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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson (Reviewed by {{YD}})
|QuestionAuthor=William J Gibson
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics
|MainCategory=Genetics
Line 21: Line 21:
|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Neurology, General Principles
|SubCategory=Neurology, General Principles
|Prompt=An 8-year-old boy is brought to the emergency department with generalized epilepsy. His mother reports that the boy's past medical history is only significant for myoclonus and resting muscle pain at the age of 6 years. His family history is significant for a similar condition in his maternal aunt, whose symptoms then progressed to generalized epilepsy, weakness, ataxia, dementia, and early death. On physical examination, the patient appears very short compared to his peers. The physician also notes optic atrophy and hearing loss. ECG reveals pre-excitation delta waves. Which additional finding will most likely be present during further work-up of this patient?
|Prompt=An 11 year old boy is brought to his pediatrician for recurrent episodes of involuntary muscle twitching. He reports that these episodes have grown more frequent and increased in duration over the past year.  The patient also suffers from poor vision at night, and exercise intolerance that began at the age of six. A maternal aunt has epilepsy. The patient has achieved all developmental milestones, but has especially short stature relative to his peers. Which of the following is true of this patient’s condition?
|Explanation=Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem disease that is caused by mutations in the mitochondrial DNA (mtDNA). Most commonly, the disease is caused by a mutation of the ''MT-TK'' gene of the mtDNA that encodes tRNA lysine. Manifestations of the disease are myoclonus, resting muscle pain, and short stature (early symptoms) followed by generalized epilepsy, hearing loss, and exercise intolerance. Some patients might develop cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome (pre-excitation delta waves on ECG), retinopathy, pyramidal signs, parkinsonism, or multiple lipomas. Patients are usually normal at birth, but symptoms progressively appear during childhood with gradual worsening. Symptoms of advanced disease include ataxia, weakness, and dementia. The diagnosis is made by detection of ragged red fibers on muscle biopsy with trichrome stain and presence of mtDNA mutation in leukocytes. Although the genetic mutation is present in all cells, heteroplasmy can lead to a variable distribution of mutated mtDNA across cells. Additional testing may be helpful for the diagnosis. CSF analysis may show elevated proteins in CSF and elevated lactate and pyruvate in blood and in CSF. ECG may show pre-excitation delta waves consistent with WPW syndrome, electroencephalogram (EEG) often demonstrates generalized spike and wave discharges, and brain MRI may show brain atrophy and calcification in the basal ganglia.
|Explanation=The patient in this vignette is suffering from myoclonic epilepsy with ragged red fibers (MERRF). It involves the following characteristics: progressive myoclonic epilepsy, short stature, hearing loss, lactic acidosis, exercise intolerance, and poor night vision. Muscle biopsy of affected patients will demonstrate clumps of diseased mitochondria and appear as ragged red fibers on trichome stain. Because MERRF is a mitochondrial condition, it can only be inherited through the mother.  The severity of the patient’s symptoms depends on the proportion of mutated mitochondria the fertilized egg contains. Expressivity refers to the range of symptoms a patient shows. Heteroplasmy is the presence of a mixture of more than one type of an mitochondrial genome within a cell or individual. Some individuals and even particular tissues within certain individuals will differ in the proportion of mitochondria carrying a mutant allele. Thus, the variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria.
|AnswerA=Hyperbilirubinemia
|AnswerA=Associated with elevated bilirubin
|AnswerAExp=MERRF is associated with elevated lactic acid that is not due to hemolysis. Hyperbilirubinemia is not usually associated with MERRF.
|AnswerAExp=MERRF is associated with elevated lactic acid not associated with hemolysis. Therefore, bilirubin is not elevated in MERRF.
|AnswerB=Ketoacidosis
|AnswerB=Associated with ketoacidosis
|AnswerBExp=MERRF is associated with elevated lactate in blood and CSF, not ketones. Thus, lactic acidosis is commonly observed in patients with MERRF, not ketoacidosis. Patients with untreated type 1 diabetes mellitus usually present with ketoacidosis.
|AnswerBExp=MERFF is not associated with ketoacidosis. MERRF can cause lactic acidosis. However a related mitochondrial condition, MELAS, is more associated with lactic acidosis.
|AnswerC=Respiratory acidosis
|AnswerC=Associated with respiratory acidosis
|AnswerCExp=MERRF is not classically associated with respiratory acidosis.
|AnswerCExp=MERRF is not associated with respiratory acidosis. MERRF can cause lactic acidosis. However a related mitochondrial condition, MELAS, is more associated with lactic acidosis.
|AnswerD=Lactic acidosis
|AnswerD=Variable expressivity due to heteroplasmy
|AnswerDExp=MERRF is associated with elevated lactate and pyruvate in the blood and in CSF. MERRF is associated with lactic acidosis.
|AnswerDExp=Expressivity refers to the range of symptoms a patient shows.  Heteroplasmy is the presence of a mixture of more than one type of an mitochondrial genome within a cell or individual.  Some individuals and even particular tissues within certain individuals will differ in the proportion of mitochondria carrying a mutant allele. Thus, the variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria.
|AnswerE=Undetectable proteins in CSF
|AnswerE=Variable expressivity due to X-inactivation in females
|AnswerEExp=Elevated proteins in CSF are often observed in patients with MERRF
|AnswerEExp=MERRF is not an X-linked disease.  Variable expressivity due to X-inactivation in females is true of fragile X syndrome.
|EducationalObjectives=Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem disease that is caused by mutations in the mitochondrial DNA (mtDNA). Manifestations of the disease are myoclonus, generalized epilepsy, short stature, hearing loss, and lactic acidosis.
|EducationalObjectives=The variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria in different patient’s tissues.
|References=DiMauro S, Hirano M. MERRF. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2003.<br>
|References=First Aid 2014 page 86
First Aid 2014 page 86
|RightAnswer=D
|RightAnswer=D
|WBRKeyword=Heteroplasmy, Mitochonria, Mitochondrial disorder, MERRF, Myoclonus, Epilepsy, mtDNA, Ragged red fibers, Myoclonic epilepsy with ragged red fibers
|WBRKeyword=Mosaicism, Heteroplasmy, Genetics, Mitochonria, Mitochondrial disorder, MERRF, Myoclonic, Myoclonus, Epilepsy,
|Approved=Yes
|Approved=Yes
}}
}}

