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Background <p>Glutaric acidemia type 1 (GA1) is a rare but treatable autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the <i>GCDH</i> gene. In the absence of newborn screening (NBS), diagnosis often occurs after irreversible neurological injury.</p> Methods <p>This retrospective, descriptive, cross-sectional study included 50 patients with biochemically and/or genetically confirmed GA1 from two tertiary centers in Turkey, where GA1 is not part of the national NBS program. Demographic, clinical, biochemical, neuroimaging, and molecular genetic data were collected from medical records. Motor and communication functions were evaluated using the Gross Motor Function Classification System (GMFCS) and the Communication Function Classification System (CFCS).</p> Results <p>The cohort comprised 29 males (58%) and 21 females (42%) from 42 unrelated families, with parental consanguinity present in 78%. Median age at diagnosis was 10 months (range: 3 months–17 years). Most patients presented with the acute-onset type (66%), followed by the insidious-onset type (34%). Encephalopathic crises occurred in 66% of patients, with gastroenteritis and respiratory infections being the most common precipitating factors. Severe motor (GMFCS level 5: 61.5%) and communication (CFCS level 5: 30.8%) impairments were frequent. Neuroimaging revealed basal ganglia involvement in 86.1% and frontotemporal atrophy in 72.2% of patients. Biochemically, 70% were high excretors, and secondary carnitine deficiency was common (84.6%). Genetic analysis (<i>n</i> = 29) identified 15 pathogenic/likely pathogenic GCDH variants, with c.743&#xa0;C &gt; T (p.Pro248Leu) being the most frequent variant (34.4%), suggesting a founder effect. Twelve patients (24%) died during follow-up (median age: 6.2 years).</p> Conclusions <p>In this large Turkish GA1 cohort diagnosed outside NBS, delayed diagnosis was associated with severe and irreversible neurological sequelae, high mortality, and multisystem complications. Our findings strongly support the urgent inclusion of GA1 in national NBS programs, especially in high-consanguinity populations, alongside structured lifelong management strategies to improve long-term outcomes.</p>

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Glutaric acidemia type 1 in a non-newborn-screened cohort: clinical, biochemical, and molecular features and neurologic outcomes

  • 期刊论文

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  • 发表日期：

    2026年5月28日

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  • Arzu Selamioğlu,
  • Melda İdrisoğlu,
  • Şebnem Kılıç,
  • Dilek Güneş,
  • Meryem Karaca,
  • Mehmet Cihan Balcı,
  • Nafiye Emel Çakar,
  • Fatmahan Atalar,
  • Asuman Gedikbaşı,
  • Gülden Gökçay

摘要

Background

Glutaric acidemia type 1 (GA1) is a rare but treatable autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the GCDH gene. In the absence of newborn screening (NBS), diagnosis often occurs after irreversible neurological injury.

Methods

This retrospective, descriptive, cross-sectional study included 50 patients with biochemically and/or genetically confirmed GA1 from two tertiary centers in Turkey, where GA1 is not part of the national NBS program. Demographic, clinical, biochemical, neuroimaging, and molecular genetic data were collected from medical records. Motor and communication functions were evaluated using the Gross Motor Function Classification System (GMFCS) and the Communication Function Classification System (CFCS).

Results

The cohort comprised 29 males (58%) and 21 females (42%) from 42 unrelated families, with parental consanguinity present in 78%. Median age at diagnosis was 10 months (range: 3 months–17 years). Most patients presented with the acute-onset type (66%), followed by the insidious-onset type (34%). Encephalopathic crises occurred in 66% of patients, with gastroenteritis and respiratory infections being the most common precipitating factors. Severe motor (GMFCS level 5: 61.5%) and communication (CFCS level 5: 30.8%) impairments were frequent. Neuroimaging revealed basal ganglia involvement in 86.1% and frontotemporal atrophy in 72.2% of patients. Biochemically, 70% were high excretors, and secondary carnitine deficiency was common (84.6%). Genetic analysis (n = 29) identified 15 pathogenic/likely pathogenic GCDH variants, with c.743 C > T (p.Pro248Leu) being the most frequent variant (34.4%), suggesting a founder effect. Twelve patients (24%) died during follow-up (median age: 6.2 years).

Conclusions

In this large Turkish GA1 cohort diagnosed outside NBS, delayed diagnosis was associated with severe and irreversible neurological sequelae, high mortality, and multisystem complications. Our findings strongly support the urgent inclusion of GA1 in national NBS programs, especially in high-consanguinity populations, alongside structured lifelong management strategies to improve long-term outcomes.