Objective
Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. ...Implementation of GA1 into newborn screening (NBS) programs has improved the short‐term outcome. It remains unclear, however, whether NBS changes the long‐term outcome and which variables are predictive.
Methods
This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children.
Results
The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999–2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre‐NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study.
Interpretation
NBS is a beneficial, disease‐changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970–979
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.
To evaluate the clinical presentation of patients with GM1 gangliosidosis and to determine whether specific clinical or biochemical signs could lead to a prompt diagnosis.
We retrospectively analyzed ...clinical, biochemical, and genetic data of 22 patients with GM1 gangliosidosis from 5 metabolic centers in Germany and Austria.
Eight patients were classified as infantile, 11 as late-infantile, and 3 as juvenile form. Delay of diagnosis was 6 ± 2.6 months in the infantile, 2.6 ± 3.79 years in the late-infantile, and 14 ± 3.48 years in the juvenile form. Coarse facial features, cherry red spots, and visceromegaly occurred only in patients with the infantile form. Patients with the late-infantile and juvenile forms presented with variable neurologic symptoms. Seventeen patients presented with dystonia and 14 with dysphagia. Laboratory analysis revealed an increased ASAT concentration (13/20), chitotriosidase activity (12/15), and pathologic urinary oligosaccharides (10/19). Genotype analyses revealed 23 causative or likely causative mutations in 19 patients, 7 of them being novel variants. In the majority, a clear genotype–phenotype correlation was found.
Diagnosis of GM1 gangliosidosis often is delayed, especially in patients with milder forms of the disease. GM1 gangliosidosis should be considered in patients with progressive neurodegeneration and spastic-dystonic movement disorders, even in the absence of visceral symptoms or cherry red spots. ASAT serum concentrations and chitotriosidase activity may be of value in screening for GM1 gangliosidosis.
Abstract
Purpose
Standardized application and evaluation of the strain ultrasound elastography method (USE) by means of a strain color scale (SCS) and a strain ratio analysis. To determine ...differences in muscle elasticity in healthy children and adults.
Materials and Methods
Initially Mm. biceps brachii, Mm. recti femoris and Mm. gastrocnemii of 22 healthy adults were examined before and after exercise. Secondly measurements were obtained at rest in 21 healthy children.
Results
There was a difference in muscle elasticity between the upper and lower extremity. Muscle elasticity tends to be higher after exercise in healthy adults. SCS and strain ratio analysis show a similar trend. In comparison to adults, healthy children show lower muscle elasticity at rest using both analysis methods.
Conclusion
Strain elastography is an easy to perform, cost-effective, non-invasive method to determine muscle stiffness, if the conditions of standardized measurements are given.
Key Points:
It is possible to perform standardized measurements with the strain elastography method in healthy adults and children
Strain color scale as well as strain ratio analysis are appropriate tools to interpret the elastogrammes
strain elastography shows higher elasticity in adults’ muscles after exercise
strain elastography shows higher elasticity in adults’ muscles than in muscles of healthy children
Citation Format
Wenz H, Dieckmann A, Lehmann T et al. Strain Ultrasound Elastography of Muscles in Healthy Children and Healthy Adults. Fortschr Röntgenstr 2019; 191: 1091 – 1098
Zusammenfassung
Ziele
Standardisierte Anwendung und Auswertung der Strain-Ultraschallelastografie (USE) anhand von Farbskala- und Deformationsquotienten-(Strain-Ratio)-Analyse. Ermittlung von Elastizitätsunterschieden der Muskulatur bei muskelgesunden Kindern und Erwachsenen.
Material und Methoden
Es wurden 22 Erwachsene (20–30 Jahre) und 21 Kinder (2–12 Jahre) beidseits an den Mm. biceps brachii, Mm. recti femoris sowie Mm. gastrocnemii nach einer Ruhephase elastografisch untersucht. Bei Erwachsenen erfolgten zudem Messungen nach standardisierter muskulärer Beanspruchung.
Ergebnisse
Es fanden sich Unterschiede zwischen den Ruhewerten der Arm- und Beinmuskulatur sowie zwischen den Geschlechtern. Farbskala- und Deformationsanalyse zeigten ähnliche Tendenzen. Bei Erwachsenen fand sich eine höhere Elastizität nach muskulärer Beanspruchung. Die muskelgesunden Kinder wiesen in Ruhe signifikant niedrigere Muskelelastizitäten auf als Erwachsene.
Schlussfolgerung
Die Strain-Elastografie ist eine einfache, kostengünstige, nichtinvasive Methode zur Beurteilung der elastischen Eigenschaften der Muskulatur, wenn die Voraussetzungen für standardisierte Messungen und Auswertungen gegeben sind.
Kernaussagen:
Die Strain-Elastografie kann standardisiert bei muskelgesunden Erwachsenen und Kindern eingesetzt werden.
Sowohl die Farbskala-Analyse als auch die Strain-Ratio-Analyse erwiesen sich als probate Auswertungsmethoden.
Mittels Strain-Elastografie-Messung wird die Muskulatur bei Erwachsenen nach Beanspruchung als elastischer beurteilt.
Mittels Strain-Elastografie-Messung weist die Muskulatur von Erwachsenen eine höhere Elastizität im Vergleich zu Kindern auf.
Zitierweise
Wenz H, Dieckmann A, Lehmann T et al. Strain Ultrasound Elastography of Muscles in Healthy Children and Healthy Adults. Fortschr Röntgenstr 2019; 191: 1091 – 1098
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.
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long‐term clinical benefit ...of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi‐center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long‐term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed.
Newborn screening (NBS) allows early identification of individuals with rare disease, such as isovaleric aciduria (IVA). Reliable early prediction of disease severity of positively screened ...individuals with IVA is needed to guide therapeutic decision, prevent life-threatening neonatal disease manifestation in classic IVA and over-medicalization in attenuated IVA that may remain asymptomatic. We analyzed 84 individuals (median age at last study visit 8.5 years) with confirmed IVA identified by NBS between 1998 and 2018 who participated in the national, observational, multicenter study. Screening results, additional metabolic parameters, genotypes, and clinical phenotypic data were included. Individuals with metabolic decompensation showed a higher median isovalerylcarnitine (C5) concentration in the first NBS sample (10.6 vs. 2.7 μmol/L; p < 0.0001) and initial urinary isovalerylglycine concentration (1750 vs. 180 mmol/mol creatinine; p = 0.0003) than those who remained asymptomatic. C5 was in trend inversely correlated with full IQ (R = -0.255; slope = -0.869; p = 0.0870) and was lower for the "attenuated" variants compared to classic genotypes median (IQR; range): 2.6 μmol/L (2.1-4.0; 0.7-6.4) versus 10.3 μmol/L (7.4-13.1; 4.3-21.7); N = 73. In-silico prediction scores (M-CAP, MetaSVM, and MetaLR) correlated highly with isovalerylglycine and ratios of C5 to free carnitine and acetylcarnitine, but not sufficiently with clinical endpoints. The results of the first NBS sample and biochemical confirmatory testing are reliable early predictors of the clinical course of IVA, facilitating case definition (attenuated versus classic IVA). Prediction of attenuated IVA is supported by the genotype. On this basis, a reasonable algorithm has been established for neonates with a positive NBS result for IVA, with the aim of providing the necessary treatment immediately, but whenever possible, adjusting the treatment to the individual severity of the disease.
Overgrowth‐intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED ...variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen‐Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.
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