5. Genetic Disorders Flashcards
- A clinical study is undertaken with subjects from families in which complications of atherosclerotic cardiovascular disease and tendinous xanthomas occurred before age 30. Some of the children in these families are observed to have early atheroma formation. It is observed that affected individuals benefit from treatment with pharmacologic agents that inhibit HMG-CoA reductase. These affected individuals are most likely to have a mutation in a gene encoding a cell surface receptor for which of the following?
□ (A) Cortisol □ (B) Insulin □ (C) LDL cholesterol □ (D) Leptin □ (E) TGF-α
(C) LDL cholesterol
Familial hypercholesterolemia results from mutations in the LDL receptor gene, causing LDL cholesterol to be increased in the blood because it is not catabolized or taken up by the liver. It is an autosomal dominant disorder with a carrier rate of 1 in 500, so the frequency of homozygosity is 1 in 1 million. Heterozygotes have total serum cholesterol levels two to three times normal; homozygotes have levels even higher, with death from myocardial infarction by age 15. The “statin” drugs inhibit the HMG-CoA reductase and reduce cholesterol levels in heterozygotes. Steroid hormone receptors, such as those for cortisol, are located in the cell nucleus. Insulin receptors play a role in glucose metabolism and glycemic control that may be part of diabetes mellitus with risk for atherosclerosis; the statin drugs have no effect on diabetes mellitus. Abnormal leptin receptors may play a role in some forms of obesity. TGF-α is a growth factor with a role in inflammation, cell proliferation, and repair.
- A 27-year-old man comes to the physician for an infertility work-up. He and his wife have been trying to conceive a child for 6 years. Physical examination shows bilateral gynecomastia, reduced testicular size, reduced body hair, and increased length between the soles of his feet and the pubic bone. A semen analysis indicates oligospermia. Laboratory studies show increased follicle-stimulating hormone level and slightly decreased testosterone level. Which of the following karyotypes is most likely to be present in this man?
□ (A) 46,X,i(Xq) □ (B) 47,XYY □ (C) 47,XXY □ (D) 46XX/47XX,+21 □ (E) 46,XY,del(22q11)
(C) 47,XXY
These findings are characteristic of Klinefelter syndrome, a relatively common chromosomal abnormality, which occurs in about 1 of 660 live-born males. The findings can be subtle. The 46,X,i(Xq) karyotype is a variant of Turner syndrome (seen only in females), caused by a defective second X chromosome. The 47,XYY karyotype occurs in about 1 in 1000 live-born males and is associated with taller-than-average stature. A person with a mosaic such as 46,XX/47,XX,+21 has milder features of Down syndrome than a person with the more typical 47,XX,+21 karyotype. The 22q11 deletion syndrome is associated with congenital defects affecting the palate, face, and heart and, in some cases, with T cell immunodeficiency.
- The parents of a male infant come to the physician because of their concern that male children over several generations in the mother’s family have been affected by a progressive disorder involving multiple organ systems. These children have had coarse facial features, corneal clouding, joint stiffness, hepatosplenomegaly, and mental retardation, and many died in childhood. At autopsy, some of the children had subendothelial coronary arterial deposits that caused myocardial infarction. Laboratory testing of the infant shows increased urinary excretion of mucopolysaccharides. Bone marrow biopsy is performed, and the accumulated mucopolysaccharides are found in macrophages (“balloon cells” filled with minute vacuoles). Which of the following enzyme deficiencies is most likely to be seen in this infant?
