A Case of Reversible Infantile Respiratory Chain Deficiency Presenting With Hypotonia, Hyperammonemia, and Failure to Thrive

2019 ◽  
Vol 22 (6) ◽  
pp. 590-593
Author(s):  
Jessenia C Guerrero ◽  
Helio Pedro ◽  
Sarah Parisotto ◽  
Debra Heller ◽  
Ada Baisre-de Leon
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Disorder ◽  
Failure To Thrive ◽  
Mitochondrial Myopathies ◽  
Genetic Syndrome ◽  
Respiratory Chain Deficiency ◽  
Presenting Symptoms ◽  
Molecular Studies ◽  
Severe Hypotonia

Reversible infantile respiratory chain deficiency, previously termed reversible infantile cytochrome c oxidase (COX) deficiency myopathy, is a rare mitochondrial disorder that is characterized by severe hypotonia and generalized muscle weakness in infancy that is associated with lactic acidosis. Affected infants will spontaneously recover, if they survive the first months of life. Here, we present the case of a 4-week-old girl who initially presented with hyperammonemia, hypotonia, and failure to thrive, for which she was referred for genetic evaluation. After several tests, a distinct genetic syndrome could not be identified and she continued to deteriorate. A muscle biopsy was performed and demonstrated severe mitochondrial myopathy with abundant COX-negative fibers. Ultrastructural abnormalities of the mitochondria, diagnostic of mitochondrial myopathy, were identified on electron microscopy. Molecular studies revealed the classic homoplasmic disease causing mutation, m.14674 T>C in the MT-TE gene, associated with reversible COX deficiency. Although hyperammonemia is an unusual presentation for mitochondrial myopathies, specifically reversible infantile respiratory chain deficiency, it should be included in the list of possible presenting symptoms for this condition.

scholarly journals Muscle biopsy essential diagnostic advice for pathologists

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ana Cotta ◽  
Elmano Carvalho ◽  
Antonio Lopes da-Cunha-Júnior ◽  
Jaquelin Valicek ◽  
Monica M. Navarro ◽  
...  
Keyword(s):  
Liquid Nitrogen ◽  
Muscle Biopsy ◽  
Diagnostic Procedures ◽  
Mitochondrial Respiratory Chain ◽  
Muscle Disease ◽  
Diagnostic Workup ◽  
Main Body ◽  
Mitochondrial Myopathies ◽  
Muscle Enzymes ◽  
Molecular Studies

Abstract Background Muscle biopsies are important diagnostic procedures in neuromuscular practice. Recent advances in genetic analysis have profoundly modified Myopathology diagnosis. Main body The main goals of this review are: (1) to describe muscle biopsy techniques for non specialists; (2) to provide practical information for the team involved in the diagnosis of muscle diseases; (3) to report fundamental rules for muscle biopsy site choice and adequacy; (4) to highlight the importance of liquid nitrogen in diagnostic workup. Routine techniques include: (1) histochemical stains and reactions; (2) immunohistochemistry and immunofluorescence; (3) electron microscopy; (4) mitochondrial respiratory chain enzymatic studies; and (5) molecular studies. The diagnosis of muscle disease is a challenge, as it should integrate data from different techniques. Conclusion Formalin-fixed paraffin embedded muscle samples alone almost always lead to inconclusive or unspecific results. Liquid nitrogen frozen muscle sections are imperative for neuromuscular diagnosis. Muscle biopsy interpretation is possible in the context of detailed clinical, neurophysiological, and serum muscle enzymes data. Muscle imaging studies are strongly recommended in the diagnostic workup. Muscle biopsy is useful for the differential diagnosis of immune mediated myopathies, muscular dystrophies, congenital myopathies, and mitochondrial myopathies. Muscle biopsy may confirm the pathogenicity of new gene variants, guide cost-effective molecular studies, and provide phenotypic diagnosis in doubtful cases. For some patients with mitochondrial myopathies, a definite molecular diagnosis may be achieved only if performed in DNA extracted from muscle tissue due to organ specific mutation load.

