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To date, more than 200 cases have been reported worldwide.

Age of onset typically ranges from infancy to childhood but exceptionally may occur in late adolescence or early adulthood. The clinical phenotype is variable with about half of affected individuals presenting global developmental delay, which usually presents in infancy. Cerebellar signs frequently include intention tremor, dysmetria, absence of smooth pursuit and gaze-evoked nystagmus and, more variably, gait ataxia and vertical gaze limitation. Pyramidal signs are typically absent in young children and may develop slowly in older patients. Extrapyramidal signs, typically dystonia, are prominent in only a few patients. Wheelchair dependence typically occurs from the end of the first decade, although half of patients remain ambulatory as adults. Cognition varies from normal to learning difficulties or mild to moderate intellectual disability (most frequent), with slow deterioration in the second decade. Expressive language and swallowing is present until late but deteriorates over time. Dental abnormalities include delayed dentition with abnormal order of deciduous teeth eruption, hypodontia and, less frequently, natal teeth. Delayed puberty or primary amenorrhea is frequent. Most patients have high myopia; optic atrophy is present in older individuals. About half of patients have short stature, and may have growth hormone deficiency. Central hypothyroidism is present in a few patients. Brain magnetic resonance imaging (MRI) shows hypomyelination along with relative T2 hypointensity of optic radiation, posterior limb of internal capsule, anterolateral thalamus, and dentate nucleus.

Mutations of the genes encoding POLR3 (RNA polymerase III) subunits, POLR3A, POLR3B and POLR1C, have been identified. POLR3 is an enzyme responsible for transcription of specific noncoding small RNAs involved in the regulation of transcription, RNA processing, and translation. It is suggested that these mutations lead to abnormal POLR3 function and abnormal production of proteins important for development of central nervous system white matter. Despite the overlap in causal genes, no genotype-phenotype correlation has been identified.

Diagnosis is suspected based on the clinical presentation and the characteristic hypomyelination findings on brain MRI. Blood tests for levels of thyroid, growth and puberty hormones can be helpful. Diagnosis is confirmed by genetic testing.

Other hypomyelinating leukodystrophies, especially when there are no typical dental abnormalities.

Genetic prenatal diagnosis is possible when causal mutations have previously been identified in an affected family.

The disease is inherited in an autosomal recessive manner and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, the risk of inheriting the disease is 25%. POLR3A pathogenic variants tend to correspond with an earlier disease onset, more rapid neurological decline and shorter life expectancy than POLR3B pathogenic variants.

Management and treatment should be multidisciplinary and tailored to the individual. Regular monitoring by an endocrinologist is required. The decision to treat sex and growth hormone deficiency, when present, is individually based. Physical aids and therapy may be required to support motor function. Good dental hygiene and monitoring is recommended to preserve teeth. Regular ophthalmologic follow-up is also necessary, as in most patients, especially with POLR3B mutations, myopia continues to increase.

Prognosis depends primarily on disease severity. At the severe end, affected individuals do not achieve independent walking and have mild to moderate intellectual disability.