To illustrate the case of a woman with Late-onset POLR3-related Leukodystrophy associated with a novel compound heterozygous mutation, and to review available literature describing the expanding phenotype of this condition. 

POLR3-related leukodystrophy is a group of autosomal recessive neurodegenerative disorders caused by variants in POLR3A or POLR3B and usually have common phenotype: early childhood-onset hypomyelinating leukodystrophy manifesting with variable combinations of cerebellar ataxia, tremor, spasticity, cognitive impairment, oligodontia and hypogonadotropic hypogonadism. Recently, a novel phenotype of adult-onset spastic ataxia was identified in individuals with the c.1909+22G>A POLR3A intronic variant in compound heterozygosity.

A 35-year-old woman presented with progressive neurological symptoms that started in her late 20s. She described difficulty with ambulation due to leg weakness, abnormal balance, frequent falls, intermittent right hand dystonia as well as spasms and numbness in her lower extremities. On exam the patient had ataxia, steppage gait, dystonia, hyporeflexia and dysrhythmia. Imaging revealed non-specific, mild T2/FLAIR hyperintensities in the periventricular white matter bilaterally. Family history was negative. Whole genome sequencing identified bi-allelic alterations in POLR3A: a heterozygous c.1909+22G>A (paternal) variant in intron 14 and a heterozygous nonsense variant, c.2617C>T (p.Arg873Ter; maternal) in exon 20.

The c.1909+22G>A variant has been identified in at least 30 unrelated individuals in a compound heterozygous state, all presenting with limb and gait ataxia near the second decade. The variant c.2617C>T creates a premature translational stop signal in the POLR3A gene, expected to result in an absent protein product. This mutation has been observed in individuals with neonatal progeroid syndrome and/or spastic ataxia.  This specific compound heterozygous mutation has not been described. 

This report supports the strong genotype-phenotype correlation of the c.1909+22G>A variant, regardless of the different secondary mutations and combinations. Thus, this specific mutation may modulate the POLR3A-related leukodystrophy phenotype away from the classical hypomyelination phenotype towards a milder ataxia type.