Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.

Sphingomyelin phosphodiesterase 4 (SMPD4) encodes a member of the Mg2+-dependent, neutral sphingomyelinase family that catalyzes the hydrolysis of the phosphodiester bond of sphingomyelin to form phosphorylcholine and ceramide. Recent studies have revealed that biallelic loss-of-function variants of SMPD4 cause syndromic neurodevelopmental disorders characterized by microcephaly, congenital arthrogryposis, and structural brain anomalies. In this study, three novel loss-of-function SMPD4 variants were identified using exome sequencing (ES) in two independent patients with developmental delays, microcephaly, seizures, and brain structural abnormalities. Patient 1 had a homozygous c.740_741del, p.(Val247Glufs*21) variant and showed profound intellectual disability, hepatomegaly, a simplified gyral pattern, and a thin corpus callosum without congenital dysmorphic features. Patient 2 had a compound heterozygous nonsense c.2124_2125del, p.(Phe709*) variant and splice site c.1188+2dup variant. RNA analysis revealed that the c.1188+2dup variant caused exon 13 skipping, leading to a frameshift (p.Ala406Ser*6). In vitro transcription analysis using minigene system suggested that mRNA transcribed from mutant allele may be degraded by nonsense-mediated mRNA decay system. He exhibited diverse manifestations, including growth defects, muscle hypotonia, respiratory distress, arthrogryposis, insulin-dependent diabetes mellitus, sensorineural hearing loss, facial dysmorphism, and various brain abnormalities, including cerebral atrophy, hypomyelination, and cerebellar hypoplasia. Here, we review previous literatures and discuss the phenotypic diversity of SMPD4-related disorders.

Structural correlates of literacy difficulties in the second language: Evidence from Mandarin-speaking children learning English.

Several neuroimaging studies have explored the neural basis of literacy difficulties in the second language (L2). However, it remains unclear whether the associated neural alterations are related to literacy abilities in the first language (L1). Using magnetic resonance imaging, we explore this issue with two experiments in Mandarin-speaking children learning English as second language. In the first experiment, we investigated children with literacy difficulties in L2 and L1 (poor in both, PB) and children with literacy difficulties only in L2 (poor in English, PE). We compared the brain structure in these two groups to a control literacy (CL) group. The results showed that the CL group had significantly less gray matter volume in the left supramarginal gyrus compared to the PB group and moderately less gray matter volume compared to the PE group. In addition, the PB group had significant greater gray matter volume in the left medial fusiform gyrus compared to the PE group and had marginally greater gray matter volume compared to the CL group. In the second experiment, we explored the relationship between the two atypical regions and literacy abilities in the two languages in an independent sample consisting of children with typical literacy. Correlation analyses revealed that the left supramarginal gyrus was significantly associated with literacy performance only in the second language, English, whereas the left medial fusiform gyrus did not correlate with the performances in either L1 or L2. Taken together, these findings suggest that literacy difficulties in an alphabetic L2 are associated with a structural abnormality in the left supramarginal gyrus, a region implicated in phonological processing, which is independent of literacy abilities in the native language.