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Inherited metabolic diseases

Nikolaus Berndt, Sascha Bulik, Iwona Wallach, Tilo Wünsch, Matthias König, Martin Stockmann, David Meierhofer, Hermann-Georg Holzhütter
The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation...
June 19, 2018: Nature Communications
B Chabrol, P Jacquin, L Francois, P Broué, D Dobbelaere, C Douillard, S Dubois, F Feillet, A Perrier, A Fouilhoux, F Labarthe, D Lamireau, K Mazodier, F Maillot, F Mochel, M Schiff, N Belmatoug
Inherited metabolic diseases (IMD) form a heterogeneous group of genetic disorders that surface primarily during childhood and result in significant morbidity and mortality. A prevalence of 1 in 2500-5000 live births is often reported. The transfer of adolescents from pediatric care to adult health facilities is often difficult for patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with IMDs associated with dietary treatment...
June 15, 2018: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
Meena Balasubramanian, Diana S Johnson
BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases due to impaired lipid and protein glycosylation. It comprises a characteristic high frequency of intellectual disability (ID) and a wide range of clinical phenotypes. OBJECTIVE: (s): To identify the underlying diagnosis in two families each with two siblings with variable level of ID through trio whole exome sequencing. METHODS: Both the families were recruited to the Deciphering Developmental Disorders (DDD) study to identify the aetiology for their ID...
June 13, 2018: European Journal of Medical Genetics
Joyeeta Rahman, Shamima Rahman
Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homoeostatic functions. Mitochondrial diseases represent one of the most common and severe groups of inherited genetic disorders, characterised by clinical, biochemical, and genetic heterogeneity, diagnostic odysseys, and absence of disease-modifying curative therapies. This Review aims to discuss recent advances in mitochondrial biology and medicine arising from widespread use of high-throughput omics technologies, and also includes a broad discussion of emerging therapies for mitochondrial disease...
June 11, 2018: Lancet
Jiemei Gu, Chun Wang, Hao Zhang, Hua Yue, Weiwei Hu, Jinwei He, Wenzhen Fu, Zhenlin Zhang
Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate reabsorption and abnormal bone mineralization. Hypophosphatemic rickets/osteomalacia consists of inherited and acquired forms, many of which have unknown aetiology. In the present study, next‑generation sequencing‑based resequencing was used on samples from Chinese subjects with hypophosphatemic rickets/osteomalacia, aiming to detect the spectrum of pathogenic genes in these patients. A total of 86 hypophosphatemic rickets/osteomalacia patients (ranging from 3 to 70 years old) were recruited...
June 13, 2018: International Journal of Molecular Medicine
Çiğdem Seher Kasapkara, Meltem Akçaboy, Fehime Kara Eroğlu, Betül Emine Derinkuyu
Mucolipidoses are metabolic disorders with autosomal recessive inheritance caused by deficiency of N-acetylglucosamine- 1-phosphotransferase leading to accumulation of glycosaminoglycans and sphingolipids intracellularly. The differential diagnosis of mucolipidosis II or III is based on the age of onset, clinical findings and degree of severity. In this article, we present four pediatric patients with mucolipidosis III or pseudo-Hurler polydystrophy who admitted to our hospital with joint stiffness. They were from consanguineous families with characteristic radiographic findings...
March 2018: Archives of Rheumatology
Xuejun Yang, Gaofu Zhang, Mo Wang, Haiping Yang, Qiu Li
Objective: To investigate the phenotype-genotype correlation in different genetic kinds of Bartter syndrome type 3 in children. Methods: Clinical and genetic data of 2 patients with different mutations in Bartter syndrome type 3 was analyzed while the prognosis was compared after a 6-year follow-up or 2-year follow-up, respectively. Results: Bartter syndrome is a kind of autosomal recessive inherited renal disorder. The manifestation and prognosis of Bartter syndrome change with mutation types, and severe mutation were often accompanied with unfavorable prognosis...
2018: Frontiers in Pediatrics
Raghav Kalia, Ray Yu-Ruei Wang, Ali Yusuf, Paul V Thomas, David A Agard, Janet M Shaw, Adam Frost
Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations...
June 13, 2018: Nature
Youhong Lin, Xiaying Cheng, Dongfeng Yang, Zongsuo Liang, Zongqi Yang
In recent years, gene engineering is developing rapidly and many recombinant proteins have been expressed. The use of plant bioreactor to express specific pharmaceutical proteins provides a new way for the prevention and treatment of some important diseases in human beings. Nowadays, chloroplast genetic transformation and expression system has become a research hotspot in plant bioreactor. Higher plant chloroplasts have unique advantages in the expression of recombinant proteins due to their special structures and inherited characteristics: such as high expression, site-specific integration, and the maternal inheritance characteristics of exogenous genes...
May 25, 2018: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Reza Alibakhshi, Keivan Moradi, Mostafa Biglari, Samaneh Shafieenia
Phenylketonuria (PKU) is one of the most common known inherited metabolic diseases. The present study aimed to investigate the status of molecular defects in phenylalanine hydroxylase ( PAH ) gene in western Iranian PKU patients (predominantly from Kermanshah, Hamadan, and Lorestan provinces) during 2014-2016. Additionally, the results were compared with similar studies in Iran. Nucleotide sequence analysis of all 13 exons and their flanking intronic regions of the PAH gene was performed in 18 western Iranian PKU patients...
