Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy.

Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing.

Pleiotropic effects of MORC2 derive from its epigenetic signature.

Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analyzed blood and fibroblast DNA methylation, transcriptomes, proteomes, and phenotypes of 53 MORC2 patients.

Natural History of Patients With Mitochondrial ATPase Deficiency Due to Pathogenic Variants of MT-ATP6 and MT-ATP8.

Background And Objectives: The mitochondrial DNA (mtDNA) genes and encode for subunits α and 8 (A6L) of the adenosine triphosphate synthase complex. Pathogenetic variants in cause incurable mitochondrial syndromes encompassing a wide spectrum of clinical features including ataxia, motor and language developmental delay, deafness, retinitis pigmentosa, and Leigh pattern in brain MRI. Typically, higher levels of mtDNA variants lead to more severe symptomatology although even individuals with similar mtDNA mutational loads exhibit high clinical variability.

Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.

Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions.

Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia.

Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families.

Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in and Vici syndrome patients.

Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms.

Riboflavin transporter deficiency in young adults unmasked by dietary changes.

Riboflavin transporter deficiency (RTD) is a genetic disorder of reduced riboflavin (vitamin B2) uptake that causes progressive, multifocal neurological dysfunction. Most patients present in early childhood; if patients present later in life, symptoms usually develop more gradually. We report three previously healthy young adults, who developed rapidly progressive neurological symptoms after decreasing dietary intake of meat and dairy.

mtDNA analysis using Mitopore.

Mitochondrial DNA (mtDNA) analysis is crucial for the diagnosis of mitochondrial disorders, forensic investigations, and basic research. Existing pipelines are complex, expensive, and require specialized personnel. In many cases, including the diagnosis of detrimental single nucleotide variants (SNVs), mtDNA analysis is still carried out using Sanger sequencing.

ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes.

Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease.

Classical homocystinuria presenting with transient basal ganglia pathology and dystonia.

Classical homocystinuria is caused by pathogenic variants in the CBS gene leading to a deficiency of the vitamin B6-dependent enzyme cystathionine beta synthase. The disease is typically associated with high blood homocysteine concentrations. Clinical features include developmental delay/intellectual disability, psychiatric problems, thromboembolism, lens dislocation, and marfanoid habitus.

De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.

Purpose: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.

Neuroimaging in Primary Coenzyme-Q-Deficiency Disorders.

Coenzyme Q (CoQ) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ supply (redox homeostasis, ferroptosis and sulfide oxidation).

Neuroimaging in mitochondrial disease.

The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage.

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.

Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases.

Mitochondrial diseases mimicking autoimmune diseases of the CNS and good response to steroids initially.

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.

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.

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 , , , ) sharing a neurological/epileptic phenotype, as well as citrin deficiency () with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects.

Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.

Background: COQ4 codes for a mitochondrial protein required for coenzyme Q (CoQ ) biosynthesis. Autosomal recessive COQ4-associated CoQ deficiency leads to an early-onset mitochondrial multi-organ disorder.

Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4.

The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.

Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP) cations is a widely applied strategy for mitochondrial targeting. We previously demonstrated that the vitamin E-derived antioxidant Trolox increases the levels of active mitochondrial complex I (CI), the first complex of the electron transport chain (ETC), in primary human skin fibroblasts (PHSFs) of Leigh Syndrome (LS) patients with isolated CI deficiency. Primed by this finding, we here studied the cellular effects of mitochondria-targeted Trolox (MitoE10), mitochondria-targeted ubiquinone (MitoQ10) and their mitochondria-targeting moiety decylTPP (C-TPP).