Ears of the Lynx on Neuroimaging in a Patient with COQ4‐Associated Hereditary Spastic Paraplegia

遗传性痉挛性截瘫 截瘫 神经影像学 神经科学 痉挛的 心理学 医学 物理医学与康复 脑瘫 生物 遗传学 脊髓 表型 基因
作者
Zhe Yu,Rongfei Wang,Shengyuan Yu,Xiangqing Wang
出处
期刊:Movement Disorders Clinical Practice [Wiley]
标识
DOI:10.1002/mdc3.14282
摘要

Hereditary spastic paraplegia (HSP) is a group of neurological disorders with heterogeneous clinical manifestations. The core symptoms are bilateral lower limb spasticity, hyperreflexia, and gait disturbances.1 Primary Coenzyme Q10 (CoQ10) deficiency is considered to be a rare mitochondrial disease with a wide range of clinical manifestations.2, 3 Coenzyme Q4 (COQ4) encodes the protein involved in the CoQ10 production, and COQ4 variants can lead to CoQ10 deficiency.2, 4 In the previous cases, the COQ4 mutations usually lead to a fatal early-onset multi-organ disease.2, 4 We read with great interest recent research articles investigating the association between COQ4 variants and HSP.5-7 Herein, we report a case of COQ4 mutation presenting with HSP that exhibited a novel neuroimaging pattern. A 17-year-old boy presented with progressive gait instability, frequent falls, and cognitive impairment for over 8 years. Neurological evaluation revealed lower-limb spasticity, brisk knee tendon reflexes, ankle clonus, and bilateral Babinski signs. Cognitive tests were performed using the Mini-Mental State Examination, scoring 21/30, and the Montreal Cognitive Assessment, scoring 19/30. Brain magnetic resonance imaging (MRI) scans showed the "ears of the lynx" sign, with no signs of cerebellar atrophy or thin corpus callosum (Fig. 1A–C). Whole-exome sequencing revealed compound heterozygous COQ4 mutations, c.472C > T and c.745C > T(Fig. 1D,E), in the patient and his 2-year-old sister, who also presented with gait instability. Any large deletions or duplications of SPAST, ATL1, REEP1, SPG7, and SPG11 were not found using the MLPA analysis. The c.472C > T variant resulted in a different amino acid change (p.Arg158Trp) at the same codon as that reported for the c.473G > A variant (p.Arg158Gln).6 The c.745C > T variant was recently reported by Lin et al.5 Our patient's serum CoQ10 was measured using ultra-high-performance liquid chromatography (1290II UHPLC system, Agilent, USA),8 and his level (0.45 μmol/L) was lower than that of healthy controls (the reference interval for plasma or serum CoQ10 is approximately 0.5–1.7 μmol/L).8 The skin biopsy was refused by his parents. CoQ10 supplementation was initiated at 30 mg/d. After it was ensured that the boy did not have any adverse effects, the CoQ10 dosage was increased to 400 mg/d. He reported that clinical symptoms partially improved with fewer falls at the 4-month follow-up. The Scale for the Assessment and Rating of Ataxia (SARA) was assessed and showed a one-point improvement after treatment. Periventricular white matter changes have been observed in autosomal recessive HSP.9 The "ears of the lynx" MRI sign, which indicates abnormalities in the forceps minor region, has shown high specificity and sensitivity for patients with SPG11 and SPG15 mutations.10 To date, a total of 13 patients with COQ4 mutation–associated HSP have been reported. One patient had cerebellar vermis hypoplasia on brain MRI, and another patient had bilateral hippocampal sclerosis. Three patients underwent spinal MRI, and one patient had thin thoracic cord sign.5-7 The current case presented with the "ears of the lynx" sign on brain MRI, which has not been reported in this subtype. The mild cognitive dysfunction with executive function impairment in this patient was consistent with a previous study showing that the abnormal signals in the forceps minor could account for the executive function deficits commonly described in HSP.9 Additionally, our case suggests that the "ears of the lynx" sign may indicate a genetic disorder in a patient with progressive spastic paraplegia or cognitive impairment.10 More than 80 different genes associated with HSP have been identified.11 Among these, the COQ4 mutation is relatively new, and its clinical spectrum and treatments have not been well studied. CoQ10 supplementation has been reported to be partially effective in some patients with CoQ10 deficiency.2 In previous studies, although all 13 patients with COQ4 mutation–associated HSP started CoQ10 supplementation, follow-up was reported in only one patient with no abnormal improvement.5-7 Our patient reported improvement with fewer falls after CoQ10 supplementation, and the SARA scales showed a one-point improvement. The efficacy of CoQ10 supplementation in patients with COQ4 mutation–associated HSP needs to be clarified in future studies. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Data analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique. Z.Y.: 1A, 1C, 2A, 2B, 2C, 3A R.F.W.: 1A, 1C, 2B, 2C, 3B Y.S.Y.: 1A, 1B, 3B X.Q.W.: 1A, 1B, 3B We thank the patient and his family for granting permission to publish this information. Ethical Compliance Statement: The study was approved by the Ethical Committee of the Chinese PLA General Hospital. The written informed consent with was obtained from the patient and his family. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: This work was partly supported by national key R&D program of China 2022YFC2703600. We declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors report no financial disclosures relevant to the manuscript.

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