A Rare Presentation of Glutaric Aciduria Type 1 in an Adult

Sir, Inborn errors of metabolism (IEM) are rare genetic disorders caused by gene mutations leading to defects in enzymes and proteins involved in cell metabolism, mostly presenting in the newborn period or early infancy. However, a few IEMs may not manifest until adolescence or adulthood. Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by a deficiency of the enzyme glutaryl CoA dehydrogenase (GCDH), affecting the metabolic pathway of the amino acids—lysine, hydroxylysine, and tryptophan—thus leading to accumulation of glutaric acid and other metabolic by-products.[1] GA1 is characterized by bilateral striatal neurodegeneration due to the accumulation of glutaric acid and related metabolites, leading to vascular dysfunction, abnormal cerebral blood flow, and blood–brain barrier damage. The late-onset type is seen in patients diagnosed after 6 years, mainly presenting with nonspecific and sometimes longstanding neurological symptoms. Here, we report a case of adult-onset GA1 in a 34-year-old male, highlighting the neuroradiological, biochemical, and genetic findings that lead to this uncommon diagnosis. A 35-year-old male presented with complaints of persistent headaches and blurring of vision in the past 3 months. On general examination, mild macrocephaly with a head circumference of 55 cm was noted. Neurological and systemic examinations were normal, with visual acuity of 6/12 and normal fundus without any evidence of papilledema. The neuropsychological assessment done was normal. All the routine blood tests were done and were normal. MRI of the brain showed hyperintensities in the subcortical white matter of frontoparietal lobes and widening of basal cisterns, left Sylvian fissure, and prominent bilateral anterior temporal cerebrospinal fluid spaces suggestive of arachnoid cysts and chronic subdural cerebrospinal fluid (CSF) collection in left frontoparietal convexity [Figure 1]. To evaluate for the cause of the striking white matter changes and atrophy observed on the brain imaging, other tests like serum antinuclear antibody by immunofluorescence and profile, HIV, VDRL, angiotensin-converting enzyme level, antiphospholipid antibody, serum homocysteine, anti–aquaporin-4 antibody, and antimyelin oligodendrocyte glycoprotein antibody level were done, which were negative. VEP of both eyes showed mild axonal optic neuropathy of the left eye. As all acquired conditions were ruled out and with the likely imaging abnormalities, differential diagnoses like glutaric aciduria type 1 and benign expansion of subarachnoid spaces were considered, and detailed family history was taken. The patient was born through second-degree consanguineous marriage via an uneventful normal delivery. No family history of genetic disorders was present, and his early development was normal.Figure 1: Axial FLAIR MR image of the brain (a) and T1-weighted image (b) shows a left frontoparietal subdural collection (white arrow in a and b) and subcortical white matter hyperintensities (black arrow in a). Axial T2-weighted image shows a widened Sylvain fissure (c) and the anterior temporal arachnoid cysts (d)As a metabolic disorder was suspected, tandem mass spectrometry was sent, which showed increased levels of glutarylcarnitine/3-hydroxyhexanoylcarnitine with low free carnitine and low levels of acetylcarnitine and butyryl carnitine, which is suggestive of GA1. For confirmation, whole-exome sequencing was sent, showing a pathogenic variant in the GCDH gene associated with GA1 [Figure 2]. The patient was advised to make dietary changes in the form of a low-lysine, tryptophan and low-protein diet and started on carnitine therapy. Avoidable foods are milk, dairy products, meat, poultry, fish, eggs, beans, nuts, and peanut butter. After initiation of therapy, symptoms improved after 3 months with a significant decrease in intensity and episodes of headache.Figure 2: Whole-exome sequencing result of the patientGA1 is a rare genetic disorder caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH) located on chromosome 19p13.2. More than 200 disease-causing mutations in the GCDH gene have been identified.[2] The estimated prevalence of GA1 reported from 1:125,000 worldwide to 1:250 newborns in genetic high-risk populations.[3] The GCDH is involved in the degradative metabolism of L-lysine, L-hydroxylysine, and L-tryptophan, converting the glutaryl-CoA to crotonyl-CoA in the mitochondrial matrix.[1] GA1 has two different phenotypes: infantile-onset type and the late-onset type. The late-onset type manifests after the first 3 years of life and presents with chronic headaches, peripheral neuropathy, white matter abnormalities, subdural bleeds or fluid collections, and subependymal nodules.[4,5] Clinically, adult-onset patients with GA1 have a wide variety of presentations. They can present with weakness, headache, memory disturbances, seizures, macrocephaly, dysarthria, dystonia, opisthotonus, difficulty with coordination, metabolic stroke, and subdural and retinal hemorrhages. The MRI findings were pivotal in raising the suspicion of GA1 as white matter changes are common in late-onset GA1 patients. MRI shows white matter signal abnormalities involving the deep frontoparietal white matter seem more frequent in adults and increase with age. Some may also have subependymal nodules localized at the roof and medial walls of the lateral ventricles, representing another useful neuroimaging marker.[5] It is important to look beyond acquired conditions in adults presenting with white matter changes on imaging and be aware of genetic and metabolic conditions that can present late in life. This case highlights a rare but likely underdiagnosed clinical and radiological presentation of GA1 in adults. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.