Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency

doi:10.1016/S1096-7192(03)00097-0

Molecular Genetics and Metabolism

Volume 79, Issue 4, August 2003, Pages 288-293

https://doi.org/10.1016/S1096-7192(03)00097-0 Get rights and content

Abstract

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonenia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I + III and II + III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiancy, possibly caused by CoQ responsive oxphos deficiency.

Introduction

Mitochondrial diseases represent a heterogeneous group of genetic disorders caused by respiratory chain dysfunction. There is a wide range of clinical presentations of the various respiratory complexes deficiencies. Coenzyme Q plays a central role in both mitochondrial electron transport and in transmembrane proton movement. By receiving electrons from complex I, II and from oxidation of fatty acids and branched chain amino acids via flavoprotein dehydrogenase complexes, and transferring them to complex III, and by generating a proton gradient, CoQ contributes to ATP synthesis in the inner mitochondrial membrane. Reduced CoQ also acts as an antioxidant, protecting mitochondrial inner membrane lipids, proteins and mitochondrial DNA against oxidative damage and against apoptotic processes.

Only a few cases of decreased muscle CoQ have been described in patients, with three major phenotypes [1], [3], [6], [8], [9], [10], [11]: (1) A myopathic form characterized by exercise intolerance, mitochondrial myopathy, myoglobinuria, epilepsy, and ataxia. (2) A generalized infantile variant with severe encephalopathy and renal disease, and (3) An ataxic form, characterized by ataxia, seizures, and cerebellar atrophy.

We describe a patient with Leigh syndrome, transient tyrosinemia and hyperammonenia, liver and pancreas insufficiency and sensorineural hearing loss, whose liver biopsy showed multiple respiratory enzyme deficiency probably ascribed to a defect in CoQ biosynthesis.

Section snippets

Case report

The patient, a two-month-old male was referred to our metabolic neurogenetic clinic for evaluation of cholestatic jaundice, pancreatic insufficiency and hypertyrosinemia. He was the first offspring of two healthy highly consanguineous Azerbaijani Jews. Family history was remarkable for three infant deaths: two severely retarded paternal aunts and a maternal aunt who died of alleged sepsis. Pregnancy was normal until the 35 week when it was terminated because of oligohydramion. Birth weight and

Liver biopsy histology and ultrastructure

Liver biopsy revealed prominent bridging, septal fibrosis and widening of portal spaces, with prominent mixed inflammatory infiltrate, associated with interface hepatitis. Bile duct proliferation with numerous bile plugs was identified. The hepatic lobules show prominent cholestatic changes: extensive feathery degeneration with liver cell regenerative changes, rosettes formation and dilated canaliculi containing bile (see Fig. 1).

Electron microscopy revealed hepatocytes with a large number of

Discussion

We describe a patient with a unique clinical presentation of neonatal liver insufficiency, hypertyrosinemia who later developed neurological involvement typical of Leigh syndrome. A liver biopsy revealed reduced activities of complexes I + III and II + III of the respiratory chain. These changes can be caused by two mechanisms: 1. An isolated defect in complex III (subunits or assembly proteins), which is the electron acceptor from both pathways and 2. CoQ deficiency. Recently, De Lonlay et al. [2]

