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Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature.

ABSTRACT: We report about a patient with infantile-onset neurodegenerative disease associated with isolated mitochondrial respiratory chain complex III (cIII) deficiency. The boy, now 13 years old, presented with language regression and ataxia at 4 years of age and then showed a progressive course resulting in the loss of autonomous gait and speaking during the following 2 years. Brain MRI disclosed bilateral striatal necrosis. Sequencing of a panel containing nuclear genes associated with cIII deficiency revealed a previously undescribed homozygous rearrangement (c.782_786delinsGAAAAG) in TTC19 gene, which results in a frameshift with premature termination (p.Glu261Glyfs(*)8). TTC19 protein was absent in patient's fibroblasts. TTC19 encodes tetratricopeptide 19, a putative assembly factor for cIII. To date TTC19 mutations have been reported only in few cases, invariably associated with cIII deficiency, but presenting heterogeneous clinical phenotypes. We reviewed the genetic, biochemical, clinical and neuroradiological features of TTC19 mutant patients described to date.

SUBMITTER: Ardissone A

PROVIDER: S-EPMC4486273 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature.

Ardissone Anna A Granata Tiziana T Legati Andrea A Diodato Daria D Melchionda Laura L Lamantea Eleonora E Garavaglia Barbara B Ghezzi Daniele D Moroni Isabella I

JIMD reports 20150313

We report about a patient with infantile-onset neurodegenerative disease associated with isolated mitochondrial respiratory chain complex III (cIII) deficiency. The boy, now 13 years old, presented with language regression and ataxia at 4 years of age and then showed a progressive course resulting in the loss of autonomous gait and speaking during the following 2 years. Brain MRI disclosed bilateral striatal necrosis. Sequencing of a panel containing nuclear genes associated with cIII deficiency ...[more]

PMID: 25772319

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Project description:Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations. It can be difficult to differentiate with other diseases such as 21-hydroxylase deficiency (21-OHD), polycystic ovary syndrome (PCOS) and Antley-Bixler syndrome (ABS). Nearly 100 cases of PORD have been reported worldwide. However, the genetic characters and clinical management are still unclear, especially in China.In this study, we report a 27-year-old female Chinese patient who first presented with amenorrhea and recurrence of large ovary cyst. She was misdiagnosed with PCOS and non-classical 21-OHD due to ovary cysts and elevated 17-hydroxy-progesterone. The patient's complaining of a mild difficulty of bending the metacarpophalangeal joints reminded us to consider PORD, which usually presents with skeletal deformities and sexual dysfunction. The diagnosis of PORD was confirmed by genetic analyses, which showed the patient harboring a homozygous missense mutation in the POR gene (R457H) and her parents carrying the heterozygous mutation. The patient was treated with low-dose corticosteroids and estrogen/progesterone sequential therapy, and her ovarian cyst gradually reduced with regular menstruation in the follow-up. Moreover, the clinical and genetic characteristics of 104 previously reported PORD cases were also summarized and analyzed.PORD is a very rare disease which can be easily misdiagnosed in mild cases. Clinicians should keep in mind of this disease in patients with sexual dysfunction, especially combined with special skeletal deformities. Our data could provide a consciously understanding of this disease for clinic practicers. Low-dose corticosteroids combined with estrogen/progesterone sequential therapy will be effective in PORD patients with recurrence of large ovary cyst. The fact that the reported PORD patients in China carrying an identical variant R457H in POR gene also give us a viewpoint that R457H mutation in POR gene maybe important in causing PORD in Chinese as same as in Japanese.

Project description:ObjectiveNoonan syndrome (NS), an autosomal dominant disease known as a RASopathy, is caused by germline mutations in mitogen-activated protein kinase pathway genes. A RIT1 gene mutation has been found to cause NS. The present study summarizes RIT1 gene mutation sites and associated clinical phenotypes.MethodsWe retrospectively analyzed the clinical characteristics of a case of NS caused by RIT1 mutation in our hospital, and searched the PubMed database, China National Knowledge Infrastructure (CNKI) database and Wanfang database with the keywords Noonan syndrome and RIT1. Studies published between May 1, 2014 and July 1, 2021 were retrieved. By reviewing the abstracts and full text of the studies, we screened NS cases associated with RIT1 mutation in children 0-18 years of age. The clinical characteristics of these cases were summarized.ResultsA total of 41 cases were analyzed, including 13 boys and 28 girls. There were 14 premature cases. The age at diagnosis was 4 days to 18 years, and 10 cases were diagnosed at 0-1 years of age. Common amino acid substitution positions included 57 (13/41), 95 (7/41), 82 (8/41), and 90 (4/41). A total of 63.63% cases had abnormal prenatal examination results, manifesting mainly as fetal neck edema, polyhydramnios and cardiac malformation. With respect to abnormal conditions after birth, 70-80% of patients had typical developmental malformations of the face, neck and thorax; 19/35 patients had abnormal lymphatic development; and a portion of patients had short stature and motor development disorders. A total of 87.80% (36/41) patients had cardiac dysplasia, among which hypertrophic cardiomyopathy (HCM) accounted for 58.53%. A total of 84.62% of patients carrying the p.A57G mutation had HCM, but no HCM was found in patients with the p.G95A mutation. A total of 34.15% of patients had pulmonary artery or pulmonary valve stenosis (PVS). In patients with the p.M90I mutation, 75% had PVS. Patients with concurrent HCM and PVS accounted for 19.51 and 48.78% of patients had supraventricular tachycardia.ConclusionA RIT1 gene mutation causing NS was associated with a high rate of abnormal prenatal examination findings. Most patients had typical NS craniofacial deformities, and some have short stature and motor development disorders. The cardiac deformity rate was high, and HCM was common. Some patients had supraventricular arrhythmias. Heart abnormalities showed high heterogeneity, given the various mutation loci.

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Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature.

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Mitochondrial Complex III Deficiency Caused by TTC19 Defects: Report of a Novel Mutation and Review of Literature.

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