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

E M Charlotte Märtner,Sarah C Grünert,Chris Mühlhausen,Johannes Krämer,Andrea Näke,Stefan Kölker,Anibh M Das,Peter Freisinger,Sylvia Roloff,Esther M Maier,Eva Thimm,Katharina A Schiergens,Georg F Hoffmann,Andrea Dieckmann,Sven F Garbade,Frank Rutsch,Magdalena Walter,Claudia M Haase ,Skadi Beblo,Martin Lindner,Iris Marquardt,Philipp Guder,Matthias R Baumgartner,Nikolas Boy

doi:10.1038/s41598-021-98809-9

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.

Highlights

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
The study sample included 107 patients with confirmed GA1, 98 of whom were identified by newborn screening (NBS), while six patients were missed by NBS and three maternal patients were diagnosed due to positive NBS results of their unaffected offspring
According to the German Society of Newborn Screening, the study cohort comprised 97.2% (69 of 71) of individuals identified by the German NBS program between 2004 and 2017

Summary

Introduction

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. Abbreviations ET Emergency treatment GA Glutaric acid GA1 Glutaric aciduria type 1 GCDH Glutaryl-CoA dehydrogenase HE High excreter LE Low excreter MD Movement disorder MT Maintenance treatment NBS Newborn screening. Implementation of GA1 into national newborn screening (NBS) programs facilitating early diagnosis as well as development and repetitive revision of evidence-based guideline recommendations have dramatically improved neurologic long-term outcome worldwide resulting in more than 90% asymptomatic individuals with GA1 without MD if treated in full accordance with the recommendations. This study aims at prospectively investigating long-term cognitive development and functions of early diagnosed and treated individuals with GA1 in Germany over a period of over 20 years

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Conclusion