WBR0385

Author	[[PageAuthor::Rim Halaby, M.D. [1], Alison Leibowitz [2] (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Renal
Prompt	[[Prompt::A 12-year-old male is brought by his mother to the physician’s office for red-colored urine. Upon further questioning, the mother explains that her son is deaf and has eye problems. The physician suspects a collagen disease. Genetic studies reveal a mutation of COL4A5 and confirm the diagnosis with mutation encoding α chains. Which of the following is most likely the mode of inheritance of the patient’s condition?]]
Answer A	AnswerA::X-linked dominant
Answer A Explanation	AnswerAExp::Alport Syndrome (AS) can be transmitted in an X-linked pattern, with a mutation of COL4A5.
Answer B	AnswerB::Autosomal recessive
Answer B Explanation	AnswerBExp::Mutations of COL4A3 and COL4A4 that lead to AS are transmitted in an autosomal recessive pattern.
Answer C	AnswerC::Autosomal dominant
Answer C Explanation	AnswerCExp::Alport syndrome is rarely transmitted in an autosomal dominant pattern.
Answer D	AnswerD::Mitochondrial
Answer D Explanation	AnswerDExp::Alport syndrome is not transmitted in a mitochondrial pattern. Examples of diseases transmitted in a mitochondrial pattern are MELAS and MERRF.
Answer E	AnswerE::Polygenic
Answer E Explanation	[[AnswerEExp::Alport syndrome is not considered a polygenic disease. Common polygenic diseases include schizophrenia and heart disease. Recall that a polygenic disease refers to a disease in which multiple genetic loci are thought to contribute to disease risk in the same individual (many risk/protective alleles of low affect size). This concept is distinct from the idea of locus heterogeneity, where mutations in separate genes can cause the same mendelian syndrome. Alport syndrom and hypertrophic cardiomyopathy are examples of mendelian diseases with locus heterogeneity.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Alport Syndrome (AS) is an inherited disorder of type IV collagen with abnormal glomerular basement membranes, hematuric nephropathy, and sensorineural deafness. Alport Syndrome may be caused by mutations in several separate genes in the collagen family (locus heterogeneity), including including COL4A3, COL4A4, and COL4A5. 85% of cases of Alport syndrome are caused by mutations in COL4A5, a gene encoding the α5 subunit of basement-membrane associated collagen type IV. COL4A5 is located on the X chromosome, and Alport syndrome related to this locus therefore follows an X-linked recessive mode of inheritance. COL4A3 and COL4A4, encoding α3 and α4 respectively, are located on chromosome 2. Alport syndrome resulting from mutations in COL4A3 and COL4A4 originates from an autosomal recessive inheritance. COL4A5, encoding α5, is a gene on the X chromosome. Educational Objective: Alport Syndrome (AS) can be transmitted either in an X-linked pattern, with a mutation of COL4A5, or in an autosomal recessive pattern, with a mutation of COL4A3 or COL4A4. References: Haas M. Alport syndrome and thin glomerular basement membrane nephropathy. A practical approach to diagnosis. Archives of Pathology and Laboratory Medicine. 2009;133(2):224-232 Hasstedt, S. J., Atkin, C. L. X-linked inheritance of Alport syndrome: family P revisited. Am. J. Hum. Genet. 35: 1241-1251, 1983. <a src='http://www.omim.org/entry/301050'> Online Mendelian Inheritance in Man: Alport syndrome; COL4A5 </a>]]
Approved	Approved::Yes
Keyword	WBRKeyword::Genetics, WBRKeyword::Deafness, WBRKeyword::Blind, WBRKeyword::Hematuria, WBRKeyword::X-linked, WBRKeyword::X-linked recessive
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