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

Abstract

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.

Introduction

Glutaric acidemia type 1 (GA1; OMIM #231670) is a rare inherited neurometabolic disorder caused by biallelic variants in the GCDH gene, which encodes a mitochondrial flavin-dependent glutaryl-CoA dehydrogenase (GCDH) essential in the catabolism of lysine, tryptophan, and hydroxylysine [1]. GCDH deficiency results in accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3HGA), glutaconic acid and glutarylcarnitine (C5DC), which can be detected in body fluids (urine, plasma, cerebrospinal fluid [CSF]) and tissues. Based on urinary GA concentrations, two biochemical subgroups have been commonly defined: low excretors (LE), who exhibit residual GCDH activity of 3–30%, and high excretors (HE), who typically show residual activity of only 0–2% [2]. The prevalence of GA1 varies widely, from approximately 1 in 125,000 in the general population to as high as 1 in 250 among high-risk groups [3].

Based on the presence and pattern of striatal injury, glutaric acidemia type 1 (GA1) is characterized by two forms of striatal involvement: an acute-onset form, marked by acute encephalopathy and severe striatal necrosis following episodes of catabolic stress, and an insidious-onset form, which is associated with chronically progressive but markedly milder striatal degeneration, usually in the absence of overt metabolic decompensation.

Late-onset presentations, with symptom onset after 6 years of age, occur without striatal involvement. Accordingly, the clinical presentation and disease course of GA1 vary widely, ranging from asymptomatic individuals (approximately 10%) to patients presenting with acute encephalopathy (up to 90%) [4]. GA1 typically manifests with dystonia and spasticity secondary to striatal injury, most often following an acute encephalopathic crisis between 3 and 24 months of age. Additional early features, including macrocephaly, muscular hypotonia, and motor developmental delay, are observed in more than half of affected infants and frequently precede metabolic crises [5].

Nowadays, GA1 is recognized as a treatable disorder. Long-term metabolic therapy during the critical period of metabolic vulnerability includes a low-lysine diet supplemented with a lysine-free, tryptophan-reduced, arginine-fortified amino acid mixture (AAM), along with oral carnitine supplementation. After the period of increased risk for striatal injury—up to 6 years of age—dietary restrictions may be gradually relaxed. Since early treatment is known to be neuroprotective, GA1 has been included in many national newborn screening (NBS) programs across developed countries worldwide [2].

In Turkey, where GA1 is not included in the national NBS program, patients are typically diagnosed only after clinical presentation or family history. The aim of this study was to characterize the clinical, biochemical, neuroradiological, and molecular genetic features of GA1 in a cohort of patients diagnosed in a setting with high consanguineous marriages but without a NBS program, and to describe their long-term clinical outcomes, with particular emphasis on the severity and functional impact of neurological sequelae resulting from delayed diagnosis.

Methods

This retrospective, descriptive, cross-sectional study was conducted in the pediatric metabolism units of two tertiary centers in Turkey: The Division of Pediatric Nutrition and Metabolism at Istanbul University Children’s Hospital, and the Division of Pediatric Metabolism at Okmeydanı Training and Research Hospital. Patients were diagnosed through a combination of selective metabolic screening and high-risk screening based on family history or suggestive clinical symptoms. In addition, a subset of patients was identified through NBS. Tandem mass spectrometry (MS/MS) was used for the detection of C5DC in dried blood spots. The diagnosis of GA1 was confirmed based on a combination of biochemical and molecular genetic analyses, including acylcarnitine profiling by tandem MS/MS, urine organic acid analysis via gas chromatography–mass spectrometry (GC-MS), GCDH enzyme activity assays, and genetic testing of the GCDH gene.

Medical records of 50 patients with confirmed GA1 were retrospectively reviewed. Data collected included sex, current age, age at diagnosis, family history of GA1, presenting complaints, time interval between symptom onset and diagnosis, clinical and laboratory findings at the time of diagnosis, neuroimaging results (particularly brain MRI), genetic analysis results, and long-term complications observed during regular follow-up. During the follow-up visits, all patients were evaluated through a standardized neurodevelopmental assessment protocol. Motor abilities were categorized using the Gross Motor Function Classification System (GMFCS), while everyday communication skills were evaluated with the Communication Function Classification System (CFCS) [6, 7]. American College of Medical Genetics (ACMG) guidelines were used for variant interpretation. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) were identified. A literature review was conducted to determine whether these variants had been previously reported. The identified variants were cross-referenced with ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and the Human Gene Mutation Database (HGMD) (https://www.hgmd.cf.ac.uk/ac/index.php) to confirm their novelty and clinical relevance [8]. Written informed consent was obtained from the parents of study participants. The study was conducted in accordance with the ethical principles outlined in the latest revision of the Declaration of Helsinki and was approved by the Ethics Committee of the Istanbul University (No. 14.10.2024–2954467). The data were imported into an Excel spreadsheet of the Microsoft Office package and were subsequently analyzed using SPSS (Statistical Package for Social Sciences) programme Version 22. Data were examined via the mean, standard deviation for quantitative variables and the frequency and percentage for qualitative variables.

Results

Patient demographics

A total of 50 patients diagnosed with GA1 from 42 unrelated families were included in the study. Of these, 29 (58%) were male and 21 (42%) were female. Consanguinity was present in 39 (78%) patients, and among these, 62% were the offspring of first-cousin marriages. The age at diagnosis (n = 50) varied between 3 months and 17 years, with a median of 10 months and a mean of 29.43 ± 46.57 months. In 49 patients (excluding the single late-onset case), the age at symptom onset ranged from birth to 36 months, with a mean of 10.0 ± 7.93 months and a median of 7.5 months. The diagnostic delay (n = 50), defined as the time from symptom onset to diagnosis, ranged from 0 to 204 months, with a mean of 25.33 ± 51.34 months and a median of 2 months. Of the patients included in the study, three were diagnosed through newborn screening, six through family-based high-risk screening, and forty-one through selective screening based on clinical presentation.

