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Mitochondrial Neurogastrointestinal Encephalomyopathy

TYMP-Related MNGIE


Presentation

  • The disease presents in childhood, but often goes unnoticed for decades.[en.wikipedia.org]
  • We present the first detailed report of a Brazilian MNGIE patient, harboring a novel ECGF1 homozygous mutation (C4202A, leading to a premature stop codon, S471X). Multiple deletions and the T5814C change were found in mitochondrial DNA.[ncbi.nlm.nih.gov]
Sepsis
  • The average age of death is 35 years (range 15–54 years) and identified causes included: pneumonia due to aspiration (eight patients); peritonitis due to intestinal rupture (two patients); suicide (two patients); electrolyte imbalance (two patients); sepsis[brain.oxfordjournals.org]
Whipple Disease
Respiratory Distress
  • However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock.[ncbi.nlm.nih.gov]
Nausea
  • MNGIE is clinically characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea) with intestinal dysmotility, and histologically abnormal mitochondria in muscle.[ncbi.nlm.nih.gov]
  • Additionally, gastrointestinal symptoms such as borborygmi, early satiety, diarrhea, constipation, gastroparesis, nausea, vomiting, weight loss, and diverticulitis may be present in MNGIE patients.[en.wikipedia.org]
  • The main symptoms of Mitochondrial Neurogastrointestinal Encephalopathy Disease are progressive gastrointestinal symptoms such as nausea, inability to swallow, reflux, vomiting, abdominal pain and diarrhea.[thinkgenetic.com]
  • These symptoms included: diarrhoea (11/36); abdominal pain (8/36); nausea/vomiting (6/36); abdominal cramps (6/36); weight loss (4/36); borborygmi (3/36); wasting/failure to thrive/thin (2/36); intestinal pseudo-obstruction (2/36); bloating (1/36); and[brain.oxfordjournals.org]
Abdominal Pain
  • Back to: « Mitochondrial DNA depletion syndrome Symptoms of Mitochondrial DNA depletion syndrome type 1 Clinical features : Imported from Human Phenotype Ontology (HPO) Abnormality of the abdomen Abdominal pain Constipation Gastrointestinal dysmotility[familydiagnosis.com]
  • The main symptoms of Mitochondrial Neurogastrointestinal Encephalopathy Disease are progressive gastrointestinal symptoms such as nausea, inability to swallow, reflux, vomiting, abdominal pain and diarrhea.[thinkgenetic.com]
  • Added to this are gastroparesis, constipation, vomiting, and intermittent diarrhea with abdominal pain. Many individuals develop diverticulosis and diverticulitis that may lead to intestinal perforations.[disorders.eyes.arizona.edu]
  • The symptoms that affected patients present vary, but the most common presenting symptoms are gastrointestinal issues such as nausea, vomiting, abdominal pain, and diarrhea, and neurologic or ocular symptoms such as hearing loss, weakness, and peripheral[en.wikipedia.org]
  • These symptoms included: diarrhoea (11/36); abdominal pain (8/36); nausea/vomiting (6/36); abdominal cramps (6/36); weight loss (4/36); borborygmi (3/36); wasting/failure to thrive/thin (2/36); intestinal pseudo-obstruction (2/36); bloating (1/36); and[brain.oxfordjournals.org]
Abdominal Cramps
  • The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged.[ncbi.nlm.nih.gov]
