Our case from the southern district of China displayed severe neurological manifestations and presented with typical childhood onset with various features such as cerebellar symptoms (spasticity and ataxia), cognitive regression, motor decline, and delayed dentition. Brain MRI indicated delayed myelination or hypomyelination of white matter in the focal area around the posterior horn of the bilateral lateral ventricles. Takanashi et al. reported that hypomyelination of the brain often indicates POLR3A mutation, which is associated with leukodystrophy disorders . To verify this, we performed medical exome sequencing and found novel compound heterozygous mutations of the POLR3A gene, reminiscent of other patients. According to the clinical manifestations, we concluded the diagnosis and identified the compound heterozygous variants as the causative variants for the disease in this patient. It is noteworthy that this disease has mostly been reported in European populations, including French-Canadian, Caucasian, and Syrian individuals [2, 7]. Occasional cases have been reported in the Indian population [13-15]. However, this is the first case reported in a Chinese family.
Neurological impairment of our case started in the infantile period with a decline in motor ability, cognitive impairment, and cerebellar features. Although cerebellar signs of this case became progressively obvious, cerebellar atrophy was not observed, which is likely related to the molecular basis or other factors. Previous studies have found that cerebellar anomalies were more severe in patients with POLR3B defects while the pattern of hypomyelinization was more evident in the MRI of patients with POLR3A mutations [2, 6]. This may be another explanation for our case. Our patient also showed classical extraneurologic features, characterized by hypodontia with delayed tooth eruption and short stature. She also displayed polytrichia, an atypical feature of POLR3-related leukodystrophy, which may be due to aberrant endocrine hormone levels or other reasons. Hypogonadotropic hypogonadism was not detected because she was too young. Previous studies have also shown that the syndrome may or may not be associated with hypodontia and/or hypogonadotrophic hypogonadism in many cases [8, 11]. The case did not show myopia and optic atrophy. This is inconsistent with most cases, which are usually accompanied by myopia . Her dysphagia phenotype was striking. She had obvious difficulty with tube feeding and forceful vomiting occurred frequently. This is likely due to the incoordination of swallowing of cerebellar syndrome, or due to other unpredictable reasons. Bronchodysplasia is another feature first observed in POLR3-related leukodystrophy, suggesting that it was not recognized previously in the POLR3-related leukodystrophy spectrum. Thus, in addition to the classical extraneurological features, abnormal body hair and visceral smooth muscle features should be carefully looked for in patients with POLR3-related. When classical features do not exist, rare manifestations will a clue in the diagnosis of this disorder. Although there is no cure for this disease to date, treatment of manifestations such as seizures, hypogonadotropic hypogonadism, dystonia, and dysphagia can be managed on an individual basis for an improved quality of life and the prevention of complications.
Our case presented with severe manifestation at early onset and diverse manifestations among those of patients with POLR3-related leukodystrophy, which may be a result of the genotype identified in this patient; further analysis is necessary. To date, four genes (POLR3A, POLR3B, POLR1C, and POLR3K) have been reported to be associated with POLR3-related leukodystrophy [11, 16]. Most of the identified mutations are point mutations in the codon region; however, non-coding DNA variants are suspected to account for a substantial portion of undiscovered causes of rare diseases [17, 18]. Minnerop et al. identified mutations in deep intronic regions of POLR3A as a common cause of hereditary spastic paraplegia and cerebellar ataxia, and > 80% of POLR3A mutation carriers presented the same deep intronic mutation (c.1909+22G>A), which leads to a novel, distinct, uniform, and severe phenotype . Jay et al. also reported alteration of mRNA splicing in POLR3A causing neonatal progeroid syndrome with severe clinical manifestations . In this study, we identified the c.1771-6C>G (NM_007055) mutation adjacent to the mRNA splice site demonstrating that exploring non-coding genomic regions was helpful in revealing the causes of related hereditary diseases.
The complexity of clinical phenotypes and the heterogeneity of genotypes raise new challenges in genetic diagnoses. In the present study, medical exome sequencing was used to explore the possible genetic defects resulting in the disease of the patient. Compared to whole genome and whole exome sequencing, medical exome sequencing focuses on clinical interpretable regions of genes; less variants of uncertain significance in medical exome sequencing greatly improve the diagnostic yield and increase the coverage depth of sequencing, improving the accuracy of sequencing and broadening the spectrum of variants. In the present study, we identified novel heterozygous mutations of POLR3A that caused POLR3-related leukodystrophy disease for the first time in a Chinese family. This study will further our understanding of the molecular mechanisms of POLR3-related leukodystrophy and contribute to further analysis of phenotype–genotype correlations of related disorders.