Abstract
Objectives:
To describe a case of Progressive Encephalopathy with or without Lipodystrophy (PELD), characterized by a late onset of neurological regression at 9 years old, due to a homozygous c.974dupG variant in the BSCL2 gene.
Methods:
An 11-year, 9-month-old girl with repeated seizures over 2 years underwent clinical assessment and genetic investigation. We also reviewed the published literature.
Results:
The patient exhibited mild intellectual disability, a lipodystrophic appearance, precocious puberty, voracious appetite, elevated transaminase levels, hyperlipidemia, hypercortisolism, hepatomegaly, fatty liver, and splenomegaly. Motor and cognitive regression occurred at 9 years. A homozygous pathogenic variant c.974dup (p.Ile326HisfsTer12) in exon 7 of BSCL2 (NM_001122955.4) was identified. Despite multiple antiseizure medications, seizures were refractory, leading to status epilepticus and rapid death after genetic diagnosis.
Conclusion:
We confirm that the BSCL2 c.974dupG variant is a cause of PELD. Regression may occur later than previously reported. Literature review suggests that the c.974dupG variant may present a milder phenotype compared to the classic c.985C>T variant. Early genetic testing and diagnosis are crucial for improving outcomes in rare neurodegenerative disorders like PELD.
Introduction
The BSCL2 gene is located on the long arm of chromosome 11 at position 11q13. It encodes the protein seipin, an integral membrane protein of the endoplasmic reticulum (ER). The gene is highly expressed in the brain (), encoding three main seipin isoforms: 462 (BSCL2-203), 398 (BSCL2-205/207/210) and 287 (BSCL2-201) amino acids long, respectively (). Biallelic mutation in the BSCL2 gene can cause progressive encephalopathy with or without lipodystrophy (PELD; MIM: #615924) and congenital generalized lipodystrophy type 2 (CGL2; MIM: #269700). Heterozygous mutations in the BSCL2 gene can cause distal hereditary motor neuronopathy type VC(HMND13; MIM: #619112) and Silver syndrome (SPG17; MIM: #270685). PELD, also known as Celia’s encephalopathy, is a rare and severe neurodegenerative disorder. It is characterized by developmental regression of motor and cognitive skills before the age of 5, often leading to death within the first decade. Patients may exhibit a mild or typical lipodystrophic appearance (). The variant c.985C>T is considered the classic genotype (). However, other variants in BSCL2 associated with severe neurodegenerative manifestations have been reported, some of which resemble PELD. We report a patient with PELD due to a homozygous c. 974dupG variant in the BSCL2 gene, who experienced motor and cognitive regression at 9 years old. We also review the features of all published PELD patients.
Methods
The study was approved by the ethics review committee of Guangdong Sanjiu Brain Hospital and conducted according to the Helsinki Declaration’s ethical guidelines. Consent for disclosure was obtained from the patient’s parents. We also reviewed published literature.
Results
Case description
An 11-year, 9-month-old girl was hospitalized in June 2024, due to repeated seizures over 2 years. She was born to non-consanguineous parents in Guangdong Province, China. The pregnancy and delivery were uneventful. Mild intellectual disability was noted at 30 months. In infancy, she exhibited a lipodystrophic appearance and acanthosis nigricans. She experienced precocious puberty, voracious appetite, elevated transaminase levels, hyperlipidemia, hypercortisolism, hepatomegaly, fatty liver, and splenomegaly. At 9 years old, the patient experienced epileptic seizures characterized by generalized tonic-clonic seizures (GTCS) and myoclonus. The seizures were refractory despite treatment with levetiracetam and topiramate. She experienced a status epilepticus (SE) episode lasting approximately 10 h. At that time, the patient demonstrated psychomotor regression. She exhibited motor deterioration, ataxia, action myoclonus, tremors, reduced speech, dysarthria, and sleep disturbances. By 11 years and 9 months, the patient could only speak single words and had no independent gait, requiring assistance for eating, bathing, and toileting. Physical examination revealed marked generalized lipoatrophy, hypotonia, ataxia, and action myoclonus. Video electroencephalography (VEEG) indicated a slow background and diffuse epileptiform discharges. Frequent myoclonus was recorded (Figure 1). Brain MRI indicated diffuse brain atrophy, particularly in the caudate nucleus (Figure 2). Gynecological ultrasound indicated a small uterine volume. Blood glucose, lipids, lactic acid, urine organic acids, electrocardiogram, echocardiogram, and abdominal ultrasound were unremarkable. After obtaining informed consent from the parents, whole exome sequencing was conducted. Genetic analysis revealed a homozygous pathogenic frameshift variant in BSCL2 (NM_001122955.4:c.974dup; p.Ile326HisfsTer12), classified as pathogenic according to ACMG guidelines, with both parents identified as heterozygous carriers. Clonazepam and perampanel were successively prescribed, providing transient seizure control. Seizure occurrences gradually increased and progressed to SE on July 23rd. She died at the age of 11 years and 11 months from SE on July 25th.