□ (A) Adenosine deaminase □ (B) α-l-iduronidase □ (C) Glucocerebrosidase □ (D) Glucose-6-phosphatase □ (E) Hexosaminidase A □ (F) Lysosomal glucosidase □ (G) Sphingomyelinase
(B) α-l-iduronidase
The findings listed are consistent with Hunter syndrome, one of the mucopolysaccharidoses (MPS) that results from deficiencies of lysosomal enzymes, such as α-l-iduronidase. The glycosaminoglycans that accumulate in MPS include dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. All of the MPS variants are autosomal recessive except for Hunter syndrome, which is X-linked recessive. Adenosine deaminase deficiency is a cause of severe combined immunodeficiency (SCID), an immunodeficiency state in which multiple recurrent infections occur after birth. Glucocerebrosidase deficiency is seen in Gaucher disease; in the most common form of the disease, there is no neurologic impairment, and patients have splenomegaly and skeletal disease as a consequence of increased lysosomal glucocerebrosides in cells of the mononuclear phagocyte system. Glucose-6-phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Hexosaminidase A deficiency occurs in Tay-Sachs disease; affected individuals manifest severe neurologic impairment, poor motor development, and blindness beginning in infancy. Lysosomal glucosidase deficiency, seen in Pompe disease, is associated with marked cardiomegaly and heart failure beginning in infancy. Sphingomyelinase deficiency occurs in Niemann-Pick disease type A, characterized by hepatosplenomegaly, lymphadenopathy, and severe motor and mental impairment.
- A 25-year-old woman stops going to her aerobic exercise class because of severe muscle cramps that have occurred during every session for the past 2 months. Several hours after each session, she notices that her urine is a brown color. On physical examination, she has normal muscle development and strength. An inherited defect in which of the following substances is most likely to explain these findings?
□ (A) Dystrophin □ (B) Fibrillin □ (C) Glucose-6-phosphatase □ (D) Hexosaminidase □ (E) Lysosomal glucosidase □ (F) Muscle phosphorylase □ (G) Spectrin
(F) Muscle phosphorylase
This woman has McArdle syndrome, a form of glycogen storage disease with onset in young adulthood. In this disorder, a deficiency of muscle phosphorylase enzyme causes glycogen to accumulate in skeletal muscle. Because strenuous exercise requires glycogenolysis and use of anaerobic metabolism, muscle cramps ensue, and the blood lactate level does not rise. Myoglobinuria is seen in about half of cases. A lack of the muscle membrane protein dystrophin characterizes Duchenne muscular dystrophy. A fibrillin gene mutation can lead to Marfan syndrome. Glucose-6- phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Hexosaminidase A deficiency occurs in Tay-Sachs disease, causing severe neurologic impairment, poor motor development, and blindness beginning in infancy. Lysosomal glucosidase deficiency is seen in Pompe disease, characterized by marked cardiomegaly and heart failure beginning in infancy. Abnormal spectrin, a red blood cell membrane cytoskeletal protein, leads to a condition known as hereditary spherocytosis.
- A female infant shows failure to thrive and failure to achieve developmental milestones. A pedigree reveals only this child is affected out of four generations on both sides of the family. Tissue fibroblasts obtained from this child shows a 46,XX karyotype. Cultured fibroblasts have increased amounts of an intermediate product in a multiple enzymic metabolic pathway from substrate to end product. What is the most likely recurrence risk for this condition in siblings of this infant?
□ (A) 3% □ (B) 8% □ (C) 15% □ (D) 25% □ (E) 50% □ (F) 100%
(D) 25%
Most inborn errors of metabolism involve mutations in genes encoding for enzymes. Because one active allele produces half the needed enzyme, this is likely sufficient to avoid disease. Inheritance of two mutant alleles, one from each parent, is required for appearance of disease, so the pattern is autosomal recessive, and the recurrence risk is 25%. Most autosomal recessive genes are infrequent in the population, so a family history is unlikely. The standard recurrence risk for any pregnancy is 3%. The recurrence risk is increased to 7% in diseases such as diabetes mellitus, or when a syndrome is identified without a defined inheritance pattern, or with multifactorial inheritance. Autosomal dominant conditions usually result from mutations in genes encoding for structural genes and have a recurrence risk of 50%.
