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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor={{Rim}}
|QuestionAuthor={{Rim}} (Reviewed by {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Biochemistry
|MainCategory=Biochemistry
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|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=General Principles
|SubCategory=General Principles
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
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|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=General Principles
|SubCategory=General Principles
|Prompt=An 18 months old boy was noted to have recurrent episodes of ptosis and swallowing difficulty. The episodes last for a couple of days and recur approximately every couple of months. The boy was normal at birth but has had generalized hypotonia throughout his development. Laboratory evaluation reveals lactic acidosis. Genetic studies reveal a defect in the E-1 alpha gene confirming the diagnosis of the patient. Counseling is provided for the parents who were instructed to strictly provide their son with a ketogenic diet. Defect in which of the following enzymes is most likely implicated in this patient's condition?
|Prompt=An 18-months-old boy is brought to the physician's office for recurrent episodes of ptosis, poor feeding, and difficulty swallowing. The mother states that each episode lasts for approximately 2 days, and episodes recur every 2 months. The boy was normal at birth but has had impaired psychomotor development throughout his development. Laboratory testing are remarkable for lactic acidosis and elevated serum alanine concentration. The physician suspects an inborn error of metabolism, and genetic studies, which demonstrate a defect in the E1 alpha gene, confirm the diagnosis. The parents are advised to maintain a strict diet that is high in leucine and lysine intake for their child. Which enzyme deficiency is responsible for this patient's condition?
|Explanation=This boy presents with neurological symptoms since infancy in the context of [[lactic acidosis]]. The defect in the E-1 alpha gene points towards the diagnosis of pyruvate dehydrogenase deficiency which is mostly an X-linked disease. There are two main types of presentations of pyruvate dehydrogenase deficiency: a metabolic presentation characterized by severe lactic acidosis at birth, or a chronic neurological presentation characterized by [[hypotonia]], [[lethargy]] and [[mental retardation]].  The treatment of this disease is a strict ketogenic diet high in fat and in the ketogenic amino acids lysine and leucine. Pyruvate dehydrogenase is also [[thiamine]] responsive.
|Explanation=Pyruvate dehydrogenase (PDH) complex defects are associated with development of ptosis, dysphagia, poor feeding, irritability, seizures, impaired psychomotor development, lactic acidosis, and elevated serum alanine concentration (accumulated pyruvate is shunted to lactate via LDH and to alanine via ALT). PDH deficiency is a genetic disorder that may be inherited in either an autosomal or X-linked pattern. This patient's diagnosis is first suspected by the findings on physical examination and lab work-up and further confirmed by genetic testing, which demonstrated E1 alpha gene defect. The majority of patients with PDH deficiency have E1 alpha gene defects (PDHA1), which are usually inherited in an X-linked pattern. Management of PDH deficiency includes a strict ketogenic diet (high intake of fat and ketogenic amino acids lysine and leucine).
 
'''Educational objective:'''
[[Pyruvate dehydrogenase deficiency]] is an X-linked disease caused by a mutation in the E1 alpha subunit of the [[pyruvate dehydrogenase]] complex leading to [[metabolic acidosis]] and neurological symptoms.
 
'''Reference:'''


