Infantile Krabbe Disease Research Articles

Determination of psychosine concentration in dried blood spots from newborns that were identified via newborn screening to be at risk for Krabbe disease

BackgroundNew York State has screened over 1.2million newborns for Krabbe disease, and we identified 4 newborns with infantile Krabbe disease. In addition, 6 other newborns were identified with very low galactosylcerebrosidase (GALC) activity. Because these patients remain asymptomatic, we investigated whether psychosine levels could be a useful marker for disease. MethodsHPLC–MS/MS methodology was used to determine the psychosine concentrations in dried blood spots (DBS) collected from the following cohorts: known Krabbe patients, screened babies that were determined to have infantile Krabbe disease, asymptomatic infants with low GALC activity, and normal controls. ResultsThe psychosine concentrations from the known Krabbe patients ranged from 7 to 50ng/ml. Newborns identified by screening who were confirmed with infantile Krabbe disease ranged from 23 to 73ng/ml. Asymptomatic individuals with low GALC activity had concentrations ranging from 1.7 to 5.7ng/ml. Concentrations in newborns with normal GALC activity were all <3ng/ml. ConclusionsThe psychosine concentrations in DBS from confirmed infantile patients are at least four times higher than the asymptomatic newborns and nearly an order of magnitude greater than normal newborns. Further studies are needed to determine if psychosine can be used as a predictor of disease status/progression in screen positive newborns.

DTI as a test for early infantile Krabbe disease

DTI as a test for early infantile Krabbe disease

Prolonged Survival and Serial Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy Changes in Infantile Krabbe Disease

Krabbe disease may present during infancy, late infancy, or adulthood. Earlier-onset disease is associated with shorter survival times. We present a case of infantile onset Krabbe disease with prolonged survival, initial intracranial optic nerves and optic chiasm hypertrophy, and serial changes on cranial magnetic resonance imaging and magnetic resonance spectroscopy.

Expanded newborn screening as an experiment

The Journal has recently published a number of studies related to specific newborn screening procedures. The current issue included another such report, but of a very different nature. Ross and Waggoner have authored a Commentary on one group of disorders, the lysosomal storage diseases (LSDs), which is sure to elicit heated debate. Briefly, the authors of this Commentary argue that LSDs are currently a bit different from some of the more classic disorders subject to newborn screening. Few would argue that phenylketonuria (PKU), in which early dietary intervention can make the difference between typical and profoundly atypical development, is not an appropriate target for screening. The same cannot be said for LSDs such as Krabbe disease, Fabre disease, and others. Unlike PKU, the natural history of a child with positive screening for some of the LSDs is not entirely clear. Furthermore, the utility and safety of early treatment (which may include bone marrow transplantation) has not at all been established. In many cases, as the authors point out, the inclusion of some LSDs in newborn screening panels was driven by public advocacy groups, and was not always informed by science. Ross and Waggoner argue in this Commentary that some disorders included in screening programs fall more appropriately into the “research” realm than standard public health programs. As such, they should be subject to Institutional Review Board oversight and informed consent prior to participation. Although this concept may seem radical, the authors make a compelling case and point out that it is already the policy in some jurisdictions. Article page 385▶ Parents: Critical Stakeholders in Expanding Newborn ScreeningThe Journal of PediatricsVol. 161Issue 3PreviewLysosomal storage diseases (LSD) are rare genetic conditions that can affect individuals at different stages of life. Hunter Kelly (February 14, 1997 to August 5, 2005), the son of former Buffalo Bills quarterback Jim Kelly, died of complications from infantile Krabbe disease, one of the LSDs.1 Bone marrow transplantation can sometimes slow down the progressive neurologic symptoms caused by Krabbe disease.2 Mr Kelly advocated that the New York State Public Health Department screen for Krabbe disease to diagnose it early enough that bone marrow transplantation is an option. Full-Text PDF

Parents: Critical Stakeholders in Expanding Newborn Screening

ysosomal storage diseases (LSD) are rare genetic conditions that can affect individuals at different stages of life. Hunter Kelly (February 14, 1997 to August 5, 2005), the son of former Buffalo Bills quarterback Jim Kelly, died of complications from infantile Krabbe disease, one of the LSDs. Bone marrow transplantation can sometimes slow down the progressive neurologic symptoms caused by Krabbe disease. Mr Kelly advocated that the New York State Public Health Department screen for Krabbe disease to diagnose it early enough that bone marrow transplantation is an option. In August 2006, New York implemented Krabbe screening into its mandatory screening program. In Illinois, in 2005, Bob and Sonya Evanosky successfully lobbied the Illinois legislature to mandate screening for 5 LSDs to be incorporated into its mandatory newborn screening program, including Krabbe disease, Pompe disease, and Fabry disease. This screening was to begin within 6 months after the establishment and verification of relevant and appropriate performance specifications; the availability of quality assurance testing methodology for these processes; and the establishment of precise threshold values ensuring defined disorder identification for each screening test. Since then, the Evanosky Foundation has convinced the Illinois legislature to add 2 additional LSDs to the mandatory newborn screening program. Through their advocacy organization, they have also lobbied for LSD screening in Missouri and New Mexico. The reports from New York should make us think twice about the clinical value of LSD screening and question the political approach to expand screening that circumvents a more evidence-based public health approach. New York was not the first jurisdiction to perform newborn screening for LSD. Both Taiwan and Italy have had research protocols to study the feasibility and utility of screening for Pompe disease (Taiwan) and Fabry disease (Taiwan and Italy). In all cases, the implementation was performed with parental consent, and the protocols underwent review by a human subjects protection committee (known as an institutional review board [IRB]). In contrast, New York implemented screening into mandatory screening, which does not require parental consent, let alone parental notification. No IRB was involved. We learned a lot from the New York experience. Data from the Hunter’s Hope Registry suggested that 90% of cases