- A 19-year-old woman, G3, P2, gives birth after an uncomplicated pregnancy to a term male infant. On physical examination soon after birth, the infant is recorded at the 60th percentile for height and weight. The only abnormal finding is a cleft lip. There is no family history of birth defects, and the mother’s other two children are healthy with no apparent abnormalities. Which of the following factors is most likely to influence the appearance of this infant?
□ (A) Chromosomal anomaly □ (B) Early amnion disruption □ (C) Maternal malnutrition □ (D) Multifactorial inheritance □ (E) Single gene defect □ (F) Teratogenicity
(D) Multifactorial inheritance
Most congenital malformations, including cleft lip, are not determined by a single gene and may be conditioned by environmental influences. This type of multifactorial inheritance accounts for 20% to 25% of all anomalies noted. Of the remaining options, all are more likely to produce multiple defects and to reduce fetal growth. Most chromosomal anomalies are not compatible with survival; the few fetuses (e.g., with sex chromosome aneuploidies and autosomal triploidies such as 13, 18, and 21) that do survive to term and beyond manifest multiple anomalies. Early amnion disruption may result in clefts, but more severe defects are present (e.g., gastroschisis and missing digits or limbs), and stillbirth is the usual consequence. Maternal malnutrition typically results in an infant who is small for gestational age. Single gene defects account for less than 10% of anomalies noted at birth. T eratogens account for no more than 1% of congenital anomalies.
7. A 25-year-old woman with amenorrhea has never had menarche. On physical examination, she is 145 cm (4 ft 9 in) tall. She has a webbed neck, a broad chest, and widely spaced nipples. Strong pulses are palpable in the upper extremities, but there are only weak pulses in the lower extremities. On abdominal MR imaging, the ovaries are small, elongated, and tubular. Which of the following karyotypes is most likely to be present in this patient?  □ (A) 45,X/46,XX □ (B) 46,X,X(fra) □ (C) 47,XXY □ (D) 47,XXX □ (E) 47,XX,+16
(A) 45,X/46,XX
The features described are those of classic Turner syndrome. Individuals who reach adulthood may have mosaic cell lines, with some 45,X cells and some 46,XX cells. A female carrier of the fragile X syndrome, X(fra), is less likely to manifest the disease than a male, but the number of triple repeat sequences (CGG) increases in her male offspring. The 47,XXY karyotype occurs in Klinefelter syndrome; affected individuals appear as phenotypic males. The “superfemale” karyotype (XXX) leads to mild mental retardation. Trisomy 16 is a cause of fetal loss early in pregnancy.
- A 37-year-old woman gives birth at 35 weeks’ gestation to a female infant. Physical examination of the infant soon after delivery shows rocker-bottom feet, a small face and mouth, and low-set ears. On auscultation of the chest, a heart murmur is detected. The appearance of the infant’s hands is shown in the figure. The infant dies at 4 months of age. Which of the following karyotypes was most likely present in this infant?
□ (A) 45,X □ (B) 46,XX □ (C) 47,XX,+18 □ (D) 47,XX,+21 □ (E) 48,XXX
(C) 47,XX,+18
This spectrum of findings correlates best with trisomy 18 (Edwards syndrome), in which survival is shortened significantly. Turner syndrome (45,X) is associated with the presence of cystic hygroma and hydrops fetalis. The severe anomalies described in this case make it unlikely that a normal 46,XX karyotype is present. Down syndrome (47,XX,+21) is associated with longer survival than described in this case, and the external features can be quite subtle at birth. The “superfemale” karyotype (XXX) leads to mild mental retardation. Generally, abnormal numbers of sex chromosomes are tolerated better than abnormalities of autosomes.
- A 10-year-old boy who is mentally retarded is able to carry out activities of daily living, including feeding and dressing himself. On physical examination, he has brachycephaly and oblique palpebral fissures with prominent epicanthal folds. A transverse crease is seen on the palm of each hand. On auscultation of the chest, there is a grade III/VI systolic murmur. Which of the following diseases is he most likely to develop by age 20?
