Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months

Abstract

Background Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, β-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients. Methods Patients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests. Results We evaluated 88 children with onset between 0 and 5 months. Median age of symptom onset was 4 months; median time to diagnosis after onset was 3 months. The most common initial symptoms were irritability, feeding difficulties, appendicular spasticity, and developmental delay. Other prevalent symptoms included axial hypotonia, abnormal deep tendon reflexes, constipation, abnormal pupillary response, scoliosis, loss of head control, and dysautonomia. Results of nerve conduction studies showed that 100% of patients developed peripheral neuropathy by 6 months of age. Median galactocerebrosidase enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years. Conclusions This is the largest prospective natural history study of Krabbe disease. It provides a comprehensive description of the disease during the first 2 years of life. With recent inclusion of state mandated newborn screening programs and promising therapeutic interventions, enhancing our understanding of disease progression in early onset Krabbe disease will be critical for developing treatments, designing clinical trials, and evaluating outcomes.

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.…”