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Long-chain L-3-hydroxyacyl-CoA dehydrogenase – (trifunctional protein) deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
In two unrelated patients, mutations were found for the first time in the HADHB gene [44]. In a French cohort of 52 patients with mitochondrial trifunctional protein deficiency, the majority of identified mutations generated premature termination codons resulting in nonsense mRNA-mediated decay [6]. It appears that both normal α and β are important for stabilization of the trifunctional protein. Lethal disease was reported in a case of uniparental disomy of chromosome 2 leading to homozygous mutation in HADHA [45]. A knock-out mouse lacking the α and β subunits of MTP has neonatal hypoglycemia and sudden death [46].
Designation of orphan conditions in Europe: regulatory observations and considerations after implementation of regulation 141/2000
Published in Expert Opinion on Orphan Drugs, 2020
Segundo Mariz, Kerstin Westermark, Bruno Sepodes
Although the COMP will often designate a condition under an umbrella term to capture as many subsets of a condition as possible. In some instances, however it has subdivided them according to how they are classified in the public domain. An example are the mucopolysaccharidosis which have been designated by type as described in the literature (Types I, II, III, IV, VI and VII) with each showing clustering of subsequent submissions and positive opinions totaling 34 positive opinions indicating that this is an area of great interest in development. A similar situation exists for mitochondrial disorders where the classification system describes several different disorders such as: mitochondria DNA depletion syndrome, myopathic form, mitochondrial trifunctional protein deficiency, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (2 designations) and mitochondrial neurogastrointestinal encephalopathy (2 designations) [11]. There are 7 designations in total retrievable for mitochondrial disorders which are classified theoretically as” various” on the EMA website indicating that there is some interest in developing products in what are very difficult conditions to study and treat.
An update on diagnosis and therapy of metabolic myopathies
Published in Expert Review of Neurotherapeutics, 2018
Disorders of the lipid metabolism are classified according to histological criteria into those with lipid depositions on histological investigations and those without lipid depositions. Those with lipid deposition include, for example, primary carnitine deficiency (PCD), multi-acyl-coenzyme-A dehydrogenase deficiency (MADD), and neutral lipid storage disease with myopathy (NLSD-M) (Table 1) [7]. Those without lipid depositions include, for example, carnitine palmitoyl-transferase-2 (CPT-2) deficiency, mitochondrial trifunctional protein deficiency (MTPD), and the very long chain acyl-coenzyme-A dehydrogenase deficiency (VLCAD). Metabolic myopathies due impaired lipid metabolism may be further divided into those with defective transport of fatty acids into mitochondria and those with impaired oxidation of fatty acids (FAODs) within mitochondria. Up to at least 25 enzymes and specific transport proteins in the β-oxidation pathway have been detected of which 18 have been associated with human disease [8]. Half of these may go along with myopathy (Table 1). Recently, mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) have been identified, which go along with either glutaric aciduria or with lipid storage myopathy.