Celia’s Encephalopathy (BSCL2-Gene-Related): Current Understanding

Abstract

Seipin, encoded by the BSCL2 gene, is a protein that in humans is expressed mainly in the central nervous system. Uniquely, certain variants in BSCL2 can cause both generalized congenital lipodystrophy type 2, upper and/or lower motor neuron diseases, or progressive encephalopathy, with a poor prognosis during childhood. The latter, Celia’s encephalopathy, which may or may not be associated with generalized lipodystrophy, is caused by the c.985C >T variant. This cytosine to thymine transition creates a cryptic splicing zone that leads to intronization of exon 7, resulting in an aberrant form of seipin, Celia seipin. It has been proposed that the accumulation of this protein, both in the endoplasmic reticulum and in the nucleus of neurons, might be the pathogenetic mechanism of this neurodegenerative condition. In recent years, other variants in BSCL2 associated with generalized lipodystrophy and progressive epileptic encephalopathy have been reported. Interestingly, most of these variants could also lead to the loss of exon 7. In this review, we analyzed the molecular bases of Celia’s encephalopathy and its pathogenic mechanisms, the clinical features of the different variants, and a therapeutic approach in order to slow down the progression of this fatal neurological disorder.

Role of Seipin in Human Diseases and Experimental Animal Models

“…Strikingly, the expression of SEIPIN in the brain is inversely correlated with age, but strongly and positively associated with anti-oxidative stress enzymes such as (superoxide dismutase 1 and 2 and PPARγ) [ 57 ]. Therefore, the mutations of BSCL2 usually induce a variety of serious clinical consequences ( Figure 1 , Table 1 and Supplementary Table S1 ), including CGL2 (OMIM #269700; highest prevalence, estimated to be 0.1–5 persons per million [ 45 , 58 ]), PELD (OMIM #615924; only nine patients reported worldwide so far) [ 59 ], and BSCL2 -associated motor neuron diseases (OMIM #619112 or OMIM #270685; secondary prevalence).…”

“…PELD is a fatal paediatric neurodegenerative disease manifested as severe progressive neurodegeneration and concomitant premature death caused by status epilepticus or pneumonia [ 59 ]. PELD is induced by a special nonsense mutation-c.985C > T in the BSCL2 gene, and the mutation can be homozygous or in compound heterozygosity with c.507_511del, c.538G > T, or c.1004A > C [ 1 , 103 ].…”

“…PELD is induced by a special nonsense mutation-c.985C > T in the BSCL2 gene, and the mutation can be homozygous or in compound heterozygosity with c.507_511del, c.538G > T, or c.1004A > C [ 1 , 103 ]. Recently, Sánchez-Iglesias et al, have comprehensively summarised the diagnosis, treatment, and mechanism of PELD [ 59 ]. The mutation can be homozygous or in compound heterozygosity with other mutations…”

“…These individuals do not suffer from fat metabolism disorder or abnormal distribution of body fat, but do suffer from many motor neuron diseases, such as Silver Syndrome (also known as spastic paraplegia type 17), distal hereditary motor neuropathy type V, and Charcot-Marie-Tooth type 2 [ 1 , 67 ], which are termed “seipinopathies” by Ito and Suzuki [ 104 ]. However, following the terminology used for diseases caused by lamin A/C ( LMNA ) gene mutations, all diseases caused by BSCL2 mutations (CGL2, PELD, and BSCL2 -associated motor neuron diseases) should be called “seipinopathies” [ 59 , 105 ]. Therefore, we call “seipinopathies termed by Ito” other than CGL2 and PELD as “ BSCL2 -associated motor neuron diseases” as per a dyadic nomenclature in this review.…”

“…To date, the main treatments for diseases caused by BSCL2 mutations are directed towards symptoms without specific and targeted therapeutic options [ 58 , 59 ], and yet, research on targeted therapy for PELD and BSCL2 -associated motor neuron diseases is limited. Here, we summarise that seipin deficiency causes phenotypes via inducing adipose tissue loss or impairing the seipin signalling pathway, and two main strategies can be proposed to treat CGL2: (1) restoration of adipose tissue itself or its function to treat metabolic complications resulting from adipocyte seipin deficiency; (2) tackling seipin or seipin upstream or downstream targets to alleviate the effects of seipin deficiency in organs in which seipin works in a cell-autonomous way.…”