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.

Figure 1

Biochemical subtype and full scale IQ at last visit (A) and over different age groups (B). (A) Patients with biochemical HE phenotype (median [horizontal line in box] 84; IQR 75–96) had lower full scale IQ than patients with biochemical LE phenotype (median [IQR] 98 [92–105]; p = 0.0164). (B) Longitudinal analysis was conducted using linear mixed model, gray area indicate 95% confidence interval bands. IQ was stable over time (p = 0.361), but, depending on the biochemical subtype, at different levels (p = 0.018). Rugs on X-axis indicate individual measurements. Black triangles indicate mean IQ. HE high excreter, LE low excreter.

Figure 2

Extended biochemical subtype and full scale IQ. Patients with intermediate subtype had similar results as LE patients (p = 0.677). Results of these two groups (median [horizontal line in box] IQ 97; IQR 86–104) differed from HE patients (median [IQR] IQ 82 [72–94]; p = 0.005). Black triangles indicate mean IQ. HE high excreter, LE low excreter.

Figure 3

Biochemical subtype, neurologic abnormalities and full scale IQ. While biochemical subtype had a strong impact on full scale IQ, neurologic abnormalities did not. Patients with HE phenotype and minor neurologic abnormalities (median IQ [horizontal line in box] 78; IQR 66–89) had lower results than LE patients (median [IQR] IQ 98 [92–105]; p = 0.0278). Results of HE patients did not differ depending on neurologic abnormalities (p = 0.4045). Black triangles indicate mean IQ. HE high excreter, LE low excreter.

Figure 4

Maintenance treatment and full scale IQ in patients beyond age six years. Results did not differ between patients following recommended protein-controlled diet (median [horizontal line in box] IQ 87; IQR 77–100), patients continuing calculated diet beyond age six years (median [IQR] 79 [71–87]) and patients not complying to any diet (median [IQR] 86 [74–94]; p = 0.563). Black triangles indicate mean IQ.

Figure 5

Subscale analysis. Results on subscale level were similar to full scale IQ and did not differ significantly (p = 0.7406). Black triangles indicate mean IQ.