Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia’s encephalopathy

Abstract

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Metreleptin for the treatment of progressive encephalopathy with/without lipodystrophy (PELD) in a child with progressive myoclonic epilepsy: a case report

“…The neurological impairment remains stable. These results are in line with a previous case reported by Araújo-Vilar and colleagues, who demonstrated a clear slowdown in neurological regression with metreleptin treatment in combination with a diet rich in polyunsaturated fatty acids in a child with PELD [9].…”

“…Conditions associated with variants in the BSCL2/seipin gene include progressive encephalopathy with/without lipodystrophy (PELD), also called Celia's encephalopathy (MIM#615924) and congenital general lipodystrophy type 2 (CGL2) [2,5]. PELD is associated with BSCL2 variants that cause skipping of exon 7 and is characterized by the development of progressive myoclonic epilepsy (PME) at a young age and severe progressive neurological impairment, which is rapidly fatal in many, but not all, cases [8][9][10][11][12][13][14].…”

“…Without effective treatment, the prognosis for patients with PELD is poor because of the intractable epilepsy and rapid neurodegeneration [ 10 , 11 , 13 ]. Preliminary data suggest that leptin replacement therapy, combined with dietary intervention, may provide some benefit in patients with PELD [ 9 ]. Metreleptin, a recombinant analogue of leptin, has been shown to improve metabolic abnormalities in patients with lipodystrophy, including pediatric patients with CGL2, and is currently the only drug indicated specifically for the treatment of generalized lipodystrophy [ 2 , 6 , 15 ].…”

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

“…In this case, the patient has both phenotypes of progressive encephalopathy and lipodystrophy. Recently, it was shown that metreleptin intervention, used for lipodystrophy treatment, could help a compound heterozygous patient with PELD [ 111 ].…”

Data on the effect of Angiotensin II and 6-hydroxydopamine on reactive oxygen species production, antioxidant gene expression and viability of different neuronal cell lines

“…Dopaminergic Mes23.5 cell line, dopaminergic N27 cell line and SH-SY5Y cell line were cultured as previously described [2] , [3] , [4] . AngII (A9525, Sigma) was used at a concentration of 100 nM 30 min before treatment with the dopaminergic neurotoxin 6-OHDA (0.02% saline ascorbate; H4381 Sigma) when used in combination, except otherwise stated.…”