Newborn screening for Krabbe disease in New York State: the first eight years' experience.

PURPOSE: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006. METHODS: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination. RESULTS: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease. CONCLUSIONS: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.

Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group.

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.

Developmental and functional outcomes in children with a positive newborn screen for Krabbe disease: a pilot study of a phone-based interview surveillance technique.

OBJECTIVE: To assess the utility of a telephone-based interview system in providing ongoing monitoring of the developmental and functional status of children with both positive newborn screens for Krabbe disease and low galactocerebrosidase activity on confirmatory testing, and to determine whether this approach provides improved compliance with follow-up compared with formal neuropsychological testing. STUDY DESIGN: Infants with low galactocerebrosidase activity (as detected by the New York State newborn screening program) were eligible for this longitudinal prospective cohort study. Consenting families were interviewed by telephone at infant ages of 4, 8, 12, 18, and 24 months. Designated instruments were the Ages and Stages Questionnaires, the Clinical Linguistic and Auditory Milestone Scale, the Gross Motor Quotient, the Warner Initial Developmental Evaluation of Adaptive and Functional Skills 50, and the WeeFIM II 0-3 instrument. Assessments with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III) were scheduled at age 12 and 24 months. RESULTS: Seventeen patients were enrolled; 16 were assessed at age 12 and 18 months, and 15 were assessed at age 24 months. Scores were within the normal range on all tests of developmental and functional status, with the exception of expressive language. Only 7 patients completed the Bayley Scales of Infant and Toddler Development, Third Edition assessments; all their scores were in the normal range. CONCLUSION: This telephone-based technique allows close monitoring of the developmental and functional status of children with a positive newborn screen for this neurometabolic disease, with special attention to detecting plateauing or regression of developmental milestones. Compliance is improved compared with formal neuropsychological testing.

Death rates in the U.S. due to Krabbe disease and related leukodystrophy and lysosomal storage diseases.

Leukodystrophies (LD) and lysosomal storage disorders (LSD) have generated increased interest recently as targets for newborn screening programs. Accurate epidemiological benchmarks are needed in the U.S. Age-specific mortality rates were estimated for Krabbe disease (KD) and nine related disorders. U.S. mortality records with E75.2 cause of death code during 1999-2004 were collected from 11 open record states. All E75.2 deaths in the United States were distributed into specific disease type based on proportions observed in these states. Yearly population sizes were obtained from the CDC and averaged. Mortality rates (per million individuals per year) by age group for the specific diseases were (for <5 or ≥5 years): Pelizaeus-Merzbacher (0.037/0.033); sudanophilic leukodystrophy (SLD) (0.037/0.004); Canavan (0.037/0.011), Alexander (0.147/0.022); Krabbe (0.994/0.007); metachromatic leukodystrophy (0.331/0.135); Fabry (0.000/0.124); Gaucher (0.221/0.073); Niemann-Pick (NP) (0.442/0.088); multiple sulfatase (0.000/0.004). This is the first report of mortality rates for the LD/LSD diseases in the U.S. Approximated birth prevalence rate for the early infantile Krabbe phenotype (onset 0-6 months) was based on the <5 year old mortality rate of one early infantile case per 244,000 births, which matches the 1 in 250,000 observed in the NYS newborn screening program as of 2011. It should be noted however that the NYS calculation refers only to the early infantile phenotype and does not include the majority of babies identified in the program with low GALC and two mutations who have remained clinically normal. It is presumed that most, if not all, will develop later onset forms of the disease, but this is by no means certain.

Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma.