Teaching Neuro Images : Intracranial optic nerve enlargement in infantile Krabbe disease

A 6-month-old boy presented with a 2-month history of developmental regression, irritability, and opisthotonic posturing. MRI demonstrated T2 hyperintensity in bilateral cerebral and peri-dentate cerebellar white matter, internal capsules, and pyramidal tracts, with hypertrophy of the intracranial optic nerves. Magnetic resonance spectroscopy (MRS) showed elevated choline peak …

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.

Peripheral neuropathy in the Twitcher mouse involves the activation of axonal caspase 3.

Infantile Krabbe disease results in the accumulation of lipid-raft-associated galactosylsphingosine (psychosine), demyelination, neurodegeneration and premature death. Recently, axonopathy has been depicted as a contributing factor in the progression of neurodegeneration in the Twitcher mouse, a bona fide mouse model of Krabbe disease. Analysis of the temporal-expression profile of MBP (myelin basic protein) isoforms showed unexpected increases of the 14, 17 and 18.5 kDa isoforms in the sciatic nerve of 1-week-old Twitcher mice, suggesting an abnormal regulation of the myelination process during early postnatal life in this mutant. Our studies showed an elevated activation of the pro-apoptotic protease caspase 3 in sciatic nerves of 15- and 30-day-old Twitcher mice, in parallel with increasing demyelination. Interestingly, while active caspase 3 was clearly contained in peripheral axons at all ages, we found no evidence of caspase accumulation in the soma of corresponding mutant spinal cord motor neurons. Furthermore, active caspase 3 was found not only in unmyelinated axons, but also in myelinated axons of the mutant sciatic nerve. These results suggest that axonal caspase activation occurs before demyelination and following a dying-back pattern. Finally, we showed that psychosine was sufficient to activate caspase 3 in motor neuronal cells in vitro in the absence of myelinating glia. Taken together, these findings indicate that degenerating mechanisms actively and specifically mediate axonal dysfunction in Krabbe disease and support the idea that psychosine is a pathogenic sphingolipid sufficient to cause axonal defects independently of demyelination.

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.

Successful cord blood transplantation in a 42-day-old boy with infantile Krabbe disease

Successful cord blood transplantation in a 42-day-old boy with infantile Krabbe disease

Axonopathy is a compounding factor in the pathogenesis of Krabbe disease.

Loss-of-function of the lysosomal enzyme galactosyl-ceramidase causes the accumulation of the lipid raft-associated sphingolipid psychosine, the disruption of postnatal myelination, neurodegeneration and early death in most cases of infantile Krabbe disease. This work presents a first study towards understanding the progression of axonal defects in this disease using the Twitcher mutant mouse. Axonal swellings were detected in axons within the mutant spinal cord as early as 1 week after birth. As the disease progressed, more axonopathic profiles were found in other regions of the nervous system, including peripheral nerves and various brain areas. Isolated mutant neurons recapitulated axonal and neuronal defects in the absence of mutant myelinating glia, suggesting an autonomous neuronal defect. Psychosine was sufficient to induce axonal defects and cell death in cultures of acutely isolated neurons. Interestingly, axonopathy in young Twitcher mice occurred in the absence of demyelination and of neuronal apoptosis. Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants.

Optic Nerve Enlargement in Krabbe Disease: A Pathophysiologic and Clinical Perspective

Krabbe disease is an infantile-onset progressive leukodystrophy. The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy. The authors report a rare case of optic nerve enlargement early in infantile Krabbe disease. Their case demonstrates proximal prechiasmatic enlargement of the nerves. They discuss the pathophysiological and clinical correlation of optic nerve enlargement in Krabbe disease and in other disorders. Although Krabbe disease does not feature in initial differential of optic nerve enlargement in children, its inclusion and early identification facilitate a timely diagnosis of this rapidly progressive fatal disease.

DTI registration in atlas based fiber analysis of infantile Krabbe disease

In recent years, diffusion tensor imaging (DTI) has become the modality of choice to investigate white matter pathology in the developing brain. To study neonate Krabbe disease with DTI, we evaluate the performance of linear and non-linear DTI registration algorithms for atlas based fiber tract analysis. The DTI scans of 10 age-matched neonates with infantile Krabbe disease are mapped into an atlas for the analysis of major fiber tracts — the genu and splenium of the corpus callosum, the internal capsules tracts and the uncinate fasciculi. The neonate atlas is based on 377 healthy control subjects, generated using an unbiased diffeomorphic atlas building method. To evaluate the performance of one linear and seven nonlinear commonly used registration algorithms for DTI we propose the use of two novel evaluation metrics: a regional matching quality criterion incorporating the local tensor orientation similarity, and a fiber property profile based metric using normative correlation. Our experimental results indicate that the whole tensor based registration method within the DTI-ToolKit (DTI-TK) shows the best performance for our application.

