeks of life. In this prospective longitudinal study, evaluations performed at baseline and follow-up included brain imaging, neurodiagnostic tests, and neurobehavioral evaluations. Of the 18 patients in this study (11 girls, 7 boys; mean follow-up 9.5 years, range 4-15), 5 died (3 of peritransplant complications, 1 of a surgical complication unrelated to Krabbe disease, 1 of disease progression). One of the surviving patients has normal cognitive function and 10 continue to develop cognitive skills at a slightly slower rate than normal. All surviving patients continue to gain receptive language skills, with 7 falling within the normal range. Ten patients receive speech therapy, and 2 of these patients require augmentative communication devices. Gross motor development varies widely, but 3 patients can walk independently, and 7 walk with assistive devices. Spasticity ranges from mild to severe, and 12 patients wear orthotics. Fine motor skills are generally preserved. Brain myelination and atrophy stabilized in 8 patients, improved in 4 patients, and worsened in 1 patient. Nerve conduction velocities initially improved but continue to be abnormal in most patients. The surviving patients function at a much higher level than untreated children or symptomatic children who underwent HSCT. These results show that early HSCT changes the natural history of this disease by improving both lifespan and functional abilities. This study provides Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improves lifespan and functional abilities.

Newborn screening for Krabbe's disease.

Live newborn screening for Krabbe's disease (KD) was initiated in New York on August 7, 2006, and started in Missouri in August, 2012. As of August 7, 2015, nearly 2.5 million infants had been screened, and 443 (0.018%) infants had been referred for followup clinical evaluation; only five infants had been determined to have KD. As of August, 2015, the combined incidence of infantile KD in New York and Missouri is ∼1 per 500,000; however, patients who develop later-onset forms of KD may still emerge. This Review provides an overview of the processes used to develop the screening and followup algorithms. It also includes updated results from screening and discussion of observations, lessons learned, and suggested areas for improvement that will reduce referral rates and the number of infants defined as at risk for later-onset forms of KD. Although current treatment options for infants with early-infantile Krabbe's disease are not curative, over time treatment options should improve; in the meantime, it is essential to evaluate the lessons learned and to ensure that screening is completed in the best possible manner until these improvements can be realized. © 2016 Wiley Periodicals, Inc.

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.

Should states adopt newborn screening for early infantile Krabbe disease?

The published experience to date regarding implementing NBS for EIKD has been dramatically enhanced by the data presented in this issue by Orsini et al. Although much has been written about the potential harms to individuals with an abnormal NBS for EIKD who do not have EIKD, several commentators have also asked whether screening provides a benefit when it leads to early identification of the disorder. Orsini and colleagues’ data suggest that the state-mandated, multimillion-dollar NBS program for EIKD in New York has failed to provide significant benefit to children with EIKD. Indeed, in addition to the potential harm to families receiving false-positive test results, NBS for EIKD appears to have resulted in a reduction in survival in individuals who have the disease. The data from the New York program suggest that NBS for EIKD should be abandoned, pending the development of improved screening or therapies shown to confer both survival and quality-of-life benefits over supportive care. The results of this experience suggest that research efforts should be focused on improving presymptomatic treatment outcomes in children identified by NBS prior to the redeployment of mandatory presymptomatic screening.

Midbrain morphology reflects extent of brain damage in Krabbe disease.

To study the relationships between midbrain morphology, Loes score, gross motor function, and cognitive function in infantile Krabbe disease. Magnetic resonance imaging (MRI) scans were evaluated by two neuroradiologists blinded to clinical status and neurodevelopmental function of children with early or late infantile Krabbe disease. A simplified qualitative 3-point scoring system based on midbrain morphology on midsagittal MRI was used. A score of 0 represented normal convex morphology of the midbrain, a score of 1 represented flattening of the midbrain, and a score of 3 represented concave morphology of the midbrain (hummingbird sign). Spearman correlations were estimated between this simplified MRI scoring system and the Loes score, gross motor score, and cognitive score. Forty-two MRIs of 27 subjects were reviewed. Analysis of the 42 scans showed normal midbrain morphology in 3 (7.1%) scans, midbrain flattening in 11 (26.2%) scans, and concave midbrain morphology (hummingbird sign) in 28 (66.7%) scans. Midbrain morphology scores were positively correlated with the Loes score (r = 0.81, p < 0.001) and negatively correlated with both gross motor and cognitive scores (r = -.84, p < 0.001; r = -0.87, p < 0.001, respectively). The inter-rater reliability for the midbrain morphology scale was κ = .95 (95% CI: 0.86-1.0), and the inter-rater reliability for the Loes scale was κ = .58 (95% CI: 0.42-0.73). Midbrain morphology scores of midsagittal MRI images correlates with cognition and gross motor function in children with Krabbe disease. This MRI scoring system represents a simple but reliable method to assess disease progression in patients with infantile Krabbe disease.

