Molecular genetics and metabolism · 2026
Expanding the clinical and molecular spectrum of NGLY1 deficiency: A multicenter cohort.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Yılmaz-Gümüş Emel, Kılavuz Sebile, Demir Şenol, Aydoğan Ayça, Genç Emine, Akar Halil Tuna, Akbeyaz İsmail Hakkı, Çakar Nafiye Emel, Er Esra, Gülbahçe Aliye, Güneş Hatice, Kardaş Fatih, Kılıç Mustafa, Teke-Kısa Pelin, Koşukcu Can, Önal Hasan, Taş İbrahim, Türkdoğan Dilşad, Dursun Ali, Öztürk-Hişmi Burcu
Аннотация
BACKGROUND: NGLY1 deficiency is an ultra-rare multisystem disorder characterized by developmental delay, hyperkinetic movement disorder, hypo-/alacrimia, peripheral neuropathy, and elevated transaminases.
METHODS: We conducted a multicenter retrospective study including 15 patients from 11 families to evaluate the clinical, biochemical, and molecular features of the disease. A literature review was also performed, and phenotypic data from published patients were evaluated.
RESULTS: All patients presented with developmental delay and dysmorphic facial features. Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5). Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4). Peripheral and auditory neuropathy findings were observed over time. Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10). We identified 10 distinct variants, including two novel variants c.629delA (p.(Lys210SerfsTer14)) and c.1036C > T (p.(Gln346Ter)). Most patients carried homozygous variants, and no clear genotype-phenotype correlation was observed.
CONCLUSION: Our findings expand the clinical and molecular spectrum of NGLY1 deficiency and highlight its dynamic and progressive course, supporting the need for long-term clinical follow-up. NGLY1 deficiency may be considered in patients with neurologic findings and dysmorphic features, especially when transient elevated transaminases and hypolipidemia are also present.
METHODS: We conducted a multicenter retrospective study including 15 patients from 11 families to evaluate the clinical, biochemical, and molecular features of the disease. A literature review was also performed, and phenotypic data from published patients were evaluated.
RESULTS: All patients presented with developmental delay and dysmorphic facial features. Common neurological findings included abnormal EEG (10/15), seizures (9/15), hyperkinetic movement disorder (8/15), reduced deep tendon reflexes (6/15), and peripheral neuropathy (3/5). Frequent non-neurological features included feeding difficulties (9/15), scoliosis (7/13), hypo-/alacrimia (6/15), constipation (6/15), and auditory neuropathy (2/4). Peripheral and auditory neuropathy findings were observed over time. Elevated transaminases were the most common laboratory abnormality (12/14) and were transient in most patients (9/12), followed by low total cholesterol (7/10) and HDL levels (5/10). We identified 10 distinct variants, including two novel variants c.629delA (p.(Lys210SerfsTer14)) and c.1036C > T (p.(Gln346Ter)). Most patients carried homozygous variants, and no clear genotype-phenotype correlation was observed.
CONCLUSION: Our findings expand the clinical and molecular spectrum of NGLY1 deficiency and highlight its dynamic and progressive course, supporting the need for long-term clinical follow-up. NGLY1 deficiency may be considered in patients with neurologic findings and dysmorphic features, especially when transient elevated transaminases and hypolipidemia are also present.