Early infantile Krabbe disease: Results from the World-Wide Krabbe Registry (WWR)

Early infantile Krabbe disease: Results from the World-Wide Krabbe Registry (WWR)

DTI registration in atlas based fiber analysis of infantile Krabbe disease

DTI registration in atlas based fiber analysis of infantile Krabbe disease

Multiple Cranial Nerve Enhancement: Uncommon Imaging Finding in Early Infantile Krabbe's Disease

Multiple cranial nerve enhancement in early infantile Krabbe's disease is an uncommon imaging finding. We present an 8-month-old infant with early infantile Krabbe's disease with enhancement of multiple cranial nerves and optic nerve hypertrophy.

Enhancing Cranial Nerves and Cauda Equina: An Emerging Magnetic Resonance Imaging Pattern in Metachromatic Leukodystrophy and Krabbe Disease

We report on three cases of infantile Krabbe disease and one case of infantile metachromatic leukodystrophy showing magnetic resonance (MR) imaging findings of diffuse and coexistent cranial nerve and cauda equina nerve roots enhancement. Such findings may be simultaneous, or even precede, typical white matter abnormalities and, in the appropriate clinical context, may facilitate an earlier diagnosis. There is a rational for the use of contrast agents and craniospinal MR imaging during the first imaging of children with a history of psychomotor regression and clinical evidence of peripheral nerve involvement to exclude differential diagnoses.

The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: Report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder of white matter resulting from deficiency of galactosylceramide beta-galactosidase (GALC) and the consequent accumulation of galactosylceramide and psychosine. Although most patients present within the first 6 months of life, i.e., the early infantile or “classic” phenotype, others present later in life including in adolescence and adulthood. The only available treatment for infants with early infantile Krabbe disease is hematopoietic cell transplantation (HCT), typically using umbilical cord blood. Although transplanted children are far better neurologically than they would have been had they followed the typical fulminant course of early infantile Krabbe disease, anecdotal reports have surfaced suggesting that the majority of presymptomatic children transplanted for Krabbe disease have developed motor and language deterioration. The cause and extent of the deterioration is unknown at this time. With the advent of universal newborn screening for Krabbe disease in New York State and the projected start of screening in Illinois in 2010, understanding the outcome of treatment becomes of paramount importance. Thus, the purpose of this workshop was to bring together child neurologists, geneticists, neurodevelopmental pediatricians, transplanters, neuroradiologists, neurophysiologists, developmental neurobiologists, neuroscientists, and newborn screeners to review the results of the transplantation experience in humans and animals and, if neurologic deterioration was confirmed, develop possible explanations as to causation. This workshop was the first attempt at a multicenter crossdiscipline evaluation of the results of HCT for Krabbe disease. A broad range of individuals participated, including clinicians, academicians, and authorities from the National Institutes of Health, American College of Medical Genetics, and Department of Health and Human Services.

Diffusion Tensor Imaging Detects Abnormalities in the Corticospinal Tracts of Neonates with Infantile Krabbe Disease

It is not possible to determine if neonates diagnosed with Krabbe disease through statewide neonate screening programs will develop the disease as infants, juveniles, or adults. The only available treatment for this fatal neurodegenerative condition is unrelated umbilical cord transplantation, but this treatment is only effective before clinical symptoms appear. Therefore, a marker of disease progression is needed. The purpose of this study was to evaluate the use of diffusion tensor imaging (DTI) with fiber tracking in identifying early changes in major motor tracts of asymptomatic neonates with infantile Krabbe disease. Six neonates with infantile Krabbe disease identified because of family history underwent brain MR imaging within the first 4 weeks of life. Six-direction DTI and quantitative tractography of the corticospinal tracts were performed. Hypothesis tests, 1 for each hemisphere, were used to determine whether the fractional anisotropy (FA) ratio of the neonates with infantile Krabbe disease was significantly different from that of 45 age- and sex-matched controls. The average FA ratio for patients with Krabbe disease was 0.89 and 0.87 for left and right tracts, respectively (P = .002 and < .001). After adjusting for gestational age, gestational age at birth, birth weight, sex, and race, the 6 patients with Krabbe disease had significantly lower FA values than the controls (P < .001). DTI with quantitative tractography detected significant differences in the corticospinal tracts of asymptomatic neonates who had the early-onset form of Krabbe disease. Once standardized and validated, this tool has the potential to be used as a marker of disease progression in neonates diagnosed through statewide neonate screening programs.

Diffusion Tensor Imaging Detects Abnormalities in the Corticospinal Tracts of Neonates with Infantile Krabbe Disease

Diffusion Tensor Imaging Detects Abnormalities in the Corticospinal Tracts of Neonates with Infantile Krabbe Disease