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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson
|QuestionAuthor=William J Gibson (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics
|SubCategory=Neurology, General Principles
|SubCategory=General Principles
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics
|SubCategory=Neurology, General Principles
|SubCategory=General Principles
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics
|SubCategory=Neurology, General Principles
|SubCategory=General Principles
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics
|SubCategory=Neurology, General Principles
|MainCategory=Genetics
|MainCategory=Genetics, Pathophysiology
|SubCategory=General Principles
|SubCategory=Neurology, General Principles
|MainCategory=Genetics
|MainCategory=Genetics, Pathophysiology
|SubCategory=General Principles
|SubCategory=Neurology, General Principles
|MainCategory=Genetics
|MainCategory=Genetics, Pathophysiology
|SubCategory=General Principles
|SubCategory=Neurology, General Principles
|MainCategory=Genetics
|MainCategory=Genetics, Pathophysiology
|SubCategory=General Principles
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics
|SubCategory=Neurology, General Principles
|MainCategory=Genetics
|Prompt=A 36 year old woman is brought by her husband to the emergency room after she suffered a seizure. She reports that she was watching television when she began to see the colors on the screen blend and the room began to “wave”. As her vision normalized she began to experience a sharp migraine headache, became nauseated and vomited. She lost consciousness for 10 minutes but regained consciousness by the time the paramedics arrived. The patient has normal speech, but marked weakness of the right upper and lower limbs.  Her gait is wide-based and ataxic. Laboratory studies are significant for a serum lactate concentration of 58.4 mmol/L (reference <2.1 mmol/L).  Which of the following tests would be most specific for diagnosing the condition which would best explain the patient’s symptoms?
|SubCategory=General Principles
|Explanation=The patient in this vignette is suffering from mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS Syndrome). MELAS is a hereditary disorder affecting the mitochondria. Individuals with MELAS develop severe lactic acidosis due to insufficient activity mitochondrial metabolism. Therefore, the body symptoms most affected by MELAS are those most dependent on oxidative phosphorylation (ie the nervous system and muscles).  Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia). Muscle biopsy of affected patients will demonstrate clumps of diseased mitochondria and appear as ragged red fibers on trichome stain.
|Prompt=A 19-year-old woman is brought to the emergency department (ED) by EMS for transient loss of consciousness. Her roommate reports that she was watching television when she began to see the colors on the screen blend, and the room began to “wave”. As her vision normalized, she experienced a sharp migraine-like headache and vomited twice. She lost consciousness for 10 minutes but regained consciousness by the time EMS arrived. The patient explains that this is not the first time she experiences stroke-like symptoms, and she had multiple similar episodes in the past. Her past medical history is also significant for multiple hospitalizations for tonic-clonic seizures. Upon further investigation, the woman states that she has been intolerant to exercise ever since she was a child. Physical examination in the ED is remarkable for transient weakness in the right upper and lower limbs and a wide-based, ataxic gait. Laboratory studies demonstrate elevated serum lactate concentration. What is the most appropriate diagnostic modality for this patient's condition?
 
|Explanation=MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a hereditary multisystem disorder caused by a mutation of the mitochondrial DNA (mtDNA). The most common mutation in MELAS is the ''MT-TL1'' gene present in the mtDNA that encodes tRNA leucine. Patients with MELAS usually have a normal early development during infancy, and symptoms often start to appear between the age of 2 to 10 years. Individuals with MELAS often develop severe lactic acidosis due to insufficient mitochondrial metabolism activity. Manifestations include generalize tonic-clonic seizures and exercise intolerance (early symptoms), migraine-like headaches, anorexia, and vomiting. Patients usually report recurrent stroke-like episodes before the age of 40. These episodes are associated with altered consciousness, transient hemiparesis, or blindness. Symptoms may be triggered by acute stresses, such as infections. MELAS is usually suspected among patients with symptoms consistent with the disease and lactic acidosis, as suggested by elevated serum lactate levels. The diagnosis is confirmed by muscle biopsy that demonstrates ragged red fibers on trichrome stain. Other helpful tests may include CSF analysis that demonstrates elevated protein and lactate, ECG that may demonstrate evidence of cardiomyopathy, pre-excitation, of heart block, and brain imaging that may demonstrate increased signals in the posterior cerebrum (but not following a major arterial distribution) during a stroke-like episode.
'''Educational Objective:'''  MELAS and other mitochondrial diseases cause ragged red fibers on muscle biopsy.
|AnswerA=Brain MRI
 
|AnswerAExp=A patient with stroke-like symptoms and lactic acidosis suggests MELAS syndrome.  An MRI might show increased signals in the posterior cerebrum during an episode, but these findings are not usually diagnostic of MELAS.
'''References:''' First Aid 2012 page 89.
 
