The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study

Abstract

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.

Rare Disease Registries Are Key to Evidence-Based Personalized Medicine: Highlighting the European Experience

“…While the first guideline mostly included grade D and a few grade C recommendations, reflecting significant uncertainty (59), the level of evidence and grade of recommendations have been improved continuously, demonstrated by the first (60) and second revision (61). This progress was much accelerated by careful long-term follow-up of national and international cohorts (38,56,57,59,(61)(62)(63)(64)(65)(66)(67)(68)(69), demonstrating that (i) newborn screening is the prerequisite of favorable neurological outcome and survival and (ii) is highly cost-effective, and that (iii) adherence to recommended maintenance and emergency treatment is associated with the most favorable neurological outcome and (iv) normal growth. Furthermore, these studies described a so far unknown renal disease manifestation, unraveled similarities (risk of striatal necrosis with concomitant complex movement disorder with predominant dystonia) and discrepancies (cognitive function, white matter changes, subdural hematoma) between biochemically delineated subgroups (high versus low excreter phenotype), and evaluated which part of the complex clinical spectrum can be specifically targeted and changed by current therapy, highlighting the need for safer and more effective medicines.…”

How longitudinal observational studies can guide screening strategy for rare diseases

“…Recommended treatment, if introduced and monitored by an experienced multi‐professional team, is safe and the major prerequisite of good neurological outcome, while deviation from recommended treatment increases the risk of striatal damage, 50,87,90,91 highlighting the importance of the quality of therapy 60 . Some lately recognized aspects of the disease, however, such as chronic kidney disease, 50 progressive white matter changes, 92,93 and slightly reduced IQ in high excreters, 91 do not seem to be impacted by currently available therapies. Besides GA1, this iterative approach of longitudinal observational studies conducted by international scientific consortia and concomitant guideline development is also successfully applied to other IMDs, such as methylmalonic and propionic aciduria, 53,94–96 urea cycle disorders, 57,58,97 cystathionine beta‐synthase deficiency, 98 remethylation disorders, 54,99,100 and tetrahydrobiopterin deficiencies 56,101 …”

“…87,90 Almost 20 years later, there is now solid evidence that GA1 is a treatable NBS condition. Recommended treatment, if introduced and monitored by an experienced multi-professional team, is safe and the major prerequisite of good neurological outcome, while deviation from recommended treatment increases the risk of striatal damage, 50,87,90,91 highlighting…”

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

“…This striatal injury often results in MD with predominantly dystonic/dyskinetic features 9 . Initially it was thought that intellect is unaffected in GA1, 10 but recent studies have shown that cognitive impairment is a feature, and that it is predicted by high excretor status 11 . Due to the early presence of subdural effusion, GA1 has been previously misdiagnosed in children as non‐accidental injury 12 …”

“…13 Traditionally it was thought that all biochemical phenotypes had a similar clinical course but recent evidence has emerged that HE patients are at increased risk of progressive white matter damage in later life, although the clinical significance of this is unknown. 11,14 Insidious onset GA1 describes striatal injury and MD occurring without apparent crisis and is estimated to account for 20% of symptomatic presentations. 9,15 This phenotype has also been described in patients diagnosed by newborn screening (NBS) with suboptimal adherence to dietary regimes, in whom it may account for up to 50% of cases of MD.…”