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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Barth syndrome, initially described as X-linked cardioskeletal myopathy with abnormal mitochondria and neutropenia, typically presents in male infants as HF associated with neutropenia and 3-methylglutaconic aciduria. The genetic basis of Barth syndrome is mutations in the gene tafazzin (TAZ), which encodes the tafazzin protein, an acyltransferase. Mutations in TAZ result in a wide range of findings, including DCM, HCM, endocardial fibroelastosis, or left ventricular noncompaction. Arrhythmias are also frequent in these patients, and syncope or sudden death, acidosis, or infectious complications occur.24
Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
The disease was first described in the Roma population, with neonatal onset of the disease and poor prognosis associated with homozygous mutation c.317-2A>G in TMEM70 gene (Fig. 2.) (Cizkova et al., 2008). It represented then very unique finding of nuclear autosomal recessive mutation of OXPHOS, encoding ancillary factor of ATP synthase biogenesis. Patients usually present in utero or in the first days of life; with metabolic crisis with hypertrophic cardiomyopathy, cardiorespiratory failure lactic acidosis, hyperammonemia. Oligohydroamnion, intrauterine growth restriction (IUGR), facial dysmorphism and hypospadias in boys are also common. Laboratory findings reveal lactic acidosis and 3-methylglutaconic aciduria. Neonatal period is extremely critical for metabolic crisis management, when complicated with heart or respiratory failure and pulmonary hypertension. Metabolic failures with hyperammonemia can also result in encephalopathy and developmental regression. Common triggers of metabolic crisis can include surgery, acute febrile illness and acute gastroenteritis. The succesful management of acute metabolic crises is crucial for prognosis, developement and life expectancy of the child. Ten-year survival is 63%, with the most critical neonatal period (Magner et al., 2015). An anaplerotic therapy with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment for affected children during metabolic crises was proposed as a promising treatment approach (Braczynski et al., 2015).
Identification of the first homozygous POLG mutation causing non-syndromic ovarian dysfunction
Published in Climacteric, 2018
B. Chen, L. Li, J. Wang, Y. Zhou, J. Zhu, T. Li, H. Pan, B. Liu, Y. Cao, B. Wang
In this study, we report that a novel homozygous POLG mutation is associated with ovarian dysfunction in a patient with consanguineous pedigree. The POLG gene encodes the catalytic subunit of DNA polymerase-γ involved in the replication of mitochondrial DNA25. Polg knock-out mice develop an mtDNA mutator phenotype associated with reduced lifespan, premature onset of aging-related phenotypes and reduced fertility29. Dominant or recessive mutations in human POLG can cause a spectrum of disorders associated with mitochondria dysfunction, including PEO, sensory ataxic neuropathy, familial Parkinsonism and progressive sclerosing poliodystrophy30–32. Most women with PEO exhibit early menopause26. The heterozygous p.Y955C, p.R943H, p.Y831C and p.S511N mutations of POLG can segregate with POF and PEO22,26,28,33,34. In addition, another heterozygous p.Y951N mutation in POLG was found in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis (a severe form of POF) and 3-methylglutaconic aciduria27. Another study screened POLG mutations in 201 patients with spontaneous primary ovarian insufficiency and found one heterozygous p.R953C variant in a patient35. Therefore, POLG heterozygous mutations, including p.S511N, p.Y831C, p.R943H, p.Y951N, p.R953C, and p.Y955C, may be associated with syndromic or non-syndromic ovarian failure.
Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy
Published in Ophthalmic Genetics, 2019
Eric D. Gaier, Inderneel Sahai, Janey L. Wiggs, Brian McGeeney, Jodi Hoffman, Crandall E. Peeler
Hereditary optic neuropathies are characterized by primary optic atrophy and are caused by mutations in multiple genes. Mutations in OPA3 are associated with optic atrophy in distinct contexts (1–3). Heterozygous mutations in OPA3 cause autosomal dominant optic atrophy with associated cataract (OMIM#165300), while mutations in both OPA3 alleles cause autosomal recessive 3-methylglutaconic aciduria type III (MGA3; Costeff Syndrome; OMIM#258501), a neuro-degenerative disorder characterized by optic atrophy, extrapyramidal signs, spastic paraparesis and ataxia.
Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum
Published in Ophthalmic Genetics, 2023
Caroline Atef Tawfik, Raghda Zaitoun, Aliaa Ahmed Farag
In vitro studies show that ATAD3A is involved in diverse cellular processes, including mitochondrial dynamics, mitochondrial DNA (mtDNA) maintenance and replication, channeling of cholesterol for steroidogenesis, and resistance of cancer cells to therapy. Mitochondrial dysfunction was suggested by a lactate peak on MR spectroscopy in our case; however, laboratory evidence of mitochondrial dysfunction such as elevated serum lactate and 3-methylglutaconic aciduria is not a consistent feature documented in all cases (1,4,10).