Initial clinical presentation of symptomatically diagnosed patients

Most of the patients presented with acute-onset type (66%), followed by insidious onset type (34%). The clinical presentation of patients varied widely, ranging from asymptomatic to severe encephalopathy. At initial presentation, the most common clinical features were acute encephalopathic crises (20 patients, 40%), acquired functional regression (18 patients, 36%), developmental delay (14 patients, 28%), and seizures (13 patients, 26%). Less common findings included macrocephaly (18%), dystonia (10%), subdural effusion (8%), hypotonia (6%), headache (2%), and motor tics (2%). The age at encephalopathic crisis did not exceed 24 months in any patient. Among those who experienced an encephalopathic crisis, the mean age at onset was 9.96 ± 5.43 months (range: 5–24 months), with a median of 8 months. Additionally, six patients (12.0%) had a positive family history of GA1, two of whom were asymptomatic at the time of diagnosis. The single late-onset patient presented with headache. Clinical features of GA1 patients are summarized below (Table 1). The distribution of clinical features according to onset pattern, biochemical phenotype, and diagnostic approach is summarized in Table 2.

Table 1.

Demographic and clinical features of patients with GA1

Patient	Gender	Consanguinity	Clinical presentation	Age at presentation (month)	Age at diagnosis (month)	Clinical follow-up
						Axial hypotonia	Encephalopathic crisis	Epilepsy	Dystonia	Macrocephaly/relative macrocephaly	Spasticity	Dysarthria-affected speech	Neurological regression	Motor-mental retardation	Subdural hemorrhage	Failure to thrive	GMFCS	CFCS
P1	M	+	Developmental delay, dystonia, seizure	5	6	+	+ 5 months	+	+	+	+	+	-	+	-	+	5	5
P2	M	+	Developmental delay, acute encephalopathy	5	8	+	+ 5 months	-	+	+	+	+	+	+	-	-	5	4
P3	F	+	Acute encephalopathy, Neurological regression	24	204	+	+ 24	-	+	-	+	+	+	+	-	-	4	1
P4	M	+	Acute encephalopathy, Neurological regression	24	180	+	+ 24	-	+	-	+	+	+	+	-	-	5	5
P5	M	+	Developmental delay, macrocephaly	36	36	-	-	-	-	+	-	-	-	-	-	-	1	1
P6	M	+	Developmental delay	From birth	180	+	+ 8 months	-	+	-	+	+	-	+	-	-	5	1
P7	M	+	Acute encephalopathy, Neurological regression, seizure	11	12	+	+ 11 months	+	+	+	+	+	+	+	-	+	5	4
P8	M	+	Neonatal screening	1	1	+	+ 12 months	+	+	+	+	+	+	+	-	+	5	3
P9	M	+	Headache, motor tic	144	144	-	-	-	-	-	-	-	-	-	-	-	1	1
P10	F	+	Family screening	90	90	-	-	-	-	-	-	-	-	-	-	-	1	1
P11	F	+	Acute encephalopathy, Neurological regression	9	10	+	+ 9	-	+	-	+	+	+	+	-	-	4	2
P12	M	+	Dystonia, seizure	4	6	+	-	+	+	+	+	+	-	+	-	+	5	4
P13	M	+	Macrocephaly	5	108	-	-	-	-	+	-	-	-	-	-	-	1	1
P14	F	-	Hypotonia, dystonia	7	9	+	+ 7	-	+	-	+	+	+	+	-	+	5	5
P15	F	-	Subdural hemorrhage, Acute encephalopathy, neurological regression	6	8	-	+ 6 months	-	+	+	+	+	+	+	+	+	4	4
P16	M	+	Family screening with dystonia	78	78	-	-	-	+	-	-	-	-	+	-	-	1	1
P17	M	+	Neonatal screening	0.83	0.83	-	-	-	-	-	-	-	-	-	-	+	1	1
P18	F	+	Acute encephalopathy	18	18	-	+ 18 months	+	+	+	-	-	-	-	-	-	1	1
P19	F	-	Developmental delay,	From birth	6	-	-	+	+	+ relative	+	+	+	+	-	+	5	4
P20	F	+	Acute encephalopathy, Seizure, neurological regression	9	28	-	+ 9 months	+	+	+	+	+	+	+	-	+	5	4
P21	M	+	Acute encephalopathy, Developmental delay, seizure	5	7	+	+ 5 months	+	+	-	+	+	+	+	-	+	5	4
P22	M	Same village	Acute encephalopathy, neurological regression, seizure	8	9	+	+ 8 months	+	+	+	+	+	+	+	-	-	5	3
P23	M	-	Macrocephaly	2	3	-	+ 11 months	+	+	+	+	+	+	+	-	-	5	5
P24	M	+	Developmental delay, hypotonia	24	24	-	-	-	-	-	-	-	-	-	-	+	2	1
P25	F	+	Acute encephalopathy, neurological regression	12	26	+	+ 12 months	+	+	+	+	+	+	+	-	+	4	4
P26	F	+	Acute encephalopathy, Seizure, dystonia, neurological regression	8	9	-	+ 8	+	+	+	+	+	+	+	-	+	5	4
P27	M	Same village	Acute encephalopathy, neurological regression	18	36	-	+ 18 months	-	+	-	+	+	+	+	-	+	5	4
P28	M	-	Acute encephalopathy, neurological regression macrocephaly,	8	10	-	+ 8 months	-	+	+	+	+	+	+	-	+	5	5
P29	M	+	Family screening	7	7	-	+ 13 months	+	+	+ relative	+	+	+	+	-	+	5	5
P30	F	+	Acute encephalopathy, Neurological regression	6	60	+	+ 6	-	+	-	++	+	+	+	-	+	NA	NA
P31	M	+	Acute encephalopathy, neurological regression, seizure	11	22	-	+ 11 months	+	+	-	-	+	+	+	-	+	2	2
P32	F	-	Acute encephalopathy, neurological regression, seizure	5	7	-	+ 5 months	+	+	-	-	-	+	+	-	-	5	5
P33	F	+	Acute encephalopathy, Developmental delay, hypotonia, seizure	6	8	+	+ 6	+	+	+ relative	+	+	+	+	-	-	NA	NA
P34	F	-	Acute encephalopathy, Seizure	4	9	-	+ 4	+	+	+ relative	+	+	+	+	-	+	5	5
P35	F	+	Family screening	10	10	-	-	-	-	-	-	-	-	-	-	-	NA	NA
P36	M	+	Acute encephalopathy, neurological regression	10	10	-	+ 10 months	+	+	+ relative	+	+	+	+	-	+	NA	NA
P37	M	+	Macrocephaly	12	12	-	-	-	-	+	-	-	-	-	-	-	5	4
P38	F	+	Neonatal screening	2	2	+	-	-	-	-	-	-	-	-	-	-	NA	NA
P39	M	+	Developmental delay, macrocephaly	5	44	+	-	-	-	+	-	-	-	-	-	-	NA	NA
P40	M	-	Seizure, neurological regression	6	7	+	+ 6	+	+	+ relative	+	+	+	+	-	+	NA	NA
P41	M	-	Macrocephaly, subdural hemorrhage	5	5	+	+ 5	+	-	+	-	-	+	-	+	-	5	5
P42	M	+	Developmental delay	12	12	-	-	+	+	-	-	-	-	-	-	-	NA	NA
P43	M	-	Developmental delay, macrocephaly	24	24	-	-	-	-	+	-	-	-	-	-	-	2	1
P44	F	+	Developmental delay, seizure	7	8	+	+ 7	+	+	+	+	+	+	+	-	-	NA	NA
P45	F	+	Subdural hemorrhage	20	20	+	+ 20	+	+	+	+	+	+	+	+	+	5	5
P46	M	-	Subdural hemorrhage	2	2	+	+ 5	-	-	+	+	+	+	+	+	+	5	5
P47	F	+	Developmental delay	6	11	+	-	+	+	+	+	+	+	+	-	+	2	2
P48	M	+	Macrocephaly, seizure	6	21	+	+ 6	+	+	+	+	+	+	+	-	+	5	5
P49	F	+	Family screening	12	69	-	+ 12	-	+	+	+	+	+	+	-	+	NA	NA
P50	F	+	Family screening	22	22	-	-	-	+	+	+	-	-	-	-	+	NA	NA

