GALC mutations in Chinese patients with late-onset Krabbe disease: a case report

Shunzhi Zhuang,Tingting Zhang,Caiming Li,Likun Chen,Lingen Kong

doi:10.1186/s12883-019-1345-z

Shunzhi Zhuang, Tingting Zhang + Show 3 more

Open Access

https://doi.org/10.1186/s12883-019-1345-z

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Journal: BMC Neurology	Publication Date: Jun 11, 2019
Citations: 6	License type: open-access

Affiliation: Huizhou Central People's Hospital

Abstract

BackgroundKrabbe disease (also known as globoid cell leukodystrophy) cause by a deficiency of the enzyme β-galactocerebrosidase (galactosylceramidase, GALC). The deficiency of GALC leads to accumulation of galactosylceramide and psychosine, the latter GALC substrate having a potential role in triggering demyelination. Typically, the disease has an infantile onset, with rapid deterioration in the first few months, leading to death before the age of 2 years. The late onset forms (late-infantile, juvenile, and adult forms) are rare with variable clinical outcomes, presenting spastic paraplegia as the main symptom.Case presentationWe recruited a family with two affected individuals. The proband (Patient 1), a 25-year-old male, was presented with slow progressive symptoms, including spastic gait disturbance and vision loss since the 5th year of life. His elder sister (Patient 2), became wheelchair-bound and demented at the age of 22 years. Brain magnetic resonance imaging (MRI) showed increased signal intensity in the white matter along with the involvement of the bilateral corticospinal tracts. GALC deficiency was confirmed by biochemical analysis. DNA sequencing revealed two mutations (c.865G > C: p. G289R and c.136G > T: p. D46Y) in GALC. The clinical characteristics, brain MRI, biochemical and molecular findings led to the diagnosis of Krabbe disease.ConclusionClinical and neuroimaged signs, positive enzymatic analysis and molecular data converged to definite diagnosis in this neurodegenerative disease.

Highlights

Krabbe disease cause by a deficiency of the enzyme β-galactocerebrosidase
Krabbe disease (MIM 245200) is a rare inherited metabolic, neurodegenerative disease, due to the deficiency of the enzyme GALC. It is a lysosomal hydrolase, and its deficiency leads to accumulation of galactosylceramide and psychosine
The latter of these GALC substrates is cytotoxic at enhanced concentrations which seem to explain rapid degeneration of myelin-generating cells in Krabbe disease

Summary

Introduction

Krabbe disease ( known as globoid cell leukodystrophy) cause by a deficiency of the enzyme β-galactocerebrosidase (galactosylceramidase, GALC). We report the GALC mutations, a known and a novel one, in Chinese siblings with late-onset Krabbe disease. The direct sequencing of the GALC gene (Reference mRNA sequence: NM_000153) in this patient identified a novel missense mutation She carried two heterozygous GALC mutations (p.G289R and p.D46Y), the same as the Patient 1 (Fig. 2). A study investigated the clinical symptoms of 22 unrelated Chinese patients diagnosed with Krabbe disease.

Results

Conclusion