SUMMARY: The role of cytology of cerebrospinal fluid (CSF) has not been established in pediatric ependymoma. Thirty-two children with metastatic ependymoma were analyzed: 11 patients had only positive CSF cytology, 6 had only positive magnetic resonance imaging (MRI) findings, and 15 had both CSF cytology and MRI positive. Twenty-two patients relapsed. Five-year event-free survival was 27.3%+/-13.4% for children with only CSF positive (M1) versus 26.1%+/-10.2% for patients with positive spine MRI positive (with or without CSF positive, M3) (P=0.87). In conclusion, 34% of the patients with metastatic ependymoma were identified based on CSF cytology only and their outcome was comparable to patients with macroscopic disease. CSF cytology is a useful tool to stage newly diagnosed patients with ependymoma.

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.

The Hunter's Hope Krabbe family database.

The objective was to identify presenting signs and symptoms, age at onset of symptoms and diagnosis, and survival in a large population of children with Krabbe disease. In 1997, Hunter's Hope Foundation began collecting clinical data on patients who had been diagnosed with Krabbe disease. As of June 2006, 334 families had returned questionnaires. Deidentified data were analyzed, including country of origin, sex, age at onset of symptoms, symptoms before diagnosis, age at diagnosis, symptoms after diagnosis, initial diagnosis, and survival. Seventy-one percent of patients developed symptoms at 0 to 6 months of age, 19% between 7 and 12 months, and 10% at 13 months + (13 months-5.5 years). The most common initial symptoms for age 0 to 12 months were crying and irritability, stiffness, and seizures. Older children were more likely to present with gait disturbances or loss of milestones. Survival differed according to age at onset of symptoms. Children with the early infantile phenotype (onset 0 to 6 months) had significantly worse survivals than either those with onset at 7 to 12 months or at 13 months to 5.5 years. Given that neither galactocerebrosidase activity nor mutation analysis reliably predict disease severity, the data from this study should help investigators recognize the earliest symptoms of the disease, as well as increase awareness of age of onset and natural history of the various phenotypes.

Newborn screening for Krabbe disease: the New York State model.

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.

Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors.

BACKGROUND: As the number of long-term survivors of childhood cancer has grown, it has become increasingly clear that central nervous system therapy may have serious long-term effects on cognition and endocrine function. These complications have been studied most extensively in children with brain tumors and leukemia. REVIEW SUMMARY: Children with acute lymphoblastic leukemia previously treated with cranial irradiation are at risk for cognitive decline. Chemotherapy-only regimens, which rely on high-dose frequently administered methotrexate, are also associated with producing cognitive dysfunction. Children irradiated for brain tumors are even more vulnerable. Risk factors include perioperative morbidity, young age, large-volume high-dose cranial irradiation, supra-tentorial location of tumor, moyamoya syndrome, and leukoencephalopathy. Cognitive decline is progressive over at least a decade. The most common radiation-induced endocrinopathies are hypothyroidism and growth hormone deficiency. Treatment effects on growth are multifactorial and include growth hormone deficiency,spinal shortening, precocious puberty, undetected hypothyroidism,and poor nutrition. Fifty percent to 80% of children treated with craniospinal radiation for brain tumors will experience growth failure. In hopes of reducing neurotoxicity, current treatments limit the dose and volume of radiation while adding chemotherapy. Results have not been uniformly positive, however, and may increase toxicity in some cases. CONCLUSIONS: The standard of care in 2004 is that children who have been treated for brain tumors and leukemia should be monitored for cognitive and endocrine dysfunction. Until effective non-neurotoxic treatment is identified, long-term effects assessments are essential to maximize the quality of life of survivors of childhood cancer.

Hyperkinetic seizures in children.