A novel homoplasmic mt-tRNAGlu m.14701C>T variant presenting with a partially reversible infantile respiratory chain deficiency

2021 ◽  
pp. 104306
Author(s):  
Alberte A. Lundquist ◽  
Stense Farholt ◽  
Malene L. Børresen ◽  
Morten Dunø ◽  
Flemming Wibrand ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Respiratory Chain Deficiency

Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

1992 ◽  
Vol 12 (2) ◽  
pp. 480-490
Author(s):  
M P King ◽  
Y Koga ◽  
M Davidson ◽  
E A Schon
Keyword(s):  
Steady State ◽  
Lactic Acidosis ◽  
Respiratory Chain ◽  
Mitochondrial Myopathy ◽  
Polyacrylamide Gel Electrophoresis ◽  
Mitochondrial Protein ◽  
Morphological Characteristics ◽  
Nucleotide Position ◽  
Mitochondrial Translation ◽  
Steady State Levels

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.

scholarly journals Detecting respiratory chain deficiency in osteoblasts of older patients

2021 ◽  
Author(s):  
Daniel Hipps ◽  
Philip Dobson ◽  
Charlotte Warren ◽  
David McDonald ◽  
Andrew Fuller ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mouse Model ◽  
Respiratory Chain ◽  
Nuclear Genome ◽  
Mitochondrial Dna Mutation ◽  
Human Osteoblasts ◽  
Dna Mutation ◽  
Respiratory Chain Deficiency ◽  
Age Related ◽  
Cellular Dysfunction

Mitochondria contain their own genome which encodes 13 essential mitochondrial proteins and accumulates somatic variants at up to 10 times the rate of the nuclear genome. These mitochondrial genome variants lead to respiratory chain deficiency and cellular dysfunction. Work with the PolgAmut/PolgAmut mouse model, which has a high mitochondrial DNA mutation rate, showed enhanced levels of age related osteoporosis in affected mice along with respiratory chain deficiency in osteoblasts. To explore whether respiratory chain deficiency is also seen in human osteoblasts with age, we developed a protocol and analysis framework for imaging mass cytometry (IMC) in bone tissue sections to analyse osteoblasts in situ. We have demonstrated significant increases in complex I deficiency with age in human osteoblasts. This work is consistent with findings from the PolgAmut/PolgAmut mouse model and suggests that respiratory chain deficiency, as a consequence of the accumulation of age related mitochondrial DNA mutations, may have a significant role to play in the pathogenesis of human age related osteoporosis.

scholarly journals Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency

2016 ◽  
Vol 98 (6) ◽  
pp. 1130-1145 ◽  
Author(s):  
Rikke K.J. Olsen ◽  
Eliška Koňaříková ◽  
Teresa A. Giancaspero ◽  
Signe Mosegaard ◽  
Veronika Boczonadi ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Respiratory Chain Deficiency

scholarly journals 1233 Mitochondrial Myopathy Making It Hard To Sleep! OSA management in Mitochondrial Myopathy with a variant in SNAPC4 and PURA genes

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A470-A471
Author(s):  
Ugorji Okorie ◽  
Brittany Monceaux ◽  
Megan Smalley ◽  
Edmond Roberts ◽  
Cesar Liendo ◽  
...  
Keyword(s):  
Mitochondrial Myopathy ◽  
Middle Eastern ◽  
Failure To Thrive ◽  
Standard Of Care ◽  
Sleep Medicine ◽  
Tube Placement ◽  
Arousal Index ◽  
Organ Systems ◽  
Titration Study

