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1.
Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review.
Palmieri, F, Scarcia, P, Monné, M
Biomolecules. 2020;(4)
Abstract
In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.
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Review of SRD5A3 Disease-Causing Sequence Variants and Ocular Findings in Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation, and a Detailed New Case.
Kousal, B, Honzík, T, Hansíková, H, Ondrušková, N, Čechová, A, Tesařová, M, Stránecký, V, Meliška, M, Michaelides, M, Lišková, P
Folia biologica. 2019;(3):134-141
Abstract
Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436G>A, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome.
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3.
Identifying mutations in epilepsy genes: Impact on treatment selection.
Perucca, P, Perucca, E
Epilepsy research. 2019;:18-30
Abstract
The last decade saw impressive advances not only in the discovery of gene mutations causing epilepsy, but also in unraveling the molecular mechanisms underlying the clinical manifestations of the disease. Increasing evidence is emerging that understanding these mechanisms is relevant for selection of the most appropriate treatment in the affected individual(s). The present article discusses the therapeutic implications of epilepsy-causing variants affecting a broad range of targets, from ion channels to genes controlling cellular metabolism and cell signaling pathways. Identification of a precise genetic etiology can direct physicians to (i) prescribe treatments that correct specific metabolic defects (e.g., the ketogenic diet for GLUT1 deficiency, or pyridoxine for pyridoxine-dependent epilepsies); (ii) avoid antiepileptic drugs (AEDs) that can aggravate the pathogenic defect (e.g., sodium channel blocking drugs in SCN1A-related Dravet syndrome), or (iii) select AEDs that counteract the functional disturbance caused by the gene mutation (e.g., sodium channel blockers for epilepsies due to gain-of-function SCN8A mutations). In some instances, different pathogenic variants of the same gene can have opposite functional effects, which determines whether certain treatments can be beneficial or deleterious (e.g., gain-of-function versus loss-of-function variants in SCN2A determine whether sodium channel blockers improve or worsen seizure control). There are also cases where functional disturbances caused by the gene defect may not be corrected by existing AEDs, but can be countered by medications already available in the market for other indications (e.g., memantine has been used to treat the epileptic encephalopathy caused by a specific gain-of-function GRIN2A mutation), thus making 'drug repurposing' a valuable tool for personalized epilepsy therapies. As our understanding of pathogenic mechanisms improve, opportunities arise for development of treatments targeting the specific gene defect or its consequences. Everolimus, an mTOR inhibitor approved for the treatment of focal seizures associated with tuberous sclerosis complex, is an example of a medication targeting the etiological mechanisms of the disease. Several treatments aimed at correcting specific pathogenic defects responsible for rare genetic epilepsies are currently in development, and range from traditional small molecules to novel approaches involving peptides, antisense oligonucleotides, and gene therapy.
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4.
Wilson disease and related copper disorders.
Lorincz, MT
Handbook of clinical neurology. 2018;:279-292
Abstract
Copper is a required cofactor for enzymes in critical metabolic pathways. Mutations in copper metabolism genes or abnormalities in copper metabolism result in disease from copper excess or deficiency. Wilson disease (WD) is an autosomal-recessive disease caused by mutations in the ATP7B gene which encodes a copper-transporting ATPase. Over 500 different WD mutations throughout the ATP7B gene have been described, most of which are missense mutations. Mutations in both ATP7B alleles result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic WD include variable combinations of dysarthria, dystonia, tremor, and choreoathetosis. Misdiagnosis and delay in treatment are clinically relevant because untreated WD progresses to hepatic failure or severe neurologic disability and death. Treatment can prevent and cure WD. Mutations in a second, closely related copper-transporting ATPase, ATP7A, cause a spectrum of copper deficiency disorders that include Menkes disease, occipital horn syndrome, and ATP7A-related distal motor neuropathy. Two important, nongenetic causes of copper deficiency myeloneuropathy are copper deficiency following gastric bypass or due to excess zinc ingestion, both of which can cause a myeloneuropathy similar to vitamin B12 deficiency. Copper deficiency following gastric bypass is preventable, and identification and elimination of the excess zinc source, most commonly dental cream, can result in recovery.
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5.
Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.
Maas, RR, Iwanicka-Pronicka, K, Kalkan Ucar, S, Alhaddad, B, AlSayed, M, Al-Owain, MA, Al-Zaidan, HI, Balasubramaniam, S, Barić, I, Bubshait, DK, et al
Annals of neurology. 2017;(6):1004-1015
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Abstract
OBJECTIVE 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.
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Recent advances in congenital ichthyoses.