FIGURE 1
FIGURE 2
Review of previous cases
Clinical, imaging and genetic findings of our patient and the other 23 reported PELD patients are summarized in Tables 1, 2 (; ; ; ; ; ; ; ; ; ; ; ; ; ).
TABLE 1
| Case | Variant | Genotype | Nation | Sex | Age of neurological symptoms onset | Age of regression | Neurological symptoms | Seizure type | Lipodystrophic appearance | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 985C>T; 538G>T | Compound heterozygote | Spain | M | 3 years | 4 years | Hyperactivity, cognitive impairment, language delay, tremor, seizures, dystonia, dysphagia | Myoclonus, focal and generalised seizures | Y | |
| 2 | 985C>T; 509_513del | Compound heterozygote | Spain | F | 2 years | N. R. | Developmental delay, neurological regression, seizures | Myoclonus | Y | |
| 3 | 985C>T; 507_511del | Compound heterozygote | Spain | M | 2 years | 5 years | Abnormal communication skills, language delay, hyperactivity, seizures, cognitive impairment, ataxic gait | Myoclonus, focal seizures, GTCS | Y | |
| 4 | 985C>T; 507_511del | Compound heterozygote | Spain | M | 3 years | N. R. | Hyperactivity, language delay, seizures | Myoclonus | Y | |
| 5 | 985C>T; 507_511del | Compound heterozygote | Spain | F | 3.5 years | no regression | Psychomotor delay | None | Y | |
| 6 | 985C>T; 1004A>C | Compound heterozygote | Spain | F | 3 years | N. R. (before 6y) | Anxiety, irritability, strabismus, dystonic hypertonia, extrapyramidal and pyramidal features, dysphagia, parkinsonism, frontal lobe syndrome, dementia | None | N | |
| 7 | 985C>T | Homozygote | Spain | F | 2 years | 3 years | Cognitive impairment, ataxic gait, tremor, dystonia, sleep disturbances, seizures, tetraparesis | GTCS, myoclonus | N | |
| 8 | 985C>T | Homozygote | Spain | F | before 19 months | 5 years | Developmental delay, irritability, dysphagia, sleep disturbances, pyramidal signs | Myoclonus | N | |
| 9 | 985C>T | Homozygote | Iranian | M | 2 years | N. R. | Hyperactivity, autistic, ataxia, generalized hypertonia, global developmental delay | NCSE, convulsive epilepsy | Y | |
| 10 | 974dupG; 757G>T | Compound heterozygote | China | M | N. R. | no regression | Dystonia, mild intellectual disability | None | Y | |
| 11 | 974dupG; 1020_1021delAA | Compound heterozygote | Italy | M | 1 years | 5 years | Developmental delay, ataxic gait, intention myoclonus, pyramidal signs, loss of language, intellectual impairment, dystonic tetraplegia | Absence seizures with myoclonia or eyelid myoclonia, myoclonus | Y | |
| 12 | 974dupG; 1015C>T | Compound heterozygote | Spain | F | 2 years | no regression | Speech delay | None | Y | |
| 13 | 974dupG | Homozygote | China | M | 1–2 years | 5 years | Psychomotor delay, hyperactivity, irritability, unstable walking, tremor, dysarthria, cognitive regression | Absence seizures, atonic seizures, myoclonic-atonic seizures, myoclonus | Y | |
| 14 | 974dupG | Homozygote | China | M | 3 years | 15 years | Dystonic hypertonia, involuntary shaking of the body, opisthotonus, seizures | Myoclonus | Y | |
| 15 | 974dupG | Homozygote | Italy | F | 3 years | 6 years | Intellectual disability, continuous erratic myoclonias, pyramidal signs, cognitive decline, tetraparetic | Absence seizures with eyelid myoclonia, myoclonic-atonic seizures | Y | |
| 16 | 974dupG | Homozygote | Italy | F | N. R. (early childhood) | 5 years | Intellectual disability, cognitive decline, progressively increasing myoclonus, pyramidal signs, tetraparesis, intellectual disability | Absence seizures with eyelid myoclonia, myoclonic-atonic seizures | Y | |
| 17 | 974dupG | Homozygote | Spain | F | 18 months | 6 years | Language delay, stereotyped movements, progressive motor, language, and cognitive deterioration, dysphagia, seizures | Myoclonus, GTCS | Y | |