F: Female; M: Male; GMFCS: Gross Motor Function Classification System; CFCS: Communication Function Classification System; NA: Not available

Table 2.

Distribution of Clinical Features in GA1 Patients by Onset Pattern, Biochemical Phenotype, and Diagnostic Approach

Clinical follow-up	Acute onset type (n = 33)	Insidious onset type (n = 17)	Low excretors (n = 8)	High excretors (n = 35)	Newborn Screening (n = 3)	Family Screening (n = 6)
Axial hypotonia	16 (48.5%)	5 (29.4%)	3 (37.5%)	17 (48.5%)	2 (66.7%)	0 (0%)
Encephalopathic crisis	33 (100%)	0 (0%)	2 (25.0%)	23 (65.7%)	1 (33.3%)	2 (33.3%)
Epilepsy	23 (69.7%)	3 (17.6%)	3 (37.5%)	24 (68.6%)	1 (33.3%)	1 (16.7%)
Dystonia	27 (81.8%)	5 (29.4%)	4 (50.0%)	29 (82.9%)	1 (33.3%)	4 (66.7%)
Macrocephaly/Relatif makrosefali	27 (81.8%)	3 (17.6%)	4 (50.0%)	28 (80.0%)	1 (33.3%)	3 (50.0%)
Spasticity	25 (75.8%)	4 (23.5%)	4 (50.0%)	26 (74.3%)	1 (33.3%)	3 (50.0%)
Dysarthria-affected speech	26 (78.8%)	4 (23.5%)	4 (50.0%)	27 (77.1%)	1 (33.3%)	2 (33.3%)
Neurological regression	26 (78.8%)	3 (17.6%)	5 (62.5%)	28 (80.0%)	1 (33.3%)	2 (33.3%)
Motor-mental retardation	24 (72.7%)	5 (29.4%)	4 (50.0%)	26 (74.3%)	1 (33.3%)	3 (50.0%)
Subdural hemorrhage	6 (18.2%)	1 (5.9%)	2 (25.0%)	6 (17.1%)	0 (0%)	0 (0%)
Failure to thrive	12 (36.4%)	2 (11.8%)	6 (75.0%)	12 (34.3%)	2 (66.7%)	3 (50.0%)

Late-onset patients

One late-onset patient (2%) was identified in the cohort, who presented at the age of 12 years with complaints of severe headache, particularly triggered by sudden movements and during episodes of infection. Brain MRI at the time of presentation revealed widened subarachnoid spaces in the opercular regions over the anterior poles of the bilateral temporal lobes and along the Sylvian fissures, as well as increased signal intensity in the periventricular white matter and basal ganglia. The patient exhibited blinking tics suggestive of dystonia but had no other complaints. Biochemical analysis showed elevated urinary GA (1418 µmol/mmol creatinine, normal < 5.3 µmol/mmol creatinine) and 3HGA (13 µmol/mmol creatinine, normal < 4.2 µmol/mmol creatinine). The patient was born to consanguineous parents, and molecular genetic analysis identified a homozygous c.1204 C > T variant in the GCDH gene.

Patients diagnosed through newborn screening

In patients identified by expanded NBS, one male patient was diagnosed at one month of age, with C0: 7.5 µmol/L (normal range:10–90 µmol/L) and C5DC: 1.0 µmol/L (normal range:0.01–0.26 µmol/L) on MS/MS, and a urinary GA level of 454 µmol/mmol creatinine (normal < 5.3 µmol/mmol creatinine). Despite early treatment initiation, he experienced an encephalopathic crisis at one year of age following rotavirus gastroenteritis, resulting in acquired loss of function. He had frequent febrile infections and died at 5.5 years due to sepsis. Genetic analysis revealed a homozygous c.743 C > T variant. Another male patient was diagnosed at 25 days of age, with C0: 15.7 µmol/L (normal range:10–90 µmol/L), C5DC: 0.74 µmol/L (normal range:0.01–0.26 µmol/L), urinary 3HGA: 5 µmol/mmol creatinine (normal < 4.2 µmol/mmol creatinine) and GA: 12 µmol/mmol creatinine (normal < 5.3 µmol/mmol creatinine). Enzyme activity was low (1.2; reference: 3.2–6.8), and genetic analysis showed compound heterozygosity for c.157 C > T and c.541G > C variants. Although he experienced three episodes of febrile seizures, he did not develop metabolic crises or neurological sequelae. At age 13 years, MRI revealed an arachnoid cyst and mild widening in the Sylvian and temporal regions. He is currently 19 years old with no clinical complaints. The third patient was a female diagnosed at 2 months of age, with C0: 7 µmol/L (normal range:10–90 µmol/L) and C5DC: 2.24 µmol/L (normal range:0.01–0.26 µmol/L) on MS/MS, and a urinary GA level of 276 µmol/mmol creatinine (normal < 5.3 µmol/mmol creatinine). At 3 months of age, clinical examination revealed absence of head control and mild hypertonia in the lower extremities. The patient was subsequently lost to follow-up.

