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

Abstract

Background A number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes. Case presentation We describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient’s lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy. Conclusions Metreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.

Role of Seipin in Human Diseases and Experimental Animal Models

“…Another seven female patients between the ages of 15 and 40 years with lipodystrophy (5 patients with CGL1 and 2 patients with acquired generalised lipodystrophy) have commenced regular menses from primary amenorrhea or abnormal menstruation after this therapy [ 96 ]. Finally, in two PELD patients, leptin-replacement therapy delayed the neurological regression and allowed better seizure control [ 119 , 120 ].…”

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

“…In 2019, Serino et al [ 89 ] published the case of a child with CGL2, myoclonic epilepsy, and progressive neurological deterioration due to the variant c.1076dupC (exon 9) in the BSCL2 gene ( Table 1 , patient 21), another condition that could be considered a new form of Celia’s encephalopathy [ 90 ]. This variant would give rise to a premature stop codon in the transcript NM_001122955.3, p.(Glu360*), [CCT (Pro) GAA (Glu) >> CCC (Pro) TGA (*)].…”

“…Along the same lines, another of the patients with the c.974dupG variant has been receiving metreleptin and fish oil since the age of 6 months and, at the time of writing ( Table 1 , patient 11), at 4.5 years of age, she does not present neurological symptoms, attends preschool and receives speech therapy but otherwise seems to have normal cognition (Dr. Melissa Crocker, personal communication). In addition, recently, Pedicelli et al [ 90 ] have reported that treatment with metreleptin for one year reduced the number of epileptic seizures in an 11-year-old boy with the homozygous c.1076dupC variant [ 89 ].…”