Challenge of phenotype estimation for optimal treatment of Krabbe disease

Sakai, Norio; Otomo, Takanobu

doi:10.1002/jnr.23914

Cited by 12 publications

(16 citation statements)

References 36 publications

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“…We also wanted to draw attention to pattern B as indicative of KD in its later onset, as according to our clinical experience, it is not as well recognized by the clinician in comparison to pattern A. Especially with respect to therapeutic options, this seems of importance, as efficacy of HSCT is essentially related to early timing of this therapeutic intervention [19].…”

Section: Discussionmentioning

confidence: 99%

“…by Wenger et al [28], assume that more than 90% of Krabbe patients suffer from the early-infantile form, newer data by Duffner et al [5] indicate that 62% of the Krabbe patients show the early-infantile and 10% the late-infantile form; they describe, in addition 22% of patients with later onset and 5% with an adolescent/adult form. Slower progressive forms with a later onset are less well known and poorly systematically investigated, and may be underestimated [4,5,19].…”

Section: Background/introductionmentioning

confidence: 99%

“…Most data are on presymptomatically transplanted children, siblings of children with the infantile form of the disease [8]. In later onset forms, transplantation may be successful, when done very early during disease course [19].…”

Section: Background/introductionmentioning

confidence: 99%

“…Until now, more than 140 different pathogenic variants of the GALC gene have been described [ 19 ]. The 30 kb-deletion (c.1161 + 6532_polyA+9kbdel) is with about 45 percent of the mutated alleles by far the most common mutation in the Caucasian population [ 6 , 22 ].…”

Section: Background/introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Background/introductionmentioning

confidence: 99%

Section: Background/introductionmentioning

confidence: 99%

Section: Background/introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…Current descriptions of KD phenotype focus upon age of onset, distinguishing EIKD from later onset variants that can emerge in later infancy, childhood, or adulthood . But the age demarcations and symptomatic characterization of the later onset variants, as well as their relative proportions, are not defined unequivocally …”

Section: Introductionmentioning

confidence: 99%

Survey of quality of life, phenotypic expression, and response to treatment in Krabbe leukodystrophy

et al. 2019

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Objectives To develop a quality of life (QOL) survey for Krabbe disease (KD), and to thereby improve understanding of its phenotypic expression and response to treatment. Methods The survey, the Leukodystrophy Quality of Life Assessment (LQLA) and the Vineland Adaptive Behavior Scales were co‐administered to 33 patients or their caretakers. These included the phenotypes of early infantile KD (EIKD; 0‐6 months old at onset), late infantile cases (LIKD; 7‐12 months old at onset), and cases that emerged after 12 months old, late onset (LOKD). The sample included cases with and without stem cell transplantation (SCT). Reliability and concurrent validity were assessed for overall and subscale scores. Analysis of variance tested differences in QOL between phenotypes and transplant groups (none, pre‐, post‐symptom). Results Good concurrent validity with the Vineland was shown for total, communication, daily activity, social, and motor scales and good reliability was observed. LOKD cases had better communication skills than either EIKD or LIKD and better overall QOL than EIKD. Analyses of individual items showed that communication items, mostly, contributed significantly to phenotype differences. Presymptomatic SCT significantly improved QOL compared to postsymptomatic SCT or no treatment. Presymptomatically treated patients had near‐normal total scores. Conclusions The LQLA is valid and reliable. Despite small sample size, phenotypic demarcation was determined to be due mainly to differences in communication skills. There was a relative enhancement of QOL in LOKD patients, and in those who had presymptomatic SCT. These results apply to the current controversy about recommendations for newborn screening for this condition.

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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

Zhou

Lei

et al. 2020

Molec Gen & Gen Med

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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.

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Challenge of phenotype estimation for optimal treatment of Krabbe disease

Cited by 12 publications

References 36 publications

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

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

Survey of quality of life, phenotypic expression, and response to treatment in Krabbe leukodystrophy

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

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