Patients diagnosed through family screening

Six patients (12.0%) were identified through family screening. Among them, two patients (33.3%) were asymptomatic and had normal neurological examinations at follow-up. However, the clinical course within this group was heterogeneous: two patients (33.3%) experienced encephalopathic crises and subsequently developed neurological regression and severe motor impairment, whereas others remained mildly affected or clinically stable. Overall, dystonia was observed in three patients (50%), and motor-mental retardation in two patients (33.3%). Among the patients identified through family screening, several demonstrated clinical outcomes that differed significantly from those of their affected siblings. One such case was a 7-year-old male who exhibited mild dystonia and ataxia, along with mild intellectual disability, although his neuromotor development was age-appropriate at the time of diagnosis. Brain MRI revealed widespread hyperintense signal changes in the subcortical deep white matter, particularly in the frontoparietal and temporal regions. At diagnosis, MS/MS showed C0: 2.7 µmol/L (normal range:10–90 µmol/L) and C5DC: 0.44 µmol/L (normal range:0.01–0.26 µmol/L). Urinary organic acid (UOA) analysis revealed elevated levels of 3HGA: 13 µmol/mmol creatinine (normal <4.2 µmol/mmol creatinine) and GA: 843 µmol/mmol creatinine (normal <5.3 µmol/mmol creatinine). He is currently 21 years old, married, with normal gait, and osteoporosis as the only long-term complication. His sibling, however, was diagnosed at 7 months of age following a seizure episode, with preexisting neuromotor delay. This sibling experienced an encephalopathic crisis and subsequently developed severe neurodevelopmental impairment, requiring tracheostomy and PEG feeding before ultimately succumbing to the disease. Another late diagnosed case, a 7.5-year-old girl who was asymptomatic at diagnosis and had age-appropriate neuromotor development, despite pathological findings on brain MRI. MS/MS at the time of diagnosis showed C0: 3.39 µmol/L (normal range:10–90 µmol/L) and C5DC: 0.28 µmol/L (normal range:0.01–0.26 µmol/L), while urinary organic acid analysis revealed 3HGA: 10 µmol/mmol creatinine (normal <4.2 µmol/mmol creatinine) and GA: 126 µmol/mmol creatinine (normal <5.3 µmol/mmol creatinine). Neuroimaging demonstrated widening of the bilateral Sylvian fissures and subarachnoid spaces in the middle cranial fossa. She is currently 24 years old, with no history of encephalopathic crisis and a normal physical examination. Her sibling presented with macrocephaly and developed acquired loss of function at the age of 11 months.

Precipitating factors

Potential precipitating factors associated with the initial clinical presentation of the disease were identified in 24 patients (48.0%). Gastroenteritis was the most common trigger, reported in 13 patients, followed by upper respiratory tract infections in 7 patients. In addition, surgical procedures were reported in two patients, while vaccination and rubella infection were each identified in one patient. A history of frequent febrile illnesses was documented in 15 patients (34.0%).

Clinical status of patients during follow-up-period and additional conditions

During clinical follow-up, dystonia was observed in 37 patients (74%), motor and intellectual disability in 35 patients (70%), spasticity and speech delay in 33 patients (66%), neurological regression in 32 patients (64%), malnutrition in 27 patients (54%), epilepsy in 25 patients, macrocephaly and axial hypotonia in 22 patients (44%), and relative macrocephaly in 8 patients (16%). At the time of final evaluation, 12 patients (24%) had died, with the age at death ranging from 16 months to 20 years (median: 6.2 years). Clinical follow-up data were available for the remaining 38 patients, of whom 29 (58%) exhibited severe neuromotor impairment. Osteoporosis and scoliosis were the most frequently observed long-term complications. Additional chronic conditions involving various organ systems were also noted, including an intracranial mass (n = 1), growth hormone therapy initiated due to short stature (n = 1), grade 1 renal parenchymal disease (n = 1), obesity (n = 1), hypertension (n = 1), hepatic steatosis (n = 1), and nephrolithiasis (n = 1). Cardiac evaluations revealed several structural abnormalities including tricuspid regurgitation, mitral regurgitation, asymmetric septal hypertrophy, tricuspid valve prolapse, and the presence of an accessory band in the left ventricle.

GMFCS and CFCS scores were available for 39 patients (78%); data from 11 patients were unavailable due to incomplete documentation or loss to follow-up. Among the evaluable patients, gross motor function, as assessed by the GMFCS, revealed that 7 patients (17.9%) had normal motor abilities (GMFCS level 1), 4 patients (10.3%) had mild motor limitations (level 2), 4 patients (10.3%) demonstrated moderate motor dysfunction (level 4), and 24 patients (61.5%) exhibited severe motor impairment (level 5). Communication abilities, evaluated using the CFCS, showed that 11 patients (28.2%) had age-appropriate communication skills (CFCS level 1), 3 patients (7.7%) had mild limitations (level 2), 2 patients (5.1%) exhibited moderate difficulties (level 3), while 11 patients (28.2%) and 12 patients (30.8%) demonstrated severe (level 4) and very severe (level 5) communication impairments, respectively.

Biochemical findings

Carnitine profiles by MS/MS at the time of diagnosis were available for 39 patients. Except for 6 individuals, all showed secondary carnitine depletion. The mean free carnitine (C0) level (normal range:10–90 µmol/L) was 9.91 ± 11.34 µmol/L (range:1.3–55.9 µmol/L), with a median of 5.9 µmol/L. C5DC levels at the time of diagnosis were available for 41 patients. Although C5DC levels were within the normal range in three patients, two of them showed elevated C5DC/C8 and C5DC/C16 ratios and were homozygous for the c.169G > A variant. The mean C5DC concentration (normal range:0.01–0.26 µmol/L) was 0.79 ± 0.60 µmol/L (n = 41, range:0.08–2.24 µmol/L), with a median of 0.63 µmol/L. Urinary GA levels (normal < 5.3 µmol/mmol creatinine) at the time of diagnosis were available for 43 patients. The mean GA level (normal < 5.3 µmol/mmol creatinine) was 1672.48 ± 2498.52 µmol/mmol creatinine, with a median of 534.5 µmol/mmol. Based on excretion patterns, 35 patients were classified as HE and 8 patients as LE. Among HE patients, the mean C0 level (normal range:10–90 µmol/L) was 8.28 ± 10.65 µmol/L (median: 4.84 µmol/L; n = 30), and the mean C5DC concentration (normal range:0.01–0.26 µmol/L) was 0.83 ± 0.60 µmol/L (median: 0.59 µmol/L; n = 30). LE patients had a mean C0 level (normal range:10–90 µmol/L) of 9.72 ± 7.44 µmol/L (median: 6.7 µmol/L; n = 6), and a mean C5DC concentration of 0.88 ± 0.62 µmol/L (median: 0.74 µmol/L; n = 7). Urinary 3HGA levels at the time of diagnosis were available for 39 patients. Values ranged from 1.6 to 943 µmol/mmol creatinine (reference: <4.2), with a mean of 83.43 ± 182.21 µmol/mmol and a median of 14.8 µmol/mmol. Three patients with normal 3HGA levels were identified as HE. Fibroblast GCDH enzyme levels were analyzed for diagnostic purposes in 13 patients. Enzyme activity ranged from 0 to 1.2 (reference: 3.2–6.8), and in 6 patients, enzyme levels were undetectable (0).

