Galactokinase deficiency:lessons from the GalNet registry

PURPOSE Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. METHODS Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020. RESULTS Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17-5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial. CONCLUSION The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed

A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net

Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results, and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions, and translations. Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128 (42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration 5 years. Convulsions, coma, or death was not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in nine different languages. Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Purpose: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. Methods: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into “severe” and “attenuated” categories based on the genotype-specific and validated in vitro enzyme activity. Results: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. Conclusion: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx—as currently performed—was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.</p

The Genetic Landscape and Epidemiology of Phenylketonuria

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A gt G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C gt T (p.Arg408Trp) (22.2%), c.1066-11G gt A (IVS10-11G gt A) (6.4%), and c.782G gt A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G gt A];[1066-11G gt A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs

True Restriction in Diffusion-Weighted Imaging in a Mistreated Patient With Phenylketonuria

INTRODUCTION: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and causes neurological manifestations because of excessive accumulation of phenylalanine (PHE). It can also affect adult patients who discontinue their treatment, even if they had been under adequate metabolic control during childhood. For that reason, it is recommended that PKU treatment should be continued throughout life and target PHE levels for adult patients should range between 120 and 600 μmol/L. CASE REPORT: The authors present an adult patient with PKU who discontinued treatment and developed cognitive dysfunction because of high blood levels of PHE. Brain magnetic resonance imaging (MRI) of the patient was characteristic for PKU, presenting periventricular and callosal white matter hyperintensities in T2 and fluid-attenuated inversion recovery sequences, which were additionally associated with true restriction in diffusion-weighted imaging sequence, a far less recognized PKU neuroimaging feature. DISCUSSION: Cognitive dysfunction and psychiatric disorders can be present in adult patients with PKU who discontinue treatment and have poor PHE metabolic control. The presence of white matter hyperintensities in T2 and fluid-attenuated inversion recovery MRI-sequences is a well-described neuroimaging feature of PKU, but diffusion-weighted imaging sequence may also be reliable in detecting brain lesions in patients with PKU. PKU lesions should be considered in the differential diagnosis of true diffusion restriction in brain MRI of patients with PKU history or those who might have escaped newborn screening diagnosis but present neurocognitive dysfunction. Appropriate treatment for the management of PKU should be initiated for the reversal of the clinical and neuroimaging findings. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Early prediction of phenotypic severity in Citrullinemia Type 1

Objective Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model. Methods We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases. Results Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future. Interpretation Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system