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

A 25-year-old male, from China, born to unrelated parents was presented to the First People’s Hospital of Huizhou city, China. The clinical manifestations were spastic gait disturbance and vision loss (Table 1). He was suffering from mild gait difficulties by the age of 5 years; the ambulation was unstable, and he could fall easily. The vision loss was reported at the age of 8 years, while the cognitive development was normal. He was born at full term by uncomplicated delivery. The neurological examination of the patient revealed ocular motility disorders, horizontal nystagmus, absence of the left pupillary light reflex, pes cavus, spastic paraparesis on lower limbs, exaggerated bilateral patellar tendon reflexes, ankle clonus, and positive Babinski sign, while no detectable defect was found in the finger-to-nose test, sensory function. The laboratory biochemical studies of full blood count, liver function, plasma electrolytes, thyroid function, vitamin B-12 and folate, sex hormone, autoantibody profile and syphilis serology exhibited typical levels. Cerebrospinal fluid tests revealed increased protein (1186 mg/L); the normal value was 140–450 mg/L. The GALC enzymatic activity [9] detected by Bio-Tek FLx 800 fluorescent analyzer in leukocytes was decreased (3.9 nmol/mg/17 h); the normal value was 18–75 nmol/mg/17 h protein.

The described findings gave reason to perform molecular analysis of the GALC gene. The direct sequencing of the GALC gene (Reference mRNA sequence: NM_000153) in this patient identified a novel missense mutation (c.865G > C: p. G289R) in exon 8 along with a known missense mutation [10] (c.136G > T: p. D46Y) in exon 1 (Figs. 1 and 2). The former mutation was heterozygous in the mother, while the latter was heterozygous in the father.

Brain MRI revealed a high-intensity signal in the left central gyrus cortex by fluid-attenuated inversion recovery (FLAIR) as well as T2-weighted images, while a decreased signal in the T1-weighted images and high-intensity lesions in the bilateral corticospinal tracts were detected (Fig. 3). Cervical spine and thoracic spine MRI showed mild atrophy of the spinal cord (Fig. 4). Moreover, electromyography indicated peripheral nerve demyelination, and both visual evoked potentials (VEP) and brainstem auditory evoked potential (BAEP) were normal.

In the family history, his elder sister’s development was normal until the age of 4 years when spastic gait disturbance and dysarthria were noticed. She suffered from mental and motor regression, and hence, faced difficulties in schooling. She became wheelchair-bound and demented at the age of 22 years. She could not understand what was said to her but responded with a smirk. Other family members, including her parents and elder brother, were unaffected at the time of this analysis (Fig. 5). The GALC enzymatic activity revealed 4.4 nmol/mg/17 h. The GALC genotype was also studied in Patient 2. She carried two heterozygous GALC mutations (p.G289R and p.D46Y), the same as the Patient 1 (Fig. 2).

The mutations were analyzed to assess their pathogenicity. The SIFT scores of the mutations were 0.003 (p.G289R) and 0.013 (p.D46Y), respectively, and the Polyphen2 scores were 0.905 (p.G289R) and 1 (p.D46Y), respectively.

Thus, Krabbe disease was diagnosed in both patients. Since effective therapy is limited, Patient 1 was treated with neuro-nutrition drugs, such as 30 mg per day vitamin B-1 and 1.5 mg per day vitamin B-12 for about 1 month. But his condition was not relieved.