Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Abstract

Background: Without neonatal initiation of treatment, 80-90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment.

Results: No late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients.

Conclusions: While clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors.

Keywords: Frontotemporal hypoplasia; Glutaric aciduria type I; High excretor; Late-onset; Long-term disease course; Subependymal nodules.

Fig. 1

Normal frontotemporal anatomy and examples of frontotemporal hypoplasia. a-c Normal Sylvian fissure and anterior temporal CSF spaces in control patient c2. NB asymmetric thalamus with focal T2-hyperintensity and facilitated diffusion (inset: ADC map). d-i Mild hypoplasia in late-onset patient p1 not extending dorsally beyond the pars opercularis (arrow in d) of the inferior frontal gyrus and remaining unchanged between first MRI at 8.6 years (d-f) and last follow-up MRI at 15.7 years (g-i). NB T2-hyperintensity of pontine white matter and dentate nucleus (H). j-l Moderate hypoplasia involving the subcentral gyrus in late-onset patient p6 (arrow in j). NB subependymal nodules and focal, asymmetric white matter changes (l). m-r Widely open Sylvian fissure and massively widened anterior temporal CSF spaces in late-onset patient p7 unchanged between MRIs at 61 and 73 years. NB large, subependymal, FLAIR-hyperintense nodule in right frontal horn (o, r; also Fig. 3). (T1w: a, g, m, p; T1w + GAD: j; T2w: b, c, e, f, h, i; FLAIR: K, l, n, o, q, r; ADC: inset in c)

Fig. 2

Examples of white and grey matter changes. a Mild, predominantly periventricular white matter changes (arrows) in control patient c1. b Focal and confluent, slightly asymmetrical white matter changes as well as mild periventricular white matter hyperintensity (arrows) in late-onset patient p5. c, d Extensive white matter changes in late-onset patient p1 at 8.5 (c) and 15.7 years (d) with slight progression during follow-up (e.g. temporal, arrows d, compare with c). NB T2-hyperintensity of pallidum and medial thalamus is only depicted at follow-up (d, arrow to right thalamus) due to different slice angulation of examinations. e, f Extensive white matter changes in control patient c6 without progression between 11 (e) and 19 years (f) involving periventricular, lobar, and subcortical white matter. Pattern of involvement is similar to p1 with a rim of near normal signal (arrows) interspersed between changes of periventricular and more peripheral white matter. g, h. White and grey matter changes in late-onset patient p7 at the age of 61 (g) and 73 years (h). At the age of 61 years there is a combination of mild, periventricular and multiple, brighter white matter hyperintensities undistinguishable from hypertensive white matter changes observed in non-GA1-patients at this age. Subacute ischemia of the right dorsolateral medulla oblongata (arrows in g _1,2), which was the cause of the acute neurological presentation, retracts over time (arrow in h ₁) as does the pre-existing anterior lenticular and caudate defect (arrow in g ₄, compare with h ₄). By the age of 73 years, white matter changes have increased. Bilateral occipital (arrows in h _2,3, compare with g ₃) and hemodynamic ischemia in the left parietal border zone (arrows in g _4,5) have left defects and gliosis and there is overall volume loss with widening of ventricles and sulci. (T2w: a-f, g ₂, h ₁; FLAIR: g ₁, g _3–6, h _2–6)

Fig. 3

Examples of subependymal lesions. a-f MRI of late-onset patient p1 at the age of 15.7 years with the (pre-existing) nodular subependymal lesion in the medial roof of the right lateral ventricle (arrows in a, d, f ₃) and four incipient lesions in the roof of both lateral ventricles (arrows in a (lat.), b and f ₂, in c and f _3,5, in e and f ₁). (a : T2w; b - f : T1w). g-l MRI of late-onset patient p2 at 14.7 years with multiple, small, FLAIR-hyperintense nodularities (g, h, arrows) resulting in a “bumpy” surface of the ventricular roof on the T2w sagittal images (i right, k left lateral ventricle) and one larger nodule in the roof of the left ventricle without enhancement (arrows in j, l ₁, l ₂). NB extensive white matter changes. (g, h: FLAIR; i-k: T2w; l ₁, l _,2: T1w ± GAD). m-r Late-onset patient p6 with the most extensive, confluent subependymal lesions with multiple, small cystic areas (hypointense on FLAIR-images m, n, arrows in n), facilitated diffusion (r), punctate susceptibility artefacts (arrows in q) and punctate enhancement (compare p with o). (m, n: FLAIR; o, p: T1w ± GAD, q: T2*; r: ADC). s-z MRIs of late-onset patient p7 at the age of 61 (S-U) and 73 years (v-z). Initially there are two lesions, a small one in the left anterior horn (arrow in s) without significant change on follow-up (arrows in v, z ₂) and a larger one in the right anterior horn (s, z ₂, arrows in t, u), which increases mildly in size from approx. 10x9x8 mm to 13x9x9 mm during the 12 year period. Punctate susceptibility artefacts (arrows in w), facilitated diffusion (x), and some superficial, linear enhancement (compare y ₁ with y ₂ and z ₁ with z ₂) are present, similar to the large lesions in p6. Two additional, small nodules in septal surface of the right anterior and the roof of the left horn (arrows in z _3,4) have been detectable and without significant changes since MRIs at 65 and 66 years. MRI at 73 years depicts an additional, incipient lesion in the roof of the right lateral ventricle (arrow in z ₅). (s, v: FLAIR; t: T2w; u, y ₁, z _2–5: T1w, y ₂,, z ₁: T1w + GAD, w: SWI; x: ADC)