May 2018: Iranian Journal of Medical Sciences
Susan Perlman, Eugen Boltshauser
There are no approved disease-modifying therapies for any of the inherited cerebellar ataxias. Drug treatment in childhood ataxia is still very limited. Effective treatments are available for only a few rare metabolic hereditary disorders. Symptomatic management of associated tremor, spasticity, dystonia, or chorea can follow the medication recommendations in general usage. The foundation of management of cerebellar ataxia in adults or children remains rehabilitation.
2018: Handbook of Clinical Neurology
Grace Yoon, Keith W Caldecott
Hereditary cerebellar ataxias are genetically and clinically heterogeneous, and an important subgroup of these disorders are caused by defects in DNA repair. These conditions are inherited in an autosomal-recessive fashion, with the main clinical feature being ataxia due to cerebellar degeneration. The nervous system in general, and the cerebellum in particular, is especially susceptible to DNA damage, although the underlying mechanism for this vulnerability has not been fully elucidated. Defects in DNA repair result in progressive accumulation of oxidative damage to DNA...
2018: Handbook of Clinical Neurology
Nidhi Prabhakar, Chirag K Ahuja, Niranjan Khandelwal
Bilateral basal ganglia lesions are a common non-specific finding seen in many diseases. One of the differential diagnoses for it, in a child, is kernicterus occurring due to hyperbilirubinemia. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common cause of severe hyperbilirubinemia. A 1-year old child presented to the hospital with history of generalized dystonia in the previous 3 days. MRI showed evidence of symmetrical lesions in bilateral globus pallidus, which were hyperintense on T2/FLAIR and isointense on T1...
April 2018: Annals of Neurosciences
Marco Savarese, Annalaura Torella, Olimpia Musumeci, Corrado Angelini, Guja Astrea, Luca Bello, Claudio Bruno, Giacomo Pietro Comi, Giuseppina Di Fruscio, Giulio Piluso, Giuseppe Di Iorio, Manuela Ergoli, Gaia Esposito, Marina Fanin, Olimpia Farina, Chiara Fiorillo, Arcomaria Garofalo, Teresa Giugliano, Francesca Magri, Carlo Minetti, Maurizio Moggio, Luigia Passamano, Elena Pegoraro, Ester Picillo, Simone Sampaolo, Filippo Maria Santorelli, Claudio Semplicini, Bjarne Udd, Antonio Toscano, Luisa Politano, Vincenzo Nigro
Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504)...
April 9, 2018: Neuromuscular Disorders: NMD
Kei Takasawa, Atsumi Tsuji-Hosokawa, Shigeru Takishima, Yasunori Wada, Keisuke Nagasaki, Sumito Dateki, Chikahiko Numakura, Atsushi Hijikata, Tsuyoshi Shirai, Kenichi Kashimada, Tomohiro Morio
BACKGROUND: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required. METHODS: We report six peripubertal cases with clinically diagnosed type A IR, including four cases with an identified INSR mutation...
June 6, 2018: Journal of Diabetes
Hasan F Cakmakli, Rosa J Torres, Araceli Menendez, Gul Yalcin-Cakmakli, Christopher C Porter, Juan Garcia Puig, H A Jinnah
PURPOSE: Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was  to describe macrocytic erythrocytes as another common aspect of the phenotype. METHODS: The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly. RESULTS: Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants...
June 6, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Jung Min Ko, Kyung Sun Park, Yeeok Kang, Seong Hyeuk Nam, Yoonjung Kim, Inho Park, Hyun Wook Chae, Soon Min Lee, Kyung A Lee, Jong Won Kim
PURPOSE: We developed a new workflow design which included results from both biochemical and targeted gene sequencing analysis interpreted comprehensively. We then conducted a pilot study to evaluate the benefit of this new approach in newborn screening (NBS) and demonstrated the efficiency of this workflow in detecting causative genetic variants. MATERIALS AND METHODS: Ten patients in Group 1 were diagnosed clinically using biochemical assays only, and 10 newborns in Group 2 were diagnosed with suspected inherited metabolic disease (IMD) in NBS...
July 2018: Yonsei Medical Journal
Stefan Kölker
Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases...
June 4, 2018: Journal of Inherited Metabolic Disease
Xiaoyan Zhou, Yazhou Cui, Jinxiang Han
Methylmalonic acidemia (MMA) is a lethal, severe heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism with poor prognosis. Two main forms of the disease have been identified, isolated methylmalonic acidurias and combined methylmalonic aciduria and homocystinuria, which is respectively caused by different gene mutations. Here, we review the improvement of pathogenesis, diagnosis and treatment in MMA. Importantly, the reported epidemiological data of MMA patients in China and the hot mutation sites in Chinese patients are listed, which will aid in improving healthcare of Chinese patients in the future...
May 2018: Intractable & Rare Diseases Research
Paola Krall, Daniela Nualart, Jean Grandy
Nephropatic cystinosis (NC) is a rare disease associated with pathogenic variants in the CTNS gene, with a common variant that consists of a 57kb-deletion involving CTNS. Patients with NC that are treated with cysteamine improve their life quality and expectancy. We report a 12-month-old girl with a poor growth rate since the 4th month of life. She was admitted to the Hospital with acute kidney injury, severe dehydration and metabolic acidosis. She was treated with volume restorative and bicarbonate. Proximal tubulopathy and Fanconi's syndrome was diagnosed...
January 2018: Revista Médica de Chile
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