Sven F. Garbade

Effects of cholesterol and simvastatin treatment in patients with Smith-Lemli-Opitz syndrome (SLOS).

SummarySmith–Lemli–Opitz syndrome (SLOS) is a malformation syndrome caused by deficiency of 7-dehydrocholesterol reductase catalysing the last step of cholesterol biosynthesis. This results in an accumulation of 7- and 8-dehydrocholesterol (7+8–DHC) and, in most patients, a deficiency of cholesterol. Current therapy consists of dietary cholesterol supplementation, which raises plasma cholesterol levels, but clinical effects have been reported in only a few patients. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were shown to reduce 7+8–DHC levels and increase cholesterol concentrations in two small trials with divergent clinical outcome. This retrolective study evaluates the effects of cholesterol only and of cholesterol plus the HMG-CoA reductase inhibitor simvastatin on plasma sterols in 39 SLOS patients and on anthropometric measures in 20 SLOS patients. Cholesterol as well as additional simvastatin decreased the plasma (7+8–DHC)/cholesterol ratio. However, the mechanism leading to the decreasing ratio was different. Whereas it was due to an increasing cholesterol concentration in the cholesterol-only cohort, a decreasing 7+8–DHC concentration was demonstrated in the cohort receiving additional simvastatin. We could not confirm a positive effect of simvastatin treatment on anthropometric measures or behaviour, as previously reported.

Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia

SummaryIn recent years several studies on tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency have been published. The molecular mechanisms of BH4 responsiveness are not conclusively understood, but there is evidence that BH4 responsiveness in hyperphenylalaninaemia (HPA) depends on the patient’s genotype and residual PAH activity. As a BH4 preparation will soon obtain marketing approval as an alternative treatment for phenylketonuria (PKU), it is particularly important to evaluate this treatment and to define criteria to identify patients with a potential benefit from it. Most of the patients found to be BH4-responsive suffered from mild PKU or mild hyperphenylalaninaemia (MHP) and some of these would not be treated at all in many countries. Of patients with moderate and classic forms of PKU, only a few were classified as responders and the clinical significance of the effect size may be small.

Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria

PurposeThe nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU.MethodsA total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm.ResultsWe identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0–2.7 for classic PKU, 2.8–6.6 for mild PKU and 6.7–10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001).ConclusionsAPV and GPV are powerful tools to investigate genotype–phenotype associations, and can be used for genetic counselling of PKU families.

Newborn screening: A disease-changing intervention for glutaric aciduria type 1: Newborn Screening for GA1

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.

Age-Related Changes and Reference Values of Bicaudate Ratio and Sagittal Brainstem Diameters on MRI

&NA; Cranial magnetic resonance imaging (MRI) plays an important role in the diagnosis of neurometabolic diseases, and, in addition, temporal patterns of signal and volume changes allow insight into the underlying pathogenesis. While assessment of volume changes by visual inspection is subjective, volumetric approaches are often not feasible with rare neurometabolic diseases, where MRIs are often acquired with different scanners and protocols. Linear surrogate parameters of brain volume, for example, the bicaudate ratio, present a robust alternative that can be derived from standard imaging sequences. Due to the continuing postnatal brain and skull development and later brain involution, it is, however, necessary to compare patient values with age age‐adapted normal values. In this article, we present age‐dependent normal values derived from 993 standard scans of patients with normal MRI findings (age range: 0‐80 years; mean = 19.9; median = 12.8 years) for bicaudate ratio as a measure of global supratentorial volume, as well as the maximal anteroposterior diameters of mesencephalon, pons, and medulla oblongata as parameters of brainstem volume. The provided data allow quantitative, objective assessment of brain volume changes instead of the usually performed visual and therefore subjective assessment.

A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease—an ultra-orphan multisystemic lysosomal storage disorder

PurposeQuantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5.MethodsAnalysis of published cases with SASD (N = 116) respecting STROBE criteria. Main outcome parameters: survival and diagnostic delay. Phenotype, phenotype–biomarker associations, and geographical patient distribution were explored.ResultsMedian age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years. The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds. Cluster analysis of disease features suggested a continuous phenotypic spectrum. Patient distribution was panethnic.ConclusionCombination of neurologic symptoms, visceromegaly, and dysmorphic features and/or nonimmune hydrops fetalis should prompt specific tests for SASD, reducing diagnostic delay. The present quantitative data inform clinical studies and may stimulate and accelerate development of specific therapies. Biomarker–phenotype association is particularly important for both counseling parents and study design.