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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. [ABSTRACT FROM AUTHOR]

Purpose Pelizaeus–Merzbacher disease (PMD) is a rare X-linked recessive hypomyelination disorder characterized by nystagmus, ataxia, impaired motor development, and progressive spasticity. Identification of proteolipid protein 1 ( PLP1 ) mutations in Chinese patients with Pelizaeus–Merzbacher disease (PMD) and confirmation of the biological impacts of the identified mutations are the aims of this study. Methods An analysis of clinical materials and a follow-up study were conducted for the patients with PMD. Sequencing and immunofluorescence were applied for molecular analysis of the causative gene PLP1 . Results We identified PLP1 mutations in seven male patients with PMD. Three novel missense mutations (c.353C>G, p.T118R; c.623G>T, p.G208V; c.709T>G, p.F237V) and three reported missense mutations (c.467C>T, p.T156I; c.517C>T, p.P173S; c.646C>T, p.P216S) of PLP1 were identified from seven Chinese PMD patients. The three mutations (F237V in patient 2, P216S in patient 5 and T156I in patient 6) were de novo . Mutant proteins were trapped in the lumen of endoplasmic reticulum. Conclusion We have identified six pathogenic mutations, enriching the specific spectrum of missense mutations in the patients with PMD. The six PLP1 mutations are probably pathogenic. By reviewing the known PLP1 mutations, we have preliminarily revealed the position of missense mutation may be associated with the severity of PMD. [ABSTRACT FROM AUTHOR]