Abstract Introduction No standard of care exists for management of sleep disorders/sleep disordered breathing (SDB) and Mitochondrial myopathies. Our case report describes our experience with this condition in a pediatric patient. Report of Case A ten-year-old middle eastern male with PMH of Mitochondrial myopathy was referred to Sleep Medicine by ENT with reported snoring, witnessed apneic spells and daytime fatigue. Flexible Video Laryngoscopy did not reveal tonsillar or adenoid hypertrophy so it was postulated that his OSA was a result of his craniofacial abnormalities and global hypotonia. Genetic workup showed Mitochondrial complex II & III deficiency from a variant in SNAPC4 gene and PURA gene leading to failure to thrive, severe developmental delay, generalized muscle weakness, bradycardia requiring pacemaker, global hypotonia requiring nocturnal oxygen for chronic respiratory failure and G-tube placement due to difficulty with feedings. Diagnostic PSG showed severe OSA with AHI of 11.3, RDI 11.8, REM AHI 56.0, REM RDI 56, and minimum oxygen saturation 85%. Subsequent PAP titration led to initiation of BIPAP therapy with settings of Auto-BiPAP EPAP min 5, IPAP max 20; PSmin 4; PSmax 6 cm H2O and continuation of nocturnal home oxygen. Sleep fragmentation improved to an arousal index of 3.1 with BIPAP. The patient and caregiver presented to the Sleep Medicine clinic 1 month after the PAP titration study with objective report showing >4 hours use >70% of the time and subjective satisfaction with BIPAP therapy with improvement in snoring and apnea. Conclusion Mitochondrial disorders lead to a deficiency of ATP affecting all organ systems and is most recognizable in the form of neuromuscular impairments. Neuromuscular impairments can translate into SDB issues such as OSA. Patients with genetic conditions such as mitochondrial myopathy should be routinely screened and evaluated for SDB and treated if warranted to significantly improve morbidity, mortality and quality of life.

Mitochondrial Myopathies Involving the Respiratory Chain: A Biochemical Analysis

1986 ◽  
Vol 488 (1 Membrane Path) ◽  
pp. 33-43 ◽  
Author(s):  
S. TAKAMIYA ◽  
W. YANAMURA ◽  
R. A. CAPALDI ◽  
N. G. KENNAWAY ◽  
R. BART ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Biochemical Analysis ◽  
Mitochondrial Myopathies

scholarly journals Mitochondrial disease: an uncommon but important cause of diabetes mellitus

2018 ◽  
Vol 2018 ◽  
Author(s):  
Ming Li Yee ◽  
Rosemary Wong ◽  
Mineesh Datta ◽  
Timothy Nicholas Fazio ◽  
Mina Mohammad Ebrahim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Weight Loss ◽  
Lactic Acidosis ◽  
Superior Mesenteric Artery ◽  
Mesenteric Artery ◽  
Mitochondrial Disorder ◽  
Superior Mesenteric Artery Syndrome ◽  
List Type ◽  
Presenting Symptoms ◽  
History Of

Summary Mitochondrial diseases are rare, heterogeneous conditions affecting organs dependent on high aerobic metabolism. Presenting symptoms and signs vary depending on the mutation and mutant protein load. Diabetes mellitus is the most common endocrinopathy, and recognition of these patients is important due to its impact on management and screening of family members. In particular, glycemic management differs in these patients: the use of metformin is avoided because of the risk of lactic acidosis. We describe a patient who presented with gradual weight loss and an acute presentation of hyperglycemia complicated by the superior mesenteric artery syndrome. His maternal history of diabetes and deafness and a personal history of hearing impairment led to the diagnosis of a mitochondrial disorder. Learning points: The constellation of diabetes, multi-organ involvement and maternal inheritance should prompt consideration of a mitochondrial disorder. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) are the most common mitochondrial diabetes disorders caused by a mutation in m.3243A>G in 80% of cases. Metformin should be avoided due to the risk of lactic acidosis. There is more rapid progression to insulin therapy and higher prevalence of diabetic complications compared to type 2 diabetes. Diagnosis of a mitochondrial disorder leads to family screening, education and surveillance for future complications. Superior mesenteric artery syndrome, an uncommon but important cause of intestinal pseudo-obstruction in cases of significant weight loss, has been reported in MELAS patients.

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