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Headache is a prominent feature in mitochondrial disorders (MIDs) but no comprehensive overview is currently available. This review aims at summarising and discussing findings concerning type, frequency, pathogenesis, and treatment of headache in MIDs.
The most frequent headache types in MIDs are migraine and migraine-like headache (MLH). MLH is classified as secondary headache. More rarely, tension-type headache, trigemino-autonomic headache, or different secondary headaches can be found. Migraine or MLH may manifest with or without aura. MLH is frequently associated with an ongoing or previous stroke-like episode (SLE) or a seizure but may also occur independently of other neurological features. MLH may be associated with prolonged aura or visual phenomena after headache. Except for MLH, treatment of headache in MIDs is not at variance from other causes of headache. Beyond the broadly accepted subtype-related headache treatment, diet, cofactors, vitamins, and antioxidants may provide a supplementary benefit. Midazolam, l-arginine, or l-citrulline may be beneficial for MLH. The pathogenesis of headache in MIDs largely remains unsolved. However, since migraine and MLH respond both to triptanes, a shared pathomechanism is likely.
In conclusion, migraine and MLH are the prominent headache types in MIDs. MLH may or may not be associated with current or previous SLEs. MLH is pathophysiologically different from migraine and requires treatment at variance from that of migraine with aura.
Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options
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Apart from neurological symptoms, non-neurological abnormalities can also be present, or may even predominate the clinical picture [41]. Non-neurological manifestations include cardiac abnormalities (mostly hypertrophic cardiomyopathy [1,85,111,133,145], but also dilated cardiomyopathy [72,133] and arrhythmia/conduction defects such as Wolff–Parkinson–White syndrome [97,123,133,136,163,169]), renal abnormalities (renal tubulopathy or diffuse glomerulocystic kidney damage [1,100,133,142,145,169]) hepatological abnormalities (structural abnormalities, elevated liver transaminases, hepatomegaly or liver failure [1,72,76,100,133,145]), other gastrointestinal symptoms (e.g., constipation, diarrhea, dysphagia, vomiting, gastritis, megacolon, intestinal paralysis [133]), and hematological abnormalities (particularly anemia [11,41,57,101,133]). Diabetes and short stature have also been reported [41].
Leigh syndrome is a progressive neurodegenerative disorder, affecting 1 in 40,000 live births. Most patients present with symptoms between the ages of three and twelve months, but adult onset Leigh syndrome has also been described. The disease course is characterized by a rapid deterioration of cognitive and motor functions, in most cases resulting in death due to respiratory failure. Despite the high genetic heterogeneity of Leigh syndrome, patients present with identical, symmetrical lesions in the basal ganglia or brainstem on MRI, while additional clinical manifestations and age of onset varies from case to case. To date, mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, have been shown to cause Leigh syndrome, still explaining only half of all cases. In most patients, these mutations directly or indirectly affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex. Exome sequencing has accelerated the discovery of new genes and pathways involved in Leigh syndrome, providing novel insights into the pathophysiological mechanisms. This is particularly important as no general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected. Timely, gene-based personalized treatment may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome, stressing the importance of early genetic diagnosis and identification of new genes/pathways. In this review, we provide a comprehensive overview of the most important clinical manifestations and genes/pathways involved in Leigh syndrome, and discuss the current state of therapeutic interventions in patients.
Hyperammonemic crisis in a child with ATP synthase deficiency caused by mtDNA mutation m.8851T>C
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The heterogenic symptoms include motor and intellectual developmental delay, bilateral brainstem disease, basal ganglia disease, elevated blood or CSF lactate levels, hypotonia, spasticity, chorea and other movement disorders, cerebellar ataxia, peripheral neuropathy, and respiratory failure secondary to brainstem dysfunction [35]. The condition may also affect the liver, heart (including hypertrophic cardiomyopathy), kidneys, and pancreas [38]. About 80% of MELAS cases are caused by a very common A3243G mutation in the mitochondrial tRNALeu(UUR) gene, whereas 10% of cases carry the T3271C mutation in the same tRNALeu(UUR) (Fig. 1), although other mtDNA point mutations have been also associated with this phenotype (MITOMAP).