The objective of this study was to delineate the clinical and video-electroencephalographic (EEG) manifestations of children with complex partial seizures with a predominant "hyperkinetic" presentation. Certain types of partial seizures can be difficult to differentiate from nonepileptic seizures because of their intense motor presentation and, at times, lack of alteration of consciousness. Based on a published semiologic seizure classification, this type of seizures can be described as "hyperkinetic," characterized by intense motor activity involving the extremities and trunk. We report five children diagnosed with hyperkinetic seizures by video-EEG monitoring. All patients were referred for video-EEG evaluation because of an initial suspicion of pseudoseizures. Presented in this study is a review of the patients' clinical data, including video-EEG evaluation. There were three boys and two girls; the mean age at presentation was 10 +/- 3 years. In four patients, there was a history of behavioral disorder, with two patients carrying a diagnosis of attention-deficit hyperactivity disorder (ADHD). One girl had significant developmental delay and an abnormal neurologic examination. Brain magnetic resonance imaging was normal in three patients and abnormal in two. The semiology of the seizures consisted of stereotypic intense motor activity, mainly upper extremity flailing and kicking. Screaming and shouting were noted in three cases, and intense fear was present in two patients. The hyperkinetic ictal activity progressed to tonic-clonic seizures in two patients. Seizures occurred out of sleep or on awakening in four patients. The interictal EEG activity was normal in one patient and revealed a continuous generalized slowing and slowing of the posterior dominant rhythm in two patients. One of the latter patients had interictal epileptiform activity in the frontal and midline regions. An intermittent rhythmic slow activity of the left hemisphere with superimposed bifrontal sharp waves was noted in the fifth patient. The ictal EEG revealed profuse superimposed electromyographic (EMG) activity in all patients, making some of the EEG interpretation difficult to analyze, particularly a longitudinal bipolar montage. However, with digital manipulation of the ictal EEG data, such as changes in EEG sensitivity, application of fast frequency filters, and use of different EEG montages, it was possible to discern an ictal EEG pattern or postictal slowing following the diffuse EMG artifact in all patients. On clinical follow-up, adequate seizure control was achieved in three patients. Based on the clinical history, one patient was diagnosed with autosomal dominant nocturnal frontal lobe epilepsy. Diagnosis of hyperkinetic seizures can be difficult because of the similarity of the clinical manifestations with nonepileptic events such as certain parasomnias and pseudoseizures. Video-EEG is the most effective way of diagnosing this type of seizure.

Do serum sodium levels predict febrile seizure recurrence within 24 hours?

The American Academy of Pediatrics Practice Parameter, The Neurodiagnostic Evaluation of a Child with a First Simple Febrile Seizure, does not recommend serum electrolytes be obtained routinely. Two reports from Europe, however, identified relative hyponatremia as a risk factor for febrile seizure recurrence within 24 hours. If confirmed, this would have potential impact on the approach to these patients. The charts of 175 sequential children ages 6 months to 5 years who presented to the Children's Hospital of Buffalo emergency room in 1999 with generalized seizures lasting less than 15 minutes were retrospectively reviewed. One hundred thirty-six patients were febrile and 39 (control group) were afebrile. Serum electrolytes were performed on all. The mean serum sodium for the 27 children with more than 1 febrile seizure in 24 hours (135.48 mmol/L) did not differ from those 109 febrile children whose seizures did not recur within 24 hours (135.56 mmol/L). Of interest, the mean serum sodium for the 109 children with simple febrile seizures, as well as those with recurrent "simple" febrile seizures were significantly lower than the control group of children with afebrile seizures. These findings reaffirm the recommendation of the American Academy of Pediatrics Practice Parameter to not routinely obtain electrolytes.

Facial palsy, an unusual presenting feature of childhood leukemia.

Facial paralysis is not a well-recognized presenting feature of leukemia in children. We present two infants and one older child in whom the initial manifestation of their leukemia was lower motor neuron facial paresis. Initial diagnosis in all the patients was Bell's palsy. The presence of Bell's palsy in young children requires a complete evaluation, including consideration of leptomeningeal disease. Leukemic children presenting with cranial neuropathy require intensive central nervous system therapy.

Supratentorial primitive neuroectodermal tumors of infancy: clinical and radiologic findings.

