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Congenital disorders of glycosylation presenting as epileptic encephalopathy with migrating partial seizures in
Carmen Barba1, Francesca Darra2, Raffaella Cusmai3
1Pediatric Neurology Unit and Laboratories, A. Meyer Children's Hospital - University of Florence, Florence, Italy.
Insights
Congenital disorders of glycosylation (CDG) can present with early-onset migrating partial seizures and multisystem involvement in infants. This pattern suggests a need for targeted CDG diagnostic work-up in affected children.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Epilepsy is a common feature in congenital disorders of glycosylation (CDG).
- A distinctive electroclinical pattern for CDG-related epilepsy has not been previously identified.
- Early diagnosis of CDG is crucial for management and can be challenging.
Purpose of the Study:
- To identify a characteristic clinical presentation of epilepsy in children with CDG.
- To guide targeted diagnostic work-up for CDG in infants with specific seizure types and systemic involvement.
Main Methods:
- Evaluation of 17 children with CDG, including an index case with migrating partial seizures.
- Analysis of clinical course, biochemical (isoelectric focusing of transferrin, enzymatic assays, lipid-linked oligosaccharide analysis), genetic, electrographic, and neuroimaging findings.
- Detailed review of seizure characteristics, developmental milestones, and organ involvement.
Main Results:
- Four out of 17 CDG patients presented with early-onset migrating partial seizures (1–4 months of age).
- These four patients exhibited developmental delay, microcephaly, multi-organ involvement, and cerebral/cerebellar atrophy on MRI.
- Genetic analysis identified variants in ALG3, RFT1, and ALG1 genes, confirming CDG-I in these cases. Two patients died, one from respiratory failure and another from refractory status epilepticus.
Conclusions:
- Migrating partial seizures appearing early in infancy, coupled with multisystem disease, should prompt investigation for CDG.
- This electroclinical phenotype may serve as a valuable clue for diagnosing CDG in pediatric neurology.
- Prompt diagnosis and management of CDG are essential, given the potential for severe neurological outcomes and mortality.
Aim:
Epilepsy is commonly observed in congenital disorders of glycosylation (CDG), but no distinctive electroclinical pattern has been recognized. We aimed at identifying a characteristic clinical presentation that might help targeted diagnostic work-up.
Method:
Based on the initial observation of an index case with CDG and migrating partial seizures, we evaluated 16 additional children with CDG and analysed their clinical course, biochemical, genetic, electrographic, and imaging findings.
Results:
Four of 17 consecutively observed children with CDG (three females, one male) were first referred between the first and fourth month of life, after early onset of migrating partial seizures. All four patients manifested developmental delay, microcephaly, and multi-organ involvement. Magnetic resonance imaging disclosed cerebral and cerebellar atrophy. Isoelectrofocusing of transferrin, enzymatic studies, and lipid-linked oligosaccharide analysis indicated CDG-I. Genetic testing demonstrated either homozygous or compound heterozygous variants involving the ALG3 gene in patients 1 and 3, the RFT1 gene in patient 2, and the ALG1 gene in patient 4. At last follow-up, patients 1 and 2 were 5 and 3(1/2) years old. Patients 3 and 4 had died due to respiratory failure during pneumonia and refractory status epilepticus respectively.
Interpretation:
Children with migrating partial seizures and concomitant multisystem involvement should be investigated for CDG.
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