|AnswerA=MRI
|AnswerAExp='''Incorrect''' - A patient with stroke-like symptoms and lactic acidosis suggests MELAS syndrome.  An MRI might show ventricular enlargement but an MRI would be nonspecific for MELAS.  Many other conditions including stroke could cause macroscopic alterations in the brain that could be visualized by MRI.  
|AnswerB=Blood smear
|AnswerB=Blood smear
|AnswerBExp='''Incorrect''' - Certain conditions such as G6PD can cause lactic acidosis due to widespread hemolysis. However, the lactic acidosis of G6PD is not typically as severe as the acidosis in this patient. Furthermore, G6PD is an X-linked condition and therefore highly unlikely to occur in a female. Blood smear would show bite cells.  
|AnswerBExp=Hematologic diseases, such as G6PD deficiency, can cause lactic acidosis due to hemolysis. However, lactic acidosis of G6PD is not typically as severe as the acidosis in this patient. Furthermore, G6PD is an X-linked condition and is therefore highly unlikely to occur in a woman.
|AnswerC=Muscle biopsy
|AnswerC=Muscle biopsy
|AnswerCExp='''Correct''' - Ragged red fibers on muscle biopsy is specific for mitochondrial diseases, including MELAS.
|AnswerCExp=Ragged red fibers on muscle biopsy are characteristic of mitochondrial diseases, including MELAS.
|AnswerD=Glucose tolerance test
|AnswerD=Glucose tolerance test
|AnswerDExp='''Incorrect''' - A glucose tolerance could be used to diagnose diabetes.
|AnswerDExp=A glucose tolerance test is helpful to diagnose diabetes mellitus.
|AnswerE=Liver enzymes
|AnswerE=Liver enzymes
|AnswerEExp='''Incorrect''' - Liver enzymes (ALT, AST) can indicate hepatitis which is not a feature of MELAS.
|AnswerEExp=Liver enzymes are not classically elevated in MELAS.
|EducationalObjectives=MELAS and other mitochondrial diseases are diagnosed by muscle biopsy, which demonstrates ragged red fibers on trichrome stain.
|References=DiMauro S, Hirano M. MELAS. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2001.<br>
First Aid 2014 page 86
|RightAnswer=C
|RightAnswer=C
|WBRKeyword=Mitochondria, Mitochonrdial disease, MELAS, MELAS, Ragged red fibers, Muscle biopsy
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:53, 27 October 2020

 
Author [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Genetics
Sub Category SubCategory::General Principles
Prompt [[Prompt::A 19-year-old woman is brought to the emergency department (ED) by EMS for transient loss of consciousness. Her roommate reports that she was watching television when she began to see the colors on the screen blend, and the room began to “wave”. As her vision normalized, she experienced a sharp migraine-like headache and vomited twice. She lost consciousness for 10 minutes but regained consciousness by the time EMS arrived. The patient explains that this is not the first time she experiences stroke-like symptoms, and she had multiple similar episodes in the past. Her past medical history is also significant for multiple hospitalizations for tonic-clonic seizures. Upon further investigation, the woman states that she has been intolerant to exercise ever since she was a child. Physical examination in the ED is remarkable for transient weakness in the right upper and lower limbs and a wide-based, ataxic gait. Laboratory studies demonstrate elevated serum lactate concentration. What is the most appropriate diagnostic modality for this patient's condition?]]
Answer A AnswerA::Brain MRI
Answer A Explanation AnswerAExp::A patient with stroke-like symptoms and lactic acidosis suggests MELAS syndrome. An MRI might show increased signals in the posterior cerebrum during an episode, but these findings are not usually diagnostic of MELAS.
Answer B AnswerB::Blood smear
Answer B Explanation [[AnswerBExp::Hematologic diseases, such as G6PD deficiency, can cause lactic acidosis due to hemolysis. However, lactic acidosis of G6PD is not typically as severe as the acidosis in this patient. Furthermore, G6PD is an X-linked condition and is therefore highly unlikely to occur in a woman.]]
Answer C AnswerC::Muscle biopsy
Answer C Explanation AnswerCExp::Ragged red fibers on muscle biopsy are characteristic of mitochondrial diseases, including MELAS.
Answer D AnswerD::Glucose tolerance test
Answer D Explanation AnswerDExp::A glucose tolerance test is helpful to diagnose diabetes mellitus.
Answer E AnswerE::Liver enzymes
Answer E Explanation AnswerEExp::Liver enzymes are not classically elevated in MELAS.
Right Answer RightAnswer::C
Explanation [[Explanation::MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a hereditary multisystem disorder caused by a mutation of the mitochondrial DNA (mtDNA). The most common mutation in MELAS is the MT-TL1 gene present in the mtDNA that encodes tRNA leucine. Patients with MELAS usually have a normal early development during infancy, and symptoms often start to appear between the age of 2 to 10 years. Individuals with MELAS often develop severe lactic acidosis due to insufficient mitochondrial metabolism activity. Manifestations include generalize tonic-clonic seizures and exercise intolerance (early symptoms), migraine-like headaches, anorexia, and vomiting. Patients usually report recurrent stroke-like episodes before the age of 40. These episodes are associated with altered consciousness, transient hemiparesis, or blindness. Symptoms may be triggered by acute stresses, such as infections. MELAS is usually suspected among patients with symptoms consistent with the disease and lactic acidosis, as suggested by elevated serum lactate levels. The diagnosis is confirmed by muscle biopsy that demonstrates ragged red fibers on trichrome stain. Other helpful tests may include CSF analysis that demonstrates elevated protein and lactate, ECG that may demonstrate evidence of cardiomyopathy, pre-excitation, of heart block, and brain imaging that may demonstrate increased signals in the posterior cerebrum (but not following a major arterial distribution) during a stroke-like episode.

Educational Objective: MELAS and other mitochondrial diseases are diagnosed by muscle biopsy, which demonstrates ragged red fibers on trichrome stain.
References: DiMauro S, Hirano M. MELAS. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2001.
First Aid 2014 page 86]]

Approved Approved::Yes
Keyword WBRKeyword::Mitochondria, WBRKeyword::Mitochonrdial disease, WBRKeyword::MELAS, WBRKeyword::MELAS, WBRKeyword::Ragged red fibers, WBRKeyword::Muscle biopsy
Linked Question Linked::
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