Late-Onset Krabbe Disease: Case Report of Two Patients in a Chinese Family and Literature Review

Abstract

Background: Krabbe disease (KD; globoid cell leucodystrophy) is a rare autosomal recessive lipid storage disorder that affects the white matter of the peripheral and central nervous. Late-onset KD is less frequently diagnosed and often presents with milder symptoms, making accurate diagnosis challenging, especially when distinguishing it from peripheral neuropathy. In this report, we present two cases of late-onset KD in a Chinese family. The first case involves a 25-year-old female who sought treatment due to long-standing spastic gait and deformities in her lower limbs. A muscle biopsy revealed muscle atrophy, and electromyography indicated neurogenic damage. Her 27-year-old sister (Case 2) exhibited similar lower limb weakness, along with more severe central and peripheral neurological symptoms.

Methods: The patients' peripheral blood was retained for galactocerebrosidase (GALC) enzyme activity assaying and whole exome gene sequencing.

Results: GALC enzyme activity assaying showed decreased GALC activity and gene sequencing revealed homozygous mutation of p.L634S (c.1901T>C) in the two cases.

Conclusion: This study broadens the scope for considering of KD in the diagnosis of patients presenting with muscle weakness and deformities in the lower limbs.

Keywords: GALC gene; Globoid cell leukodystrophy; Krabbe disease; case report; late‐onset.

FIGURE 1

Physical and imaging examination of the patient (Case 1). (A) Physical examination showed the right gastrocnemius muscle was slightly thinner compared to the left side. Flexion deformities in the interphalangeal joints of the distal toes (yellow arrow) in both feet, and elevated arches (red arrow) in right feet. (B) Anteroposterior and lateral x‐ray images of both ankle joints (weight‐bearing). The results of x‐ray of ankle joints revealed elevated arches (red arrow) in right feet and flexion deformities of the distal interphalangeal joints in both feet (yellow arrow). (C) Brain MRI (T2W) revealed symmetrical strip‐like abnormal signals (yellow arrow) in the corticospinal tract, suggestive of demyelinating changes. The images are shown in coronal (left) and axial (right) views.

FIGURE 2

Muscle biopsy pathology of the patient's right fibular muscle. (A–C) H&E staining. The results showed small clusters of muscle atrophy (indicated by the yellow box), with the formation of nuclear chains (yellow arrows) and angulated muscle fibers (yellow circle). There was no significant proliferation of fibrous or adipose tissue, and no marked infiltration of inflammatory cells. These findings were consistent with neurogenic muscle atrophy. Considering the clinical context, the possibility of peroneal muscular atrophy could not be ruled out. (D–F) Electron microscope images, which revealed mild focal tearing and dissolution of myofibrils, with a slight increase in lipid droplets between individual myofibrils and sub‐sarcolemmal regions of some muscle cells.

FIGURE 3

Brain MRI (T2W) of the patient's sister (Case 2). The MRI revealed symmetrical strip‐like abnormal signals (yellow arrow) in the periventricular region and corticospinal tract, suggestive of demyelinating changes. Enlargement of the bilateral lateral ventricles, third ventricle, suprasellar cistern, ambient cistern, prepontine cistern, and bilateral cerebellopontine angle cisterns was also observed. The images are shown in coronal (left) and axial (right) views.

FIGURE 4

Pedigree chart and genetic testing results of the family. (A) Pedigree chart (autosomal recessive inheritance pattern). (B–F) Genetic testing results. The results indicated that the patient (Case 1) and her sister (Case 2) carried a missense mutation on chromosome 14 in the GALC gene: NM_000153.4(GALC).1901T>C (p.Leu634Ser) (Reference genome version Human GRCH37/hg19), a homozygous variant inherited from both parents. Her parents and brother were heterozygous for the mutation.

FIGURE 5

Prediction of functional effect using PolyPhen‐2. The prediction scores for both HumDiv and HumVar were 1.00, which indicating a very high probability to affect GALC protein structure and function.