Leigh syndrome-like MRI changes in a patient with biallelic HPDL variants treated with ketogenic diet

Numata‐Uematsu, Yurika; Uematsu, Mitsugu; Yamamoto, Toshiyuki; Saitsu, Hirotomo; Katata, Yu; Oikawa, Yoshitsugu; Saijyo, Naoya; Inui, Tomoyuki; Murayama, Kei; Ohtake, Akira; Osaka, Hitoshi; Takanashi, Jun ichi; Kure, Shigeo; Inoue, Ken

doi:10.1016/j.ymgmr.2021.100800

Cited by 7 publications

(3 citation statements)

References 9 publications

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“…Cerebellar atrophy and bilateral inferior olivary hyperintensities on T2-weighted MRI images were shown for the intermediate phenotype. One individual with a severe phenotype presented with an MRI consistent with Leigh syndrome, and MR spectroscopy showed a lactate peak [ 62 ].…”

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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Section: Resultsmentioning

confidence: 99%

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

et al. 2023

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“…The pedigrees of both patients with the detected genotypes and a schematic of the HPDL protein with all the mutations reported so far in the HPDL -related disease patients ( Ghosh et al, 2020 ; Husain et al, 2020 ; Morgan et al, 2021 ; Numata-Uematsu et al, 2021 ; Sun et al, 2021 ; Wiessner et al, 2021 ; Yu et al, 2021 ) is provided in the Figure 2 .…”

Section: Hpdl Variantsmentioning

confidence: 99%

“…Pedigree of proband 1 (A) and proband 2 (B) with the harboured genotypes. Schematic of the HPDL protein and different disease-associated variants published so far (C) ( Ghosh et al, 2020 ; Husain et al, 2020 ; Morgan et al, 2021 ; Numata-Uematsu et al, 2021 ; Sun et al, 2021 ; Wiessner et al, 2021 ; Yu et al, 2021 ). MTS, mitochondrial targeting sequence; Fe BS, iron binding site; variants reported in this manuscript are indicated in bold.…”

Section: Hpdl Variantsmentioning

confidence: 99%

Case Report: Two Families With HPDL Related Neurodegeneration

et al. 2022

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There are recent reports of associations of variants in the HPDL gene with a hereditary neurological disease that presents with a wide spectrum of clinical severity, ranging from severe neonatal encephalopathy with no psychomotor development to adolescent-onset uncomplicated spastic paraplegia. Here, we report two probands from unrelated families presenting with severe and intermediate variations of the clinical course. A homozygous variant in the HPDL gene was detected in each proband; however, there was no known parental consanguinity. We also highlight reductions in citrate synthase and mitochondrial complex I activity detected in both probands in different tissues, reflecting the previously proposed mitochondrial nature of disease pathogenesis associated with HPDL mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.

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