Novel GALC Mutations Cause Adult-Onset Krabbe Disease With Myelopathy in Two Chinese Families: Case Reports and Literature Review

Junfei Zhong,Fei Jiang,Qiuming Zeng,Huan Yang,Qian Xu,Jian Cheng,Jing Li

doi:10.3389/fneur.2020.00830

Abstract

Krabbe disease (KD), also referred to as globoid cell leukodystrophy, is a rare autosomal recessive lysosomal storage disorder caused by β-galactocerebrosidase (GALC) deficiency. Most patients affected by this disease are infants, and <10% of cases suffer from adult-onset KD. In this study, two Chinese males presented with long-term progressive weakness in their limbs. Magnetic resonance imaging of the brain and spinal cord of these patients revealed lesions with abnormally high signal intensity on T2-weighted (T2W) and T2W fluid-attenuated inversion recovery images. Whole-exome sequencing was performed for both patients, and four GALC mutations were identified. Case 1 carried a novel deletion mutation (p.T633Tfs*2) and a known missense mutation (p.T529M), while case 2 carried a novel missense mutation (p.W355C) and a known missense mutation (p.P154H). Previous literature has rarely reported myelopathy in patients with KD; in this study, we report two cases of adult-onset KD who both experienced myelopathy. We also conducted a literature review of KD and its association with myelopathy. Our findings provide a better understanding of the phenotypic and genotypic profiles associated with adult-onset KD. We recommend that physicians consider KD as a possible diagnosis in cases showing progressive motor dysfunction or gait disorder in association with typical myelopathy.

Highlights

Krabbe disease (KD), referred to as globoid cell leukodystrophy, is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme β-galactocerebrosidase (GALC)
We reviewed the existing literature relating to KD patients with myelopathy (Table 1)
We reported two Han Chinese males with adult-onset KD with myelopathy

Summary

INTRODUCTION

Krabbe disease (KD), referred to as globoid cell leukodystrophy, is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme β-galactocerebrosidase (GALC). The patient’s 35 year-old brother was asymptomatic, clinical examination revealed Pes Cavus, tendon hyperreflexia, bilateral ankle clonus, and positive Babinski signs. Their father had died in an accident at 62 years of age, and their mother had a 19 year history of schizophrenia. The younger brother of the proband carried the same compound heterozygous mutations (p.T633Tfs∗2 and p.T529M), while their mother and the paternal uncle were heterozygous carriers of p.T633Tfs∗2 and p.T529M, respectively (Figure 2B) This information indicates that p.T633Tfs∗2 is a pathogenic mutation and causes KD. At 30 years of age, he had noticed that he could not hold objects stably with the right hand Since he developed progressive weakness in the four limbs, an unsteady gait, numbness, and mild dysarthria. This information indicates that p.W355C is a pathogenic mutation and causes KD

DISCUSSION

CONCLUSION

ETHICS STATEMENT