Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Garone Caterina,Tadesse Saba,Hirano Michio Brain : a journal of neurology Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (<10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11-59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A>G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype-phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan-Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation. 10.1093/brain/awr245

Mitochondrial neurogastrointestinal encephalomyopathy associated with progressive hearing loss. Hiraki N,Udaka T,Yamamoto H,Kadokawa Y,Ohkubo J,Suzuki H The Journal of laryngology and otology OBJECTIVE:We report a rare case of mitochondrial neurogastrointestinal encephalomyopathy with hearing loss. CASE REPORT:A 46-year-old woman presented with a three-year history of progressive, bilateral hearing loss and tinnitus. She had been suffering from unexplained abdominal pain and diarrhoea for 20 years. When first seen, her otoscopic findings were normal, and pure tone audiometry showed mild and moderate hearing loss in her right and left ears, respectively. She also had: bilateral ophthalmoparesis, neck and limb muscle weakness, and hypoactive deep tendon reflexes on neurological examination; diffuse leukoencephalopathy on magnetic resonance imaging of the brain; and markedly reduced leukocyte thymidine phosphorylase activity. On the basis of these findings, the patient was diagnosed with mitochondrial neurogastrointestinal encephalomyopathy. CONCLUSION:Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disease caused by mutation of the thymidine phosphorylase gene, and is characterised by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, gastrointestinal symptoms and abnormal mitochondria in muscle cells. Current advances in genetic research may reveal a higher prevalence of mitochondrial disorders than had previously been thought. Otolaryngologists should be aware of mitochondrial neurogastrointestinal encephalomyopathy and other rare genetic disorders when managing patients with progressive hearing loss. 10.1017/S0022215110001477

ENT characteristics and therapeutic results in multisystemic disorders of mitochondrial encephalomyopathy. European journal of medical research Here we report the evaluation of the frequency of subjective and objective otolaryngologic findings and therapeutic results in 32 patients with mitochondrial encephalomyopathy (MEM) from September 2001 to June 2021. Our analysis included studying the patients' family histories, the clinical manifestations of MEM, and the therapeutic effects of treatments. The patients' ages ranged from 2 to 77 years, with a median age of 12.3 years. We found that MEM ENT symptoms were characterized by hearing loss, dysphagia, and facial weakness. Most cases of sensorineural hearing loss were bilateral symmetrical progressive or sudden deafness since adolescence, which were often underestimated. Associated neuromuscular symptoms required mtDNA testing. Dysphagia and facial weakness occurred preferentially in middle-aged patients, and muscle biopsies were advised. Distortion product otoacoustic emissions and auditory brainstem responsetesting were more sensitive and reliable than pure tone averages for objective monitoring of pathogenesis. Administration of the mitochondrial synthase complex benefited patients with acute episodes. If patients did not fully recover and exhibitedresidual language deficits, hearing aids or cochlear implants were recommended. Counsel was given regarding synthetical treatments for facial weakness, endoscopic circopharyngealmyotomy for dysphagia, and surgical correction of ptosis. This study demonstrates that increased awareness of these symptoms is important to address appropriate interventions and avoid complications such as ablepsia, aphasia, social isolation, malnutrition, aspiration pneumonia, and heart failure in the setting of MEM. 10.1186/s40001-022-00832-7