bims-symami 2023-05-14 papers

Issue of 2023–05–14
three papers selected by
The Lily Foundation

Ned Tijdschr Geneeskd. 2023 May 10. pii: D7360. [Epub ahead of print]167

[Couples with risk of a child with a mitochondrial disease: wat are the reproductive options?]

Debby M E I Hellebrekers, Christine E M de Die-Smulders, Mirian C H Janssen.

Mitochondrial diseases are the most common inborn errors of metabolism. These severe multisystem disorders cause serious morbidity and mortality. Generally no treatment is available. This underlines the importance of counseling about the reproductive options to prevent the transmission of mitochondrial disorders. The majority of mitochondrial disorders is caused by a defect in a nuclear gene, in which cases the standard reproductive options can be applied, such as prenatal diagnosis (PND) and preimplantation genetic testing (PGT). For mitochondrial disorders caused by a mitochondrial DNA (mtDNA) mutation, reproductive options are determined by the recurrence risk, requiring specific reproductive counseling. For de novomtDNA mutations and inherited mtDNA mutations with a low recurrence risk, PND is possible. In case of a moderate or higher recurrence risk, PGT is the best option. In case the risk of a healthy embryo is (very) low, mitochondrial replacement therapy (MRT) may be a possibility in the future.

J Prim Care Community Health. 2023 Jan-Dec;14:14 21501319231172697

Mitochondrial Myopathy in a 21-Year-Old Man Presenting With Bilateral Lower Extremity Weakness and Swelling.

Kavya Bharathidasan, Abbie Evans, Fabiana Monte Alegre Olmos Fernandez, Arunee Tansrisook Motes, Kenneth Nugent.

Bilateral lower extremity weakness and swelling can have several causes. Although often underdiagnosed, mitochondrial myopathy is more prevalent in the general population than more commonly suspected diseases, such as Guillain-Barre syndrome. The clinical manifestations of mitochondrial disease can be broadly classified into 3 categories: chronic progressive external ophthalmoplegia, skeletal muscle-central nervous system syndromes, or pure myopathy. Cardiac abnormalities occur in 30% to 32% of cases, mostly in the form of hypertrophic cardiomyopathy, dilated cardiomyopathy, or conduction abnormalities. We report a case of a 21-year-old student who developed bilateral lower limb weakness, pain, and swelling diagnosed with mitochondrial myopathy on muscle biopsy. Initial laboratory tests revealed elevated creatinine kinase, brain natriuretic peptide, troponin, myoglobin, and lactic acid and reduced serum bicarbonate. Cardiac workup revealed systolic heart failure with a reduced ejection fraction. Endomyocardial biopsy revealed punctate foci of lymphocytic myocarditis. However, cardiac magnetic resonance imaging did not reveal either myocarditis or an infiltrative cardiac disease. An extensive autoimmune and infection work-up was negative. A muscle biopsy from the patient's rectus femoris revealed scattered ragged-blue fibers (stained with NADH dehydrogenase), scattered ragged-red fibers on modified Gomori trichrome stain, and cytochrome-c oxidase negative fibers with increased perimysial and endomysial connective tissue, consistent with active and chronic primary mitochondrial myopathy. The patient was treated successfully with furosemide, metoprolol, and methylprednisolone. Adult-onset mitochondrial myopathy is a rare clinical disorder, and our experience stresses the importance of using an inter-disciplinary team approach to diagnose uncommon clinical disorders with widely variable multisystem involvement.

Keywords: cardiomyopathy; mitochondrial disease; muscle weakness; myopathy

DOI: https://doi.org/10.1177/21501319231172697

JIMD Rep. 2023 May;64(3): 223-232

Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2-related mitochondrial disease.

Jessie Poquérusse, Melinda Nolan, David R Thorburn, Johan L K Van Hove, Marisa W Friederich, Donald R Love, Juliet Taylor, Christopher A Powell, Michal Minczuk, Russell G Snell, Klaus Lehnert, Emma Glamuzina, Jessie C Jacobsen.

Disorders of mitochondrial function are a collectively common group of genetic diseases in which deficits in core mitochondrial translation machinery, including aminoacyl tRNA synthetases, are key players. Biallelic variants in the CARS2 gene (NM_024537.4), which encodes the mitochondrial aminoacyl-tRNA synthetase for cysteine (CARS2, mt-aaRScys; MIM*612800), result in childhood onset epileptic encephalopathy and complex movement disorder with combined oxidative phosphorylation deficiency (MIM#616672). Prior to this report, eight unique pathogenic variants in the CARS2 gene had been reported in seven individuals. Here, we describe a male who presented in the third week of life with apnoea. He rapidly deteriorated with paroxysmal dystonic crises and apnoea resulting in death at 16 weeks. He had no evidence of seizure activity or multisystem disease and had normal brain imaging. Skeletal muscle biopsy revealed a combined disorder of oxidative phosphorylation. Whole-exome sequencing identified biallelic variants in the CARS2 gene: one novel (c.1478T>C, p.Phe493Ser), and one previously reported (c.655G>A, p.Ala219Thr; rs727505361). Northern blot analysis of RNA isolated from the patient's fibroblasts confirmed a clear defect in aminoacylation of the mitochondrial tRNA for cysteine (mt-tRNACys). To our knowledge, this is the earliest reported case of CARS2 deficiency with severe, early onset dystonia and apnoea, without epilepsy.

Keywords: CARS2; mitochondrial disorders; neurodevelopmental disorder; tRNA synthetases; whole‐exome sequencing

DOI: https://doi.org/10.1002/jmd2.12360