Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form

Hossain, Mohammad Arif; Otomo, Takanobu; Saito, Seiji; Ohno, Kazuki; Sakuraba, Hitoshi; Hamada, Yusuke; Ozono, Keiichi; Sakai, Norio

doi:10.1016/j.gene.2013.11.003

Cited by 49 publications

(68 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Distribution of a common mutation in adult-onset KD, GALC (p.L634S), for example, has been reported to be susceptible to a late-onset, mild form of KD [23]. However, the patients with the p.L634S mutation combined with other mutations or with the homozygous p.L634S mutation in the GALC gene exhibited a broad range of GALC activities, indicating that lower enzymatic activity does not always track the clinical severity [2–4]. Moreover, another common mutation in adult-onset KD GALC (p.G286D) exhibits a broad range of GALC activities when combined with another mutation or with the homozygous p.G286D mutation [4, 24], again indicating a limited correlation between the loss of enzymatic activity and clinical severity.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, another common mutation in adult-onset KD GALC (p.G286D) exhibits a broad range of GALC activities when combined with another mutation or with the homozygous p.G286D mutation [4, 24], again indicating a limited correlation between the loss of enzymatic activity and clinical severity. Interestingly, GALC (p.G286D) was reported to directly cause slow progressive late-onset KD, whereas GALC (p. N228_S232delinsTP) was documented to be responsible for infantile-onset KD [2, 25, 26]. However, when the two mutations were combined in KD2 patient, the patient showed slow progression of the disease, which suggests limitations in studies identifying the disease exclusively based on the genotype and enzymatic activity measurements.…”

Section: Discussionmentioning

confidence: 99%

“…While frequently detected in infants, KD has also been found as an adult-onset disease [1, 2]. Compared to rapid clinical progression in infants, adult-onset KD patients show less severe phenotype with slower disease progression [2]. In most enzymatic lysosomal diseases, deficiencies in lysosomal enzyme activities are correlated with the degree of clinical severity.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

Lim

Choi

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective β-galactosylceramidase (GALC), a lysosomal enzyme responsible for cleavage of several key substrates including psychosine. Accumulation of psychosine to the cytotoxic levels in KD patients is thought to cause dysfunctions in myelinating glial cells based on a comprehensive study of demyelination in KD. However, recent evidence suggests myelin-independent neuronal death in the murine model of KD, thus indicating defective GALC in neurons as an autonomous mechanism for neuronal cell death in KD. These observations prompted us to generate induced neurons (iNeurons) from two adult-onset KD patients carrying compound heterozygous mutations (p.[K563*];[L634S]) and (p.[N228_S232delinsTP];[G286D]) to determine the direct contribution of autonomous neuronal toxicity to KD. Here we report that directly converted KD iNeurons showed not only diminished GALC activity and increased psychosine levels, as expected, but also neurite fragmentation and abnormal neuritic branching. The lysosomal-associated membrane proteins 1 (LAMP1) was expressed at higher levels than controls, LAMP1-positive vesicles were significantly enlarged and fragmented, and mitochondrial morphology and its function were altered in KD iNeurons. Strikingly, we demonstrated that psychosine was sufficient to induce neurite defects, mitochondrial fragmentation, and lysosomal alterations in iNeurons derived in healthy individuals, thus establishing the causal effect of the cytotoxic GALC substrate in KD and the autonomous neuronal toxicity in KD pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

Lim

Choi

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…However, there are several reports that a higher frequency of patients belong to the late‐onset phenotype (Lyon et al, ; Debs et al, ). We have reported the infantile phenotype in only 41% of patients in Japan, with 20%, 10%, and 29% being classified as late‐infantile, juvenile, and adult phenotypes, respectively (Hossain et al, ). Furthermore, this ratio is very similar to that reported by Duffner and colleagues from the worldwide registry of patients with Krabbe disease (Duffner et al, ), which suggests that the late‐onset phenotype might have been underestimated in the past.…”

Section: The Diversity Of Clinical Manifestation In Krabbe Diseasementioning

confidence: 99%

Challenge of phenotype estimation for optimal treatment of Krabbe disease

Sakai

Otomo

2016

J of Neuroscience Research

Self Cite

View full text Add to dashboard Cite

Krabbe disease is an autosomal recessive, inherited demyelinating disease caused by deficiency of the lysosomal enzyme galactocerebrosidase. It is recognized as one of the predominant genetic diseases showing leukodystrophy from infancy to adulthood. The clinical phenotype and genotype for this disease show considerable variation worldwide, which makes accurate diagnosis difficult. Effective therapy is limited, although hematopoietic stem cell transplantation at an early stage has been established to some extent. We report here the long-term clinical effect on juvenile Krabbe disease for two brothers who underwent hematopoietic stem cell transplantation at an early stage of their disease. We review research into genotype-phenotype correlation for the possibility of early diagnosis at a presymptomatic stage. Medical care for this intractable disease will improve in the near future as a result of the increasing awareness of its molecular pathology and improvements in medical treatment. © 2016 Wiley Periodicals, Inc.

show abstract

“…Homozygosity for this particular missense mutation results in a mild variant of GLD with adult onset, slow progression and a clinical course of more than 20 years (Furuya et al, 1997;Hossain et al, 2014). Also compound heterozygous patients with the G270D mutation on one and a functional null mutation on the other allele present with late-onset GLD De Gasperi et al, 1999).…”

Section: Generation Of a Humanized Mouse Model Of Gldmentioning

confidence: 99%

Enzyme replacement therapy of a novel humanized mouse model of globoid cell leukodystrophy

Matthes

Andersson²,

Stein

et al. 2015

Experimental Neurology

View full text Add to dashboard Cite

Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form

Cited by 49 publications

References 40 publications

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

Challenge of phenotype estimation for optimal treatment of Krabbe disease

Enzyme replacement therapy of a novel humanized mouse model of globoid cell leukodystrophy

Contact Info

Product

Resources

About