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Contains fulltext : 290862.pdf (Publisher’s version ) (Open Access) Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogeneous subgroup of inherited metabolic disorders. Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS-CDG can be challenging. Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia. Glycomics confirmed accumulation of a Glc(3) Man(7) GlcNAc(2) glycan in plasma. For quantification of the diagnostic Glcα1-3Glcα1-3Glcα1-2Man tetrasaccharide in urine, we developed and validated a liquid chromatography-mass spectrometry method of 2-aminobenzoic acid (2AA) labeled urinary glycans. As an internal standard, isotopically labeled (13) C(6) -2AA Glc(3) Man was used, while labeling efficiency was controlled by use of (12) C(6) -2AA and (13) C(6) -2AA labeled laminaritetraose. Recovery, linearity, intra- and interassay coefficients of variability of these labeled compounds were determined. Furthermore, Glc(3) Man was specifically identified by retention time matching against authentic MOGS-CDG urine and compared with Pompe urine. Glc(3) Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference

Contains fulltext : 287948.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022.

Objective By loading transfer RNAs with their cognate amino acids, aminoacyl-tRNA synthetases (ARS) are essential for protein translation. Both cytosolic ARS1-deficiencies and mitochondrial ARS2 deficiencies can cause severe diseases. Amino acid supplementation has shown to positively influence the clinical course of four individuals with cytosolic ARS1 deficiencies. We hypothesize that this intervention could also benefit individuals with mitochondrial ARS2 deficiencies. Methods This study was designed as a N-of-1 trial. Daily oral L-phenylalanine supplementation was used in a 3-year-old girl with FARS2 deficiency. A period without supplementation was implemented to discriminate the effects of treatment from age-related developments and continuing physiotherapy. Treatment effects were measured through a physiotherapeutic testing battery, including movement assessment battery for children, dynamic gait index, gross motor function measure 66, and quality of life questionnaires. Results The individual showed clear improvement in all areas tested, especially in gross motor skills, movement abilities, and postural stability. In the period without supplementation, she lost newly acquired motor skills but regained these upon restarting supplementation. No adverse effects and good tolerance of treatment were observed. Interpretation and Conclusion Our positive results encourage further studies both on L-phenylalanine for other individuals with FARS2 deficiency and the exploration of this treatment rationale for other ARS2 deficiencies. Additionally, treatment costs were relatively low at 1.10 €/day.

Background Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted. Methods We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria. Results Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0–4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients. Conclusions Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype–phenotype correlations that may help to improve the diagnostic approach and patient management.

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties.

Purpose Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions. Unlabelled Image

ZusammenfassungDas Spektrum der Entwicklungsstörungen gehört zum Alltag des Facharztes für Kinder- und Jugendmedizin. Durch den zunehmenden Einsatz von „Next-generation sequencing“-Methoden in den letzten 10 Jahren werden die genetischen Hintergründe besser verstanden. Hiermit eröffnen sich Möglichkeiten in der Routinediagnostik und auch für pathomechanismusbasierte individuelle Therapieansätze („personalized precision medicine“). Dieser Beitrag beschreibt die patientenzentrierte Einbettung einer multidisziplinären Tagesklinik („Murmeltiersprechstunde“) zu zeit- und ressourcensparender Diagnostik und Behandlung von Entwicklungsstörungen. Bei 43 an der Murmeltiersprechstunde teilnehmenden Kindern (Durchschnittsalter 4,9 Jahre) mit einer Entwicklungsstörung konnte in 24 Fällen (56 %) eine pathogene Variante in einem bereits bekannten Krankheitsgen, in 4 weiteren Fällen (12 %) in einem Kandidatengen gefunden werden und somit eine Diagnose gestellt werden. Hierdurch konnte in 6 Fällen (14 %) eine pathomechanismusbasierte Therapie erfolgreich eingeleitet werden. Die durchschnittliche Dauer zwischen der Aufnahme in der Tagesklinik und der Befundmitteilung betrug 6 Monate. Die Murmeltiersprechstunde zeigt, wie „personalized precision medicine“ in den Alltag einer Kinderklinik eingebaut werden kann und direkten Einfluss auf die Behandlung hat.

