Background Biallelic variants in SMPD4 have recently been associated with a severe neurodevelopmental syndrome characterized by congenital and progressive microcephaly, epilepsy, congenital arthrogryposis and early demise. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. The association between insulin-dependent diabetes and microcephaly was previously observed in rare recessive microcephalies related to endoplasmic reticulum stress and apoptosis. Loss of SMPD4 has been shown to affect endoplasmic reticulum membrane structure by causing dilatation of rough endoplasmic reticulum cisternae and increased autophagy in patient-derived cells in previous studies. However, the effect of SMPD4 loss on the membrane dynamics of the nuclear envelope and their contribution to human disease is unknown. In individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert nuclear pore complexes in the nuclear envelope, is impaired in the absence of SMPD4, and interferes with cerebral corticogenesis and survival of pancreatic beta cells.

Case Report (R) is 5-year-old boy, preterm (35+1/7 weeks), born by emergency cesarian section, birth weight 1.5 kg, for consanguineous parents with similarly affected sibling and intra-uterine fetal death at 7 months gestational age, with Neonatal intensive care unit admission immediately after birth for prematurity and respiratory distress in which he had microcephaly, dysmorphic features, leukoencephalopathy/lissencephaly, arthrogryposis, seizures, ventilator dependent due to respiratory failure and then discharged on home ventilator and anti-epileptics. Other medical disorders: included dysphagia, gastro-esophageal reflux disease, tube feeding, tracheostomy and ventilator dependence, intermittent sinus bradycardia. He was diagnosed at the age of 4 years with type 1 diabetes mellitus presented with hyperglycemic hyperosmolar state. (Genetic test: SMPD4 variant Homozygous2:g.130931103C>A;c.370G>T;p.E124).

Conclusion SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes neurodevelopmental abnormalities and diabetes