A 42-Year-Old Woman with 4H Leukodystrophy Caused by a Homozygous Mutation in POLR3A Gene
4H leukodystrophy is a rare inherited disorder characterized by the triad of hypomyelination, hypogonadotropic hypogonadism, and hypodontia. It is caused by mutations in POLR3A or POLR3B, genes encoding subunits of RNA polymerase III. This report describes the first case in China of a 42-year-old woman with 4H leukodystrophy harboring a homozygous mutation in POLR3A (c.1911+18C>T), providing insights into the clinical trajectory, diagnostic challenges, and genetic underpinnings of this condition.
Clinical Presentation and Disease Course
The patient, born to non-consanguineous parents without a family history of neurological disorders, exhibited a prolonged and atypical disease course. Early signs of hypodontia emerged at age 1, with delayed tooth eruption and absence of permanent teeth by age 5. Growth arrest occurred at age 15, resulting in a final height below 150 cm. Notably, her cognitive function remained intact until age 35, when mild intellectual impairment became apparent. Secondary amenorrhea developed at age 38, followed by progressive cerebellar ataxia at age 39, which gradually impaired daily functioning by age 42.
Clinical examination revealed short stature (height <150 cm), tooth dysplasia, and cerebellar ataxia. Neurological evaluation showed no nystagmus or optic atrophy, and the Mini-Mental State Examination (MMSE) score of 19 indicated mild cognitive decline. Despite these deficits, the patient had a normal reproductive history, delivering a healthy son via cesarean section at age 23. Her son and brother exhibited no neurological symptoms, though genetic testing confirmed they were heterozygous carriers of the POLR3A mutation.
Diagnostic Investigations
Endocrine and Imaging Findings:
Pelvic ultrasound revealed a postmenopausal uterine morphology. Hormonal assays confirmed hypogonadotropic hypogonadism, with markedly reduced levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Supplementary Table 1). Brain MRI demonstrated diffuse white matter hypomyelination in bilateral cerebral hemispheres on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, alongside global cortical atrophy on T1-weighted images (Figure 1A, 1B). Dental panoramic radiographs confirmed hypodontia, showing abnormal tooth eruption and shortened roots (Supplementary Figure 2A, 2B).
Genetic Analysis:
Whole-exome sequencing identified a homozygous mutation in POLR3A (c.1911+18C>T), located in intron 13. Sanger sequencing validated this variant in the proband and confirmed heterozygous carrier status in her son and brother (Supplementary Figure 3A–C). The mutation, documented in the Online Mendelian Inheritance in Man (OMIM #607694), was classified as pathogenic under American College of Medical Genetics and Genomics (ACMG) guidelines. Parental genetic testing was unavailable, but the brother’s heterozygosity and the parents’ unaffected phenotypes supported an autosomal recessive inheritance pattern.
Diagnostic Considerations
The diagnosis of 4H leukodystrophy was established based on clinical, imaging, and genetic evidence:
- Triad of Hypomyelination, Hypogonadism, and Hypodontia: The patient fulfilled all three criteria, with MRI confirming hypomyelination, hormonal deficits indicating hypogonadotropic hypogonadism, and dental imaging revealing hypodontia.
- Genetic Confirmation: The homozygous POLR3A mutation, previously associated with 4H leukodystrophy, provided molecular validation.
- Differential Diagnosis Exclusion: Other leukodystrophies (e.g., Pelizaeus-Merzbacher disease) and congenital hypogonadotropic hypogonadism syndromes were ruled out through genetic testing and clinical correlation.
Disease Progression and Management
The patient’s late-onset neurological symptoms contrasted with typical 4H leukodystrophy presentations, which often manifest in childhood or adolescence. Initial symptoms (hypodontia, growth delay) emerged in early life, but significant neurological decline occurred decades later. This indolent progression underscores the phenotypic variability of POLR3A-related disorders, which can range from severe infantile forms to milder adult-onset cases.
Hormone replacement therapy (HRT) was recommended to address hypogonadism, though the report does not specify whether the patient initiated treatment. Previous studies suggest HRT can improve quality of life by alleviating hormonal deficiencies and associated complications.
Implications for Clinical Practice
- Early Diagnosis: Recognition of non-neurological features (e.g., dental anomalies, growth failure) is critical for early diagnosis, particularly in regions with limited access to advanced genetic testing.
- Genetic Counseling: Families should be informed of the 25% recurrence risk for autosomal recessive conditions and offered carrier testing for relatives.
- Multidisciplinary Care: Management requires collaboration between neurologists, endocrinologists, dentists, and geneticists to address multisystem involvement.
Unanswered Questions and Future Directions
- Genotype-Phenotype Correlations: The c.1911+18C>T mutation’s effect on RNA polymerase III function remains unclear. Further studies are needed to elucidate how this intronic variant disrupts splicing or gene expression.
- Long-Term Outcomes: The patient’s preserved reproductive capacity and delayed neurological decline highlight the need for longitudinal studies to define natural history and optimize interventions.
- Therapeutic Strategies: While no disease-modifying therapies exist, research into RNA polymerase III biology may identify targets for molecular interventions.
Conclusion
This case expands the geographic and phenotypic spectrum of 4H leukodystrophy, emphasizing the importance of genetic testing in adults with unexplained neurological deterioration. The identification of a novel POLR3A mutation in China underscores the global prevalence of this condition and the need for increased awareness among clinicians.
doi.org/10.1097/CM9.0000000000000328
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