A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life
Nicholas Bascou, Anthony DeRenzo, Michele D Poe, Maria L Escolar, Nicholas Bascou, Anthony DeRenzo, Michele D Poe, Maria L Escolar
Abstract
Background: Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase. Patients with Krabbe disease present with a variable disease course depending on their age of onset. The purpose of this prospective cohort study was to characterize the natural progression of Krabbe disease in a large group of patients with disease onset between 6 and 36 months of life who were evaluated with a standardized protocol.
Methods: All patients with Krabbe disease who had onset between 6 and 36 months of age and were prospectively evaluated between 2000 to 2017 were included. Standardized neurodevelopmental, physical, and neurological examinations were performed. Other assessments included neuroradiologic and neurophysiologic tests, enzyme level, cerebrospinal fluid analysis, and GALC pathogenic variants when available. Descriptive statistics were used for analysis. Survival curve was estimated using the Kaplan-Meier method.
Results: Thirty-five patients (26 boys, 9 girls) with disease onset between 6 and 36 months of age were evaluated. Median age at symptom onset was 11.5 months, with a median delay of 3.5 months between onset of symptoms and diagnosis. Of the 32 symptomatic patients, 23 presented with initial signs or symptoms of disease between 6 and 12 months of life; nine presented after 12 months. The most common initial signs and symptoms were loss of acquired developmental milestones, irritability, abnormal gait, motor delay, and abnormal muscle tone. The most common magnetic resonance imaging abnormality was increased T2 signal in the periventricular white matter. Nerve conduction velocity results were abnormal for 21 of 24 patients. Patients with onset after 12 months had less peripheral nerve involvement and slower disease progression. Abnormal cerebrospinal fluid protein levels were obtained for 13 of 16 symptomatic children. Protein levels were normal in all asymptomatic children.
Conclusions: Based on our findings, we propose reclassifying the group of patients with onset ≤12 months as infantile and the > 12 month group as late-infantile. Patients with onset > 12 months are more likely to benefit from hematopoietic stem cell transplantation. The proposed change in classifications will allow physicians to improve their ability to recognize and diagnose patients and more precisely assess potential treatment effects after transplantation.
Keywords: Globoid cell leukodystrophy; Infantile; Krabbe disease; Late-infantile; Natural history; Newborn screening.
Conflict of interest statement
All patients and/or guardians provided written informed consent before entering into the study. All research was conducted with the approval of the institutional review boards (IRB) from the University of North Carolina (IRB-08-0237) and the University of Pittsburgh (IRB-PRO11050036).
All patients and/or guardians provided written informed consent for publication of individual data. Approval was granted by the institutional review boards (IRB) from the University of North Carolina (IRB-08-0237) and the University of Pittsburgh (IRB-PRO11050036).
There are no potential conflicts of interest among the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References
- Suzuki K. Globoid cell leukodystrophy (Krabbe’s disease): update. J Child Neurol. 2003;18(9):595–603. doi: 10.1177/08830738030180090201.
- Wenger DA, Rafi MA, Luzi P, et al. Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70:1–9. doi: 10.1006/mgme.2000.2990.
- Moser HW. Peripheral nerve involvement in Krabbe disease: a guide to therapy selection and evaluation. Neurology. 2006;67:201–202. doi: 10.1212/01.wnl.0000231531.73713.a9.
- Castelvetri LC, Givogri MI, Zhu H, et al. Axonopathy is a compounding factor in the pathogenesis of Krabbe disease. Acta Neuropathol. 2011;122:35–48. doi: 10.1007/s00401-011-0814-2.
- Hagberg B, Sourander P, Svennerholm L. Diagnosis of Krabbe’s infantile leucodystrophy. J Neurol Neurosurg Psychiatry. 1963;26:195–198. doi: 10.1136/jnnp.26.3.195.
