Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H leukodystrophy/syndrome), Ataxia, delayed dentition, and hypomyelination (ADDH), Tremor-ataxia with central hypomyelination (TACH), Leukodystrophy with oligodontia (LO), Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC).[1]
This illustration shows patients with POLR3-HLD, who have typical features of that disease (except for subject 28, who also has Treacher-Collins syndrome), such as: flat midface, smooth philtrum, and pointed chin.
With POLR3A mutation, the prognosis is worse than in patients with POLR3B mutations.
POLR3-Related Leukodystrophy (also known as 4H leukodystrophy) is a rare hereditary disorder which is caused by mutations in RNA polymerase III subunit genes, such as: POLR3A, POLR3B, POLR3K, POLR3D, POLR1C.[2] Patients with POLR3-related leukodystrophy usually experience cognitive deficits, with/without endocrine problems (such as: short stature, hypogonadotropic hypogonadism), dental anomalies (such as: hypodontia, and delayed dentition), and/or nearsightedness.[3][1] This disease usually debuts in early childhood, although there are late-onset cases.[1][4]
POLR3-Related Leukodystrophy is inherited in autosomal recessive fashion.[5] There are 321 reported cases of POLR3-related leukodystrophy.[6]
Symptoms
MRI of the brain of the patient with POLR3-HLD. Extensive signal abnormalities of the whole white matter appearing hyperintense on T2 axial-weighted image (A) and hypointense on T1 axial-weighted image (B), which indicates hypomyelination, volume of basal ganglia is normal. On figure C, T2-weighted midline sagittal image showed corpus callosum hypoplasia (arrowheads) and cerebellar atrophy (arrow).
Facial features might include a smooth philtrum, a flat midface, and a pointy chin. Patients with POLR3B mutation usually have a thin upper lip, and in patients with POLR1C a bitemporal narrowing can be seen.[10] One patient with POLR1C mutation got diagnosed with POLR3-related leukodystrophy and Treacher-Collins syndrome.[11]
Diagnosis
Diagnosis of POLR3-Related Leukodystrophy can be made by its classical symptoms and brain MRI and pathogenic biallelic variants in RNA polymerase III subunits genes (such as POLR3A).[1]
Cause
This illustration shows RNA polymerase III complex. POLR3A, POLR3B, POLR3K, POLR3D, POLR1C are implicateed in this disorder
POLR3-Related Leukodystrophy is caused by a biallelic mutations in RNA polymerase III subunits, such as: POLR3A, POLR3B, POLR3D, POLR3K, POLR1C.[12][6] Much more severe mutation in POLR3A and POLR3B can cause Wiedemann-Rautenstrauch syndrome, and POLR1C mutations can also cause Treacher-Collins syndrome.[6] Patients with heterozygous might also experience Charcot-Marie-Tooth disease type 1I, who develop symptoms in the first years of life with gait abnormalities, hyporeflexia, sensory ataxia, spasticity, and distal sensory problems due to sensorimotor neuropathy that usually affects lower limbs.[13] Also patients with POLR3B variant can develop isolated hypogonadism.[14]
Pathophysiology
RNA polymerase III transcribes non-coding RNAs (RNA that don't encode any proteins) such as 5S ribosomal RNA, tRNA genes, U6 small nuclear RNA, selenocysteine tRNA gene, 7SL RNA gene, vault RNA genes, and BC200 RNA gene.[12][15] tRNA genes might participate in MBP (Myelin Basic Protein) translation and 7SL RNA might participate in translocation of mRNA of transmembrane or secreted proteins to endoplasmic reticulum, and in this disease this mechanism might be hampered and cause hypomyelination.[12] Decreased levels of BC200 RNA might cause dysregulated post-synaptic translation (by preventing assembly of 48S ribosomal complex), which might contribute to cerebellar symptoms (and in rare cases striatum), and dysregulated synthesis of MBP, which also can contribute to hypomyelination.[16][12] RNA polymerase III mutations can decrease levels of ARX gene, which in turn decreases GABAergicsynapses, which might cause seizures in patients.[17] Hypogonadism might be caused by aberrant small RNA synthesis, resulting in defective transcription of key mediators mandatory for the function of the GnRH receptor protein or for gonadotropin synthesis.[18]
Due to decreased amount of RNA polymerase III might decrease level of RMRP, which in turn might cause hypodontia (RMRP participates in dentition).[14]
Treatment
This disease doesn't have a cure.[12] Management is multidisciplinary and should be tailored to each patient Monitoring by endocrinologist might be necessary for endocrine problems, and ophthalmologist monitoring for myopia. Physical aids and therapy might be necessary for motor function support, and good dental hygiene is necessary to prevent teeth loss.[7]
History
This disorder was first described by Atrouni and colleagues in a consanguineous Syrian family in 2003, and name 4H leukodystrophy was coined in 2006 by Timmons and colleagues.[19][20] The first gene (POLR3A) to cause that disorder was discovered by Bernard and colleagues in 2011 (In 2010, Bernard and colleagues mapped this disorder to 10q22.3-10q23.31 region).[21][22]
References
12345Bernard, Geneviève; Vanderver, Adeline (1993), Adam, Margaret P.; Bick, Sarah; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "POLR3-Related Leukodystrophy", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID22855961, retrieved 2026-03-02
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