  • These symptoms included: diarrhoea (11/36); abdominal pain (8/36); nausea/vomiting (6/36); abdominal cramps (6/36); weight loss (4/36); borborygmi (3/36); wasting/failure to thrive/thin (2/36); intestinal pseudo-obstruction (2/36); bloating (1/36); and[brain.oxfordjournals.org]
Borborygmi
  • Additionally, gastrointestinal symptoms such as borborygmi, early satiety, diarrhea, constipation, gastroparesis, nausea, vomiting, weight loss, and diverticulitis may be present in MNGIE patients.[en.wikipedia.org]
  • These symptoms included: diarrhoea (11/36); abdominal pain (8/36); nausea/vomiting (6/36); abdominal cramps (6/36); weight loss (4/36); borborygmi (3/36); wasting/failure to thrive/thin (2/36); intestinal pseudo-obstruction (2/36); bloating (1/36); and[brain.oxfordjournals.org]
Abdominal Distension
  • Case 2: This 6½-month-old boy born to a non-consanguineous couple presented with persistent jaundice and abdominal distension since four months of age.[indianpediatrics.net]
Kinky Hair
  • Danks DM, Cartwright E, Stevens BJ, Townley RRW (1973) Menkes' kinky hair disease: further definition of the defect in copper transport. Science 179:1140–1142 Google Scholar 6.[doi.org]
Leg Cramp
  • In our cohort, 9/63 (14%) patients presented with: peripheral neuropathy manifesting as numbness or foot drop (5/9); limb weakness and paraesthesia (1/9); leg cramps (1/9); tripping (1/9); or hearing loss (1/9).[brain.oxfordjournals.org]
Arthritis
  • In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance[ncbi.nlm.nih.gov]
Hearing Impairment
  • The disease can cause the slowing down of thoughts and a reduction in physical movement, hearing impairment and seizures.[thesun.co.uk]
  • Hearing impairment associated to severe encephalomyopathy has been only reported in one family with MDS caused by SUCLA2 mutations ( 14 ).[nature.com]
  • impairment and ophthalmoplegia [ 6 ].[ijponline.biomedcentral.com]
Tinnitus
  • Other initial symptoms have sporadically been reported in some (6/63, 10%) patients: dry mouth and tinnitus (1/6); tinnitus (2/6); or myopathy (3/6 with exercise intolerance or weakness).[brain.oxfordjournals.org]
Psychiatric Manifestation
  • A small number of patients reported depression (four patients) or anxiety (two patients), but it is unclear whether these psychiatric manifestations are due to CNS involvement or secondary reactions to the disease.[brain.oxfordjournals.org]
Amenorrhea
  • Malnutrition caused anaemia in four patients and amenorrhea in two patients. Other sporadic findings included: pigmentary retinopathy (three patients); dry mouth/eyes (three patients); psoriasis (one patient); and coarse bronze skin (one patient).[brain.oxfordjournals.org]
Areflexia
  • The myopathic form is characterized by progressive weakness, hypotonia, areflexia, and respiratory failure before 10 years of age.[pediatricneurologybriefs.com]
Trigeminal Neuralgia
  • To our knowledge, this is the first case in the literature of MNGIE with trigeminal neuralgia. An analogy is suggested between multiple sclerosis and MNGIE as a cause for trigeminal neuralgia in this patient.[ncbi.nlm.nih.gov]
Cranial Neuropathy
  • This finding may also explain the cranial neuropathies that patients with MNGIE have.[ncbi.nlm.nih.gov]

