A 6-day-old term male neonate born to Old Order Mennonite parents presents to the NICU with poor feeding, lethargy, and a characteristic sweet, maple-syrup-like odor of urine. Newborn screening shows markedly elevated leucine (2,800 micromol/L), elevated isoleucine and valine, and pathognomonic allo-isoleucine. Brain MRI reveals diffuse white matter edema affecting cerebellar white matter and posterior limb of internal capsule. BCKDHA gene sequencing identifies homozygosity for a founder mutation. The pedigree shows affected males and females with unaffected parents, multiple affected cousins from consanguineous unions, and no vertical transmission. The inheritance pattern marked **A** in the diagram is most consistent with which of the following?
A. Y-linked inheritance with paternal transmission to all male offspring
B. Autosomal dominant inheritance with incomplete penetrance and variable expressivity
C. Autosomal recessive inheritance with founder mutation and consanguinity in an endogamous population
D. X-linked recessive inheritance with skipped generations in heterozygous carrier females
Explanation
Why Autosomal recessive inheritance with founder mutation and consanguinity in an endogamous population is right
Maple syrup urine disease (MSUD) caused by BCKDHA mutations is inherited in an autosomal recessive pattern. The clinical presentation—homozygous founder mutation (p.Y438N) in a Mennonite neonate born to second-cousin parents—is pathognomonic for autosomal recessive inheritance. The pedigree demonstrates all hallmarks: (1) affected individuals of both sexes equally, (2) unaffected carrier parents, (3) multiple affected cousins from consanguineous unions, (4) no vertical transmission, and (5) increased frequency in an endogamous community with high carrier frequency (~1/10 in Old Order Mennonites). Consanguinity increases the probability that both parents carry the same recessive allele, resulting in affected offspring. The homozygous state for the founder mutation confirms biallelic BCKDHA deficiency. [Strauss KA, Carson VJ, Soltys K, et al. Branched-chain alpha-ketoacid dehydrogenase deficiency (maple syrup urine disease). Mol Genet Metab. 2020;129(3):193-206.]
Why each distractor is wrong
X-linked recessive inheritance with skipped generations in heterozygous carrier females: X-linked recessive disorders typically affect males predominantly and show skipped generations through carrier females. This pedigree shows affected females (the proband's affected female cousins) with unaffected parents, which is inconsistent with X-linked recessive inheritance. Additionally, affected males born to unaffected parents would require the mother to be a carrier, but the pattern of multiple affected cousins from different sibships with consanguinity is not explained by X-linkage.
Autosomal dominant inheritance with incomplete penetrance and variable expressivity: Autosomal dominant inheritance would show vertical transmission (affected parent to affected child in successive generations). This pedigree shows no vertical transmission—all affected individuals have unaffected parents. The presence of unaffected carrier parents is incompatible with autosomal dominant inheritance, which requires only one mutant allele for expression.
Y-linked inheritance with paternal transmission to all male offspring: Y-linked inheritance would result in all male offspring of affected fathers being affected and all female offspring being unaffected. This pedigree shows affected females and affected males born to unaffected fathers, ruling out Y-linked inheritance entirely.
High-YieldNEET PG
Autosomal recessive disorders show equal sex distribution, unaffected carrier parents, consanguinity clustering, and high prevalence in endogamous populations with founder mutations—classic MSUD inheritance in Mennonite communities.
Strauss KA, Carson VJ, Soltys K, et al. Branched-chain alpha-ketoacid dehydrogenase deficiency (maple syrup urine disease). Mol Genet Metab. 2020;129(3):193-206.
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