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<jats:title>Abstract</jats:title><jats:p>The <jats:italic>HSD17B10</jats:italic> gene is located on chromosome Xp11.2 and codes for a multifunctional protein called 17β‐hydroxysteroid dehydrogenase type 10 (HSD10). This protein catalyzes the 2‐methyl‐3‐hydroxybutyryl‐CoA dehydrogenation (MHBD) reaction in isoleucine metabolism and is an essential component of mitochondrial RNase P required for the processing of mtDNA transcripts. HSD10 is required for normal mitochondrial maintenance, and complete loss of HSD10 is incompatible with life. Mutations in the <jats:italic>HSD17B10</jats:italic> gene have been reported in 19 families. The classical infantile form of what is best named HSD10 disease is characterized by a period of more or less normal development in the first 6‐18 months of life. Some patients showed transient metabolic derangement in the neonatal period, with good clinical recovery but often persistent lactate elevation. Usually from age 6‐18 months affected boys show a progressive neurodegenerative disease course in conjunction with retinopathy and cardiomyopathy leading to death at age 2‐4 years or later. A more severe presentation in the neonatal period with little neurological development, severe progressive cardiomyopathy, and early death, is denoted neonatal form. Juvenile and atypical/asymptomatic forms of HSD10 disease have been recognized. Heterozygous females often show non‐progressive developmental delay and intellectual disability but may also be clinically normal. The pathogenesis is poorly understood but is unrelated to MHBD function. Diagnosis is based on typical abnormalities in urinary organic acid analysis and molecular studies. The same de novo mutation p.R130C was found in over half of patient families; it is associated with the infantile disease form. There is no effective treatment.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Lysosomal dysfunction may be an important factor in the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). Heterozygous mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (<jats:italic>GBA1</jats:italic>) have been found in PD patients, and some but not all mutations in other lysosomal enzyme genes, for example, <jats:italic>NPC1</jats:italic> and <jats:italic>MCOLN1</jats:italic> have been associated with PD. We have examined the behaviour and brain structure of mice carrying a D31N mutation in the sulphamidase (<jats:italic>Sgsh</jats:italic>) gene which encodes a lysosomal sulphatase. Female heterozygotes and wildtype mice aged 12‐, 15‐, 18‐ and 21‐months of age underwent motor phenotyping and the brain was comprehensively evaluated for disease‐associated lesions. Heterozygous mice exhibited impaired performance in the negative geotaxis test when compared with wildtype mice. Whilst the brain of <jats:italic>Sgsh</jats:italic> heterozygotes aged up to 21‐months did not exhibit any of the gross features of PD, Alzheimer's disease or the neurodegenerative lysosomal storage disorders, for example, loss of striatal dopamine, reduced GBA activity, α‐synuclein‐positive inclusions, perturbation of lipid synthesis, or cerebellar Purkinje cell drop‐out, we noted discrete structural aberrations in the dendritic tree of cortical pyramidal neurons in 21‐month old animals. The overt disease lesions and resultant phenotypic changes previously described in individuals with heterozygous mutations in lysosomal enzyme genes such as glucocerebrosidase may be enzyme dependent. By better understanding why deficiency in, or mutant forms of some but not all lysosomal proteins leads to heightened risk or earlier onset of classical neurodegenerative disorders, novel disease‐causing mechanisms may be identified.</jats:p>

<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Since the identification of the first disorder of mitochondrial fatty acid oxidation (FAOD) in 1973, more than twenty defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.</jats:p></jats:sec><jats:sec><jats:title>Take home message</jats:title><jats:p>Tentative hypotheses to improve the diagnosis and the treatment of fatty acid oxidation defects.</jats:p><jats:p>This article is protected by copyright. All rights reserved.</jats:p></jats:sec>