□ (A) Acute leukemia □ (B) Hepatic cirrhosis □ (C) Chronic renal failure □ (D) Acute myocardial infarction □ (E) Aortic dissection
(A) Acute leukemia
This boy has Down syndrome (trisomy 21), one of the trisomies that can result in a live-born infant. Although children with Down syndrome can function well, they often have many associated congenital anomalies. Among the more common is congenital heart disease, including ventricular septal defect. There is also a 10-fold to 20-fold increased risk of acute leukemia. Virtually all individuals with Down syndrome who live to age 40 have evidence of Alzheimer disease. Hepatic cirrhosis is a feature of galactosemia. Chronic renal failure may be seen in genetic disorders that produce polycystic kidneys. Myocardial infarction at a young age suggests familial hypercholesterolemia. Aortic dissection is seen in individuals with Marfan syndrome.
- The left hand of an infant born at 38 weeks’ gestation to a 25-year-old woman, G2, P1, has the appearance shown in the figure. The infant is small for gestational age. Which of the following chromosomal abnormalities is most likely to be present?
□ (A) 45,X □ (B) 47,XX,+21 □ (C) 47,XY,+18 □ (D) 69,XXY □ (E) 47,XXY
(B) 47,XX,+21
The figure shows a single palmar flexion crease and a single flexion crease on the fifth digit, both features of trisomy 21. Although there is an increased risk of Down syndrome with increasing maternal age, most infants with Down syndrome are born to younger women because there are far more pregnancies at younger maternal ages. Monosomy X may be marked by a short fourth metacarpal. With trisomy 18, the fingers are often clenched, with digits 2 and 5 overlapping digits 3 and 4. Triploidy may be marked by syndactyly of digits 3 and 4. There are no characteristic hand features in males with Klinefelter syndrome.
- A 19-year-old man is referred to a neurologist because of failing eyesight and progressive muscle weakness. The neurologist takes a history and finds that several of the patient’s male and female relatives have similar symptoms. His mother, her brother and sister, and two of the aunt’s children are affected, but the uncle’s children are not. Which of the following types of genetic disorders is most likely to be present in this patient?
□ (A) Trinucleotide repeat expansion □ (B) Genetic imprinting □ (C) X-linked inheritance pattern □ (D) Mitochondrial mutation □ (E) Uniparental disomy
(D) Mitochondrial mutation
This is a classic pattern of maternal inheritance resulting from a mutation in mitochondrial DNA. Males and females are affected, but affected males cannot transmit the disease to their offspring. Because mitochondrial DNA encodes many enzymes involved in oxidative phosphorylation, mutations in mitochondrial genes exert their most deleterious effects on organs most dependent on oxidative phosphorylation, including the central nervous system and muscles. The other listed options do not exhibit strict maternal inheritance.
- A healthy 20-year-old woman, G3, P2, Ab1, comes to the physician for a prenatal visit. She has previously given birth to a liveborn infant and a stillborn infant, both with the same karyotypic abnormality. On physical examination, she is at the 50th percentile for height and weight. She has no physical abnormalities noted. Which of the following karyotypic abnormalities is most likely to be present in this patient?
□ (A) Robertsonian translocation □ (B) Ring chromosome □ (C) Isochromosome □ (D) Paracentric inversion □ (E) Deletion of q arm
(A) Robertsonian translocation
Almost all of the normal genetic material is present in the case of a robertsonian translocation because only a small amount of the p arm from each chromosome is lost. Statistically, one of six fetuses in a mother who carries a robertsonian translocation will also be a carrier. In balanced reciprocal translocation, the same possibility of inheriting the defect exists. The other listed structural abnormalities are likely to result in loss of significant genetic material, reducing survivability, or to interfere with meiosis.
- A 36-year-old woman gives birth at 34 weeks’ gestation to a male infant who lives for only 1 hour after delivery. On physical examination, the infant is at the 30th percentile for height and weight. Anomalies include microcephaly, a cleft lip and palate, and postaxial polydactyly, with six digits on each hand and foot. Which of the following karyotypes is most likely to be present in this infant?
