Mutations in SLC25A22: hyperprolinaemia, vacuolated fibroblasts and presentation with developmental delay

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Mutations in the SLC25A22 gene are associated with neonatal epileptic encephalopathy and infantile migrating partial seizures.
• Previous studies have not documented abnormal metabolite levels in patients with SLC25A22 mutations.

Purpose of the Study:

• To identify novel mutations in SLC25A22 and investigate their clinical and biochemical consequences.
• To explore the role of SLC25A22 in amino acid metabolism and cellular function.

Main Methods:

• Whole exome sequencing was used to identify SLC25A22 mutations in three families.
• Clinical data was collected for six affected children.
• Metabolite levels (plasma amino acids) and fibroblast ultrastructure (electron microscopy) were analyzed.

Main Results:

• Four novel SLC25A22 mutations were identified in six children.
• Five patients exhibited typical features of neonatal epileptic encephalopathy; one presented with isolated developmental delay and late-onset seizures.
• Elevated plasma proline and abnormal amino acid profiles were observed in some patients, suggesting a role for SLC25A22 in hepatic amino acid transport and metabolism.
• Fibroblast electron microscopy revealed widespread vacuolation, potentially linked to impaired proline/pyrroline-5-carboxylate shuttle function.

Conclusions:

• This study expands the spectrum of clinical presentations associated with SLC25A22 mutations.
• SLC25A22 plays a critical role in mitochondrial glutamate transport in the liver and brain, impacting amino acid metabolism and potentially cellular integrity.