A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life

Abstract

BackgroundKrabbe 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.MethodsAll 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.ResultsThirty-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.ConclusionsBased 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.

Spontaneous Third Ventriculostomy in Krabbe Disease

“…1,2 Although most patients present before the age of 12 months (early infantile onset), later-onset forms with more variable presentation, late infantile (12 months to three years), juvenile (three to eight years), and adult (eight years and older), have been well characterized. [3][4][5][6] Common presenting symptoms in early infantile Krabbe disease include regression of developmental milestones, irritability, developmental delays, feeding difficulties, and abnormal muscle tone. 3 The median survival rates in early infantile disease range from two to three years of age.…”

General anesthesia safety in progressive leukodystrophies: A retrospective study of patients with Krabbe disease and metachromatic leukodystrophy

“…Krabbe disease, also known as globoid cell leukodystrophy, is an autosomal recessive disease caused by a deficiency in galactocerebrosidase activity. The disease is categorized by onset: infantile (0‐12 months) late infantile (13‐36 months), and later‐onset phenotypes (>3 years) . Common clinical manifestations of infantile onset Krabbe include hypertonia with reduced deep tendon reflexes (DTR), hypotonia, vision problems, and peripheral neuropathy.…”

“…Common clinical manifestations of infantile onset Krabbe include hypertonia with reduced deep tendon reflexes (DTR), hypotonia, vision problems, and peripheral neuropathy. Later‐onset Krabbe disease is associated with ataxia, weakness, blindness, spastic paraparesis, behavioral problems, and dementia . Like Krabbe, MLD is a lysosomal storage disorder and is caused by an arylsulfatase A or saposin B deficiency.…”

“…The disease is categorized by onset: infantile (0-12 months) late infantile (13-36 months), and later-onset phenotypes (>3 years). [1][2][3] Common clinical manifestations of infantile onset Krabbe include hypertonia with reduced deep tendon reflexes (DTR), hypotonia, vision problems, and peripheral neuropathy. Later-onset Krabbe disease is associated with ataxia, weakness, blindness, spastic paraparesis, behavioral problems, and dementia.…”

“…Later-onset Krabbe disease is associated with ataxia, weakness, blindness, spastic paraparesis, behavioral problems, and dementia. 1,3 Like Krabbe, MLD is a lysosomal storage disorder and is caused by an arylsulfatase A or saposin B deficiency.…”