Neuroimaging findings

Brain MRI findings were available for 36 patients. Basal ganglia involvement was observed in 31 patients (86.1%), frontotemporal atrophy in 26 patients (72.2%), and periventricular white matter signal abnormalities in 20 patients (55.6%). Subdural hemorrhage was detected in 4 patients (11.1%), and hydrocephalus in 6 patients (16.7%). Arachnoid cysts or widening of the temporal lobes and Sylvian fissures were noted in 9 patients (25.0%), while delayed myelination was observed in 3 patients (8.3%). Additionally, thinning of the genu and body of the corpus callosum was reported in 2 patients (5.6%) who underwent MRI at 10 and 15 years of age, respectively.

Genetic findings

Molecular genetic analysis was available for 29 patients. A homozygous variant in the GCDH gene was identified in 28 patients. In total, 15 different pathogenic variants were detected. Ten (34.4%) patients were homozygous for the c.743 C > T (p.Pro248Leu) variant, 19 (65.6%) were homozygous or compound heterozygous for other GCDH alleles (Table 3). In this cohort, all identified GCDH variants were classified as either pathogenic or likely pathogenic according to ACMG criteria. The most frequent variant was c.743 C > T (p.Pro248Leu) suggesting a possible founder effect in certain regions with high consanguinity. Several other recurrent variants were observed in two patients each, including c.1044 C > A (p.His348Gln), c.169G > A (p.Glu57Lys), c.383G > A (p.Arg128Gln), c.1173dupG (p.Asn392Glufs*5), c.382 C > T (p.Arg128Ter), and c.1132G > A (p.Ala378Thr). The remaining variants, c.299T > C, c.1204 C > T, c.157 C > T/c.541G > C, c.553G > A, c.1018 C > T, c.349G > A, and c.541G > C, were detected in single individuals. One patient carried a compound heterozygous genotype (c.157 C > T and c.541G > C).

Table 3.

Biochemical Findings at Diagnosis and GCDH Gene pathogenic variants in Patients with GA1

Patient No	Genotype								Enzyme activity (n:3.2–6.8)	3HGA (N < 4.2)	GA (N < 5.3)	C0 (µmol/L)	C5DC (µmol/L)	C5DC/C8	C5DC/C16
	DNA variant (NM_000159.3)	Protein variant	Exon/intron	Type of mutation	Mutation state	dbSNP NM_000159.3	Known/ Novel	ACMG
P1	c.299T > C	p.Met100Thr	E4	Missense	Homozygous	PMID:34,504,725	Known	LP	0.00	46	4747	5.9	0.53	1.89	0.47
P2	c.1044 C > A	p.His348Gln	E9	Missense	Homozygous	PMID:32,777,384	Known	LP	-	high	high	-	-	-	-
P3	c.169G > A	p.Glu57Lys	E4	Missense	Homozygous	rs776643576	Known	LP	-	-	-	28.5	0.14	2.23	-
P4	c.169G > A	p.Glu57Lys	E4	Missense	Homozygous	rs776643576	Known	LP	-	-	-	39.8	0.15	2.73	-
P7	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	-	45	1439	3.85	0.53	15.9	1.96
P8	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	-	-	454	7.5	1.0	-	-
P9	c.1204 C > T	p.Arg402Trp	E11	Missense	Homozygous	rs121434369	Known	P	-	13	1418	-	-	-	-
P10	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	-	10	126	3.39	0.28	12.1	1.38
P11	c.383G > A	p.Arg128Gln	E6	Missense	Homozygous	rs755586631	Known	P	-	943	5005	4.48	0.4	-	-
P12	c.1173dupG	p.Asn392Glufs*5	E11		Homozygous	rs754002357	Known	P	0	8	310	6.73	0.42	-	-
P13	c.1173dupG	p.Asn392Glufs*5	E11		Homozygous	rs754002357	Known	P	-	440	29	4.3	1.73	42.5	1.38
P15	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	0.09	43	617	5.5	0.3		-
P17	c.157 C > T/c.541G > C	p.Pro53Ser/p.Glu181Gln	E4, E7	Missense	Compound heterozygote	rs768532620, rs745852738	Known	P, P	1.2	5	12	15.7	0.74	5.54	0.28
P18	c.553G > A	p.Gly185Arg	E6	Missense	Homozygous	rs576948027	Known	P	-	14	968	1.3	1.22	-	-
P19	c.1018 C > T	p.Leu340Phe	E9	Missense	Homozygous	rs1599617735	Known	LP	-	36	2882	6.59	0.42	13.2	1.22
P20	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	0.03	-	100	2.27	0.31	2.38	1.29
P21	c.382 C > T	p.Arg128Ter	E7	Missense	Homozygous	rs752334462	Known	P	0.03	13	860	20	1.87	29.5	7.08
P22	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	0.04	4	4402	4.0	0.4	12.3	3.12
P23	c.382 C > T	p.Arg128Ter	E7	Missense	Homozygous	rs752334462	Known	P	-	3	1059	22.6	1.07	26.75	1.60
P24	c.1044 C > A	p.His348Gln	E9	Missense	Homozygous	PMID:32,777,384	Known	LP	0.17	35	16.3		0.15	-	-
P25	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	0.00	15	1703	24	0.93	14.30	2.07
P26	c.349G > A	p.Gly117Arg	E5	Missense	Homozygous	PMID:28,062,662, PMID:32,777,384	Known	LP	0.00	433	12,830	3.16	0.48	-	1.71
P27	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	0.03	high	12	6.59	0.33	6.0	1.50
P29	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	-	63	1881	11.7	0.26	31.7	1.77
P40	c.743 C > T	p.Pro248Leu	E7	Missense	Homozygous	rs1057516344	Known	P	-	213.5	4919	55.9	2.12	7.82	1.12
P42	c.383G > A	p.Arg128Gln	E6	Missense	Homozygous	rs755586631	Known	P	-	254.3	6416.5	2.69	0.72	16.9	1.21
P43	c.541G > C	p.Glu181Gln	E7	Missense	Homozygous	rs745852738	Known	P	0	6	391	-	1.05	9.98	0.87
P48	c.1132G > A	p.Ala378Thr	E11	Missense	Homozygous	rs1442597198	Known	LP	-	14.6	1061	6.7	1.42	142	2.4
P49	c.1132G > A	p.Ala378Thr	E11	Missense	Homozygous	rs1442597198	Known	LP	-	7.4	142.6	1.58	0.7	35	5

