(Choice B) Genetic heterogeneity describes different genetic mutations causing the same disease (eg. tuberous sclerosis). This mechanism is inconsistent with this patient’s symptoms because affected members of the same family would have the same mutation. Moreover, this mother and child have markedly different disease manifestations.
(Choice C) Germline mosaicism occurs when an unaffected parent has gametes with a mutated allele that is passed to offspring; it is typically suspected when multiple siblings have an autosomal dominant disorder with phenotypically normal parents.
(Choice D) Prader-Willi syndrome often occurs due to maternal imprinting, in which a loss-of-function mutation in the paternal allele is inherited while the maternally inherited allele is silenced. Infants can have profound disease
(eg. hypotonia, feeding difficulties), but the mother would not be affected.
(Choice E) Single nucleotide polymorphism (SNP) refers to a variation at a single base pair within a DNA sequence. SNPs occur frequently throughout the genome and contribute to genetic variation within the population. If located near or within a gene, they may be markers of certain genetic diseases but would not cause the increasingly severe manifestations seen in this family’s successive generations.

(Choice A) Small amounts of glycogen are engulfed by lysosomes and broken down by acid alpha-glucosidase (acid maltase). Acid maltase deficiency (Pompe disease) is characterized by cardiomegaly, severe generalczed
hypotonia, and lysosomal glycogen accumulation (hypoglycemia is not seen).
(Choice B) Glucose-6-phosphatase deficiency (von Gierke disease) affects mainly the liver and kidney because the enzyme is not expressed in significant quantities in muscle tissue. Major symptoms include hypoglycemia, lactic acidosis, and hyperlipidemia. Hepatic steatosis is a cardinal manifestation.
(Choice D) Liver glycogen phosphorylase deficiency (Hers disease) presents in early childhood with mild hypoglycemia, ketosis, and hepatomegaly.
However, it does not affect skeletal muscles and shows an excess of normally structured glycogen (not abnormally short “limit dextrins”) on liver biopsy.
(Choice E) Muscle glycogen phosphorylase deficiency (McArdle disease) presents with decreased exercise tolerance, muscle cramping during strenuous activity, and myoglobinuria. Blood lactate is often very low after exercise, and muscle biopsy shows an excess of normally structured glycogen.
(Choice F) Pyruvate kinase (PK) converts phosphoenolpyruvate to pyruvate during glycolysis. PK deficiency causes chronic hemolytic anemia because
glycolysis is the main source of energy for erythrocytes.

(Choice A) Double-strand DNA breakage can occur following exposure to ionizing radiation. Compared to singlestrand breaks, double-strand breaks are more likely to result in faulty repair, leading to mutations, malignancy, or cell death.
(Choice 8) Histone acetylation facilitates active transcription, as seen with euchromatin. In contrast, histone deacetylation increases interaction between histones and DNA and contributes to the formation of condensed chromatin (ie, heterochromatin) that is less transcriptionally active.
(Choice C) Repair of mismatched bases occurs throughout the genome during DNA replication. Impaired mismatch repair is associated with hereditary nonpolyposis colorectal cancer.
(Choice E) DNA supercoiling refers to the amount of twisting in a double-stranded DNA molecule; increased positive supercoiling means the DNA helix becomes more tightly wound, which allows for more compact DNA packaging but also limits access by transcriptional machinery. Inactive X chromosomes are formed from condensed heterochromatin with a positively supercoiled structure compared to transcriptionally active euchromatin.