| 1. |
- Jennions, Elizabeth, et al.
(författare)
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A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype
- 2024
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Ingår i: AMERICAN JOURNAL OF MEDICAL GENETICS PART A. - 1552-4825 .- 1552-4833.
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Tidskriftsartikel (refereegranskat)abstract
- Cytochrome c oxidase (COX) deficiency is a phenotypically diverse group of diseases caused by variants in over 30 genes. Biallelic pathogenic variants in COX6B1 have been described in four patients to date with varying disease manifestations. We describe the clinical features and follow-up of a patient with a novel homozygous pathogenic variant in COX6B1 who presented acutely with severe encephalomyopathy associated with an infection. New findings include ophthalmological evaluation and follow-up of neuroradiological investigations. The novel p.Trp31Arg variant was predicted to be pathogenic in silico, and further functional analyses with biochemical analysis of mitochondrial function showed isolated COX deficiency. Muscle biopsy showed a specific lack of COX6B1 protein together with complex IV deficiency on western blot, enzyme histochemistry, and immuno-histochemistry.
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| 2. |
- Jennions, Elizabeth, et al.
(författare)
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TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism
- 2019
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 42:5, s. 898-908
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Tidskriftsartikel (refereegranskat)abstract
- Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2-related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism-induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post-mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.
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| 3. |
- Savvidou, Antri, et al.
(författare)
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Drug-induced hyperthermia with rhabdomyolysis in CLN3 disease
- 2022
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Ingår i: European Journal of Paediatric Neurology. - : Elsevier BV. - 1090-3798 .- 1532-2130. ; 39, s. 74-78
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Tidskriftsartikel (refereegranskat)abstract
- CLN3 disease (MIM# 204200), the most prevalent of the neuronal ceroid lipofuscinoses (NCL), is an autosomal recessive disorder with juvenile onset characterized by blindness, epilepsy, dementia, psychiatric manifestations, and motor deterioration. Problems related to behavior, emotions and thought are among the main features. Antidepressant and antipsychotic drugs have been employed with variable results. Neuroleptic malignant syndrome (NMS) has previously been described in two patients with NCL, one with CLN3 disease and one with adult onset NCL of unclear genetic origin. Our aims were to describe the occurrence of drug-induced hyperthermia in pediatric patients with CLN3 disease from West and South Sweden and to delineate the range of associated clinical features. Our study identified four patients presenting with seven episodes of severe drug-induced hyperthermia and either NMS-like or Serotonin syndrome (SS)-like features. Possibly provoking drugs were risperidone, clozapine, olanzapine, haloperidol, quetiapine, and sertraline. The course was atypical, frequently prolonged, associated with rhabdomyolysis and status dystonicus, and resulted in the death of three of the patients. Our study points to a vulnerability to drug-induced hyperthermia in patients with CLN3 disease which we believe could be underreported. Interestingly the proposed pathophysiological mechanisms behind NMS and SS on one hand and CLN3 on the other hand seem to converge in a common mechanism involving dysregulation of the sympathetic nervous system.
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| 4. |
- Shahim, Pashtun, et al.
(författare)
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Cerebrospinal Fluid Brain Injury Biomarkers in Children: A Multicenter Study
- 2013
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Ingår i: Pediatric Neurology. - : Elsevier BV. - 0887-8994 .- 1873-5150. ; 80
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebrospinal fluid (CSF) biomarkers reflecting neuronal and astroglial injury, such as total tau (T-tau), glial flbrillary acidic protein (GFAP), and neurofilament light (NFL), have been extensively investigated in neurologic diseases in adults, but no large study has investigated these biomarkers in children. METHODS: This study presents a detailed evaluation of CFS T-tau, GFAP, NFL, and CSF:albumin ratio in a large cohort of pediatric patients. This is a retrospective multicenter study on pediatric patients aged <16 years (n = 607), where neuronal injury biomarkers T-tau, GFAP, NFL, and CSF albumin ratio were analyzed during 2000-2010 at the Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Sweden. The patients were grouped into eight categories: epilepsy, infectious and inflammatory central nervous system disorders, progressive encephalopathy, static encephalopathy, tumors, movement disorders, miscellaneous disorders, and a control group. RESULTS: T-tau, GFAP, and NFL were increased in progressive encephalopathy (P < 0.001), epilepsy (P < 0.001), and infectious and inflammatory central nervous system disorders (P < 0.001) compared with controls. T-tau was the biomarker with the highest diagnostic accuracy with the area under the curve of 0.83 (95% confidence interval (CI), 0.77-0.90; P < 0.0001) for progressive encephalopathy followed by epilepsy 0.80 (95% CI, 0.75-0.87; P < 0.0001). The combination of all four biomarkers further improved the area under the curve for the progressive encephalopathy 0.87 (95% CI, 0.77-0.89; P < 0.0001), followed by epilepsy 0.81 (95% CI, 0.74-0.80; P = 0.030). The combination of the biomarkers also separated progressive from static encephalopathy 0.88 (95% CI, 0.83-0.93; P < 0.0001). CONCLUSIONS: CSF T-tau, GFAP, and NFL are differently altered across different neurologic diseases in children. Importantly, the biomarker pattern distinguishes between progressive and static neurologic disorders. (c) 2013 Elsevier Inc. All rights reserved.
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| 5. |
- Xia, Zhi Jie, et al.
(författare)
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The Swedish COG6-CDG experience and a comprehensive literature review
- 2023
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Ingår i: JIMD Reports. - : Wiley. - 2192-8304 .- 2192-8312. ; , s. 79-89
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Here, we present the first two Swedish cases of Conserved Oligomeric Golgi complex subunit 6-congenital disorders of glycosylation (COG6-CDG). Their clinical symptoms include intellectual disability, Attention Deficit/Hyperactivity Disorder (ADHD), delayed brain myelinization, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections, and enamel hypoplasia. In one family, compound heterozygous variants in COG6 were identified, where one (c.785A>G; p.Tyr262Cys) has previously been described in patients of Moroccan descent, whereas the other (c.238G>A; p.Glu80Lys) is undescribed. On the other hand, a previously undescribed homozygous duplication (c.1793_1795dup) was deemed the cause of the disease. To confirm the pathogenicity of the variants, we treated patient and control fibroblasts with the ER-Golgi transport inhibitor Brefeldin-A and show that patient cells manifest a significantly slower anterograde and retrograde ER-Golgi transport.
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