One hundred ninety-eight children were entered on POG 8633, "Prolonged Postoperative Chemotherapy and Delayed Radiation for Children <3 years of age with Malignant Brain Tumors" (1986-1990). Thirteen manifested supratentorial nonpineoblastoma primitive neuroectodermal tumors, making this the second most common supratentorial tumor in the study. Symptoms and signs included seizures, nausea, vomiting, lethargy, irritability, headache, focal motor weakness, and increased head circumference. Twelve of 13 had symptoms for less than 1 month before diagnosis. The average tumor size was 5.96 cm (+/- 0.37) x 5 cm (+/- 0.28) x 5.15 cm (+/- 0.31). Eight tumors were predominantly hemispheral, and five were midline. Computed tomographic scans on nine patients revealed tumor hyperdensity (nine), midline shift (eight), hydrocephalus (seven), cysts (six), well-defined borders (five), and calcification (four). No patients exhibited peritumoral edema. Contrast enhancement, primarily heterogeneous, was present in all patients. Magnetic resonance imaging appearance of the tumor (six patients) demonstrated midline shift (four), well-defined margins (four), necrosis (two), cysts (three), and hemorrhage (two). No peritumoral edema was present. Most enhanced heterogeneously. The diagnosis of supratentorial nonpineoblastoma primitive neuroectodermal tumors should be suspected when a large, sharply marginated, hyperdense supratentorial mass is observed in a young child, particularly when no peritumoral edema is present.

Patterns of magnetic resonance imaging abnormalities in symptomatic patients with Krabbe disease correspond to phenotype.

BACKGROUND: Initial magnetic resonance imaging studies of individuals with Krabbe disease were analyzed to determine whether the pattern of abnormalities corresponded to the phenotype. METHODS: This was a retrospective, nonblinded study. Families/patients diagnosed with Krabbe disease submitted medical records and magnetic resonance imaging discs for central review. Institutional review board approval/informed consents were obtained. Sixty-four magnetic resonance imaging scans were reviewed by two neuroradiologists and a child neurologist according to phenotype: early infantile (onset 0-6 months) = 39 patients; late infantile (onset 7-12 months) = 10 patients; later onset (onset 13 months-10 years) = 11 patients; adolescent (onset 11-20 years) = one patient; and adult (21 years or greater) = three patients. Local interpretations were compared with central review. RESULTS: Magnetic resonance imaging abnormalities differed among phenotypes. Early infantile patients had a predominance of increased intensity in the dentate/cerebellar white matter as well as changes in the deep cerebral white matter. Later onset patients did not demonstrate involvement in the dentate/cerebellar white matter but had extensive involvement of the deep cerebral white matter, parieto-occipital region, and posterior corpus callosum. Late infantile patients exhibited a mixed pattern; 40% had dentate/cerebellar white matter involvement while all had involvement of the deep cerebral white matter. Adolescent/adult patients demonstrated isolated corticospinal tract involvement. Local and central reviews primarily differed in interpretation of the early infantile phenotype. CONCLUSION: Analysis of magnetic resonance imaging in a large cohort of symptomatic patients with Krabbe disease demonstrated imaging abnormalities correspond to specific phenotypes. Knowledge of these patterns along with typical clinical signs/symptoms should promote earlier diagnosis and facilitate treatment.

Lifetime risk estimators in epidemiological studies of Krabbe Disease: Review and Monte Carlo comparison.

This review addresses difficulties arising in estimating epidemiological parameters of leukodystrophies and lysosomal storage disorders, with special focus on Krabbe disease. Although multiple epidemiological studies of Krabbe disease have been published, these studies are difficult to reconcile since they have used different study populations and varying methods of calculation. Confusion exists regarding which epidemiological parameters have been estimated; the current review shows that most previous estimates can be properly interpreted as lifetime risk at birth. One of the most common estimation methods is shown to be inaccurate, while two other methods are shown to be approximately accurate. Based on the results of the current paper, recommendations are made that are expected to improve the quality of future studies of Krabbe disease. It is anticipated that these recommendations will be applicable to epidemiological studies of other lysosomal storage disorders, as well as any other rare diseases diagnosed with enzymatic screening.

