Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients

Abstract

Objective: Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population.

Methods: 119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing.

Results: Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively.

Significance: This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.

Fig 1. MRI findings of patients with hypomyelinating disorders.

(A)–(C) P65 with PMD at 69 months of age. Homogeneous T2 hyperintensity in white matter and atrophy of corpus callosum is seen in axial T2WI (A) and sagittal T1WI (C). Axial T1WI (B) shows mild hyperintensity. (D)–(E) P106 with HABC at 7 years of age shows atrophy of cerebrum, relative preserved putamen, mild atrophy in caudate nucleus in axial T2WI (D), atrophy of cerebellum and corpus callosum in saggital T1WI (E). (F)–(G) P111 with GM1 gangliosidosis at 69 months of age showing T2 hyperintensity and cerebral atrophy. (H)–(I) P115 with GM2 gangliosidosis at 14 months old. T2WI shows diffuse hyperintensity in white matter and hypointensity in bilateral thalami (H), and mild hypointensity in white matter in T1WI (I). (J) Axial T2WI in P117 with Pol III-related leukodystrophy at 3 years of age showing diffuse T2 hyperintensity in deep white matter and posterior limb of internal capsules. T2 hypointensity was presented in anterior limb of internal capsules and corpus callosum. Axial T2WI (K) and saggital T1WI (L) of P118 with HLD9 at 18 months of age showing diffuse T2 hyperintensity in white matter and atrophy of cerebrum and corpus callosum.

Fig 2. P117’s and P118’s pedigrees.

(A) Compound heterozygous mutations of POLR3A c.2722G>T (p.D908Y) and c.200G>A (p.R67H) in P117. (B) Compound heterozygous mutations of RARS c.5A>G (p.D2G) and c.1625+2T>G in P118.

Fig 3. High-resolution G-banding chromosome analysis for P119 with chromosome 18q deletion syndrome.

(A) A mosaic karyotype of 46,XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18 of P119. (B) Detailed illustrations of 46,XX,del(18)(q21.3). (C) Detailed illustrations of 46,XX,r(18)(p11.32q21.3).