Adult‐onset Krabbe disease due to a homozygous <i>GALC</i> mutation without abnormal signals on an MRI in a consanguineous family: A case report

Zhou, Xia; Lei, Yu; Hu, Panpan; Zhu, Xiaoqun; Sun, Zimin

doi:10.1002/mgg3.1407

Cited by 8 publications

(5 citation statements)

References 21 publications

(28 reference statements)

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“…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).…”

Section: Review Of Literaturementioning

confidence: 99%

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

2020

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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.

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Section: Review Of Literaturementioning

confidence: 99%

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

2020

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“…In these studies, all of the patients had a heterozygous c.1901T>C variant along with a heterozygous missense or canonical splice site variant (c.195+1G>A) 19 . Homozygous c.1901T>C variants have been detected in an adult‐onset KD patient and also in apparently normal individuals 34,35 . In a functional study using COS1 cells, the presence of c.1901C>T resulted in low GALC activity 36 .…”

Section: Discussionmentioning

confidence: 99%

“…19 Homozygous c.1901T>C variants have been detected in an adult-onset KD patient and also in apparently normal individuals. 34,35 In a functional study using COS1 cells, the presence of c.1901C>T resulted in low GALC activity. 36 In our study, c.1901T>C variant was detected in seven patients; four later-onset and three infantile/late infantile-onset KD patients.…”

Section: Age Of Onset Yearsmentioning

confidence: 99%

Clinical feature, GALC variant spectrum, and genotype–phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years

Hwang,

Kim,

Kim

et al. 2024

Clinical Genetics

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Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype–phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months–34 years) and the most common phenotype was adult‐onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30‐kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later‐onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult‐onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

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“…This may suggest that GALC G 41 S/G 41 S mutants are less anxious, and/or more curious. There are very few studies that have studied cognitive aspects on in KD, with most research focused on infantile cases and fewer on adult-onset cases ( Patrick and Wilson, 1972 ; Crome et al, 1973 ; Loonen et al, 1985 ; Olmstead, 1987 ; Kolodny et al, 1991 ; Jardim et al, 1999 ; Debs et al, 2013 ; Xia et al, 2020 ; Yoon et al, 2021 ). In general, most neurodevelopmental deficits in KD have been associated with the loss of myelin and motor skills, which undoubtedly impacts on the capacity of the patient to reach neurodevelopmental milestones.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β–Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease

Rebiai

Rue

Zaldua

et al. 2022

Front. Mol. Neurosci.

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Krabbe Disease (KD) is a lysosomal storage disorder characterized by the genetic deficiency of the lysosomal enzyme β-galactosyl-ceramidase (GALC). Deficit or a reduction in the activity of the GALC enzyme has been correlated with the progressive accumulation of the sphingolipid metabolite psychosine, which leads to local disruption in lipid raft architecture, diffuse demyelination, astrogliosis, and globoid cell formation. The twitcher mouse, the most used animal model, has a nonsense mutation, which limits the study of how different mutations impact the processing and activity of GALC enzyme. To partially address this, we generated two new transgenic mouse models carrying point mutations frequently found in infantile and adult forms of KD. Using CRISPR-Cas9 gene editing, point mutations T513M (infantile) and G41S (adult) were introduced in the murine GALC gene and stable founders were generated. We show that GALCT513M/T513M mice are short lived, have the greatest decrease in GALC activity, have sharp increases of psychosine, and rapidly progress into a severe and lethal neurological phenotype. In contrast, GALCG41S/G41S mice have normal lifespan, modest decreases of GALC, and minimal psychosine accumulation, but develop adult mild inflammatory demyelination and slight declines in coordination, motor skills, and memory. These two novel transgenic lines offer the possibility to study the mechanisms by which two distinct GALC mutations affect the trafficking of mutated GALC and modify phenotypic manifestations in early- vs adult-onset KD.

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Adult‐onset Krabbe disease due to a homozygous GALC mutation without abnormal signals on an MRI in a consanguineous family: A case report

Cited by 8 publications

References 21 publications

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

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

Clinical feature, GALC variant spectrum, and genotype–phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β–Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease

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