| 18 | 974dupG | Homozygote | China | F | 30 months | 9 years | Seizures, developmental delay, language and motor regression, tremor, sleep disturbances, ataxic gait, myoclonus | GTCS, myoclonus | Y | Our case |
| 19 | 566T>A | Heterozygote | Spain | M | 6 months | N. R. | Seizures, intellectual disability, autism spectrum disorder, ataxic gait | GTCS, absences with eyelid myoclonia, atonic seizures | N | |
| 20 | 566T>A | Heterozygote | Spain | F | 3 months | 8 months | Seizures, psychomotor delay | Spasms, SE | N | |
| 21 | 1048C>T | Homozygote | Italy | F | N. R. | 5 years | Language delay, irritability, psychomotor agitation, progressive language impairment, bulbar signs, lost gait | Myoclonus, sGTCS | Y | |
| 22 | 1048C>T | Homozygote | Italy | F | N.R. | 5 years | Language delay, irritability, psychomotor agitation, progressive language impairment, bulbar signs, lost gait | Myoclonus, sGTCS | Y | |
| 23 | 445C>G | Heterozygote | USA | M | 2 weeks | 7 years | Seizures | Spasms, SE | N | |
| 24 | 1076dupC | Homozygote | Macedoniay | M | 1 years | 3 years | Psychomotor delay, hyperactivity, ataxic gate, seizures | Generalized tonic seizures, absence seizures with eyelid myoclonia, NCSE | Y | , |
Clinical features of PELD patients (part 1).
F: female. M: male. GTCS: generalized tonic-clonic seizures. SE: status epilepticus. NCSE: Non convulsive status epilepticus. Y: Yes. N: No. N. R.: Not reported.
TABLE 2
| Case | Variant | Other non-neurological symptoms | Treatment | Age of decease (cause) or Age of last follow-up | Brain MR | EEG | Reference |
|---|---|---|---|---|---|---|---|
| 1 | 985C>T; 538G>T | None | N. R. | 8 years (SE) | Normal | Generalised spike | |
| 2 | 985C>T; 509_513del | Hepatomegaly, hypertriglyceridemia, hyperinsulinemia, hypertransaminasemia, low plasma leptin levels | Metreleptin, diet rich in PUFA, omega-3 fatty acid supplementation, ASMs | survival at 7 years 10 months | Atrophy of caudate nuclei, thalami and outer capsules, hypersignal of periventricular white matter | Frequent bursts of spike activity at both central-parieto-temporo-occipital lobes | |
| 3 | 985C>T; 507_511del | None | N. R. | 7 years (respiratory infection) | N. R. | N. R. | |
| 4 | 985C>T; 507_511del | Hepatomegaly, hypertriglyceridaemia | N. R. | 7 years (respiratory infection) | N. R. | N. R. | |
| 5 | 985C>T; 507_511del | None | N. R. | survival at 11 years | N. R. | N. R. | |
| 6 | 985C>T; 1004A>C | None | levodopa | 28 years (pneumonia) | Caudate nucleus atrophy | Normal | |
| 7 | 985C>T | Hepatomegaly, hypertriglyceridaemia, coarse facies, striking muscle induration of the limbs | N. R. | 8 years (aspiration pneumonia) | Subcortical atrophy | Multifocal and sporadic generalised spike | |
| 8 | 985C>T | None | N. R. | 6 years (N. R.) | N. R. | N. R. | |
| 9 | 985C>T | Hypertrichosis | ASMs | 8 years (SE) | An arachnoid cyst in the left hippocampus | NCSE | |
| 10 | 974dupG; 757G>T | Diabetes, hypertriglyceride, fatty liver, splenomegaly | N. R. | survival at 28 years | Normal | N. R. | |
| 11 | 974dupG; 1020_1021delAA | Feeding problems, reduced alertness, hypertriglyceridemia, hypertransaminasemia, hepatic steatosis, hypertrophic cardiomyopathy | low-fat diet, ASMs | 9 years 10 months (cachexia) | Progressive cortico-subcortical cerebral atrophy, particularly involving the caudate head and the lenticulate nucleus, hypersignal of subcortical structures and periventricular white matter | Theta activity and diffuse spike; Background activity deterioration, nearly continuous myoclonic, photoparoxysmal response | |
| 12 | 974dupG; 1015C>T | Failure-to-thrive, hypertriglyceridemia, liver steatosis | Metreleptin | survival at 2 years | N. R. | N. R. | |
| 13 | 974dupG | Hepatomegaly, hepatic Insufficiency, insulin resistance | Low fat and low glycemic index diet, hypoglycemic drugs, ASMs | survival at 5 years 8 months | N. R. | Multifocal and generalized spike | |
