Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene

Abstract

Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various signaling pathways of the cellular machinery. They function ubiquitously with a predominant role in the central nervous system. Neutral sphingomyelinase type 3, encoded by SMPD4 gene has recently been reported to cause a severe autosomal recessive neurodevelopmental disorder with congenital arthrogryposis and microcephaly. We report a 22-month-old girl having characteristic features of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brainstem. Additionally, she was noted to have nystagmus and visual impairment secondary to macular dystrophy and retinal pigment epithelial stippling at posterior pole. Copy number variant analysis from trio whole exome sequencing (ES) enabled identification of a homozygous 11kb deletion encompassing exons 18 −20 of SMPD 4 gene, confirming the diagnosis of SMPD4-related disorder in her.

Prenatal diagnosis of SMPD4 loss ‐ A neurodevelopmental disorder with microcephaly, arthrogryposis and structural brain anomalies

“…In previous reports, most fetuses presented with fetal growth restriction (73,7%), microcephaly (63,2%) as well as clenched fists and foot deformity such as talus verticalis/rocker bottom feet (52,6%) (Table 1). 1–5 The outcome of the affected children is described as unfavorable: one third die before the age of 1 year. If the above‐mentioned phenotypes are detected during a prenatal sonogram, we suggest performing genetic testing of the fetus and the parents using trio exome sequencing looking for mutations leading to pathogenic variants in the SMPD4 gene, as well as mutations in other potentially relevant genes.…”

“…In previous reports, most fetuses presented with fetal growth restriction (73,7%), microcephaly (63,2%) as well as clenched fists and foot deformity such as talus verticalis/rocker bottom feet (52,6%) (Table 1). [1][2][3][4][5] The outcome of the affected children is described as unfavorable: one third die before the age of 1 year. If…”

Meta-Analysis of Clinical Phenotype and Patient Survival in Neurodevelopmental Disorder with Microcephaly, Arthrogryposis, and Structural Brain Anomalies Due to Bi-allelic Loss of Function Variants in SMPD4

“…(Table 3). This format was used as a template to align other written case reports identified in the literature (Ravenscroft et al, 2021;Monies et al, 2019;Bijarnia-Mahay et al, 2022;Ji et al, 2022). These were manually entered to conform to this template to allow the data to be combined for further analysis.…”

“…An individual reported in Monies et al (2019) presented with distinct symptoms of brain atrophy and skeletal dysplasia whereas the case in Magini et al (2019) with the same variant exhibited more typical clinical features. A recent study by Bijarnia-Mahay et al (2022) presents the case of a 22-month old girl presenting with the typical phenotype of neurodevelopmental delay, prenatal onset growth failure, arthrogryposis, microcephaly and brain anomalies including severe hypomyelination, simplified gyral pattern and hypoplasia of corpus callosum and brainstem. Notably, there was also additional non-typical clinical findings of nystagmus and visual impairment secondary to macular dystrophy and retinal pigment epithelial stippling at posterior pole.…”

“…Many of the clinical features are represented as text descriptions and a variety of non-standard terminologies are applied between cases, making machine interpretation of the data difficult. Other studies (Ji et al, 2022; Bijarnia-Mahay et al, 2022) present only written case reports with some tabulated summaries. While larger studies (Ravenscroft et al, 2021; Monies et al, 2019) focus more on genetic data, with less detail included on the clinical presentation of individuals.…”