Homozygous p.V116* mutation in<i>C12orf65</i>results in Leigh syndrome

Imagawa, Eri; Fattal‐Valevski, Aviva; Eyal, Ori; Miyatake, Satoko; Saada, Ann; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Miyake, Noriko; Matsumoto, Naomichi

doi:10.1136/jnnp-2014-310084

Cited by 12 publications

(9 citation statements)

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“…The same abnormalities were reported in previous cases, but histologic analysis had not been performed. 12 , 14 Pathologic analysis of the present patient showed bilateral rarefaction in part of the medial hypothalamus, mesencephalic tegmentum, pontine tegmentum, ventral medulla, and upper cervical spinal cord tissues, surrounded by mild gliosis. These tissues contained white matter and gray matter, which suggests that there is no association with specific anatomical tracts and structures.…”

Section: Discussionmentioning

confidence: 58%

Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction

et al. 2017

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Objective:To describe the autopsy case of a patient with a homozygous 2-base deletion, c171_172delGA (p.N58fs), in the C12orf65 gene.Methods:We described the clinical history, neuroimaging data, neuropathology, and genetic analysis of the patients with C12orf65 mutations.Results:The patient was a Japanese woman with a history of delayed psychomotor development, primary amenorrhea, and gait disturbance in her 20s. She was hospitalized because of respiratory failure at the age of 60. Pectus excavatum, long fingers and toes, and pes cavus were revealed by physical examination. Her IQ score was 44. Neurologic examination revealed ophthalmoplegia, optic atrophy, dysphagia, distal dominant muscle weakness and atrophy, hyperreflexia at patellar tendon reflex, hyporeflexia at Achilles tendon reflex, and extensor plantar reflexes. At age 60, she died of pneumonia. Lactate levels were elevated in the patient's serum and CSF. T2-weighted brain MRI showed symmetrical hyperintense brainstem lesions. At autopsy, axial sections exposed symmetrical cyst formation with brownish lesions in the upper spinal cord, ventral medulla, pons, dorsal midbrain, and medial hypothalamus. Microscopic analysis of these areas demonstrated mild gliosis with rarefaction. Cell bodies in the choroid plexuses were eosinophilic and swollen. Electron microscopic examination revealed that these cells contained numerous abnormal mitochondria. Whole-exome sequencing revealed the 2-base deletion in C12orf65.Conclusions:We report an autopsy case of the C12orf65 mutation, and findings suggest that mitochondrial dysfunction may underlie the unique clinical presentations.

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Section: Discussionmentioning

confidence: 58%

Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction

et al. 2017

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“…Growth hormone deficiency and/or short stature has also been documented in nuclear-encoded defects of mitochondrial translation, e.g. mutations in IARS2, MTFMT and C12orf65 [61][62][63] .…”

Section: Short Stature and Growth Hormone Deficiencymentioning

confidence: 99%

Mitochondrial disease and endocrine dysfunction

et al. 2016

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Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases.

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“…LS is an early-onset progressive MID, characterized by elevated lactate and pyruvate and bilateral symmetric hyperintense lesions in the basal ganglia, thalamus, brainstem, cerebral white matter, or spinal cord on T2-weighted MRI. [ 17 ] LS is the most frequent disorder of energy production in children. [ 18 ] Typical abnormalities on spinal MRI include bilaterally symmetric, high-signal alterations in the spinal cord.…”

Section: R Esultsmentioning

confidence: 99%

Involvement of the Spinal Cord in Mitochondrial Disorders

Finsterer

Zarrouk‐Mahjoub

2018

Journal of Neurosciences in Rural Practice

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This review aims at summarising and discussing the current status concerning the clinical presentation, pathogenesis, diagnosis, and treatment of spinal cord affection in mitochondrial disorders (MIDs). A literature search using the database Pubmed was carried out by application of appropriate search terms and their combinations. Involvement of the spinal cord in MIDs is more frequent than anticipated. It occurs in specific and non-specific MIDs. Among the specific MIDs it has been most frequently described in LBSL, LS, MERRF, KSS, IOSCA, MIRAS, and PCH and only rarely in MELAS, CPEO, and LHON. Clinically, spinal cord involvement manifests as monoparesis, paraparesis, quadruparesis, sensory disturbances, hypotonia, spasticity, urinary or defecation dysfunction, spinal column deformities, or as transverse syndrome. Diagnosing spinal cord involvement in MIDs requires a thoroughly taken history, clinical exam, and imaging studies. Additionally, transcranial magnetic stimulation, somato-sensory-evoked potentials, and cerebro-spinal fluid can be supportive. Treatment is generally not at variance compared to the underlying MID but occasionally surgical stabilisation of the spinal column may be necessary. It is concluded that spinal cord involvement in MIDs is more frequent than anticipated but may be missed if cerebral manifestations prevail. Spinal cord involvement in MIDs may strongly determine the mobility of these patients.

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Homozygous p.V116* mutation inC12orf65results in Leigh syndrome

Abstract: We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features, suggesting the involvement of unknown modifiers.

Cited by 12 publications

References 14 publications

Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction

Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction

Mitochondrial disease and endocrine dysfunction

Involvement of the Spinal Cord in Mitochondrial Disorders

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