Mitochondria are essential organelles within the cell where most of the energy production occurs by the oxidative phosphorylation system (OXPHOS). Critical components of the OXPHOS are encoded by the mitochondrial DNA (mtDNA) and therefore, mutations involving this genome can be deleterious to the cell. Post-mitotic tissues, such as muscle and brain, are most sensitive to mtDNA changes, due to their high energy requirements and non-proliferative status. It has been proposed that mtDNA biological features and location make it vulnerable to mutations, which accumulate over time. However, although the role of mtDNA damage has been conclusively connected to neuronal impairment in mitochondrial diseases, its role in age-related neurodegenerative diseases remains speculative. Here we review the pathophysiology of mtDNA mutations leading to neurodegeneration and discuss the insights obtained by studying mouse models of mtDNA dysfunction. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.
Ubiquinol-10 ameliorates mitochondrial encephalopathy associated with CoQ deficiency
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Notably, ubiquinol-10 was more powerful than ubiquinone-10 in reducing the histopathological changes in Coq9X/X mice, resulting in an increase in the body weight. These results are particularly important because patients with CoQ10 deficiency showed variable responses to ubiquinone-10 treatment and, in some cases, the treatment failed or did not show a clear response [31–40], which may be due to the reduced uptake of ubiquinone-10 [7]. Thus, our results suggest that ubiquinol-10 supplementation could improve the efficacy showed by ubiquinone-10 supplementation, which will be especially important in patients with encephalopathy or cerebellar ataxia associated to CoQ10 deficiency.
Coenzyme Q10 (CoQ₁₀) deficiency (MIM 607426) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ₁₀ deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model (Coq9^X/X) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ₁₀. Our results show that CoQ₁₀ was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ₁₀ with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ₁₀ in mitochondria from cerebrum of Coq9^X/X mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum–striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ₁₀ therapy in primary and secondary CoQ₁₀ deficiencies, other mitochondrial diseases and neurodegenerative diseases.
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Other associated neurological features include abnormalities in tone, muscle weakness, movement disorders, ataxia, tremor, peripheral neuropathy, central respiratory disturbance, bulbar symptoms (dysarthria, dysphagia), and abnormalities of thermoregulation (Lee et al., 2009; Rahman et al., 1996; Thorburn and Rahman, 2003). Extraneurologic features include diabetes, short stature, hypertrichosis, anemia, cardiomyopathy (hypertrophic or dilated), hepatomegaly, renal tubulopathy or diffuse glomerulocystic kidney damage, and optic atrophy, retinitis pigmentosa, and ophthalmoplegia to varying degrees (Agapitos et al., 1997; Lee et al., 2009; Leshinsky-Silver et al., 2003; Tay et al., 2005; Yamakawa et al., 2001). The course of illness is one of episodic deterioration interspersed with plateaus, during which development may be staple or even progress.
Leigh syndrome (LS) is a progressive neurodegenerative disease caused by either mitochondrial or nuclear DNA mutations resulting in dysfunctional mitochondrial energy metabolism. Mutations in genes encoding for subunits of the respiratory chain or assembly factors of respiratory chain complexes are often documented in LS cases. Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) enzyme deficiencies account for a significant proportion of mitochondrial disorders, including LS. In an attempt to expand the repertoire of known mutations accounting for LS, we describe the clinical, radiological, biochemical and molecular data of six patients with LS found to have novel mutations in two complex I subunits (NDUFV1 and NDUFS2). Two siblings were homozygous for the previously undescribed R386C mutation in NDUFV1, one patient was a compound heterozygote for the R386C mutation in NDUFV1 and a frameshift mutation in the same gene, one patient was a compound heterozygote for the R88G and R199P mutations in NDUFV1, and two siblings were compound heterozygotes for an undescribed E104A mutation in NDUFS2. After the novel mutations were identified, we employed prediction models using protein conservation analysis (SIFT, PolyPhen and UCSC genome browser) to determine pathogenicity. The R386C, R88G, R199P, and E104A mutations were found to be likely pathogenic, and thus presumably account for the LS phenotype. This case series broadens our understanding of the etiology of LS by identifying new molecular defects that can result in complex I deficiency and may assist in targeted diagnostics and/or prenatal diagnosis of LS in the future.

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Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency

Abstract

Introduction

Section snippets

Case report

Liver biopsy histology and ultrastructure

Discussion

J. Neurol. Sci.

FEMS Microbiol. Lett.

Lancet

Clin. Chim. Acta

A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure

Nat. Genet.

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familialCoQ10 deficiency

Neurology