E: Exon; P: pathogenic; LP: Likely pathogenic; C0: Free carnitine; C5DC: glutarylcarnitine; GA: Glutaric acid; 3HGA: 3-Hydroxyglutaric acid

3HGA are given as µmol/mmol creatinine, GA are given as µmol/mmol creatinine

Discussion

In this study, we present the clinical, biochemical, neuroimaging, and molecular genetic characteristics of patients with GA1, along with clinical follow-up data and long-term complications. Owing to the absence of a national NBS program for GA1 in Turkey, the majority of patients in our cohort were diagnosed based on clinical presentation and presented severe neurologic sequela underscoring the importance of early diagnosis.

In our study, 66% of the patients exhibited an acute-onset phenotype, while 34% followed an insidious course characterized by gradually progressive neurological symptoms without preceding metabolic crises. These results are comparable to those of Zhou et al., in which 64.7% of clinically diagnosed patients experienced at least one encephalopathic crisis and 35.3% presented with insidious onset. In both studies, movement disorders, seizures, and developmental delay were among the most frequently reported symptoms. In our cohort, dystonia (74%), intellectual disability (70%), spasticity (66%), speech delay (66%), and encephalopathic crises (66%) were prominent findings, whereas Zhou et al. reported movement disorders in 52.9%, seizures in 47%, and mental retardation in 41% [9]. This difference likely reflects the more severe neurological burden observed in our patients, most of whom were diagnosed after the onset of symptoms and had limited access to early intervention.

The reliability of C5DC as a standalone biomarker in NBS for GA1 is limited, as it is prone to both false-positive and false-negative results. In particular, individuals with the LE phenotype may be missed during screening due to C5DC concentrations falling within the normal range. To enhance diagnostic specificity, it has been proposed that C5DC should be interpreted alongside ratios such as C5DC/C8 and C5DC/C16, as well as additional secondary metabolic indicators [10]. In our cohort, three patients had C5DC levels within the normal reference range at the time of diagnosis; however, two of these patients exhibited elevated C5DC/C8 and C5DC/C16 ratios, supporting the utility of these ratios as complementary diagnostic parameters. It is also important to note that elevated C5DC levels can be observed in patients with multiple acyl-CoA dehydrogenase deficiency (MADD). Nonetheless, this condition can usually be differentiated from GA1 by the presence of additional characteristic acylcarnitine abnormalities [10].

All patients in our study demonstrated markedly elevated urinary GA levels at the time of diagnosis. In contrast, LE patients reported in the literature often exhibit only subtly elevated or even normal levels of plasma C5DC and urinary GA, which may complicate both screening and diagnostic efforts. Recently, 2-methylglutaconic acid (2MGA) has been proposed as a supportive biomarker in such diagnostically challenging cases, particularly when conventional markers are inconclusive. Although the absence of 2MGA does not rule out GA1, its presence, especially in the context of clinical suspicion and elevated C5DC, may increase diagnostic confidence. Given that 2MGA can also be elevated in other organic acidurias, it should be interpreted with caution, but routinely monitored within extracted ion chromatograms during UOA analysis [11].

Although elevated urinary or plasma levels of 3HGA are typically considered a biochemical hallmark of GA1, normal concentrations cannot reliably exclude the diagnosis—particularly in individuals with the LE phenotype [11]. In our study, three patients had normal 3HGA levels despite confirmed GA1. Importantly, as highlighted in prior studies, urinary or plasma concentrations of GA and 3HGA do not correlate with disease severity or clinical trajectory and therefore should not be relied upon as biomarkers for monitoring disease progression or guiding therapeutic decisions [2].

Previous studies have suggested that residual GCDH enzyme activity ranging from 1% to 25% may be associated with the LE phenotype, whereas complete absence of enzymatic activity (0%) is typically linked to the HE phenotype. In a comprehensive study evaluating the predictive value of residual enzyme activity, concordance with the expected phenotype was observed in only 58.9% of patients, while 30.4% exhibited a more severe phenotype than predicted, and 10.7% had a milder clinical course than anticipated. These findings suggest that although patients with residual GCDH enzyme activity exceeding 5% are more likely to present with a milder LE phenotype, enzyme activity alone is insufficient for precise phenotype prediction [3]. In our study, GCDH enzyme activity was assessed in fibroblast cultures from 13 patients with GA1, nearly half of whom exhibited undetectable enzymatic activity. Among these patients with absent enzyme activity, one was lost to follow-up, one had a favorable clinical outcome, and four demonstrated severe neurological impairments. Notably, three of these patients were classified as having an LE phenotype. Although enzymatic analysis remains a valuable diagnostic tool, its prognostic utility is considerably limited due to the inconsistent correlation with clinical severity. In our cohort, patients harboring the same pathogenic variants displayed variable enzyme activity levels, accompanied by marked differences in neurological outcomes. Previous reports have shown that specific missense pathogenic variants—such as p.Ala298Thr, p.Val400Met, and p.Met263Val—are often associated with the LE phenotype and retain partial residual activity [3]. However, our observations further support that severely reduced or even absent enzymatic function does not necessarily predict a poor clinical prognosis. Conversely, individuals with minimal enzyme activity may exhibit relatively preserved neurologic function. This phenotypic discordance underscores the limited prognostic value of enzymatic assays alone and points to the complex interplay of genetic, epigenetic, and environmental modifiers in disease expression. The pronounced genotype–phenotype heterogeneity observed in our cohort, consistent with prior studies, reinforces the urgent need for additional biomarkers that more accurately reflect disease trajectory and support individualized therapeutic decision-making in GA1.