ZusammenfassungGenetische Defekte werden vielfach noch als Schicksal empfunden, mit dem man sich Zeit seines Lebens abfinden muss. Es stimmt, dass vererbte Anlagen in vielen Fällen zu schweren Krankheiten führen, allerdings stimmt es auch, dass der Anteil von genetischen Defekten, bei denen eine Therapieoption besteht, stetig wächst und sich der Ausbruch von Krankheitssymptomen bei einigen davon bestenfalls gänzlich verhindern lässt. Die Kenntnis des genauen molekularen Krankheitsmechanismus liefert oft die Grundlage für einen Therapieansatz. Zum Auffinden des genetischen Defekts haben die Möglichkeiten der genomweiten Sequenzierung und ihr mittlerweile breiter Einsatz in der Diagnostik entscheidend beigetragen. Nach dem Nachweis einer genetischen Veränderung braucht es aber noch die Untersuchung der pathobiochemischen Konsequenzen auf zellulärer und systemischer Ebene. Dabei handelt es sich oft um einen längeren Prozess, da der volle Umfang von Funktionsausfällen nicht immer auf Anhieb erkennbar ist. Bei metabolischen Defekten kann die Therapie ein Auffüllen von fehlenden Produkten oder eine Reduktion von giftigen Substraten sein. Oft lässt sich auch die Restfunktion von betroffenen „pathways“ verbessern. Neuerdings haben Therapien mit direkter Korrektur des betroffenen Gendefekts Einzug in die therapeutische Anwendung gefunden. Da die ersten Krankheitssymptome in vielen Fällen früh im Leben auftreten, trifft die Kinderheilkunde eine Vorreiterrolle in der Entwicklung von Therapieansätzen.

Background No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD. Methods We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis. Results Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD. Conclusion Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this—individually—promising management option more (prospective) studies using adequate outcome measures are crucial.

BackgroundThe Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disability (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation.MethodsTwo independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classification of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features.ResultsOur review identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case–control studies) for 19% and 4–5 (case-report, expert opinion) for 81% of treatments. Reported effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%.ConclusionThe number of treatable IDs identified by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.

BackgroundATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) inATAD3Alead to neurological syndromes in humans.MethodsTo expand the mutational spectrum ofATAD3Avariants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) inATAD3Ain individuals with neurological and mitochondrial phenotypes. ADrosophila Atad3a Gal4knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.ResultsWe report 13 individuals from 8 unrelated families with biallelicATAD3Avariants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated withATAD3Apathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy.Drosophilastudies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.ConclusionOur findings expand the allelic spectrum ofATAD3Avariants and exemplify the use of a functional assay inDrosophilato aid variant interpretation.

Contains fulltext : 283140.pdf (Publisher’s version ) (Open Access) The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Contains fulltext : 231549.pdf (Publisher’s version ) (Closed access) PURPOSE: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. METHODS: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. RESULTS: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. CONCLUSION: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) deficiency (MIM 261680, EC 4.1.1.32, encoded by PCK1) is a rare disorder of gluconeogenesis presenting with recurrent hypoglycemia, hepatic dysfunction, and lactic acidosis. We report on a previously healthy 3-year-old boy who was initially admitted under the suspicion of a febrile seizure during an upper airway infection. Diagnostic workup revealed hypoglycemia as well as a cerebral edema and ruled out an infection. After a complicated course with difficult to treat symptomatic seizures, the child died on the 5th day of admission due to progressive cerebral edema. The metabolic screening showed elevated urinary lactate and Krebs cycle intermediates in line with a primary or secondary energy deficit. Due to the unclear and fatal course, trio exome sequencing was initiated postmortem (“molecular autopsy”) and revealed the diagnosis of cytosolic PEPCK deficiency based on the compound heterozygosity of a known pathogenic (c.925G > A, p.(Gly309Arg)) and a previously unreported (c.724G > A, p.(Gly242Arg)) variant in PCK1 (NM_002591.3). Sanger sequencing ruled out the disease and carrier status in three older brothers. Molecular autopsy was performed due to the unclear and fatal course. The diagnosis of a cytosolic PEPCK deficiency not only helped the family to deal with the grief, but especially took away the fear that the siblings could be affected by an unknown disease in the same manner. In addition, this case increases the genetic and phenotypic spectrum of cytosolic PEPCK deficiency.

