Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

Abstract

In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises--in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.

Glutaric Acidemia Type 1-Clinico-Molecular Profile and Novel Mutations in GCDH Gene in Indian Patients

“…Category 2 patients had mainly motor regression due to incapacitating dystonia. A correlation between MRI findings and dystonia has been studied in detail earlier by Harting et al (2009) and Garbade et al (2014). These authors clearly showed that the severity of striatal lesions on MRI did correlate with the severity of the movement disorder.…”

“…He has good compliance and is developmentally normal. All patients with or without crises had MRI abnormalities (Harting et al 2009). Eighty two percent of the patients (14/17) were already neurologically compromised (categories 2-4) at the time of presentation.…”

Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation

“…The late-onset case of GA-I presented here is remarkable for the following reasons: Few well-documented late-onset GA-I case reports have been published heretofore (B€ ahr et al 2002;Twomey et al 2003;Fernandez-Alvarez et al 2003;K€ ulkens et al 2005;Sonmez et al 2007;Harting et al 2009;Chen et al 2011). Our patient was asymptomatic at 16 years of age, apart from macrocephaly and mild psychomotor delay since infancy, and the diagnosis was made incidentally after a fainting episode during physical exercise without encephalopathy.…”

“…There have been scant reports in the medical literature, and in fact, some cases reported as "adult-onset GA-I" were simply childhood-onset GA-I diagnosed in adulthood (Prevett et al 1996;Corral I et al 2001;B€ ahr et al 2002;Twomey et al 2003;Fernandez-Alvarez et al 2003;K€ ulkens et al 2005;Sonmez et al 2007;Harting et al 2009;Chen J et al 2011). According to the few reports of truly adult-onset GA-I (onset at the age of 18 years or older), (1) the patients were paucisymptomatic or asymptomatic at the time of diagnosis, (2) the disease followed either an acute encephalopathic or a non-encephalopathic clinical course, and (3) in all cases supratentorial, diffuse, symmetric U-fiber-sparing leukoencephalopathy involving periventricular and deep white matter was seen in cranial MRI.…”

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

“…Furthermore, because during brain development, energy requirements are high and in their most vulnerable phase (87,88), other brain-specific effects of 2HG could also be envisioned. D-2HG is taken up by astrocytes at high rates, potentially interfering with the uptake of ␣KG via the Na ϩ -dependent dicarboxylate transporter 3 (89,90).…”