| 14 | 974dupG | Unable to feed | ASMs | survival at 17 years | Cerebral atrophy, basal ganglia atrophy | Focal epileptiform discharges | |
| 15 | 974dupG | Hepatomegaly, skin hyperpigmentation, reduced alertness, hypertriglyceridemia, cardiomegaly | N. R. | 7 years 9 months (N. R.) | Enlarged ventricles and liquoral spaces (pneumoencephalography) | Multifocal or diffuse spike | |
| 16 | 974dupG | Hypertriglyceridemia | N. R. | 11 years 10 months (N. R.) | Diffuse cerebral atrophy, with marked involvement of caudate and lenticular nuclei | Background activity deterioration, increasing action myoclonus | |
| 17 | 974dupG | Hepatomegaly, hypertriglyceridemia, feeding difficulties, hyporeactive, somnolent | ASMs | 9 years 9 months (N. R.) | Progressive atrophy of striated regions | Diffuse theta and delta waves and low-voltage beta rhythm and multifocal epileptiform anomalies | |
| 18 | 974dupG | Hypertriglyceridaemia, splenomegaly, fatty liver | ASMs | 11 years (SE) | Cerebral atrophy | Slow background, focal and diffuse spike | Our case |
| 19 | 566T>A | None | Ketogenic diet, ASMs | survival at 10 years | Normal | Slow background, focal and generalized spike | |
| 20 | 566T>A | None | ASMs | 10 months (SE) | Normal | Slow background, multifocal epileptiform activity | |
| 21 | 1048C>T | Coarse facial features, synophrys, bulbous nasal tip, large ear pinnae, wide mouth, long fingers and toes, and hypertrichosis | ASMs | survival at 15 years | Hyperintensity and shrinkage of the putamen and caudate head, ventricular system enlargement | Slow background, multifocal and diffuse spike, cortical myoclonia | |
| 22 | 1048C>T | Coarse facial features, synophrys, bulbous nasal tip, large ear pinnae, wide mouth, long fingers and toes, and hypertrichosis | ASMs | 18 years (N. R.) | Hyperintensity and shrinkage of the putamen and caudate head, ventricular system enlargement | Slow background, multifocal and diffuse spike, cortical myoclonia | |
| 23 | 445C>G | None | ASMs | 7 months (N. R.) | Normal | Slowed and disorganized background, multifocal and generalized spike | |
| 24 | 1076dupC | Hypertriglyceridaemia, hypertransaminasaemia | Metreleptin, low-fat diet, ASMs, VNS | survival at 7 years | Normal | Abnormal background activity, photosensitivity, diffuse origin during ictal period | , |
Clinical features of PELD patients (part 2).
ASMs: antiseizure medications. SE: status epilepticus. N. R.: Not reported.
The patient cohort consisted of 11 males and 13 females, with cases distributed as follows: 12 from Spain, 5 from Italy, 4 from China, 1 from the United States, 1 from Iran, and 1 from Macedonia. 79.2% (19/24) of patients had neurological symptoms before the age of 3. (87.5%) 21 of cases experienced regression, with 14 regressing before the age of 6. 75% (18/24) of cases exhibited a lipodystrophic appearance. The cohort included homozygous (12/24), compound heterozygous (9/24), and heterozygous cases (3/24), with the c.985C>T and c.974dupG variants being the most common mutations. 15 patients died prematurely, with 11 dying before the age of 10. Nine patients were alive, with the oldest reported being 28 years old.
Discussion
This study reports a girl with PELD caused by a c.974dupG biallelic mutation in the BSCL2 gene. A literature review revealed no gender differences among individuals with PELD. These cases were commonly reported in European and Asian countries. Most patients exhibited neurological symptoms before the age of 3 and experienced regression before the age of 6. Developmental delay and neurological regression were the most common neurological symptoms. The prognosis was poor, with most patients dying prematurely. Typical imaging showed brain atrophy, primarily in the caudate nucleus, and EEG findings indicated a slow background with multifocal or generalized epileptiform discharges.
