{"id":90356,"date":"2026-03-17T16:25:03","date_gmt":"2026-03-17T15:25:03","guid":{"rendered":"https:\/\/cegat.com\/?p=90356"},"modified":"2026-04-08T16:59:22","modified_gmt":"2026-04-08T14:59:22","slug":"glutaminase-deficiency-provides-insight-to-the-role-of-glutamine-accumulation-and-neurotoxicity","status":"publish","type":"post","link":"https:\/\/cegat.com\/de\/glutaminase-deficiency-provides-insight-to-the-role-of-glutamine-accumulation-and-neurotoxicity\/","title":{"rendered":"Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity"},"content":{"rendered":"

Andr\u00e9 B P van Kuilenburg 1<\/sup>, Hanna Mandel 2<\/sup>, Tameemi Abdalla Moady 3<\/sup>, Ronen Sloma 4<\/sup>, Ayalla Fedida 2<\/sup>, Ren\u00e9 Leen 5<\/sup>, Judith Jansen-Meijer 5<\/sup>, Tamar Paperna 3<\/sup>, Vered Fleisher Sheffer 6<\/sup>, Doreen Dobritzsch 7<\/sup>, Ori Hochwald 8<\/sup>, Nicole N van der Wel 9<\/sup>, Anita E Grootemaat 9<\/sup>, Semyon Chulsky 10<\/sup>, Mika S Rootman 10<\/sup>, Ayelet Eran 11<\/sup>, Maha A Yousef 12<\/sup>, April Dinwiddie 13<\/sup>, Joshua Manor 14<\/sup>, Clara D M Van Karnebeek 15<\/sup>, Limor Kalfon 2<\/sup>, Tova Hershkovitz 2<\/sup>, Galit Tal 16<\/sup>, Tzipora C Falik Zaccai 17<\/sup><\/p>\n<\/div><\/div><\/div><\/div><\/div>

Abstract<\/h2><\/div><\/div><\/div>

Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy. We describe three infants from two unrelated families who presented clinically with neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure, progressing to either a persistent vegetative state or early death. One patient remains alive at the age of six years. Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range. Notably, brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects. Exome sequencing identified a homozygous, unreported missense variant in GLS (NM_014905.5:c.1174G > A; p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant (NM_014905.5:c.1031 T > C; p.Leu344Pro) in the proband from family 2. Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency. In addition, patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired mitochondrial respiratory function. The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and\/or urea cycle defects.<\/p>\n

Keywords<\/strong>: Encephalopathy; GLS; Glutaminase deficiency; Glutamine; Hyperammonemia.<\/p>\n<\/div><\/div><\/div><\/div><\/div>