- Sakai N. Pathogenesis of leukodystrophy for Krabbe disease: molecular mechanism and clinical treatment. Brain Dev. 2009;31(7):485–487. doi: 10.1016/j.braindev.2009.03.001.
- Brodsky MC, Hunter JS. Positional ocular flutter and thickened optic nerves as sentinel signs of Krabbe disease. J AAPOS. 2011;15(6):595–597. doi: 10.1016/j.jaapos.2011.05.024.
- Morse LE, Rosman NP. Myoclonic seizures in Krabbe disease: a unique presentation in late-onset type. Pediatr Neurol. 2006;35(2):154–157. doi: 10.1016/j.pediatrneurol.2006.02.004.
- Wenger DA, Suzuki K, Suzuki Y, Suzuki K, et al. Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease) In: Scriver CR, Sly WS, Childs B, et al., editors. The metabolic and molecular bases of inherited disease. 8. New York: McGraw-Hill; 2001. pp. 3669–3694.
- Duffner PK, Jalal K, Carter RL. The Hunter's hope Krabbe family database. Pediatr Neurol. 2009;40(1):13–18. doi: 10.1016/j.pediatrneurol.2008.08.011.
- Duffner PK, Barczykowski A, Jalal K, Yan L, Kay DM, Carter RL. Early infantile Krabbe disease: results of the world-wide Krabbe registry. Pediatr Neurol. 2011;45(3):141–148. doi: 10.1016/j.pediatrneurol.2011.05.007.
- Wenger DA, Escolar ML, Luzi P, Rafi MA. Scriver’s The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID) 2013. Krabbe disease (globoid cell leukodystrophy)
- Duffner PK, Barczykowski A, Kay DM, Jalal K, Yan L, Abdelhalim A, Gill S, Gill AL, Carter R. Later onset phenotypes of Krabbe disease: results of the world-wide registry. Pediatr Neurol. 2012;46(5):298–306.190. doi: 10.1016/j.pediatrneurol.2012.02.023.
- Zhao S, Zhan X, Wang Y, Ye J, Han L, Qiu W, Gao X, Gu X, Zhang H. Large-scale study of clinical and biochemical characteristics of Chinese patients diagnosed with Krabbe disease. Clin Genet. 2018;93(2):248–254. doi: 10.1111/cge.13071.
- Shao Y, Choquet K, Piana RL, et al. B. Mutations in GALC cause late-onset Krabbe disease with predominant cerebellar ataxia. Neurogenetics. 2016;17(2):137–141. doi: 10.1007/s10048-016-0476-2.
- Wenger DA, Luzi P, Rafi MA. Krabbe disease: are certain mutations disease-causing only when specific polymorphisms are present or when inherited in trans with specific second mutations? Mol Genet Metab. 2014;111(3):307–308. doi: 10.1016/j.ymgme.2013.12.009.
- Krabbe K. A new familial, infantile form of diffuse brain-sclerosis. Brain. 1916;39(1–2):74–114. doi: 10.1093/brain/39.1-2.74.
- Hagberg B, Kollberg H, Sourander P, Akesson HO. Infantile globoid cell leukodystrophy (Krabbe’s disease): a clinical and genetic study of 32 Swedish cases 1953-1967. Neuropadiatrie. 1969;1:74–88. doi: 10.1055/s-0028-1091865.
- Aldosari M, Altuwaijri M, Husain AM. Brain-stem auditory and visual evoked potentials in children with Krabbe disease. Clin Neurophysiol. 2004;115(7):1653–1656. doi: 10.1016/j.clinph.2004.02.022.
- Husain AM, Altuwaijri M, Aldosari M. Krabbe disease neurophysiologic studies and MRI correlations. Neurology. 2004;63(4):617–620. doi: 10.1212/01.WNL.0000134651.38196.F8.
- Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe’s disease. New Engl J Med. 2005;352(20):2069–2081. doi: 10.1056/NEJMoa042604.
