Long-term neurodevelopmental outcomes of hematopoietic stem cell transplantation for late-infantile Krabbe disease.

Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe disease cases are the infantile subtypes, among which ∼20% are late infantile. Prior studies have demonstrated that HSCT is effective for early-infantile patients (0-6 months of age) who undergo transplantation while asymptomatic, compared with those receiving transplants while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6-36 months). In this prospective, longitudinal study, patients were evaluated at a single site according to a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using mixed regression models to account for within-person repeated measures. Nineteen late-infantile patients underwent HSCT (March 1997 to January 2020). Compared with untreated patients, transplant recipients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected, with variable results. Asymptomatic patients benefitted the most from transplantation, with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset at >12 months of age had better cognitive outcomes than untreated patients. Those with disease onset at ≤12 months were comparable to untreated patients. We found that HSCT prolonged the lifespan and improved the functional abilities of late-infantile patients with Krabbe disease, particularly those who underwent transplantation before onset of symptoms. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset at 12 to 36 months of age.

Pathogenic Variants in GALC Gene Correlate With Late Onset Krabbe Disease and Vision Loss: Case Series and Review of Literature.

Background: Krabbe disease is an autosomal recessive demyelinating disorder resulting from deficiency of the lysosomal enzyme galactocerebrosidase. While blindness is often described as a characteristic finding of the disease, it is more common in the infantile phenotype, where vision loss typically arises in the late stages of disease. In comparison, reports of vision loss in late onset phenotypes are less well-described and may be subject to variation between genotypes. Methods: Charts of Krabbe patients with a confirmed diagnosis, who presented with substantial visual impairment, were retrospectively reviewed from a larger group of 199 Krabbe patients. Assessment of clinical status was obtained through review of neurological evaluations, neurodevelopmental assessments, ophthalmological evaluations, visual evoked potentials (VEP), electroretinogram (ERG), nerve conduction velocity (NCV) studies, auditory brainstem responses (ABR), and brain magnetic resonance imaging. Results: Five late onset patients with Krabbe disease (four juvenile and one late-infantile) were included. Three patients were homozygous for c.956A>G_p.Y319C, one was compound heterozygous for c.296+1G>T and c.956A>G_p.Y319C, and one was compound heterozygous for c.1186C>T_p.R396W and c.1901T>C_p.L634S. All patients were of Asian descent and presented initially with vision impairment. Notably, the patients did not present with marked appendicular spasticity or axial hypotonia and all five reached developmental milestones within the normal time frame. For neurophysiological testing, no patient showed abnormalities in NCV or ABR. However, abnormalities in VEP or ERG were seen in all patients. The one patient who underwent transplantation stabilized following treatment. Conclusions: Depending on their genotype, patients with late onset Krabbe disease may initially present with vision loss. Furthermore, patients with p.L634S and p.Y319C should be closely monitored for changes in vision and VEP. This knowledge will become increasingly important as physicians may otherwise overlook these signs and symptoms when monitoring children identified through newborn screening who have the variants described in this report.

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

BACKGROUND: Krabbe disease and metachromatic leukodystrophy are leukodystrophies characterized by neurologic degeneration and early death. Patients often require general anesthesia for diagnostic and therapeutic interventions. METHODS: A retrospective review of medical records was conducted for patients with Krabbe disease and metachromatic leukodystrophy receiving general anesthesia at a large children's hospital between 2012 and 2017. Patient complications and American Society of Anesthesiologists Physical Status were recorded for all procedures. The Neurodevelopment in Rare Disorders classification system was created to categorize the severity of the patient's disease progression based on clinical markers. Descriptive and inferential statistics were used to compare: (a) complication rate of affected patients vs the general hospital population; (b) the accuracy of the novel Neurodevelopment in Rare Disorders classification system vs American Society of Anesthesiologists Physical Status regarding the assessment of complication risk; (c) complication rate in patients with hematopoietic stem cell transplantation vs those without transplantation; (d) complication rate in immunosuppressed patients vs nonimmunosuppressed patients; and (e) complication rate of the three most commonly performed procedures. RESULTS: A total of 96 patients underwent 287 procedures. Of these, 11 cases had complications, yielding a rate of 3.8%. This is significantly higher than the overall complication rate at our institution of 0.246%. Statistical analysis showed better correlation between the Neurodevelopment in Rare Disorders classification system and complication rate than American Society of Anesthesiologists Physical Status and complication rate. The system also showed better accuracy in differentiating low-risk and high-risk patients. No statistically significant difference in complication rate was found for patients with transplantation vs those without transplantation or for immunosuppressed vs nonimmunosuppressed patients. Of the three most common procedures, central catheter placement/removal exhibited the highest complication rate. CONCLUSIONS: Although the complication rate for patients with Krabbe disease and metachromatic leukodystrophy is higher than the general population, most complications were mild and self-limiting. These results suggest that, in experienced hands, general anesthesia is well tolerated in most children. Findings show that the Neurodevelopment in Rare Disorders classification system is a better indicator for assessing complication risk in patients with Krabbe and metachromatic leukodystrophy than American Society of Anesthesiologists Physical Status.

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

BACKGROUND: Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, ß-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.