View source for WBR0126

{{WBRQuestion
|QuestionAuthor=Mahmoud Sakr M.D. (Reviewed by William J Gibson and {{YD}})
|ExamType=USMLE Step 1
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|SubCategory=General Principles
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=General Principles
|Prompt=An 18-year-old male adolescent is brought for medical evaluation. He states that he recently developed multiple blood clots in his legs and vertebral fractures in the past. As a child, he has missed several developmental milestones. Ophthalmic examination reveals sublaxated lens of the right eye. Which of the following disorders is the most likely diagnosis?
|Explanation=Homocystinuria is an inherited metabolic disorder of methionine metabolism. Elevated levels of homocysteine in the blood are primarily associated with an increased risk of atherosclerosis and thrombosis. Cystathionine beta-synthase (CbS) deficiency is an autosomal recessive disease that is causes ''classical' homocystinuria. Normally CbS converts homocysteine to cystathionine and requires pyridoxal 5-phosphate (vitamin B6), vitamin B12, and folate cofactors. 

Patients with homocystinuria classically have signs and symptoms that involve 4 major organ systems: Skeletal, eyes, CNS, and vascular system. Patients tend to be tall individuals. Other skeletal abnormalities may include genu valgum, pes cavus, dolichostenomelia, pectus excavatum or carinatum, kyphosis, scoliosis, and early spinal osteoporosis that may be evident during the first years of life. Other facial features include protruded frontal teeth and high-arched palate.  Ophthalmological features most characteristically include ectopia lentis and high myopia. CNS symptoms, such as mental retardation and waddling "Charlie-Chaplin-like" gait, may be evident. Finally, the vascular hallmark of homocystinuria is early arterial and venous thromboembolism that affects patients at all ages. 

Marfan syndrome should always be considered in the differential diagnosis of homocystinuria, but homocysturinia can be distinguished from Marfan syndrome by an increased risk of thrombosis.  Finally, recall that homocystinuria is an autosomal recessive disease and Marfan syndrome is autosomal dominant. While Marfan syndrome can occur ''de novo'', the absence of a family history of similar symptoms supports the diagnosis of homocystinuria over Marfan syndrome.
|AnswerA=Marfan syndrome
|AnswerAExp=[[Homocystinuria]] and [[Marfan syndrome]] have overlapping signs and symptoms, including tall stature, subluxation of the lens and kyphosis. However, homocysteinuria is more classically associated with mental retardation, osteoporosis, and thrombosis.
|AnswerB=Cystathionine beta-synthase deficiency
|AnswerBExp=[[Homocystinuria]] is an inherited metabolic disorder of methionine metabolism. Homocystinuria is caused by cystathionine beta-synthase deficiency.
|AnswerC=Vitamin B12 deficiency
|AnswerCExp=Because [[Vitamin B12]] is a cofactor in the conversion of homocysteine to methionine by methionine synthase, B12 deficiency can cause elevated homocysteine levels. However, patients with B12 deficiency would not present with severe "classic" homocystinuria as observed in this patient. Vitamin B12 deficiency causes macrocytic anemia and [[subacute combined degeneration]].
|AnswerD=Folic acid deficiency
|AnswerDExp=Folate deficiency causes macrocytic anemia and elevated homocysteine levels with no neurologic involvement. However, folate deficiency would not cause a phenotype as severe as the classic homocystinuria phenotype observed in this patient.
|AnswerE=Riboflavin deficicency
|AnswerEExp=Riboflavin (Vitamin B2) deficiency causes [cheilosis] and corneal vascularization (bloodshot eyes).
|EducationalObjectives=Classical [[homocystinuria]] is caused by cystathionine beta-synthase deficiency.
|References=Yap S. Homocystinuria due to cystathionine beta-synthase deficiency. Orphanet encyclopedia. 2005.<br>
First Aid 2014 page 111
|RightAnswer=B
|WBRKeyword=Homocystinuria, Marfan syndrome, Cystathionine beta synthase deficiency, Classical homocystinuria, Beta-synthase deficiency, Cystathionine beta-synthase deficiency, Cystathionine beta-synthase, Tall stature, Thromboembolism
|Approved=Yes
}}