MRI plays a crucial role in the diagnosis of GA1 by revealing characteristic structural and signal abnormalities, including the widening of the Sylvian fissures and frontotemporal subarachnoid spaces, as well as atrophy and signal changes in the supratentorial white matter and deep gray matter. In line with previous literature, all patients in our study exhibited neuroradiological features consistent with GA1. The widening of the Sylvian fissures and anterior subarachnoid spaces, commonly described as the “bat-wing” sign, was present in the majority of our patients, consistent with the 100% prevalence reported by Ntorkou et al. Bilateral globus pallidus T2 hyperintensity was observed in all patients who had experienced a metabolic crisis, and bilateral symmetric T2 hyperintensities in the putamen were among the most common findings. These striatal lesions, frequently accompanied by diffusion restriction, are indicative of acute metabolic injury and align with prior studies identifying the putamen as the most vulnerable region during catabolic stress. Importantly, globus pallidus involvement and supratentorial white matter abnormalities were also observed in patients without a documented metabolic crisis, supporting the hypothesis that such changes may result from chronic metabolic imbalance rather than acute decompensation alone [12]. Routine MRI investigations for detection and/or monitoring of extrastriatal abnormalities (subependymal noduli, white matter abnormalities) can be started from age 10 years and repeated depending on clinical features, for example, every 2–5 years [2]. Although Ntorkou et al. described T2 signal changes in the optic chiasm and anterior visual pathways in a subset of patients, these regions were not systematically assessed in our study [12].

However, as emphasized by Bian et al., conventional MRI may fail to capture the microstructural integrity of the brain and does not correlate reliably with clinical severity in GA1. Although all patients in their study exhibited classical radiological signs, such as widening of the Sylvian fissures and basal ganglia abnormalities, these findings were not associated with dystonia severity. In contrast, diffusional kurtosis imaging (DKI) provided more sensitive markers of neuronal injury. Kurtosis metrics, including mean (MK), axial (AK), and radial (RK) kurtosis, were significantly elevated in deep gray matter structures and showed strong correlations with dystonia scores. Notably, kurtosis values in the temporal lobe and basal ganglia demonstrated the highest diagnostic accuracy [13]. These findings highlight the potential utility of DKI-derived parameters as surrogate biomarkers for disease severity and emphasize the widespread neuroanatomical involvement in GA1 beyond the striatum.

The clinical variability observed in our newborn-screened GA1 cohort is consistent with the largest meta-analysis to date, which evaluated neurological outcomes in 647 patients diagnosed either through NBS or after clinical symptom onset. In that study, 74.7% of individuals identified through NBS remained neurologically asymptomatic, whereas 25.3% developed movement disorders, indicating that early detection substantially improves prognosis but does not eliminate the risk of neurological complications. The residual risk was mainly attributed to deviations from dietary protocols and delays in emergency treatment during catabolic stress, emphasizing the importance of timely and adequate therapy [2]. Our findings are in line with these observations: while one patient in our cohort remained neurologically intact into late adolescence under consistent treatment, another developed severe neurological deterioration following an encephalopathic crisis despite early diagnosis, most likely due to suboptimal crisis management. These findings suggest that although NBS is crucial for early detection, long-term outcomes in GA1 depend largely on effective maintenance therapy, prompt emergency management, and adherence to established treatment guidelines.

Acute metabolic decompensations in individuals with GA1 most commonly occur before the age of six years, particularly during the first three years of life, and are typically precipitated by catabolic stressors such as infections, febrile illnesses, vaccinations, or surgical procedures [14]. In our cohort, 48.0% of patients exhibited a clearly identifiable trigger at the time of initial presentation, with gastroenteritis and upper respiratory tract infections being the most frequently reported factors. Although vaccination has been sporadically suggested as a potential trigger, current clinical guidelines strongly advocate for adherence to national immunization schedules without modification in patients with GA1, emphasizing that the benefits of preventing febrile illnesses far outweigh the theoretical risks [14]. Furthermore, 34.0% of our patients had a documented history of recurrent febrile episodes, reinforcing the increased vulnerability of this population to metabolic instability. These findings underscore the necessity of vigilant clinical monitoring and early recognition of prodromal symptoms such as persistent vomiting, decreased oral intake, or evolving neurological signs followed by urgent referral to a metabolic center or a designated hospital to ensure timely initiation of emergency treatment protocols [14].

Patients identified through family screening are generally expected to have a more favorable clinical course, as earlier recognition allows timely initiation of dietary treatment and metabolic management. However, despite detailed counseling regarding treatment adherence and sick-day management, outcomes were not uniformly favorable in our cohort. In one illustrative case, delayed access to the recommended metabolic formula and postponement of medical evaluation during an intercurrent illness led to a metabolic crisis with subsequent neurological regression and dystonia. These findings highlight that although family screening facilitates earlier detection, favorable neurological outcomes are not guaranteed and may still be influenced by metabolic crises, intercurrent illness, treatment adherence, and access to specialized dietary management.

To date, 494 pathogenic variants in the GCDH gene have been reported in the Human Gene Mutation Database (HGMD; www.hgmd.cf.ac.uk). In our cohort, the most frequent variant was c.743 C > T (p.Pro248Leu), which is consistent with the findings of Kılavuz et al., who also identified this variant among the most common alleles in their Turkish cohort [5]. While the majority of GCDH pathogenic variants are considered private and occur in single families or small groups of patients, several recurrent variants exhibit distinct geographic clustering. Notably, the p.Arg402Trp variant has been documented at relatively high frequencies in European populations. Furthermore, founder effects have led to the predominance of specific pathogenic variants within genetically isolated populations, exemplified by p.Ala421Val in the Amish community of Lancaster County, Pennsylvania, USA, and IVS1 + 5G > T (c.91 + 5G > T) among the Ojibwe First Nations in Manitoba and Ontario, Canada [3].

