We report a case of HBSL in a 45-year old Han Chinese man of Sichuan Province. He had a history of normal birth and development of bilateral lower limb paralysis and delay in motor functions since 2 years of age. He complained of difficulty in walking, abnormal posture, and difficulty in standing after squatting down. By the age of 4 years, the patient could walk only with support, and by 5 years of age, he required support to stand as well. However, both the upper limbs had normal motor and cognitive functions. The patient did not receive any treatment due to poor economic background leading to a delay in diagnosis and treatment. He came for medical advice 1-year back due to progressive weakening in both upper limbs. At the time of consultation, the patient was unable to stand up, faced difficulty in raising upper limbs, and his cognitive function was deranged. On physical examination, findings were muscle strength grade 3 in both the upper limbs, hypermyotonia, hyperreflexia in bilateral upper and lower limbs (+++), positive bilateral Hoffman sign, higher muscle tension in both lower limbs, and a positive bilateral Babinski sign. Laboratory examination revealed plasma thrombin time 15.8 s, rheumatoid factor 21 IU/ml, and blood transferrin level 1.79 g/L. Routine blood test, urine test, and stool test were within normal limits. Liver and kidney function tests, electrolytes, tumor marker, and autoimmune antibody profile revealed no abnormality. An electrocardiogram showed a sinus heart rate of 69 beats per minute. The heart ultrasound showed no significant abnormalities in cardiac structure and blood flow. The electromyogram demonstrated normal right anterior tibial nerve insertion potential, incomplete light and strong contraction, the right dorsal inter bone muscle and bilateral medial femoral myoneurogenic injury, and myogenic damage. Multifocal lesions were detected on MRI by a decreased signal on the T1 sequence, increased signal intensity on the T2/FLAIR, and diffusion-weighted imaging (DWI) sequence showed a of the bilateral basal, centrum ovale, frontal lobe, and parietal lobe, and increased signal on the T2 sequence showed a of ganglia cervical cord (Figure 1).
Whole-exome sequencing analysis was performed using whole-exome capture with NimbleGen2.0, detecting the distribution and concentration of qPCR amplified libraries by AgilentBioanalyzer2100 and Hiseq2500 sequencing. Variant annotation was performed using the PolyPhen-2.2.2 software, ANNOVAR software, HGMD, dbSNP, and 1,000 genome database. Mutations in DARS1 detected were, c.1363T > C (p.Y455H) (of maternal origin) and c.821C > G (p.A274G). Moreover, his elder brothers and sister's mutations in DARS1 detected were c.1363T > C (p.Y455H) and c.821C > G (p.A274G). And his mother's mutations in DARS1 were detected, namely, c.1363T > C (p.Y455H). The two elder brothers and sister of the proband developed weakness of lower limbs and walking unstable, when they were teenagers. The mother of proband has no obvious clinical symptoms at present, but it couldn not rule out the possibility she has no clinical symptoms in the future. (Figure 2). The mutations in DARS1 of the proband and his sibings were c.1363T > C (p.Y455H) (of maternal origin) and c.821C > G (p.A274G) (of paternal origin), and his father died when he was 12 and his gene could not be detected. We speculated that the cause of his father's death was gene mutation (Figure 2; Table 1). The mutations are termed as "pathogenic" and "likely pathogenic" according to the American College of Medical Genetics and Genomics (ACMG) guidelines, and a diagnosis of HBSL was made. The c.1363T > C (p.Y455H) gene was obtained from his mother.
Since HBSL is characterized by hypomyelination, the treatment is essential to promote myelin repair. The patient was prescribed vitamin B1 (Yangzhou Eddie Pharmaceutical Co., Ltd.) 10 mg orally three times a day, methylcobalamin tablets (Wei Material, China Pharmaceutical Co., Ltd.) 0.5 mg three times a day, and cytophosphate choline sodium tablets (Sichuan Zitonggong Pharmaceutical Co., Ltd.) 0.2 g three times a day for a year. On a follow-up visit after 1 year, the patient could lift heavy weight and ambulate with the support of crutches.