Late onset Krabbe disease due to the new GALC p.Ala543Pro mutation, with intriguingly high residual GALC activity in vitro

Krägeloh-Mann, I.; Harzer, K.; Rostásy, Kevin; Beck-Wödl, Stefanie; Bornemann, Antje; Böhringer, Judith; Bevot, Andrea; Beck, V.; Merkel, Gisela; Pechan, Maria

doi:10.1016/j.ejpn.2016.12.012

Cited by 6 publications

(8 citation statements)

References 18 publications

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“…Next, we determined GALC enzyme activity in white blood cells and fibroblasts. Using a diagnostically certified fluorometric substrate assay for leukocytes, 29,30 GALC activity was determined to be 0.54 and 0.98 nmol/h/mg, which are both in the reference range of GALC metabolic rate (Fig. 2G).…”

Section: Galc Activity Is Reduced In Patient's White Blood Cells and ...mentioning

confidence: 99%

Late‐onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D

Mächtel,

Dobert,

Hehr

et al. 2024

Ann Clin Transl Neurol

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ObjectiveKrabbe disease (KD) is a multisystem neurodegenerative disorder with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late‐onset phenotypes, symptoms are often milder and difficult to diagnose. We here present a translational approach combining diagnostic and biochemical analyses of a male patient with a progressive gait disorder starting at the age of 44 years, with a final diagnosis of late‐onset KD (LOKD).MethodsAdditionally to cerebral MRI, protein structural analyses of the β‐galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of β‐glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts.ResultsExome sequencing revealed biallelic likely pathogenic variants: GALC exons 11–17: 33 kb deletion; exon 4: missense variant (c.334A>G, p.Thr112Ala). We detected a reduced GALC activity in leukocytes and fibroblasts. While histological KD phenotypes were absent in fibroblasts, they showed a significantly decreased activities of GCase, CTSB, and CTSD in lysosomal fractions, while expression levels were unaffected.InterpretationThe presented LOKD case underlines the age‐dependent appearance of a mildly pathogenic GALC variant and its interplay with other lysosomal proteins. As GALC malfunction results in reduced ceramide levels, we assume this to be causative for the here described decrease in CTSB and CTSD activity, potentially leading to diminished GCase activity. Hence, we emphasize the importance of a functional interplay between the lysosomal enzymes GALC, CTSB, CTSD, and GCase, as well as between their substrates, and propose their conjoined contribution in KD pathology.

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Section: Galc Activity Is Reduced In Patient's White Blood Cells and ...mentioning

confidence: 99%

Late‐onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D

Mächtel,

Dobert,

Hehr

et al. 2024

Ann Clin Transl Neurol

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“…1 The clinical phenotype of Krabbe is variable, and implementation of newborn screening (NBS) and development of therapy has been complicated by the rarity of Krabbe and difficulty in predicting disease course. [2][3][4][5][6][7] The only current treatment for Krabbe is hematopoietic stem cell transplant, which is only effective if given prior to symptom onset. 5 However, over the past few years there has been a rapid progression in understanding disease pathophysiology, predicting severity, and developing new therapies for Krabbe including gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Hospitalization Burden and Incidence of Krabbe Disease

et al. 2021

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Objective: The purpose of our study was to understand the healthcare burden and incidence of Krabbe disease (Krabbe). Methods: Retrospective analysis of Krabbe patients identified October 1, 2015 through December 31, 2020, ages birth through age 3, evaluated in two national databases. We estimated point prevalence and incidence from year 2016 data. Results: We identified 98 unique Krabbe patients with 736 visits including 260 were inpatient admissions. Total healthcare charges were $51.5 million dollars. We determined a point prevalence of 34 68 Krabbe patients in 2016 ages 0 3 years. This estimates a birth incidence of ~1 in 310,000 live births. Significance: Krabbe disease patients had over $51 million in health care charges and hundreds of hospitalizations. Estimated prevalence and birth incidence is similar to rates observed from newborn screening. Our findings show the tremendous health impacts of Krabbe disease, and provide guidance for efforts in screening and treatment planning.

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“…Diagnosis via measurement of GALC enzyme activity presents certain challenges, even when using a radio-labelled natural enzyme substrate [13]. And pathologically reduced enzyme activity has to be distinguished from low activity found in clinically healthy people due to pseudodeficiency (usually below 15% of normal level) [29].…”

Section: Background/introductionmentioning

confidence: 99%

Natural history of Krabbe disease – a nationwide study in Germany using clinical and MRI data

Krieg

Krägeloh‐Mann

Groeschel

et al. 2020

Orphanet J Rare Dis

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Background Krabbe disease or globoid cell leukodystrophy is a severe neurodegenerative disorder caused by a defect in the GALC gene leading to a deficiency of the enzyme ß-galactocerebrosidase. The aim of this work was to describe the natural disease course covering the whole spectrum of the disease. Methods Natural history data were collected with a standardized questionnaire, supplemented by medical record data. We defined different forms of the disease according to Abdelhalim et al. (2014). Developmental and disease trajectories were described based on the acquisition and loss of milestones as well as the time of first clearly identifiable symptoms and needs such as spasticity, seizures and tube feeding. MRI was assessed using the scoring system by Loes et al. (1999) and in addition a pattern recognition approach, based on Abdelhalim et al. (2014). Results Thirty-eight patients were identified, from 27 of these patients 40 MRIs were available; 30 (79%) had an infantile onset, showing first symptoms in their first year of life, almost all (27 out of 30) starting in the first six months. A later onset after the first year of life was observed in 8 patients (21%, range 18 months to 60 years). Irritability, abnormalities in movement pattern as well as general developmental regression were the first symptoms in the infantile group; disease course was severe with rapid progression, e.g. loss of visual fixation, need for tube feeding and then an early death. Gait disorders were the first symptoms in all patients of the later onset groups; progression was variable. The different forms of the disease were characterized by different MRI patterns (infantile: diffuse white matter involvement and cerebellar structures specifically affected, later onset: parieto-occipital white matter and splenium affected, adult: motor tracts specifically affected). Conclusion This is the first description of the natural history of Krabbe disease in a larger European cohort using developmental, clinical and MRI data. We would like to highlight the very different clinical and MRI characteristics of the later onset forms. These data are important for counselling affected patients and families and may serve as a basis for future treatment trials.

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Late onset Krabbe disease due to the new GALC p.Ala543Pro mutation, with intriguingly high residual GALC activity in vitro

Cited by 6 publications

References 18 publications

Late‐onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D

Late‐onset Krabbe disease presenting as spastic paraplegia – implications of GCase and CTSB/D

Hospitalization Burden and Incidence of Krabbe Disease

Natural history of Krabbe disease – a nationwide study in Germany using clinical and MRI data

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