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. ispartof: GENETICS IN MEDICINE vol:23 issue:1 pages:202-210 ispartof: location:United States status: published

ZusammenfassungDie in den vergangenen Jahren zunehmende Verfügbarkeit molekularer Untersuchungstechniken führt zu einer steigenden Anzahl diagnostizierter genetischer Varianten im Genom untersuchter Patienten. Am Beispiel der hereditären Innenohrschwerhörigkeit wird bei Betrachtung der Vielzahl publizierter Berichte über die mögliche Beteiligung einzelner Gene an der Pathogenese deutlich, welche Herausforderungen die Zunahme molekularer Informationen für die Interpretation mit sich bringt.In dieser Übersichtsarbeit werden anhand des Beispiels des SLC26A4-Gens und den damit verbundenen Formen einer hereditären Innenohrschwerhörigkeit die derzeit vorhandenen Möglichkeiten einer systematischen Abklärung und Interpretation dargestellt. Neben einer Beschreibung der physiologischen Funktion des resultierenden Pendrin-Proteins werden molekulare Untersuchungsmöglichkeiten zur Beurteilung der Funktion im Fall von nachgewiesenen Genvarianten erläutert. Die im Rahmen eines primär wissenschaftlichen Ansatzes resultierenden Ergebnisse auf molekularer Ebene dienen im klinischen Alltag der Interpretation hinsichtlich des kausalen Zusammenhangs zwischen einer nachgewiesenen Genvariante (Genotyp) und der Innenohrschwerhörigkeit (Phänotyp). Schließlich wird auf die mögliche Notwendigkeit einer weiteren interdisziplinären Abklärung, z. B. mithilfe einer Perchlorat-Testung der Schilddrüse, sowie therapeutische Möglichkeiten eingegangen.

TPK deficiency due to TPK1 mutations is a rare neurodegenerative disorder, also known as thiamine metabolism dysfunction syndrome 5 (OMIM no.: 614458). Here, we report a new patient with compound heterozygous TPK1 mutations, of which one has not been described so far. The individual reported here suffered from acute onset encephalopathy, ataxia, muscle hypotonia, and regression of developmental milestones in early infancy, repeatedly triggered by febrile infections. Initiation of high-dose thiamine and magnesium supplementation led to a marked and sustained improvement of alertness, ataxia, and muscle tone within days. Contrary to the described natural history of patients with TPK deficiency, the disease course was favorable under thiamine treatment without deterioration or developmental regression during the follow-up period. TPK deficiency is a severe neurodegenerative disease. This case report demonstrates that this condition is potentially treatable. High-dose thiamine treatment should therefore be initiated immediately after diagnosis or even upon suspicion.

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

Context Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. Objective We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts. Methods We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene. Results We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment. Conclusion A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies. This research was supported using resources of the Core Facility Cell Imaging and Ultrastructure Research, University of Vienna, a member of the Vienna Life-Science Instruments (VLSI) and the VetCore Facility (Imaging) of the University of Veterinary Medicine Vienna. We acknowledge International Centre for Genomic Medicine in Neuromuscular Diseases. This research was funded in part, by the Wellcome Trust (WT093205MA, WT104033AIA, and the Synaptopathies Strategic Award, 165908). This study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetrees Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research United Kingdom, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy United Kingdom (MDUK), Muscular Dystrophy Association (MDA USA) and Senior Non-Clinical Fellow ship to A. Spinazzola, (MC_PC_13029). K.N. and S.E.M.M. were supported by the Austrian Science Funds FWF-P29077 and P31471. A. Spinazzola receives support also from The Lily Foun dation and Brain Research UK. R.K. was supported by European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\100042). info:eu-repo/semantics/publishedVersion

Contains fulltext : 283128.pdf (Publisher’s version ) (Open Access) Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Contains fulltext : 287938.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Neuroimmunological diseases such as autoimmune encephalitis (AE) or acquired demyelinating syndromes (ADS), can present with neurological symptoms and imaging features that are indistinguishable from mitochondrial diseases (MD) in particular at initial presentation. METHODS: Retrospective analysis of the clinical, laboratory and neuroimaging features of five patients who presented with signs of a neuroimmunological disease but all had pathological pathogenic variants in genes related to mitochondrial energy metabolism. RESULTS: Four patients presented with an acute neurological episode reminiscent of a possible AE and one patient with a suspected ADS at initial presentation. MRI findings were compatible with neuroimmunological diseases in all patients. In two children cerebrospinal fluid (CSF) studies revealed a mildly elevated cell count, two had elevated CSF lactate, none had oligoclonal bands (OCBs). All patients improved rapidly with intravenous steroids or immunoglobulins. Four patients had one or more relapses. Three patients showed worsening of their neurological symptoms with subsequent episodes and one patient died. Relapses in conjunction with new and progressive neurological symptoms, led to additional work-up which finally resulted in different genetic diagnosis of MD in all patients (MT-TL1, MT-ND5, APOA1-BP, HPDL, POLG). DISCUSSION: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. Absence of CSF pleocytosis, elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of a MD even in patients with good response initially to immunomodulating therapies.