Revision as of 17:00, 7 December 2016
Author PageAuthor::William J Gibson
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Genetics
Sub Category SubCategory::Neurology, SubCategory::General Principles
Prompt [[Prompt::An 11 year old boy is brought to his pediatrician for recurrent episodes of involuntary muscle twitching. He reports that these episodes have grown more frequent and increased in duration over the past year. The patient also suffers from poor vision at night, and exercise intolerance that began at the age of six. A maternal aunt has epilepsy. The patient has achieved all developmental milestones, but has especially short stature relative to his peers. Which of the following is true of this patient’s condition?]]
Answer A AnswerA::Associated with elevated bilirubin
Answer A Explanation AnswerAExp::MERRF is associated with elevated lactic acid not associated with hemolysis. Therefore, bilirubin is not elevated in MERRF.
Answer B AnswerB::Associated with ketoacidosis
Answer B Explanation AnswerBExp::MERFF is not associated with ketoacidosis. MERRF can cause lactic acidosis. However a related mitochondrial condition, MELAS, is more associated with lactic acidosis.
Answer C AnswerC::Associated with respiratory acidosis
Answer C Explanation AnswerCExp::MERRF is not associated with respiratory acidosis. MERRF can cause lactic acidosis. However a related mitochondrial condition, MELAS, is more associated with lactic acidosis.
Answer D AnswerD::Variable expressivity due to heteroplasmy
Answer D Explanation [[AnswerDExp::Expressivity refers to the range of symptoms a patient shows. Heteroplasmy is the presence of a mixture of more than one type of an mitochondrial genome within a cell or individual. Some individuals and even particular tissues within certain individuals will differ in the proportion of mitochondria carrying a mutant allele. Thus, the variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria.]]
Answer E AnswerE::Variable expressivity due to X-inactivation in females
Answer E Explanation AnswerEExp::MERRF is not an X-linked disease. Variable expressivity due to X-inactivation in females is true of fragile X syndrome.
Right Answer RightAnswer::D
Explanation [[Explanation::The patient in this vignette is suffering from myoclonic epilepsy with ragged red fibers (MERRF). It involves the following characteristics: progressive myoclonic epilepsy, short stature, hearing loss, lactic acidosis, exercise intolerance, and poor night vision. Muscle biopsy of affected patients will demonstrate clumps of diseased mitochondria and appear as ragged red fibers on trichome stain. Because MERRF is a mitochondrial condition, it can only be inherited through the mother. The severity of the patient’s symptoms depends on the proportion of mutated mitochondria the fertilized egg contains. Expressivity refers to the range of symptoms a patient shows. Heteroplasmy is the presence of a mixture of more than one type of an mitochondrial genome within a cell or individual. Some individuals and even particular tissues within certain individuals will differ in the proportion of mitochondria carrying a mutant allele. Thus, the variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria.

Educational Objective: The variable phenotype of MERRF can be caused by differing proportions of mutant mitochondria in different patient’s tissues.
References: First Aid 2014 page 86]]

Approved Approved::Yes
Keyword WBRKeyword::Mosaicism, WBRKeyword::Heteroplasmy, WBRKeyword::Genetics, WBRKeyword::Mitochonria, WBRKeyword::Mitochondrial disorder, WBRKeyword::MERRF, WBRKeyword::Myoclonic, WBRKeyword::Myoclonus, WBRKeyword::Epilepsy
Linked Question Linked::
Order in Linked Questions LinkedOrder::
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