Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders

Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings

Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy

To accomplish a diagnosis in patients with a rare unclassified disorder is difficult. In this study, we used magnetic resonance imaging pattern recognition analysis to identify patients with the same novel heritable disorder. Whole-exome sequencing was performed to discover the mutated gene. We identified seven patients sharing a previously undescribed magnetic resonance imaging pattern, characterized by initial swelling with T2 hyperintensity of the basal nuclei, thalami, cerebral white matter and cortex, pons and midbrain, followed by rarefaction or cystic degeneration of the white matter and, eventually, by progressive cerebral, cerebellar and brainstem atrophy. All patients developed a severe encephalopathy with rapid deterioration of neurological functions a few weeks after birth, followed by respiratory failure and death. Lactate was elevated in body fluids and on magnetic resonance spectroscopy in most patients. Whole-exome sequencing in a single patient revealed two predicted pathogenic, heterozygous missense mutations in the SLC19A3 gene, encoding the second thiamine transporter. Additional predicted pathogenic mutations and deletions were detected by Sanger sequencing in all six other patients. Pathology of brain tissue of two patients demonstrated severe cerebral atrophy and microscopic brain lesions similar to Leigh's syndrome. Although the localization of SLC19A3 expression in brain was similar in the two investigated patients compared to age-matched control subjects, the intensity of the immunoreactivity was increased. Previously published patients with SLC19A3 mutations have a milder clinical phenotype, no laboratory evidence of mitochondrial dysfunction and more limited lesions on magnetic resonance imaging. In some, cerebral atrophy has been reported. The identification of this new, severe, lethal phenotype characterized by subtotal brain degeneration broadens the phenotypic spectrum of SLC19A3 mutations. Recognition of the associated magnetic resonance imaging pattern allows a fast diagnosis in affected infant

Universally Composable Accumulators

Accumulators, first introduced by Benaloh and de Mare (Eurocrypt 1993), are compact representations of arbitrarily large sets and can be used to prove claims of membership or non-membership about the underlying set. They are almost exclusively used as building blocks in real-world complex systems, including anonymous credentials, group signatures and, more recently, anonymous cryptocurrencies. Having rigorous security analysis for such systems is crucial for their adoption and safe use in the real world, but it can turn out to be extremely challenging given their complexity. In this work, we provide the first universally composable (UC) treatment of cryptographic accumulators. There are many different types of accumulators: some support additions, some support deletions and some support both; and, orthogonally, some support proofs of membership, some support proofs of non-membership, and some support both. Additionally, some accumulators support public verifiability of set operations, and some do not. Our UC definition covers all of these types of accumulators concisely in a single functionality, and captures the two basic security properties of accumulators: correctness and soundness. We then prove the equivalence of our UC definition to standard accumulator definitions. This implies that existing popular accumulator schemes, such as the RSA accumulator, already meet our UC definition, and that the security proofs of existing systems that leverage such accumulators can be significantly simplified. Finally, we use our UC definition to get simple proofs of security. We build an accumulator in a modular way out of two weaker accumulators (in the style of Baldimtsi et. al (Euro S&P 2017), and we give a simple proof of its UC security. We also show how to simplify the proofs of security of complex systems such as anonymous credentials. Specifically, we show how to extend an anonymous credential system to support revocation by utilizing our results on UC accumulators

Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake

Compressed σ-protocol theory and practical application to plug & play secure algorithmics

