Differences in Circulating Carnitine Status of Preterm Infants Fed Fortified Human Milk or Preterm Infant Formula

Objective:The aim of the study was to compare plasma carnitine profiles in fortified human milk (HM)-fed preterm infants or formula-fed preterm infants.Methods:Plasma acylcarnitine concentrations were determined in 20 formula-fed and 18 HM-fed preterm infants (birth weights between 1000 and 2200 g) by isotope dilution ESI MS/MS technique on study days 0, 14, and 28.Results:Concentrations of free carnitine (FC) and different acylcarnitines did not change during the 4 weeks of the study in infants fed HM. In contrast, in infants fed formula FC increased markedly (day 0: 29.989 16.646] mol/L, median interquartile range], day 14: 43.972 8.455], P<0.05) along with increases of short-chain esters (C2 day 0: 5.300 3.272], day 14: 6.773 2.127], P<0.05; C3 day 0: 0.070 0.059], day 14: 0.110 0.069], P<0.05). In contrast, some medium-chain (C8:1, C12) and long-chain esters (C14, C16) decreased significantly in infant formula by day 14, whereas FC and C2 and C3 esters increased further by day 28 (FC: 47.672 14.753], C2: 7.430 4.688], C3: 0.107 0.047]).Conclusions:The altered carnitine ester profile likely reflects active involvement of the carnitine molecule in the buffering, metabolism, and elimination of nonphysiological acyl moieties

Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI

New Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel CACNA1C Loss-of-Function Mutation

Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy

Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations

New Variant of MELAS Syndrome With Executive Dysfunction, Heteroplasmic Point Mutation in the MT-ND4 Gene (m.12015T>C; p.Leu419Pro) and Comorbid Polyglandular Autoimmune Syndrome Type 2

Background: Mitochondrial diseases are caused by dysfunctions in mitochondrial metabolic pathways. MELAS syndrome is one of the most frequent mitochondrial disorders; it is characterized by encephalopathy, myopathy, lactic acidosis, and stroke-like episodes. Typically, it is associated with a point mutation with an adenine-to-guanine transition at position 3243 of the mitochondrial DNA (mtDNA; m.3243A&gt;G) in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene. Other point mutations are possible and the association with polyglandular autoimmune syndrome type 2 has not yet been described.Case presentation: We present the case of a 25-year-old female patient with dysexecutive syndrome, muscular fatigue, and continuous headache. Half a year ago, she fought an infection-triggered Addison crisis. As the disease progressed, she had two epileptic seizures and stroke-like episodes with hemiparesis on the right side. Cerebral magnetic resonance imaging showed a substance defect of the parieto-occipital left side exceeding the vascular territories with a lactate peak. The lactate ischemia test was clearly positive, and a muscle biopsy showed single cytochrome c oxidase-negative muscle fibers. Genetic testing of blood mtDNA revealed a heteroplasmic base exchange mutation in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4) gene (m.12015T&gt;C; p.Leu419Pro; heteroplasmy level in blood 12%, in muscle tissue: 15%). The patient suffered from comorbid autoimmune polyglandular syndrome type 2 with Hashimoto's thyroiditis, Addison's disease, and autoimmune gastritis. In addition, we found increased anti-glutamic acid decarboxylase 65, anti-partial cell, anti-intrinsic factor, and anti-nuclear antibodies.Conclusion: We present an atypical case of MELAS syndrome with predominant symptoms of a dysexecutive syndrome, two stroke-like episodes, and fast-onset fatigue. The symptoms were associated with a not yet described base and aminoacid exchange mutation in the MT-ND4 gene (m.12015T&gt;C to p.Leu419Pro). The resulting changed protein complex in our patient is part of the respiratory chain multicomplex I and might be the reason for the mitochondriopathy. However, different simulations for pathogenetic relevance are contradictory and rather speak for a benign variant. To our knowledge this case report is the first reporting MELAS syndrome with comorbid polyglandular autoimmune syndrome type 2. Screening for autoimmune alterations in those patients is important to prevent damage to end organs

Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype

BACKGROUND: Kleefstra syndrome is a rare genetic disorder, with core phenotypic features encompassing developmental delay/intellectual disability, characteristic facial features - brachy(micro)cephaly, unusual shaped eyebrows, flat face with hypertelorism, short nose with anteverted nostrils, thickened lower lip, carpmouth with macroglossia - and childhood hypotonia. Some additional symptoms are observed in different percentage of the patients. Epilepsy is common symptom as well. The underlying cause of the syndrome is a submicroscopic deletion in the chromosomal region 9q34.3 or disruption of the euchromatin histone methyl transferase 1. CASE PRESENTATION: We describe two Hungarian Kleefstra syndrome patients, one with the classic phenotype of the syndrome, the diagnosis was confirmed by subtelomeric FISH. Meanwhile in our second patient beside the classic phenotype a new symptom - abnormal antiepileptic drug metabolic response - could be observed. Subtelomere FISH confirmed the 9q34.3 terminal deletion. Because of the abnormal drug metabolism in our second patient, we performed array CGH analysis as well searching for other rearrangements. Array CGH analysis indicated a large - 1.211 Mb -, deletion only in the 9q subtelomeric region with breakpoints ch9:139,641,471-140,852,911. CONCLUSIONS: This is the first report on Kleefstra syndrome in patients describing a classical and a complex phenotype involving altered drug metabolism. KEYWORDS: 9q subtelomeric deletion syndrome; Drug metabolism; Epilepsy; Kleefstra syndrom

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.</p

The Role of Next-Generation Sequencing in the Diagnosis of Lysosomal Storage Disorders

Next-generation sequencing (NGS) panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders (LSDs). Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in LSDs. Given that NGS can be applied in a way that takes into account the many issues raised by international consensus guidelines, it can have a significant role even early in the course of the diagnostic process, in combination with biochemical and clinical data. Besides decreasing the delay in diagnosis for many patients, a precise molecular diagnosis is extremely important as new therapies are becoming available within the LSD spectrum for patients who share specific types of mutations. A genetic diagnosis is also the prerequisite for genetic counseling, family planning, and the individual choice of reproductive options in affected families

Differences in Circulating Carnitine Status of Preterm Infants Fed Fortified Human Milk or Preterm Infant Formula

Objective:The aim of the study was to compare plasma carnitine profiles in fortified human milk (HM)-fed preterm infants or formula-fed preterm infants.Methods:Plasma acylcarnitine concentrations were determined in 20 formula-fed and 18 HM-fed preterm infants (birth weights between 1000 and 2200 g) by isotope dilution ESI MS/MS technique on study days 0, 14, and 28.Results:Concentrations of free carnitine (FC) and different acylcarnitines did not change during the 4 weeks of the study in infants fed HM. In contrast, in infants fed formula FC increased markedly (day 0: 29.989 16.646] mol/L, median interquartile range], day 14: 43.972 8.455], P<0.05) along with increases of short-chain esters (C2 day 0: 5.300 3.272], day 14: 6.773 2.127], P<0.05; C3 day 0: 0.070 0.059], day 14: 0.110 0.069], P<0.05). In contrast, some medium-chain (C8:1, C12) and long-chain esters (C14, C16) decreased significantly in infant formula by day 14, whereas FC and C2 and C3 esters increased further by day 28 (FC: 47.672 14.753], C2: 7.430 4.688], C3: 0.107 0.047]).Conclusions:The altered carnitine ester profile likely reflects active involvement of the carnitine molecule in the buffering, metabolism, and elimination of nonphysiological acyl moieties