Peripheral Neuropathy Expands the Neurological Phenotype in Glutaric Aciduria Type 1

Glutaric aciduria type 1 (GA1) is a neurometabolic disorder characterized by striatal injury in infancy and extrastriatal central nervous system abnormalities, the latter depending on the biochemical subtype. Whether the peripheral nervous system (PNS) is also affected has not been systematically studied. Therefore, we conducted a cross-sectional study of 21 GA1 patients (15 high excretor [HE], 6 low excretor [LE]), identified either by newborn screening (NBS, n = 11) or targeted metabolic diagnostics (TMD, n = 10). All underwent clinical evaluation, cerebral MRI, neurophysiology, and MR-neurography (MRN) of the sciatic nerve with magnetization transfer imaging and diffusion tensor imaging (DTI). Nerve magnetization transfer ratio (MTR) was analyzed across subgroups and against 21 age-matched controls, while fractional anisotropy (FA) was assessed within the patient cohort. MRN revealed frequent abnormalities in GA1, particularly among HE patients, who showed lower MTR and FA values, indicating neuropathic changes. These alterations correlated with age, extrastriatal MRI abnormalities, and subependymal nodules, but not with striatal lesions or movement disorder. Clinical neuropathic symptoms were rare (4/15 HE patients) yet consistently associated with abnormal MRN. In HE patients exclusively, neurophysiology demonstrated reduced compound motor action potentials, slowed nerve conduction, and prolonged tibial somatosensory evoked potential latencies. Within the HE subgroup, NBS-identified patients showed higher MTR values than those identified by targeted metabolic diagnostics, suggesting less severe nerve involvement. These results expand the GA1 phenotype by demonstrating frequent, predominantly subclinical PNS involvement in HE patients, linked to chronic metabolic toxicity. They underscore the need for further research into long-term complications and therapeutic strategies for HE individuals.