Clinical and molecular analysis of a novel variant in heme oxygenase-1 deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.

Heme oxygenase 1 (HO-1) is the pivotal catalyst for the primary and rate-determining step in heme catabolism, playing a crucial role in mitigating heme-induced oxidative damage. Pathogenic variants in the HMOX1 gene which encodes HO-1, are responsible for a severe, multisystem disease characterized by recurrent inflammatory episodes, organ failure, and an ultimately fatal course. Chronic hemolysis and abnormally low bilirubin levels are cardinal laboratory features of this disorder. In this study, we describe a patient with severe interstitial lung disease, frequent episodes of hyperinflammation non-responsive to immunosuppression, and fatal pulmonary hemorrhage. Employing exome sequencing, we identified two protein truncating variants in HMOX1, c.262_268delinsCC (p.Ala88Profs*51) and a previously unreported variant, c.55dupG (p.Glu19Glyfs*14). Functional analysis in patient-derived lymphoblastoid cells unveiled the complete absence of HO-1 protein expression and a marked reduction in cell viability upon exposure to hemin. These findings confirm the pathogenicity of the identified HMOX1 variants, further underscoring their association with severe pulmonary manifestations . This study describes the profound clinical consequences stemming from disruptions in redox metabolism.

Mitochondrial DNA mutations in Medulloblastoma.

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups-WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient's mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations' impact on carcinogenesis and cancer treatment.

3-Hydroxyisobutyrate dehydrogenase (HIBADH) deficiency-A novel disorder of valine metabolism.

3-Hydroxyisobutyric acid (3HiB) is an intermediate in the degradation of the branched-chain amino acid valine. Disorders in valine degradation can lead to 3HiB accumulation and its excretion in the urine. This article describes the first two patients with a new metabolic disorder, 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, its phenotype and its treatment with a low-valine diet. The detected mutation in the HIBADH gene leads to nonsense-mediated mRNA decay of the mutant allele and to a complete loss-of-function of the enzyme. Under strict adherence to a low-valine diet a rapid decrease of 3HiB excretion in the urine was observed. Due to limited patient numbers and intrafamilial differences in phenotype with one affected and one unaffected individual, the clinical phenotype of HIBADH deficiency needs further evaluation.

Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy-A Case Report.

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction.

SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.

Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.

Transient N-glycosylation abnormalities likely due to a de novo loss-of-function mutation in the delta subunit of coat protein I.

Accurate glycosylation of proteins is essential for their function and their intracellular transport. Numerous diseases have been described, where either glycosylation or intracellular transport of proteins is impaired. Coat protein I (COPI) is involved in anterograde and retrograde transport of proteins between endoplasmic reticulum and Golgi, where glycosylation takes place, but no association of defective COPI proteins and glycosylation defects has been described so far. We identified a patient whose phenotype at a first glance was reminiscent of PGM1 deficiency, a disease that also affects N-glycosylation of proteins. More detailed analyses revealed a different disease with a glycosylation deficiency that was only detectable during episodes of acute illness of the patient. Trio-exome analysis revealed a de novo loss-of-function mutation in ARCN1, coding for the delta-COP subunit of COPI. We hypothesize that the capacity of flow through Golgi is reduced by this defect and at high protein synthesis rates, this bottleneck also manifests as transient glycosylation deficiency.

News on Clinical Details and Treatment in PGM1-CDG.

Phosphoglucomutase 1 deficiency has recently been reported as a novel disease that belongs to two different classes of metabolic disorders, congenital disorders of glycosylation (CDG) and glycogen storage diseases.This paper focuses on previously reported siblings with short stature, hypothyroidism, increased transaminases, and, in one of them, dilated cardiomyopathy (DCM). An intronic point mutation in the PGM1-gene (c.1145-222 G>T) leads to a complex alternative splicing pattern and to almost complete absence of PGM1 activity.Exercise-induced muscle fatigue, chest pain, and rhabdomyolysis persisted into adulthood. Fainting occurred during the first minutes of strong exercise due to glucose depletion and serum heart troponin was increased. A second wind phenomenon with an improvement in exercise capacity after some minutes of training was observed. Regular aerobic training improved fitness and helped to avoid acute damage. DCM improved during therapy.Glycosylation deficiency was most prominent in childhood. Glycosylation improved with age and further improved with oral galactose supplementation even in adulthood. Optimal improvement of glycosylation-dependent phenotypes should be achieved by early and permanent galactose treatment.However, in case of mutations in ZASP, DCM can develop as a consequence of impaired binding of PGM1 to the heart-specific isoform of ZASP, independently of overall glycosylation efficiency. Thus, even if mutations in PGM1 impair the function of the ZASP-PGM1 complex, supplementation of galactose cannot be expected to restore that function. Therefore, knowledge of PGM1 deficiency in a patient should prompt surveillance of early signs of DCM and specific treatment if necessary.