Hernández-Martín, A, González-Sarmiento, R
Current opinion in pediatrics. 2015;(4):473-9
Abstract
PURPOSE OF REVIEW In 2010, a new classification of the congenital ichthyoses was published. At the time, the causative genes were known in many but not all instances. The goal of this review is to provide an update on molecular and clinical findings in congenital ichthyosis and to revise evidence-based and emerging treatments. RECENT FINDINGS Mutations in genes encoding for desmosomal components have recently been shown to cause three clinically overlapping entities: peeling skin disease; severe dermatitis, multiple allergies and metabolic wasting syndrome; and Netherton syndrome. Mutations in keratin 10 have been identified as the cause of ichthyosis with confetti, a rare form of ichthyosis characterized by severe erythroderma in which healthy spots gradually develop since childhood. There is no curative treatment for the congenital ichthyoses. A recent systematic review of randomized clinical trials of ichthyosis treatments revealed that research evidence of therapy is poor. SUMMARY The expanding phenotype and genotype of the ichthyoses facilitates accurate clinical diagnosis and permits a deeper knowledge of the epidermal pathophysiology. Although curative treatment is yet to come, N-acetylcysteine has recently been added to the therapeutic armamentarium and topical enzyme replacement therapy has emerged as a promising alternative in TG1-deficient individuals.
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Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD).
Chakraborty, PK, Schmitz-Abe, K, Kennedy, EK, Mamady, H, Naas, T, Durie, D, Campagna, DR, Lau, A, Sendamarai, AK, Wiseman, DH, et al
Blood. 2014;(18):2867-71
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Abstract
Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.
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8.
Early onset (childhood) monogenic neuropathies.
Landrieu, P, Baets, J
Handbook of clinical neurology. 2013;:863-91
Abstract
Hereditary neuropathies (HN) with onset in childhood are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission and, in selected cases, pathological findings. Especially relevant to pediatrics are the items "secondary" versus "primary" neuropathy, "syndromic versus nonsyndromic," and "period of life." Different combinations of these parameters frequently point toward specific monogenic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first concern in pediatrics. As a rule, metabolic diseases include additional, orienting symptoms or signs, and their biochemical diagnosis is based on logical algorithms. Primary, motor sensory are the most frequent HN and are dominated by demyelinating autosomal dominant (AD) forms (CMT1). Other forms include demyelinating autosomal recessive (AR) forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Peripheral motor neuron disorders are dominated by AR SMN-linked spinal muscular atrophies. (Distal) hereditary motor neuropathies represent <10% of HN but exhibit large clinical and genetic heterogeneity. Sensory/dysautonomic HN involves five classic subtypes, each one related to specific genes. However, genetic heterogeneity is larger than initially suspected. Syndromic HN distinguish "purely neurological syndromes", which are multisystemic, such as spinocerebellar atrophies +, spastic paraplegias +, etc. Peripheral neuropathy is possibly the presenting feature, including in childhood. Autosomal recessive forms, on average, start more frequently in childhood. "Multiorgan syndromes", on the other hand, are more specific to Pediatrics. AR forms, which are clearly degenerative, prompt the investigation of a large set of pleiotropic genes. Other syndromes expressed in the perinatal period are mainly developmental disorders, and can sometimes be related to specific transcription factors. Systematic malformative workup and ethical considerations are necessary. Altogether, >40 genes with various biological functions have been found to be responsible for primary HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait, and some for various types of transmission.
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A novel mutation in COQ2 leading to fatal infantile multisystem disease.
Jakobs, BS, van den Heuvel, LP, Smeets, RJ, de Vries, MC, Hien, S, Schaible, T, Smeitink, JA, Wevers, RA, Wortmann, SB, Rodenburg, RJ
Journal of the neurological sciences. 2013;(1-2):24-8
Abstract
Coenzyme Q10 (ubiquinone or CoQ10) serves as a redox carrier in the mitochondrial oxidative phosphorylation system. The reduced form of this lipid-soluble antioxidant (ubiquinol) is involved in other metabolic processes as well, such as preventing reactive oxygen species (ROS) induced damage from the mitochondrial membrane. Primary coenzyme Q10 deficiency is a rare, autosomal recessive disorder, often presenting with neurological and/or muscle involvement. Until now, five patients from four families have been described with primary coenzyme Q10 deficiency due to mutations in COQ2 encoding para-hydroxybenzoate polyprenyl transferase. Interestingly, four of these patients showed a distinctive renal involvement (focal segmental glomerular sclerosis, crescentic glomerulonephritis, nephrotic syndrome), which is only very rarely seen in correlation with mitochondrial disorders. The fifth patient deceases due to infantile multi organ failure, also with renal involvement. Here we report a novel homozygous mutation in COQ2 (c.905C>T, p.Ala302Val) in a dizygotic twin from consanguineous Turkish parents. The children were born prematurely and died at the age of five and six months, respectively, after an undulating disease course involving apneas, seizures, feeding problems and generalized edema, alternating with relative stable periods without the need of artificial ventilation. There was no evidence for renal involvement. We would like to raise awareness for this potentially treatable disorder which could be under diagnosed in patients with fatal neonatal or infantile multi-organ disease.
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10.
PRPS1 mutations: four distinct syndromes and potential treatment.
de Brouwer, AP, van Bokhoven, H, Nabuurs, SB, Arts, WF, Christodoulou, J, Duley, J
American journal of human genetics. 2010;(4):506-18
Abstract
Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data).