de Meirleir, L., Specola, N., Seneca, S., Lissens, W. Pyruvate dehydrogenase E1-alpha deficiency in a family: different clinical presentation in two siblings. J. Inherit. Metab. Dis. 21: 224-226, 1998.<br>
|AnswerA=Acyl-coA dehydrogenase
Brown, G. K., Otero, L. J., LeGris, M., Brown, R. M. Pyruvate dehydrogenase deficiency. J. Med. Genet. 31: 875-879, 1994.<br>
|AnswerAExp=Acyl-co dehydrogenase is involved in the [[fatty acid]] metabolism.
First aid for USMLE step 1, 2013.  Page 101.
|AnswerB=Alpha-ketoglutarate dehydrogenase
|AnswerA=Acyl-co dehydrogenase
|AnswerBExp=Alpha-ketoglutarate dehydrogenase is involved in [[Krebs cycle]].  The defect in the E1 alpha gene in this patient is consistent with the diagnosis of pyruvate dehydrogenase deficiency, not alpha-ketoglutarate dehydrogenase deficiency.
|AnswerAExp=Acyl-co dehydrogenase is involved in the [[fatty acid]] metabolism.  Deficiency in acyl-co A dehydrogenase leads to elevated levels of dicarboxylic acid and decreased levels of [[glucose]] and [[ketone]]s.  The defect in the E-1 alpha gene points towards the diagnosis of pyruvate dehydrogenase deficiency.
|AnswerB=Alpha ketoglutarate dehydrogenase
|AnswerBExp=Alpha ketoglutarate dehydrogenase is involved in [[Krebs cycle]].  The defect in the E-1 alpha gene in this patient points towards the diagnosis of pyruvate dehydrogenase deficiency and not alpha ketoglutarate dehydrogenase deficiency.
|AnswerC=Pyruvate dehydrogenase
|AnswerC=Pyruvate dehydrogenase
|AnswerCExp=Pyruvate dehydrogenase links [[glycolysis]] to [[Krebs cycle]]. Pyruvate dehydrogenase is associated with the accumulation of [[pyruvate]] and [[alanine]] as well as with [[lactic acidosis]] as seen in this patient. The defect in the E-1 alpha gene points towards the diagnosis of pyruvate dehydrogenase deficiency.
|AnswerCExp=Pyruvate dehydrogenase links [[glycolysis]] to [[Krebs cycle]]. Pyruvate dehydrogenase deficiency is associated with the accumulation of [[pyruvate]], which is shunted to lactate via LDH and to alanine via ALT. The patient's presentation and the defect in the E1 alpha gene are suggestive of pyruvate dehydrogenase deficiency.
|AnswerD=Branched-chain alpha ketodehydrogenase
|AnswerD=Alpha-keto acid dehydrogenase
|AnswerDExp=Branched-chain alpha ketodehydrogenase is involved in the breakdown of branched amino acids such as [[leucine]], [[isoleucine]] and [[lysine]]. Deficiency in branched-chain alpha ketodehydrogenase is the underlying cause of [[maple syrup disease]].  The defect in the E-1 alpha gene in this patient points towards the diagnosis of pyruvate dehydrogenase deficiency.
|AnswerDExp=Alpha-keto acid dehydrogenase is involved in the breakdown of branched amino acids ([[leucine]], [[isoleucine]], and [[valine]]). Maple syrup urine disease is characterized by alpha-keto acid dehydrogenase deficiency.  
|AnswerE=Lactate dehydrogenase
|AnswerE=Lactate dehydrogenase
|AnswerEExp=The defect in the E-1 alpha gene points towards the diagnosis of pyruvate dehydrogenase deficiency and not lactate dehydrogenase.
|AnswerEExp=Lactate dehydrogenase catalyzes the conversion from lactate to pyruvate.
|EducationalObjectives=The majority of patients with PDH deficiency have E1 alpha gene defects (PDHA1), which are usually inherited in an X-linked pattern. Management of PDH deficiency includes a strict ketogenic diet (high intake of fat and ketogenic amino acids lysine and leucine).
|References=De Meirleir L, Specola N, Seneca S, et al. Pyruvate dehydrogenase E1 alpha deficiency in a family: different clinical presentation in two siblings. J Inherit Metab Dis.1998;21:224-6.<br>
Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet. 1994;31:875-9.<br>
First Aid 2014 page 102
|RightAnswer=C
|RightAnswer=C
|WBRKeyword=Pyruvate dehydrogenase
|WBRKeyword=Pyruvate dehydrogenase, PDH, Pyruvate dehydrogenase deficiency, PDH deficiency, E1 alpha gene, PDHA1, X-linked, Convulsions, Enzyme, Pyruvate, ALT, Lactate, LDH, Alanine, Leucine, Lycine, Ketogenic diet, Ketogenic amino acids, Pyruvate dehydrogenase complex deficiency, Psychomotor development
|Approved=No
|Approved=Yes
}}
}}

