# Delayed Diagnosis of Glutaric Aciduria Type 1: A Case Report

## TL;DR

A child with glutaric aciduria type 1 was misdiagnosed for years due to normal newborn screening and inconclusive tests, eventually diagnosed through genetic sequencing.

## Contribution

Highlights the limitations of biochemical testing and newborn screening in diagnosing GA1, emphasizing the value of genetic testing.

## Key findings

- GA1 can be missed by newborn screening and biochemical tests due to low excretor phenotypes and normal biomarkers.
- Exome sequencing confirmed GA1 in a patient with atypical symptoms and inconclusive MRI and biochemical results.
- False negatives in GA1 screening persist even with lowered thresholds due to variable biochemical presentations.

## Abstract

Newborn screening (NBS) is performed to screen for conditions where early intervention can make a difference in a patient’s prognosis. We present the case of a patient with glutaric aciduria type 1 (GA1) that was missed on NBS but was diagnosed through exome sequencing (ES) at eight years of age. We report the case of a patient who was born in Florida in 2011 and underwent routine NBS, which was negative for all tested conditions, including amino acidemias. At 11 months of age, the patient presented with seizures. Upon physical examination, she had hypotonia, ptosis, and macrocephaly. A urinary tract infection was found, and the seizures were attributed to fever from an infectious source. Laboratory testing revealed marginally elevated levels of pyruvate, acylcarnitine, and total carnitine. Magnetic resonance imaging and spectroscopy (MRI/MRS) showed signs of basal ganglia damage. At 12 months of age, she was tested for pathogenic variants in PDHA1, PTEN, and the mitochondrial genome, to look for an underlying molecular diagnosis for her symptoms. No pathogenic variants were found. At eight years of age, ES revealed that the patient was a compound heterozygote for pathogenic variants in GCDH, confirming a diagnosis of GA1. There is little correlation between biochemical markers and phenotype severity in GA1; therefore, biochemical markers can potentially be within normal limits in a symptomatic patient. Diagnosis is complicated by low excretor phenotypes: some patients excrete lower levels of organic acids in the urine. Furthermore, there are no pathognomonic clinical findings, and these patients do not always have MRI findings. ES of our patient led to the diagnosis of GA1, where biomarkers and imaging did not, highlighting the clinical utility of gene sequencing. As we will explore, this is not an isolated case of disease missed in biochemical testing. GA1 should be included in a differential if a patient has symptoms consistent with the condition and/or if biochemical markers are marginally normal. Lowering the threshold for positive biochemical results is not sufficient to address this issue, as it would create an excess of false positives. Since GA1 can also result in inconclusive biochemical tests, false-negative results will still occur. As NBS cannot unequivocally rule out GA1 in these patients, enzyme and/or genetic testing may yield a diagnostic result and inform appropriate management.