Glutaric aciduria type 1: Diagnosis, clinical features and long-term outcome in a large cohort of 34 Irish patients

Abstract

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder that can lead to encephalopathic crises and severe dystonic movement disorders. Adherence to strict dietary restriction, in particular a diet low in lysine, carnitine supplementation and emergency treatment in pre-symptomatic patients diagnosed by high-risk screen (HRS) or newborn screen (NBS) leads to a favourable outcome. We present biochemical and clinical characteristics and long-term outcome data of 34 Irish patients with GA1 aged 1-40 years. Sixteen patients were diagnosed clinically, and 17 patients by HRS, prior to introduction of NBS for GA1 in the Republic of Ireland in 2018. One patient was diagnosed by NBS. Clinical diagnosis was at a median of 1 year (range 1 month to 8 years) and by HRS was at a median of 4 days (range 3 days to 11 years). 14/18 (77.8%) diagnosed by HRS or NBS had neither clinical manifestations nor radiological features of GA1, or had radiological features only, compared to 0/16 (0%) diagnosed clinically (p < 0.001). Patients diagnosed clinically who survived to school-age were more likely to have significant cerebral palsy and dystonia (7/11; 63.6% vs. 0/13; 0%, p < 0.001). They were less likely to be in mainstream school versus the HRS group (5/10; 50% vs. 12/13; 92.3%; p = 0.012). Clinical events occurring after 6 years of age were unusual, but included spastic diplegia, thalamic haemorrhage, Chiari malformation, pituitary hormone deficiency and epilepsy. The exact aetiology of these events is unclear.

Keywords: gluatric aciduria type 1; high‐excretor; high‐risk screen; low‐excretor; newborn screening; retrospective analysis.

FIGURE 1

Sagittal T1 MRI of male patient diagnosed by HRS as a neonate aged 16 demonstrates mild inferior herniation of the cerebellar tonsils with a syrinx of the cervical cord (A) and hyperintensity of the white matter and corpus striatum on Axial T2 MRI in keeping with GA type I (B). Follow‐up midline sagittal T1 images shows interval improvement of the cervical cord syrinx aged 22 (C) and 27 (D) years.

FIGURE 2

Axial T2 MRI of female patient diagnosed by HRS, aged 14 years demonstrates mild ventricular dilatation. Ventricles are larger than on baseline prior MRI studies. There is extensive hyperintensity of the white matter in keeping with GA type I (A). Axial T2 MRI obtained 1 week later (B) and 1 day post an Endoscopic Third Ventriculostomy (ETV) shows an interval slight decrease in ventricular size. There is a small bubble of air in the nondependent aspect of the right lateral ventricle.