Clinical Guidance

POLR3A

• Individuals with POLR3A pathogenic variants tend to have a later disease onset than those with POLR3B pathogenic variants but more rapid disease progression .

• A single female infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have biallelic truncating pathogenic variants in POLR3A .

POLR3B

Source: GeneReviews — "POLR3-Related Leukodystrophy"

Diagnostic Criteria

Suggestive Findings

POLR3-related leukodystrophy should be suspected in individuals with the following major/shared clinical features, which may or may not be present:

• Neurologic dysfunction: progressive cerebellar features, including:

• Gait ataxia, dysarthria, dysmetria, tremor, eye movement abnormalities; and

• To a lesser extent, extrapyramidal (typically dystonia), pyramidal, and cognitive features

• Abnormal dentition (e.g., hypodontia, oligodontia, delayed teeth eruption)

• 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

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

Source: GeneReviews — "POLR3-Related Leukodystrophy"

Differential Diagnosis

The differential diagnosis of POLR3-related leukodystrophy includes other hypomyelinating leukodystrophies. See .

Table 2.

Hypomyelinating Leukodystrophies to Consider in the Differential Diagnosis of POLR3-Related Leukodystrophy

Diff Dx Disorder | Gene(s) | MOI | Clinical Features of DiffDx Disorder

Overlapping w/POLR3-related leukodystrophy | Distinguishing from POLR3-related leukodystrophy

PLP1 disorders

| PLP1 | XL | • Variable age of onset

• Severe hypomyelination in earlier-onset forms on brain MRI

• Prominent cerebellar features in severe "connatal" form of PLP1 disorders

| • Severity ranging from: neonatal presentation w/nystagmus, axial hypotonia evolving into spastic quadraparesis, ataxia (PMD); to an infantile-onset disorder (HEMS); to a later-onset presentation w/spastic paraparesis (SPG2)

Source: GeneReviews — "POLR3-Related Leukodystrophy"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a POLR3-related leukodystrophy, the following are recommended:

• Pediatric neurology consultation

• Swallowing assessment

• Physiotherapy evaluation

• Occupational therapy evaluation

• Speech and language pathology assessment

• Rehabilitation physician (i.e., physiatrist) consultation

• Neuropsychology evaluation

• Brain MRI, if not performed at the time of diagnosis

• Dentistry consultation

• Endocrine consultation

• Ophthalmologic evaluation

• Ear-nose-and-throat specialist consultation for hypersalivation and swallowing issues

• Consultation with a clinical geneticist and/or genetic counselor

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. Manifestations such as ambulation difficulties and seizures are managed in a routine manner. Special caution needs to be taken when managing dysphagia in this disorder as it is known to be quite variable, even in a single day. This is probably due to the prominent cerebellar involvement, leading to more incoordination of swallowing with fatigue, but also with some unpredictability. Dysphagia management is therefore important.

Source: GeneReviews — "POLR3-Related Leukodystrophy"

Clinical Guidance

Avoid the following:

• Foods that are likely to lead to choking

• Medications acting on D2 receptor blockers (e.g., neuroleptics such as haloperidol or risperidone, anti-nausea medications such as metoclopramide) as these can exacerbate the extrapyramidal features

Source: GeneReviews — "POLR3-Related Leukodystrophy"

Therapies Under Investigation

Search ClinicalTrials.gov and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "POLR3-Related Leukodystrophy"

Surveillance Guidelines

No general surveillance guidelines have been developed to date; monitoring should be individualized.

Source: GeneReviews — "POLR3-Related Leukodystrophy"