Impact of interventional and non‐interventional variables on anthropometric long‐term development in glutaric aciduria type 1: A national prospective multi‐centre study

Abstract

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl‐CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long‐term outcome. This national prospective, observational, multi‐centre study included 79 patients identified by NBS and investigated effects of interventional and non‐interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non‐adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS −1.07; P = .023) and body length (mean SDS −1.34; P = −.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS −0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS −0.68; P = .016). In GA1, recommended long‐term treatment is effective and allows for normal anthropometric long‐term development up to adolescence, with gender‐ and excreter type‐specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

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

“…Lately, malignant brain tumours have been reported in three HE patients not receiving recommended therapy 27 . A recent study also reported on larger head circumferences in HE compared to LE patients 25 . In fact, the clinical impact of these observations is still unknown.…”

“…The phenotypic spectrum was extended by insidious-onset dystonia, which is still observed in screened individuals not adhering to or not receiving recommended MT 1,10 . Anthropometric and MRI studies elucidated phenotypic differences between the two biochemical phenotypes; HE individuals more often than LE individuals developed macrocephaly and progressive white matter abnormalities with unclear clinical relevance 24,25 . Recently, chronic kidney dysfunction, which was not impacted by recommended therapy or the neurologic phenotype, was identified as a first non-neurologic disease manifestation 1,4 , and malignant brain tumours and audiological manifestations were described in single patients 26,27 .…”

“…Other forms of dietary treatment or experimental therapeutic approaches in animal models, such as inhibition of upstream enzymes, have been less effective or failed to prevent the clinical phenotype 13,[47][48][49] . Effectiveness of dietary treatment in patients beyond age six years receiving a liberalized protein-controlled diet is less clear, but a stable clinical and anthropometric longterm disease course up to adulthood has recently been reported 25,50 . However, prospective studies during the last decades have shown that the effect of dietary treatment in GA1 seems to be limited since (1) white matter changes are already found in patients identified by NBS while still following a low lysine diet, (2) MT may not stop or slow the progression of white matter changes 7 , and (3) chronic renal abnormalities are found in both HE and LE patients regardless the quality of therapy 1 .…”

“…Whether further restriction of lysine intake could prevent cognitive impairment in HE patients seems doubtful. Since lysine intake below the minimal requirement affects normal growth and neurological development and increases the risk of insidious-onset dystonia, a deviation from recommended dietary management should not be considered as safe 1,25 .…”

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.…”