Our case presents unique features including late-onset regression at 9 years old, rapid progression to death within 2 years after regression, and the presence of both lipodystrophic appearance and PME symptoms, which distinguishes it from previously reported cases. Among the documented cases, a notable c.974dupG mutation carrier manifested neurological regression at 15 years of age, representing the latest reported onset in the literature (). Remarkably, the longest documented survival was observed in a 28-year-old patient harboring the same mutation (). These clinical observations collectively suggest that individuals with c.974dupG mutation exhibit delayed disease progression and extended survival compared to c.985C>T mutation carriers, potentially reflecting the differential impact of these variants on BSCL2 function.
The pathogenesis of Celia’s encephalopathy involves abnormal splicing of BSCL2 gene, leading to exon 7 skipping. This results in increased expression of BSCL2-201 transcript, which generates truncated seipin protein. The accumulation of aberrant seipin induces endoplasmic reticulum (ER) stress and the formation of intranuclear aggregates, ultimately triggering neuronal apoptosis (). Notably, patients with c.974dupG mutation exhibit lower expression of BSCL2-201 transcript compared to c.985C>T carriers (), correlating with relatively milder neurological manifestations. In this case, the progression from regression to death was rapid, with the cause of death being SE. SE was common in PELD and always difficult to treat, having been the cause of death in at least four reported cases (; ; ).
Epilepsy was common in PELD, affecting 20 out of 24 patients. Among these, myoclonic seizures were the most common type. The high expression of the BSCL2 gene in the brain and the widespread deposition of aberrant protein may contribute to this phenomenon. The presence of myoclonic seizures, ataxia, and progressive neurological deterioration in this patient supports the diagnosis of Progressive Myoclonus Epilepsy (PME). This finding strengthens the evidence for the coexistence of PME and BSCL2 mutations, as previously suggested in the literature (; ; ; ). In the literature review, we found that PME is underdiagnosed in PELD. Therefore, we propose that PELD should be considered as one of the PMEs. The BSCL2 gene should be considered in gene panels for PME diagnostics.
All patients with 974dupG, 1048C>T, and 1076dupC variants displayed a lipodystrophic appearance. In contrast, those with the 445C>G and 566T>A heterozygous variants did not, while the phenotype for patients with the 985C>T variant remains uncertain. This suggests a potential link between genotype and lipodystrophic appearance. Given the small number of cases, this link still needs further investigation. We found that both compound heterozygotes and homozygotes may or may not display a lipodystrophic appearance, indicating that these features are independent of zygosity type, which is inconsistent with previous studies ().
It has been reported that leptin-replacement therapy delayed neurological regression or allowed better seizure control in patients with PELD (; ; ). Unfortunately, the patient died 23 days after genetic cause confirmation, highlighting the importance of early diagnosis. Early genetic testing and diagnosis are crucial for improving outcomes in rare neurodegenerative disorders like PELD.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics statement
The studies involving humans were approved by the ethics review committee of Guangdong Sanjiu Brain Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
Author contributions
YW: Conceptualization, Data curation, Investigation, Methodology, Software, Writing–original draft, Writing–review and editing. JG: Supervision, Writing–review and editing. PZ: Data curation, Writing–review and editing. FL: Investigation, Writing–review and editing. HL: Conceptualization, Supervision, Writing–review and editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Acknowledgments
We would like to thank the patient for permission of using her clinical data shown in this report.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Summary
Keywords
BSCL2 gene, progressive encephalopathy with or without lipodystrophy, celia’s encephalopathy, progressive myoclonus epilepsy, neurological regression
Citation
Wang Y, Guo J, Zhang P, Liu F and Li H (2025) Case Report: A case of progressive encephalopathy with or without lipodystrophy caused by BSCL2 variant and literature review. Front. Genet. 16:1528563. doi: 10.3389/fgene.2025.1528563
Received
15 November 2024
Accepted
10 February 2025
Published
28 February 2025
Volume
16 - 2025
Edited by
David Araujo-Vilar, University of Santiago de Compostela, Spain
Reviewed by
Lourdes Loidi, Galician Public Foundation of Genomic Medicine, Spain
Josivan Gomes Lima, Federal University of Rio Grande do Norte, Brazil
Updates
Copyright
© 2025 Wang, Guo, Zhang, Liu and Li.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hua Li, lihua1051@163.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.