Currently, data on the clinical and genetic characteristics of adult-onset GA1 remain limited. To date, only nine adult-onset cases have been reported in the literature [15], most of which presented with nonspecific neurological symptoms such as headache, dizziness, transient ataxia, or stroke-like episodes, without a history of encephalopathic crisis [14]. Our late-onset patient presented at 12 years of age with headache and no acute encephalopathic crisis, and was found to carry the c.1204 C > T (p.Arg402Trp) variant—reported as the most common variant in adult-onset GA1 cases [15]. The correlation between GA1 genotype, biochemical phenotype, and clinical phenotype remains complex. However, current evidence indicates that there is no consistent association between specific variants and clinical presentation, and these genetic findings cannot reliably predict early or late onset [15].

With advances in the clinical management of GA1 and improved survival, an increasing number of reports have described complications beyond the nervous system. Recent findings suggest that chronic kidney disease, malignant brain tumours, cognitive dysfunction, hearing impairment, polyneuropathy, and incontinence may represent emerging non-neurological manifestations of GA1 [2]. Strauss et al. reported renal impairment, skeletal complications such as osteoporosis, and endocrine abnormalities during long-term follow-up of a large cohort of treated patients, highlighting the growing burden of systemic morbidity beyond the early neurodevelopmental phase [1]. Similarly, a case presented by Baskara et al. described a young adult with GA1 who developed acute myeloneuropathy and chronic kidney disease, thereby expanding the phenotypic spectrum to include spinal cord involvement and suggesting mitochondrial dysfunction in non-neuronal tissues [16]. Furthermore, Serrano Russi et al. reported malignant brain tumours in individuals with GA1, raising concerns about a potential tumour-promoting metabolic environment associated with chronic metabolite accumulation and delayed treatment [17]. Consistent with these observations, our cohort also revealed a range of chronic complications affecting various organ systems, including renal parenchymal disease, hepatic steatosis, nephrolithiasis, short stature requiring growth hormone therapy, obesity, and hypertension. Moreover, the detection of an intracranial mass in one patient, diagnosed at a later stage, further supports the potential for atypical and severe extra-neurological manifestations. These findings underscore the importance of holistic, long-term follow-up protocols in GA1, incorporating regular assessment of renal, hepatic, cardiac, endocrine, and possibly neoplastic complications, particularly in all individuals.

In our study, neurodevelopmental assessments revealed a high prevalence of severe functional impairment. Specifically, 61.5% of patients were classified as GMFCS level 5, indicating profound motor dysfunction, while 30.8% exhibited CFCS level 5, reflecting very severe communication impairment. Similar to our findings, Paria et al. reported from India where there is absence of national NBS, the majority of children with GA1 were non-ambulatory, with 62.5% (15/24) classified as GMFCS level 4 or 5 and only 8.3% (2/24) at level I at the time of assessment. Moreover, 58.3% (14/24) of the children had severe communication impairment based on the CFCS, while only two were classified as level I [18]. In a systematic review including 647 patients with GA1, Boy et al. demonstrated that individuals identified through NBS exhibited a significantly higher proportion of normal motor development (mean: 84.4%) compared to those diagnosed after clinical onset, in whom the rate was only 6.0% [19].

Kılavuz et al. described the first GA1 case series from Turkey, comprising 41 patients, and similar to our study, demonstrated significant diagnostic delays, high rates of parental consanguinity, and a broad spectrum of clinical manifestations, all of which contributed to the severity of neurological sequelae. In their cohort, 25 patients were severely affected, 10 were bedridden, and 2 had died due to severe pneumonia [5]. The striking clinical and radiological parallels between the two cohorts, coupled with uniformly poor outcomes in late-diagnosed patients, strongly support the urgent inclusion of GA1 in the national NBS program in Turkey.

Conclusions

The prevention of irreversible neurologic damage in GA1 critically depends on early diagnosis, timely initiation and sustainability of treatment. It is well established that dietary management, combined with aggressive intervention during intercurrent illnesses, significantly reduces the risk of acute encephalopathic crises during the critical vulnerability period of early childhood, thereby minimizing long-term neurological sequelae. As GA1 is now recognized as a treatable neurometabolic disorder, our findings reinforce the need for urgent inclusion of GA1 in national NBS programs, particularly in regions with a high prevalence of consanguineous marriages, where the incidence of autosomal recessive disorders is elevated. Additionally, comprehensive family education on the natural course of the disease, recognition of early warning signs, and the importance of metabolic emergency management during catabolic stress is essential for optimizing long-term outcomes. Ultimately, the integration of early screening, targeted genetic counseling, and structured follow-up protocols will be key to preventing severe neurodevelopmental disability in patients with GA1.

What is Known.

1. Glutaric acidemia type 1 (GA1) is a rare but treatable neurometabolic disorder caused by biallelic pathogenic variants in the GCDH gene.

2. Early diagnosis and treatment, particularly through newborn screening (NBS) programs, can markedly reduce the risk of acute encephalopathic crises and permanent neurological damage.

What’s new.

1. This study provides comprehensive clinical, biochemical, radiological, molecular genetic, and long-term follow-up data from a large GA1 cohort in Turkey, diagnosed outside of newborn screening programs in a population with high consanguinity.

2. The c.743 C > T variant was identified as the most frequent pathogenic allele, and several additional recurrent variants (c.1044 C > A, c.169G > A, c.383G > A, c.1173dupG, c.382 C > T, c.1132G > A) were detected, expanding the known mutational spectrum in this population.

Authors’ contributions

Arzu Selamioğlu conceptualized and designed the study, coordinated data collection, performed data analysis and interpretation, and drafted and revised the manuscript. Melda İdrisoğlu and Şebnem Kılıç contributed to patient identification and data collection. Asuman Gedikbaşı and Fatmahan Atalar provided expert input on the genetic analyses and contributed to the interpretation of genetic findings. Dilek Güneş, Meryem Karaca, Mehmet Cihan Balcı, and Nafiye Emel Çakar were involved in the clinical follow-up of the patients and data acquisition. Gülden Gökçay supervised the study and provided critical intellectual input throughout the research process. All authors reviewed and approved the final version of the manuscript.

Funding

There is no funding source.

Data availability

All data generated or analysed during this study are included in this. Further enquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

All study procedures adhered to the principles outlined in the Declaration of Helsinki and received approval from the Istanbul University Ethical Committee (Approval No.2954467). Participation in the study was voluntary, and informed consent was obtained from the parents, who acted as legal guardians, to ensure compliance with ethical standards for participants under 18.

Consent for publication

Written informed consent for publication of the anonymised patient quote was obtained from the child’s parents.

Competing interests

The authors declare no competing interests.