Σ-Protocols provide a well-understood basis for secure algorithmics. Recently, Bulletproofs (Bootle et al., EUROCRYPT 2016, and Bünz et al., S&P 2018) have been proposed as a drop-in replacement in case of zero-knowledge (ZK) for arithmetic circuits, achieving logarithmic communication instead of linear. Its pivot is an ingenious, logarithmic-size proof of knowledge BP for certain quadratic relations. However, reducing ZK for general relations to it forces a somewhat cumbersome “reinvention” of cryptographic protocol theory. We take a rather different viewpoint and reconcile Bulletproofs with Σ-Protocol Theory such that (a) simpler circuit ZK is developed within established theory, while (b) achieving exactly the same logarithmic communication. The natural key here is linearization. First, we repurpose BPs as a blackbox compression mechanism for standard Σ-Protocols handling ZK proofs of general linear relations (on compactly committed secret vectors); our pivot. Second, we reduce the case of general nonlinear relations to blackbox applications of our pivot via a novel variation on arithmetic secret sharing based techniques for Σ-Protocols (Cramer et al., ICITS 2012). Orthogonally, we enhance versatility by enabling scenarios not previously addressed, e.g., when a secret input is dispersed across several commitments. Standard implementation platforms leading to logarithmic communication follow from a Discrete-Log assumption or a generalized Strong-RSA assumption. Also, under a Knowledge-of-Exponent Assumption (KEA) communication drops to constant, as in ZK-SNARKS. All in all, our theory should more generally be useful for modular (“plug & play”) design of practical cryptographic protocols; this is further evidenced by our separate work (2020) on proofs of partial knowledge

Two-Sided Malicious Security for Private Intersection-Sum with Cardinality

Private intersection-sum with cardinality allows two parties, where each party holds a private set and one of the parties additionally holds a private integer value associated with each element in her set, to jointly compute the cardinality of the intersection of the two sets as well as the sum of the associated integer values for all the elements in the intersection, and nothing beyond that. We present a new construction for private intersection sum with cardinality that provides malicious security with abort and guarantees that both parties receive the output upon successful completion of the protocol. A central building block for our constructions is a primitive called shuffled distributed oblivious PRF (DOPRF), which is a PRF that offers oblivious evaluation using a secret key shared between two parties, and in addition to this allows obliviously permuting the PRF outputs of several parallel oblivious evaluations. We present the first construction for shuffled DOPRF with malicious security. We further present several new sigma proof protocols for relations across Pedersen commitments, ElGamal encryptions, and Camenisch-Shoup encryptions that we use in our main construction, for which we develop new batching techniques to reduce communication. We implement and evaluate the efficiency of our protocol and show that we can achieve communication cost that is only 4-5 times greater than the most efficient semi-honest protocol. When measuring monetary cost of executing the protocol in the cloud, our protocol is 25 times more expensive than the semi-honest protocol. Our construction also allows for different parameter regimes that enable trade-offs between communication and computation

Accumulators in (and Beyond) Generic Groups: Non-Trivial Batch Verification Requires Interaction

We prove a tight lower bound on the number of group operations required for batch verification by any generic-group accumulator that stores a less-than-trivial amount of information. Specifically, we show that $\Omega(t \cdot (\lambda / \log \lambda))$ group operations are required for the batch verification of any subset of $t \geq 1$ elements, where $\lambda \in \mathbb{N}$ is the security parameter, thus ruling out non-trivial batch verification in the standard non-interactive manner. Our lower bound applies already to the most basic form of accumulators (i.e., static accumulators that support membership proofs), and holds both for known-order (and even multilinear) groups and for unknown-order groups, where it matches the asymptotic performance of the known bilinear and RSA accumulators, respectively. In addition, it complements the techniques underlying the generic-group accumulators of Boneh, B{ü}nz and Fisch (CRYPTO \u2719) and Thakur (ePrint \u2719) by justifying their application of the Fiat-Shamir heuristic for transforming their interactive batch-verification protocols into non-interactive procedures. Moreover, motivated by a fundamental challenge introduced by Aggarwal and Maurer (EUROCRYPT \u2709), we propose an extension of the generic-group model that enables us to capture a bounded amount of arbitrary non-generic information (e.g., least-significant bits or Jacobi symbols that are hard to compute generically but are easy to compute non-generically). We prove our lower bound within this extended model, which may be of independent interest for strengthening the implications of impossibility results in idealized models

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