POLR3-related leukodystrophy panel [5 genes]
Hypomyelinating leukodystrophies are a group of neurodevelopmental disorders in which a permanent deficiency in [5 genes] the amount of myelin occurs in the central nervous system, either due to its abnormal formation or to altered oligodendrocyte differentiation or migration. Generally, this group of diseases are clinically characterized by developmental retardation, hypotonia, ataxia, spasticity, and a variable degree of intellectual disability. In radiologic terms, hypomyelination is characterized by diffuse hyperintensity on T2/FLAIR imaging that often seems to uniformly affect white matter. On the other hand, unlike demyelinating disorders where the T1-weighed sequence signal is hypointense, changes in this sequence can be isointense or slightly hypo- or hyperintense. This pattern can be overlooked unless several consecutive sequences are examined; thus, it needs to be observed in at least two images taken within an interval of at least six months in a patient over age 1.
Among the most frequent disorders is Pelizaeus-Merzbacher disease (PMD), caused by pathogenic variants in the PLP1 gene, as well as a series of diseases with similar clinical and radiologic features, known as PMD-like diseases (PMDL), caused by defects in GJC2, AIMP1, or HSPD. Among the rest of hypomyelinating diseases, it is worth noting Pol III-associated disorders, Cockayne syndrome, tricotiodystrophy with photosensitivity or Tay syndrome, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and hypomyelination and congenital cataract (HCC).
Priority Genes : Genes where there is sufficient evidence (clinical and functional) to consider them associated with the disease; they are included in the clinical practice guidelines.
Secondary Genes: Genes related to the disease, but with a lower level of evidence or that constitute sporadic cases.
* Candidate Genes: Not enough evidence in humans, but potentially associated with the disease.
- FOLR1 Cerebral folate transport deficiency
- GJA1: Oculodentodigital dysplasia
- SLC17A5:Free sialic acid storage disease
- FUCA1: Fucosidosis
- GALT: Galactosemia
- RARS: RARS-associated hypomyelination
- BCAP31: Deafness, dystonia, and cerebral hypomyelination
- SLC25A12: Global cerebral hypomyelination
- DARS: Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL)
- TUBB4A:Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)
- FAM126A Hypomyelination and congenital cataract (HCC)
- AIFM1: X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD)
- PYCR2: Hypomyelinating leukodystrophy-10 (HDL10)
- VPS11: Hypomyelinating leukodystrophy-12 (HDL12
- HIKESHI: Hypomyelinating leukodystrophy-13 (HDL13)
- UFM1: Hypomyelinating leukodystrophy-14 (HDL14)
- EPRS: Hypomyelinating leukodystrophy-15 (HDL15)
- TMEM106B: Hypomyelinating leukodystrophy-16 (HDL16)
- AIMP2: Hypomyelinating leukodystrophy-17 (HDL17)
- DEGS1: Hypomyelinating leukodystrophy-18 (HDL18)
- NKX6-2: Leukodystrophies with intracranial cysts or cavitating lesions
- MCOLN1: Mucolipidosis type IV
- PLP1, GJC2, AIMP1, HSPD1, SLC16A2: PMD-PMLD
- POLR3A, POLR3B, POLR1C, POLR3K, POLR1A: POLR3-related disorders or 4H syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia)
- ERCC6, ERCC8: Cockayne syndrome
- SOX10: Waardenburg-Hirschsprung syndrome
- ERCC2, ERCC3, GTF2H5, MPLKIP: Trichothiodystrophy/Tay syndrome
- RNF113A: Trichothiodystrophy/Tay syndrome