Case Report: Two Families With HPDL Related Neurodegeneration

Mičule, Ieva; Lāce, Baiba; Wright, Nathan T.; Chrestian, Nicolas; Strautmanis, Jurgis; Dīriks, Mikus; Stavusis, Janis; Kidere, Dita; Kleina, Elfa; Zdanovica, Anna; Laflamme, Nataly; Rioux, Nadie; Setty, Samarth Thonta; Pajusalu, Sander; Droit, Arnaud; Lek, Monkol; Rivest, Serge; Inashkina, Inna

doi:10.3389/fgene.2022.780764

Cited by 6 publications

(4 citation statements)

References 18 publications

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“…In 2022, Micule et al described two individuals with disease-causing HPDL variants [ 64 ]. One child presented with muscular hypertonia, seizures and regression at the age of 6 weeks.…”

Section: Resultsmentioning

confidence: 99%

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

et al. 2023

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Coenzyme Q10 (CoQ10) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ10 supply (redox homeostasis, ferroptosis and sulfide oxidation). The CoQ10 biosynthesis pathway consists of several enzymes, which are encoded by the nuclear DNA. The majority of these enzymes are responsible for modifications of the CoQ-head group (benzoquinone ring). Only three enzymes (PDSS1, PDSS2 and COQ2) are required for assembly and attachment of the polyisoprenoid side chain. The head-modifying enzymes may assemble into resolvable domains, representing COQ complexes. During the last two decades, numerous inborn errors in CoQ10 biosynthesis enzymes have been identified. Thus far, 11 disease genes are known (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9 and HPDL). Disease onset is highly variable and ranges from the neonatal period to late adulthood. CoQ10 deficiency exerts detrimental effects on the nervous system. Potential consequences are neuronal death, neuroinflammation and cerebral gliosis. Clinical features include encephalopathy, regression, movement disorders, epilepsy and intellectual disability. Brain magnetic resonance imaging (MRI) is the most important tool for diagnostic evaluation of neurological damage in individuals with CoQ10 deficiency. However, due to the rarity of the different gene defects, information on disease manifestations within the central nervous system is scarce. This review aims to provide an overview of brain MRI patterns observed in primary CoQ10 biosynthesis disorders and to highlight disease-specific findings.

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“…In 2022, Micule et al described two individuals with disease-causing HPDL variants [ 64 ]. One child presented with muscular hypertonia, seizures and regression at the age of 6 weeks.…”

Section: Resultsmentioning

confidence: 99%

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

et al. 2023

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“…Numerous studies have associated the HPDL gene with a broad range of neurodegenerative phenotypes across various clinical scenarios. The reported cases include individuals who exhibited symptoms spanning from neonatal encephalopathy to adolescent-onset uncomplicated spastic paraplegia [27].…”

Section: Resultsmentioning

confidence: 99%

Machine Learning Analysis of Alzheimer’s Disease Single-Cell RNA-Sequencing Data across Cortex and Hippocampus Regions

Krokidis,

Vrahatis,

Lazaros

et al. 2023

CIMB

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Advancements in molecular biology have revolutionized our understanding of complex diseases, with Alzheimer’s disease being a prime example. Single-cell sequencing, currently the most suitable technology, facilitates profoundly detailed disease analysis at the cellular level. Prior research has established that the pathology of Alzheimer’s disease varies across different brain regions and cell types. In parallel, only machine learning has the capacity to address the myriad challenges presented by such studies, where the integration of large-scale data and numerous experiments is required to extract meaningful knowledge. Our methodology utilizes single-cell RNA sequencing data from healthy and Alzheimer’s disease (AD) samples, focused on the cortex and hippocampus regions in mice. We designed three distinct case studies and implemented an ensemble feature selection approach through machine learning, also performing an analysis of distinct age-related datasets to unravel age-specific effects, showing differential gene expression patterns within each condition. Important evidence was reported, such as enrichment in central nervous system development and regulation of oligodendrocyte differentiation between the hippocampus and cortex of 6-month-old AD mice as well as regulation of epinephrine secretion and dendritic spine morphogenesis in 15-month-old AD mice. Our outcomes from all three of our case studies illustrate the capacity of machine learning strategies when applied to single-cell data, revealing critical insights into Alzheimer’s disease.

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“…Whilst not part of the COQ1–COQ10 gene mutation series described above, the enzyme 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) has also been shown to have a role in CoQ10 biosynthesis [ 99 ]. Patients with HPDL deficiency have been reported by Husain et al (17 individuals, [ 100 ]), Wiessner et al (34 individuals, [ 101 ]), Wang et al (1 individual, [ 102 ]), and Micule et al (2 individuals, [ 103 ]). The patient ages in these studies ranged from 6 months to 39 years; the clinical presentation typically included development delay, seizures, and spasticity.…”

Section: Clinical Studies Relating To Coq Gene Mutationsmentioning

confidence: 99%

“…Whilst not part of the COQ1-COQ10 gene mutation series described above, the enzyme 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) has also been shown to have a role in CoQ10 biosynthesis [99] [103]). The patient ages in these studies ranged from 6 months to 39 years; the clinical presentation typically included development delay, seizures, and spasticity.…”

Section: Hpdl Deficiencymentioning

confidence: 99%

Primary Coenzyme Q10 Deficiency: An Update

Mantle,

Millichap,

Castro-Marrero

et al. 2023

Antioxidants

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Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extra-mitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant and plays an important role in fatty acid beta-oxidation and pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. Due to the multiplicity of roles in cell function, it is not surprising that a deficiency in CoQ10 has been implicated in the pathogenesis of a wide range of disorders. CoQ10 deficiency is broadly divided into primary and secondary types. Primary CoQ10 deficiency results from mutations in genes involved in the CoQ10 biosynthetic pathway. In man, at least 10 genes are required for the biosynthesis of functional CoQ10, a mutation in any one of which can result in a deficit in CoQ10 status. Patients may respond well to oral CoQ10 supplementation, although the condition must be recognised sufficiently early, before irreversible tissue damage has occurred. In this article, we have reviewed clinical studies (up to March 2023) relating to the identification of these deficiencies, and the therapeutic outcomes of CoQ10 supplementation; we have attempted to resolve the disparities between previous review articles regarding the usefulness or otherwise of CoQ10 supplementation in these disorders. In addition, we have highlighted several of the potential problems relating to CoQ10 supplementation in primary CoQ10 deficiency, as well as identifying unresolved issues relating to these disorders that require further research.

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Case Report: Two Families With HPDL Related Neurodegeneration

Cited by 6 publications

References 18 publications

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

Machine Learning Analysis of Alzheimer’s Disease Single-Cell RNA-Sequencing Data across Cortex and Hippocampus Regions

Primary Coenzyme Q10 Deficiency: An Update

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