Workup

  • His weight was 6 kg and height was 60 cm (both His metabolic workup, including screening for Galactosemia, Tyrosinemia type 1, amino acids, organic acids and fatty acid oxidation defects, was normal. Plasma lactate was elevated on several occasions.[indianpediatrics.net]
Amylase Increased
  • The clinical course was complicated by an endocrine or exocrine pancreatic insufficiency in nine patients: diabetes (four patients); amylase increase (two patients); glucose intolerance (one patient); or exocrine insufficiency (two patients).[brain.oxfordjournals.org]
Prolonged QT Interval
  • Uncommon clinical features included short stature (five patients) and cardiopathy (three patients with prolonged QT interval, cardiac arrest or supraventricular tachycardia).[brain.oxfordjournals.org]
White Matter Lesions
  • BAEPs may be useful in the neurophysiological evaluation of central white matter lesions in MNGIE. Similar neurophysiological findings have been reported in other myelin disorders in the central nervous system.[ncbi.nlm.nih.gov]
  • The white matter lesions appear hyperintense on T 2 -weighted or fluid-attenuated inversion recovery images and may initially be patchy, but eventually become diffuse and confluent.[brain.oxfordjournals.org]

Treatment

  • Management and treatment Management is mainly symptomatic, involving treatment of the chronic intestinal pseudo-obstruction. Thymidine and deoxyguanosine clearance appears to be an efficient approach.[orpha.net]
  • Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial.[ncbi.nlm.nih.gov]
  • Because of the intense rarity of the condition, there are currently no widely available treatments for patients like Charlie.[frontlinegenomics.com]
  • Very few people who develop the condition in infancy survive to their teenage years, and there is currently no known treatment for it.[metro.co.uk]

Prognosis

  • Prognosis The prognosis is unfavorable due to the severity of the digestive involvement with infections and the need for permanent parenteral nutrition. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • These are severe disorders with poor prognosis in the majority of cases. So far, no therapy or cure exists to help patients, although nutritional interventions or supplementation can be beneficial for some children.[ibtimes.co.uk]
  • Conversely, the absence of eye abnormalities may portend a better prognosis and a possible beneficial effect of liver transplantation.[journals.lww.com]
  • The prognosis for MELAS is poor. Typically, the age of death is between 10 to 35 years, although some patients may live longer.[umdf.org]
  • PROGNOSIS Prognosis depends upon which disorder, which symptoms and the severity of those symptoms. Some of the conditions we thought were uniformly progressive and fatal are not (Leigh syndrome, for example).[childneurologyfoundation.org]

Etiology

  • Etiology MNGIE syndrome is inherited in an autosomal recessive manner and is caused by mutations in the TYMP gene (22q13.32-qter), encoding a protein involved in thymidine phosphorylation.[orpha.net]
  • Other genes may also be involved in the etiology of myopathic MDS.[pediatricneurologybriefs.com]
  • Liver transplant was not performed in view of mitochondrial etiology and neurological involvement (as evident on neuroimaging).[indianpediatrics.net]
  • Table 1 summarizes the main clinical manifestations and molecular etiologies associated with these different forms.[ijponline.biomedcentral.com]
  • Houston Recruiting NCT02023866 Open-Label, Dose-Escalating Study to Assess Safety, Tolerability, Efficacy, PK and PD of RP103 in Children With Inherited Mitochondrial Disease Genetically diagnosed mitochondrial disease Raptor Pharma Completed NCT02003170 Etiology[mitoaction.org]

Epidemiology

  • Summary Epidemiology So far, just under 100 sporadic and familial cases have been reported. Clinical description The first clinical manifestations generally appear between the ages of 10 and 40 (most often before 20 years of age).[orpha.net]
  • Results Epidemiology A cohort of 102 patients (50 females) with an average age of 32.4 years (range 11–59 years) was collected between 1988 and 2011.[brain.oxfordjournals.org]
  • The incidence is unknown, although the epidemiological studies of the MELAS-3243 mtDNA mutation have estimated the prevalence to be 1-16/100,000 in the adult population. There is no cure or specific treatment for MELAS.[umdf.org]
Sex distribution
Age distribution

Pathophysiology

  • TP deficiency alone is unlikely to explain all clinical signs, and other factors, including the possible development of anti-TP antibodies, which may play a role in the pathophysiology.[ncbi.nlm.nih.gov]
  • […] article is freely available re-usable Review Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, Department of Pathophysiology[mdpi.com]

Prevention

  • We used formulas enriched with medium-chain triglyceride content and fractional meals with enteral nutrition at night for adequate nutrition to prevent hypoglycemia. He continued to deteriorate rapidly, leading to death at 4 months of age.[journals.lww.com]
  • . : Mitochondrial DNA depletion can be prevented by dGMP and dAMP supplementation in a resting culture of deoxyguanosine kinase-deficient fibroblasts. Hum. Molec. Genet. 12: 1839-1845, 2003. PubMed ID : 12874104 Tadiboyina, V.[humpath.com]
  • Our report has thus direct important implications for clinical practice: it prevents a burdensome, long-term invasive, but finally probably ineffective procedure in MNGIE patients.[ncbi.nlm.nih.gov]
  • Prevention There are no current guidelines to prevent mitochondrial myopathies. If you have a family history of the disorder, you can talk to a genetic counselor when deciding whether to have children.[azkrmc.com]
  • Can we prevent Mitochondrial Disease? Yes.[mitochondrialdisease.nhs.uk]

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