Revision as of 15:06, 11 March 2015

 
Author [[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Biochemistry
Sub Category SubCategory::General Principles
Prompt [[Prompt::An 18-months-old boy is brought to the physician's office for recurrent episodes of ptosis, poor feeding, and difficulty swallowing. The mother states that each episode lasts for approximately 2 days, and episodes recur every 2 months. The boy was normal at birth but has had impaired psychomotor development throughout his development. Laboratory testing are remarkable for lactic acidosis and elevated serum alanine concentration. The physician suspects an inborn error of metabolism, and genetic studies, which demonstrate a defect in the E1 alpha gene, confirm the diagnosis. The parents are advised to maintain a strict diet that is high in leucine and lysine intake for their child. Which enzyme deficiency is responsible for this patient's condition?]]
Answer A AnswerA::Acyl-coA dehydrogenase
Answer A Explanation [[AnswerAExp::Acyl-co dehydrogenase is involved in the fatty acid metabolism.]]
Answer B AnswerB::Alpha-ketoglutarate dehydrogenase
Answer B Explanation [[AnswerBExp::Alpha-ketoglutarate dehydrogenase is involved in Krebs cycle. The defect in the E1 alpha gene in this patient is consistent with the diagnosis of pyruvate dehydrogenase deficiency, not alpha-ketoglutarate dehydrogenase deficiency.]]
Answer C AnswerC::Pyruvate dehydrogenase
Answer C Explanation [[AnswerCExp::Pyruvate dehydrogenase links glycolysis to Krebs cycle. Pyruvate dehydrogenase deficiency is associated with the accumulation of pyruvate, which is shunted to lactate via LDH and to alanine via ALT. The patient's presentation and the defect in the E1 alpha gene are suggestive of pyruvate dehydrogenase deficiency.]]
Answer D AnswerD::Alpha-keto acid dehydrogenase
Answer D Explanation [[AnswerDExp::Alpha-keto acid dehydrogenase is involved in the breakdown of branched amino acids (leucine, isoleucine, and valine). Maple syrup urine disease is characterized by alpha-keto acid dehydrogenase deficiency.]]
Answer E AnswerE::Lactate dehydrogenase
Answer E Explanation AnswerEExp::Lactate dehydrogenase catalyzes the conversion from lactate to pyruvate.
Right Answer RightAnswer::C
Explanation [[Explanation::Pyruvate dehydrogenase (PDH) complex defects are associated with development of ptosis, dysphagia, poor feeding, irritability, seizures, impaired psychomotor development, lactic acidosis, and elevated serum alanine concentration (accumulated pyruvate is shunted to lactate via LDH and to alanine via ALT). PDH deficiency is a genetic disorder that may be inherited in either an autosomal or X-linked pattern. This patient's diagnosis is first suspected by the findings on physical examination and lab work-up and further confirmed by genetic testing, which demonstrated E1 alpha gene defect. The majority of patients with PDH deficiency have E1 alpha gene defects (PDHA1), which are usually inherited in an X-linked pattern. Management of PDH deficiency includes a strict ketogenic diet (high intake of fat and ketogenic amino acids lysine and leucine).

Educational Objective: The majority of patients with PDH deficiency have E1 alpha gene defects (PDHA1), which are usually inherited in an X-linked pattern. Management of PDH deficiency includes a strict ketogenic diet (high intake of fat and ketogenic amino acids lysine and leucine).
References: De Meirleir L, Specola N, Seneca S, et al. Pyruvate dehydrogenase E1 alpha deficiency in a family: different clinical presentation in two siblings. J Inherit Metab Dis.1998;21:224-6.
Brown GK, Otero LJ, LeGris M, Brown RM. Pyruvate dehydrogenase deficiency. J Med Genet. 1994;31:875-9.
First Aid 2014 page 102]]

Approved Approved::Yes
Keyword WBRKeyword::Pyruvate dehydrogenase, WBRKeyword::PDH, WBRKeyword::Pyruvate dehydrogenase deficiency, WBRKeyword::PDH deficiency, WBRKeyword::E1 alpha gene, WBRKeyword::PDHA1, WBRKeyword::X-linked, WBRKeyword::Convulsions, WBRKeyword::Enzyme, WBRKeyword::Pyruvate, WBRKeyword::ALT, WBRKeyword::Lactate, WBRKeyword::LDH, WBRKeyword::Alanine, WBRKeyword::Leucine, WBRKeyword::Lycine, WBRKeyword::Ketogenic diet, WBRKeyword::Ketogenic amino acids, WBRKeyword::Pyruvate dehydrogenase complex deficiency, WBRKeyword::Psychomotor development
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