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axial FlaiR (A–E) and coronal T2-weighted (F) MRi images. Notes: Figure shows high intensities in the bilateral corticospinal tracts from the centrum semiovale through the posterior internal capsule to the brainstem (white arrows). There are no abnormalities of the dentate and cerebellar white matter. Abbreviations: FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.
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A case of late-infantile Krabbe disease in a patient who presented with developmental regression and spastic quadriplegia in late infancy is reported. Brain magnetic resonance imaging (MRI) at 11 months of age showed predominant corticospinal tract involvement, which usually appears in adult Krabbe disease. Galactocerebrosidase activity in lymphocy...
Citations
... Early-infantile KD has a more diffuse cerebellar and deep cerebral WM disorder, late-infantile cases show a crossover pattern with less or absent cerebellar involvement and adolescent/adult patients have isolated corticospinal tract involvement [4]. This last pattern has also been reported in one late-infantile [5] and few late-onset KD patients [6][7][8]. Genotype-phenotype correlations indicate that early-infantile KD results from severe GALC deficiency, which is usually associated with homozygosity for the GALC 30 kb deletion or a loss-of-function variant (i.e., frameshift, nonsense, missense substitutions affecting the catalytic activity of the enzyme), or compound heterozygosity for these "severe" variants. ...
Krabbe disease (KD) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in GALC. Most patients manifest the severe classic early-infantile form, while a small percentage of cases have later-onset types. We present two siblings with atypical clinical and neuroimaging phenotypes, compared to the classification of KD, who were found to carry biallelic loss-of-function GALC variants, including a recurrent 30 kb deletion and a previously unreported deep intronic variant that was identified by mRNA sequencing. This family represents a unique description in the KD literature and contributes to expanding the clinical and molecular spectra of this rare disorder.
... This study, along with the previous literature, saw limited and variable outcomes for gross motor function after transplantation. 9,29 One explanation is that corticospinal tracts are the first structures to be myelinated and are the most heavily myelinated, making them particularly vulnerable to a GALC deficiency. 30,31 Another explanation is that there may be differences in the degree of peripheral nerve involvement and thus, a difference in the response to treatment. ...
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 cases are the infantile subtypes, among which ~20% are late-infantile. Prior studies demonstrated that HSCT is effective for early-infantile patients (0 - 6 months of age) transplanted while asymptomatic, compared to those transplanted 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 following 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 (1997 - 2020). Compared to untreated patients, transplanted patients 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 > 12 months of age had better cognitive outcomes than untreated patients. Those with disease onset £ 12 months were comparable to untreated patients. We found that HSCT prolongs the lifespan and improves the functional abilities of late-infantile Krabbe patients, particularly for those transplanted before symptom onset. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset 12 to 36 months of age.
... Notably, the two homozygous patients did not develop signs or symptoms until 22 and 38 years of age. Of the 13 patients with sufficient clinical information, five (38%) presented with significant visual impairment ( Table 2) (6,11,13,14,(21)(22)(23)(24)(25)(26)(27)29). ...
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.
... This study, along with previous literature, saw limited and variable outcomes for gross motor following transplantation. 9,29 One explanation is that corticospinal tracts are the first structures to be myelinated and are the most heavily myelinated, making them particularly vulnerable to a GALC deficiency. 30,31 Another explanation is that there may be differences in the degree of peripheral nerve involvement and thus, a difference in the response to treatment. ...
... Characteristic MRI findings include increased signal in periventricular and deep cerebral white matter, often sparing U-fibers [98,100]. Prominent corticospinal involvement has also been seen in older patients [101]. ...
The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.
Krabbe disease (KD), also known as globoid cell leukodystrophy, is a rare autosomal recessive condition caused by mutations in the galactocerebrosidase (GALC) gene. KD is more common in infants and young children than in adults. We reported the case of an adult-onset KD presenting with progressive myoclonic epilepsy (PME) and cortical lesions mimicking mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. The whole-exome sequencing (WES) identified a pathogenic homozygous missense mutation of the GALC gene. Parents of the patient were heterozygous for the mutation. The clinical, electrophysiological, and radiological data of the patient were retrospectively analyzed. The patient was a 24-year-old woman presenting with generalized seizures, progressive cognitive decline, psychiatric symptoms, gait ataxia, and action-induced myoclonus. The brain magnetic resonance imaging (MRI) revealed a right occipital cortical ribbon sign without any other damage. This single case expands the clinical phenotypes of adult-onset KD.
Background
The most frequent and common form of Krabbe disease (KD) is early‐onset KD in infants, and late‐onset KD has been reported to be a rare disease. In the present study, we reported an adult‐onset KD patient in a consanguineous Chinese family.
Methods
Clinical and radiological data were collected for a family pedigree. The patient was diagnosed with late‐onset KD through next‐generation sequencing. The result was confirmed by Sanger sequencing. GALC enzyme activity was also examined by the colorimetry method. Both the grey matter volume (GMV) and white matter volume values were examined and compared with the average values from ten age‐matched normal controls. Moreover, we reviewed all the available KD studies on PubMed to understand the correlation between the phenotype and genotype of the identified mutation.
Results
The main manifestations of the proband were sudden onset seizures and cognitive decline. Mutation analysis of the GALC revealed a homozygous c.1901T>C mutation in exon 16, which resulted in an amino acid change in p.L634S. Sanger sequencing results showed that the homozygous mutation was inherited from the patient's parents, both of whom were revealed to be heterozygous carriers. Moreover, a decrease in GALC enzyme activity was also detected. However, no abnormal signals were found in the brain MRI. Further structural MRI analysis revealed a significantly decreased GMV in the proband compared to the normal controls. Moreover, it is of interest that all patients with the c.1901T>C mutation had late‐onset KD and were selected from Asian countries, especially Japan and China.
Conclusions
This patient with a homozygous GALC mutation expands the clinical presentation and characteristics of adult‐onset KD, as indicated by grey matter atrophy without abnormal white matter signals.
