POLR3A – 4H syndrome (leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome)

POLR3A encodes the largest subunit of RNA polymerase III, which transcribes small noncoding RNAs required for myelin production and oligodendrocyte function. Biallelic pathogenic variants in POLR3A underlie 4H syndrome (leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome), an autosomal-recessive disorder characterized by hypomyelination on brain MRI, cerebellar atrophy, hypodontia, and hypogonadotropic hypogonadism. Patients often present in childhood with motor delays and progressive neurologic features.

Genetic studies have identified at least 5 affected individuals from 4 families with compound heterozygous or homozygous POLR3A variants: c.3991G>A (p.Ala1331Thr) and c.3014G>A (p.Arg1005His) in a 20-year-old male (1 proband) (PMID:22451160); c.3745A>C (p.Asn1249His) and c.2554A>G (p.Met852Val) in a 33-year-old male (1 proband) (PMID:22819058); neuropathologic confirmation of oligodendrocyte loss and myelin deficiency in a single patient (1 proband) (PMID:23242285); and two siblings with a homozygous POLR3A variant presenting with classic 4H features plus type 1 diabetes mellitus (2 probands) (PMID:36974356).

The variant spectrum is dominated by missense substitutions (e.g., c.3991G>A (p.Ala1331Thr)), with fewer splice-site and deep-intronic alleles. All reported variants are predicted damaging at evolutionarily conserved residues and segregate with disease in affected sibships. No recurrent founder alleles have been described to date.

Segregation analysis supports autosomal-recessive inheritance, with at least 1 additional affected sibling demonstrating concordant biallelic variants in one family (PMID:36974356). Brain MRI in all cases revealed diffuse central hypomyelination (HP:0003429) with preservation of U-fibers and cerebellar involvement, correlating with clinical ataxia (HP:0001251), intellectual disability (HP:0001249), hypodontia (HP:0000668), delayed tooth eruption (HP:0000684), and hypogonadotropic hypogonadism (HP:0000044).

Functional and experimental evidence demonstrates that POLR3A mutations impair Pol III transcription, leading to oligodendrocyte dysfunction. Neuropathologic examination of brain tissue showed marked loss of oligodendrocytes and severe myelin depletion with patchy preservation of white matter (PMID:23242285). In patient fibroblasts carrying splice-region and missense POLR3A mutations, quantitative RT-PCR revealed reduced expression of Pol III targets (HNRNPH2, UBB, LTF, HSP90AA1) with restoration to normal levels only by wild-type POLR3A overexpression (PMID:33134517).

Collectively, these data support a “Moderate” level of clinical validity for the POLR3A–4H syndrome association, with multiple unrelated probands, segregation, and concordant functional findings. Characterization of the molecular mechanism highlights Pol III hypofunction as the pathogenic driver. Key Take-home: Biallelic POLR3A variants cause 4H syndrome, and genetic testing informs diagnosis, prognosis, and potential therapeutic targeting of Pol III–related pathways.

References

• Archives of neurology • 2012 • 4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations. PMID:22451160
• Journal of the neurological sciences • 2012 • Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III. PMID:22819058
• Journal of neuropathology and experimental neurology • 2013 • More than hypomyelination in Pol-III disorder. PMID:23242285
• Journal of clinical research in pediatric endocrinology • 2025 • The First Case of 4H Syndrome with Type 1 Diabetes Mellitus PMID:36974356
• Neurology. Genetics • 2020 • Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations. PMID:33134517

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