Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl‐CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3‐hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre‐symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long‐term outcomes is still unclear. This third revision of evidence‐based recommendations aims to re‐evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75–101; Kolker et al., J Inherit Metab Dis 2011;34(3):677–694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5–22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non‐interventional variables and treatment quality on clinical outcomes.

Purpose Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome. Methods Systematic literature search for articles published from 2000 to 2019 was performed using the PRISMA protocol. Studies reporting on more than one individual identified by NBS were included. We investigated effects of interventional and noninterventional variables on neurological outcome. Results Fifteen publications reporting on 647 GA1 patients were included. In the NBS group (n = 261 patients), 195 patients remained asymptomatic (74.7%), while 66 patients (25.3%) developed a MD. Compared with the NBS group, a much higher proportion of patients (349/386; 90.4%; p < 0.0001) diagnosed after the manifestation of neurologic symptoms had a MD and an abnormal motor development (285/349; 81.7%; p < 0.0001). For NBS patients, deviations from the recommended diet increased the risk of insidious onset MD, while delayed start of emergency treatment increased the risk of acute onset MD. Conclusions This meta-analysis demonstrates that NBS programs for GA1 have an overall positive effect on the neurological outcome of affected individuals but their success critically depends on the quality of therapy.

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. 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. 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.

Exome sequencing and Drosophila modeling revealed variants in SMARCA5 as a novel cause of a neurodevelopmental disorder.

The aim of the study was a systematic evaluation of cognitive development in individuals with glutaric aciduria type 1 (GA1), a rare neurometabolic disorder, identified by newborn screening in Germany. This national, prospective, observational, multi-centre study includes 107 individuals with confirmed GA1 identified by newborn screening between 1999 and 2020 in Germany. Clinical status, development, and IQ were assessed using standardized tests. Impact of interventional and non-interventional parameters on cognitive outcome was evaluated. The majority of tested individuals (n = 72) showed stable IQ values with age (n = 56 with IQ test; median test age 11 years) but a significantly lower performance (median [IQR] IQ 87 [78–98]) than in general population, particularly in individuals with a biochemical high excreter phenotype (84 [75–96]) compared to the low excreter group (98 [92–105]; p = 0.0164). For all patients, IQ results were homogenous on subscale levels. Sex, clinical motor phenotype and quality of metabolic treatment had no impact on cognitive functions. Long-term neurologic outcome in GA1 involves both motor and cognitive functions. The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. These findings implicate the necessity of new treatment concepts.