- Lim ZY, Ho AY, Abrahams S, et al. Sustained neurological improvement following reduced-intensity conditioning allogenic hematopoietic stem cell transplantation for late-onset Krabbe disease. Bone Marrow Transpl. 2008;41(9):831–2. doi: 10.1038/sj.bmt.1705984.
- Escolar ML, Yelin K, Poe MD. Neurodevelopmental outcomes of children with infantile Krabbe disease treated with umbilical cord blood transplantation: 10 years of follow up. CML: Lysosomal Storage Disease. 2006;6(3):72–79.
- Escolar ML, Poe MD, Martin HR, Kurtzberg J. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics. 2006;118(3):e879–e889. doi: 10.1542/peds.2006-0747.
- Lantos JD. Dangerous and expensive screening and treatment for rare childhood diseases: the case of krabbe disease. Dev Disabil Res Rev. 2011;17(1):15–18. doi: 10.1002/ddrr.133.
- Orsini JJ, Saavedra-Matiz CA, Gelb MH, Caggana M. Newborn screening for Krabbe's disease. J Neurosci Res. 2016;94(11):1063–1075. doi: 10.1002/jnr.23781.
- Wasserstein MP, Andriola M, Arnold G, Aron A, Duffner P, Erbe RW, Escolar ML, Estrella L, Galvin-Parton P, Iglesias A, Kay DM. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York state. Genet Med. 2016;18(12):1235. doi: 10.1038/gim.2016.35.
- Kwon JM, Matern D, Kurtzberg J, Wrabetz L, Gelb MH, Wenger DA, Ficicioglu C, Waldman AT, Burton BK, Hopkins PV, Orsini JJ. Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease. Orphanet J Rare Dis. 2018;13(1):30. doi: 10.1186/s13023-018-0766-x.
- Escolar ML, Kiely B, Shawgo, et al. Psychosine, a marker of Krabbe phenotype and treatment effect. Mol Genet Metab. 2017;121(3):271–278. doi: 10.1016/j.ymgme.2017.05.015.
- Biffi A, Aubourg P, Cartier N. Gene therapy for leukodystrophies. Hum Mol Genet. 2011;20(1):R42–R53. doi: 10.1093/hmg/ddr142.
- Matthes F, Andersson C, Stein A, et al. Enzyme replacement therapy of a novel humanized mouse model of globoid cell leukodystrophy. Exp Neurol. 2015;271:36–45. doi: 10.1016/j.expneurol.2015.04.020.
- Martin HR, Poe MD, Reinhartsen D, et al. Methods for assessing neurodevelopment in lysosomal storage diseases and related disorders: a multidisciplinary perspective. Acta Paediatr Suppl. 2008;97:69–75. doi: 10.1111/j.1651-2227.2008.00651.x.
- Bruininks RH, Woodcock RW, Weatherman RF, Hill BK. Scales of independent behavior-revised. Itasca: Riverside Publishing; 1996.
- Folio MR, Fewell RR. Peabody developmental motor scales, 2nd ed. Austin: Pro-Ed; 2000.
- Mullen EM. Mullen scales of early learning AGS edition. Circle Pines: American Guidance Service. Inc.; 1995.
- Russell DJ, Rosenbaum PL, Wright M, Avery LM. Gross motor function measure (GMFM-66 and GMFM-88) User's manual. 2nd ed. London: Mac Keith Press; 2013.
- Burger-Caplan R, Saulnier CA, Sparrow SS. Vineland adaptive behavior scales. InEncyclopedia of clinical neuropsychology: Springer International Publishing; 2018. p. 1–5.
- Kuczmarski RJ, Ogden CL, Guo SS, et al. 2000 CDC growth charts for the United States: methods and development. National Center for Health Statistics Vital Health Stat. 2002;11:1.
- den Dunnen JT. Describing sequence variants using HGVS nomenclature. InGenotyping. New York: Humana press; 2017. pp. 243–251.
Source: PubMed