Regional differences in fiber tractography predict neurodevelopmental outcomes in neonates with infantile Krabbe disease.

BackgroundKrabbe disease is a fatal neurodegenerative disease caused by rapid demyelination of the central and peripheral nervous systems. The only available treatment, unrelated umbilical cord blood transplantation, is effective only if performed before clinical symptoms appear. Phenotypic expressions of disease-causing mutations vary widely, but genotype–phenotype relationships are unclear. Therefore, we evaluated diffusion tensor imaging (DTI) tractography with volumetric analysis as a biomarker of early white matter changes and functional disability in presymptomatic infants.MethodsWe obtained DTI and structural scans of newborns with early-infantile Krabbe disease (n = 9) diagnosed by family history or newborn screening. We compared white matter fiber tract properties to those of normal controls (n = 336) and assessed the ability of tract-based properties to predict longitudinal development in four functional domains (cognitive, fine motor, gross motor, adaptive behavior) after treatment with unrelated umbilical cord blood transplantation. We also assessed the relationship between the standard evaluation (modified Loes score) and DTI results, and the volumetric differences between the Krabbe subjects and normal controls.FindingsReductions in fractional anisotropy were significant in the corticospinal tract in the Krabbe patients compared to controls, which strongly correlated with motor and cognitive outcomes after transplantation. Significant regional differences were observed in the splenium and uncinate fasciculus in Krabbe patients and these differences correlated only with cognitive outcomes. Regional brain volumes of Krabbe patients were slightly larger than controls. Loes scores did not correlate with DTI results.InterpretationNeonatal microstructural abnormalities correlate with neurodevelopmental treatment outcomes in patients treated for infantile Krabbe disease. DTI with quantitative tractography is an excellent biomarker for evaluating infants with Krabbe disease identified through newborn screening.

DTI as a test for early infantile Krabbe disease

DTI as a test for early infantile Krabbe disease

Intracranial calcification in early infantile Krabbe disease: nothing new under the sun

We report the cases of three children, one male and two females, with a diagnosis of early infantile Krabbe disease demonstrating intracranial calcification on computed tomography (CT). The pattern of calcification was similar in all individuals and involved the internal capsule and cerebral white matter. The presence of calcification caused some diagnostic confusion in what was otherwise a typical clinical and radiological presentation. This finding is not new and has previously been described in publications from the 1980s and 1990s reporting the CT and magnetic resonance imaging appearances of Krabbe disease. With increasing use of magnetic resonance as the first imaging modality for investigation of neurological disorders, characteristic CT appearances may be forgotten. This report serves as a reminder that Krabbe disease should be included in the differential diagnosis of disorders causing intracranial calcification.

Early Infantile Krabbe Disease: Results of the World-Wide Krabbe Registry

New York State began screening for Krabbe disease in 2006 to identify infants with Krabbe disease before symptom onset. Because neither galactocerebrosidase activity nor most genotypes reliably predict phenotype, the World Wide Registry was developed to determine whether other clinical/neurodiagnostic data could predict early infantile Krabbe disease in the newborn screening population. Data on disease course, galactocerebrosidase activity, DNA mutations, and initial neurodiagnostic studies in 67 symptomatic children with early infantile Krabbe disease were obtained from parent questionnaires and medical records. Initial signs included crying/irritability, cortical fisting, and poor head control. Galactocerebrosidase activity was uniformly low. Eight of 17 manifested novel mutations. Ninety-two percent (n = 25) exhibited elevated cerebrospinal fluid protein; 76% (n = 42) demonstrated abnormal magnetic resonance images; 67% (n = 15) exhibited abnormal computed tomography findings; 43% (n = 28) produced abnormal electroencephalogram findings; 100% (n = 5) demonstrated abnormal nerve conduction velocities; 83% (n = 6) produced abnormal brainstem evoked responses; and 50% (n = 6) exhibited abnormal visual evoked responses. One, 2, and 3 year survivals were 60%, 26%, and 14%, respectively. Although most symptomatic patients with the early infantile phenotype manifested abnormal cerebrospinal fluid protein, magnetic resonance imaging, brainstem evoked responses, and nerve conduction velocities, studies of affected children may be normal. Other biomarkers are needed to predict phenotype in the newborn screening population.