POLR3-Related Leukodystrophy

Clinical characteristics: POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings:

1. Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions)

2. Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth)

3. Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty

4. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe

POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include:

1. Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome);

2. Ataxia, delayed dentition, and hypomyelination (ADDH);

3. Tremor-ataxia with central hypomyelination (TACH);

4. Leukodystrophy with oligodontia (LO);

5. Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC).

Age of onset is typically in early childhood but later-onset cases have also been reported.

An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.

Diagnosis/testing: POLR3-related leukodystrophy is diagnosed by the combination of classic clinical findings, typical brain MRI features, and the presence of biallelic pathogenic variants in POLR3A, POLR3B, or POLR1C.

Management: Treatment of manifestations: Individualized care by a multidisciplinary team including a pediatric neurologist, clinical geneticist, physiotherapist, occupational therapist, speech and language pathologist, neuropsychologist, rehabilitation physician, dentist, endocrinologist, ophthalmologist, ear-nose-and-throat specialist, and primary care physician is recommended. Special caution needs to be taken when managing dysphagia in this disorder as it is known to vary widely, even in a single day. Swallowing difficulties will progress over time and dystonia should be monitored and treated to prevent complications and improve the quality of life.

Genetic counseling: POLR3-related leukodystrophy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants in the family are known.