Array CGH improves detection of mutations in the GALC gene associated with Krabbe disease.

BACKGROUND: Krabbe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GALC gene. The most common mutation in the Caucasian population is a 30-kb deletion of exons 11 through 17. There are few other reports of intragenic GALC deletions or duplications, due in part to difficulties detecting them. METHODS AND RESULTS: We used gene-targeted array comparative genomic hybridization (CGH) to analyze the GALC gene in individuals with Krabbe disease in whom sequence analysis with 30-kb deletion analysis identified only one mutation. In our sample of 33 cases, traditional approaches failed to identify two pathogenic mutations in five (15.2%) individuals with confirmed Krabbe disease. The addition of array CGH deletion/duplication analysis to the genetic testing strategy led to the identification of a second pathogenic mutation in three (9.1%) of these five individuals. In all three cases, the deletion or duplication identified through array CGH was a novel GALC mutation, including the only reported duplication in the GALC gene, which would have been missed by traditional testing methodologies. We report these three cases in detail. The second mutation remains unknown in the remaining two individuals (6.1%), despite our full battery of testing. CONCLUSIONS: Analysis of the GALC gene using array CGH deletion/duplication testing increased the two-mutation detection rate from 84.8% to 93.9% in affected individuals. Better mutation detection rates are important for improving molecular diagnosis of Krabbe disease, as well as for providing prenatal and carrier testing in family members.

Does galactocerebrosidase activity predict Krabbe phenotype?

This study sought to determine whether galactocerebrosidase activity is predictive of Krabbe onset age, or of survival from onset when controlling for age at onset of signs. We analyzed data on 55 symptomatic patients from the Hunter James Kelly Research Institute's World-Wide Registry. They were tested for galactocerebrosidase activity at Jefferson Medical College (Philadelphia, PA), using survival models in a path model context. Higher galactocerebrosidase activity was predictive of later symptom onset times (P = 0.0011), but did not predict survival after symptom onset (P = 0.9064) when controlling for the logarithm of age at onset. No child with early infantile (aged 0-6 months) phenotype demonstrated galactocerebrosidase activity >0.1 nmol/hour/mg protein. Survival times within a given phenotype did not vary with galactocerebrosidase activity. Although low galactocerebrosidase activity does not predict phenotype, higher activity in the abnormal range (>0.1 nmol/hour/mg protein in this sample) was not identified in the early infantile variant. Galactocerebrosidase activity may be important to consider when predicting phenotype in the newborn screening population. Our findings provide empiric evidence that the upper end (0.15 nmol/hour/mg protein) of the high-risk galactocerebrosidase group in the New York State newborn screening program is conservatively appropriate.

Later onset phenotypes of Krabbe disease: results of the world-wide registry.

The majority of newborns screening positive for Krabbe disease have not exhibited the expected early infantile phenotype, with most clinically normal despite low galactocerebrosidase activity and two mutations. Most are expected to develop the later onset phenotypes. The World-Wide Krabbe Registry was developed in part to expand our understanding of the natural history of these rare variants. As of June 2011, 122 patients were enrolled in the registry: 62% manifested early infantile onset (previously reported), 10% manifested onset at 7-12 months (late infantile), 22% manifested onset at 13 months to 10 years (later onset), and 5% manifested adolescent/adult onset. Data on disease course, galactocerebrosidase activity, DNA mutations, and results of neurodiagnostic studies were obtained from questionnaires and medical records. Initial signs (late infantile) included loss of milestones and poor feeding, whereas later onset and adolescent/adult phenotypes presented with changes in gait. Elevated cerebrospinal fluid protein and abnormal magnetic resonance imaging results were present in most, but not all, patients at diagnosis. Phenotypic variability occurred in four sibships. Five-year and 10-year survivals for all later onset phenotypes were at least 50%. The later onset Krabbe phenotypes differ from those with early infantile disease, but no specific predictor of phenotype was identified.