□ (A) 45,X □ (B) 46,XY □ (C) 47,XXY □ (D) 47,XY,+13 □ (E) 47,XY,+18 □ (F) 69,XXY
(D) 47,XY,+13
Cleft lip and palate, along with microcephaly and polydactyly, are features of trisomy 13 (Patau syndrome). These infants also commonly have severe heart defects. For monosomy X (45,X) to be considered, the infant must be female. The severe anomalies described in this case may occur with a normal karyotype (46,XY), but the spectrum of findings, particularly the polydactyly, suggests trisomy 13. Klinefelter syndrome (47,XXY) results in phenotypic males who are hard to distinguish from males with a 46,XY karyotype. Infants with trisomy 18 lack polydactyly and are more likely to have micrognathia than are infants with trisomy 13. Triploidy with 69 chromosomes leads to stillbirth in virtually all cases.
- A 6-month-old male infant is brought to the physician because of failure to thrive and abdominal enlargement. His parents are concerned that he has shown minimal movement since birth. On physical examination, the infant has marked muscle weakness and hepatosplenomegaly. A chest radiograph shows marked cardiomegaly. He dies of congestive heart failure at age 19 months. The microscopic appearance of myocardial fibers at autopsy is shown in the figure. A deficiency of which of the following enzymes is most likely to be present in this infant?
□ (A) Glucocerebrosidase □ (B) Glucose-6-phosphatase □ (C) Hexosaminidase A □ (D) Homogentisic oxidase □ (E) Lysosomal glucosidase □ (F) Myophosphorylase □ (G) Sphingomyelinase
(E) Lysosomal glucosidase
This infant has Pompe disease, a form of glycogen storage disease that results from a deficiency in lysosomal glucosidase (acid maltase). The glycogen stored in the myocardium results in massive cardiomegaly and heart failure within 2 years. Glucocerebrosidase deficiency occurs in Gaucher disease. In the most common form of the disease, there is no neurologic impairment, and patients have splenomegaly and skeletal disease as a consequence of increased lysosomal glucocerebrosides in cells of the mononuclear phagocyte system. Glucose-6-phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Hexosaminidase A deficiency occurs in Tay-Sachs disease and is associated with severe neurologic impairment, poor motor development, and blindness beginning in infancy. Homogentisic oxidase deficiency leads to alkaptonuria with ochronosis or to deposition of a blue-black pigment in joints, resulting in arthropathy. Myophosphorylase deficiency leads to McArdle disease, characterized by muscle cramping after strenuous exercise. Sphingomyelinase deficiency occurs in Niemann-Pick disease; affected individuals with type A have hepatosplenomegaly, lymphadenopathy, and severe motor and mental impairment.
- A 10-year-old child has had recurrent otitis media for the past 8 years. On physical examination, there is hepatosplenomegaly. No external anomalies are present. Laboratory findings include anemia and leukopenia. A bone marrow biopsy is performed, and high magnification of the sample shows the findings depicted in the figure. An inherited deficiency of which of the following enzymes is most likely to produce these findings?
□ (A) Glucocerebrosidase □ (B) Acid maltase □ (C) Glucose-6-phosphatase □ (D) Sphingomyelinase □ (E) Hexosaminidase A
(A) Glucocerebrosidase
This child has one of the three forms of Gaucher disease. Type 1, seen in this child, accounts for 99% of cases and does not involve the central nervous system (CNS). It is caused by a deficiency of glucocerebrosidase, and infusion with this enzyme reduces severity and progression. Type 2 involves the CNS and is lethal in infancy. Type 3 also involves the CNS, although not as severely as type 2. A deficiency of acid maltase is a feature of Pompe disease. Von Gierke disease results from deficiency of glucose-6-phosphatase. Sphingomyelinase deficiency leads to Niemann-Pick disease types A and B. Type A, the more common form, is associated with severe neurologic deterioration. Type B, the less common form, may resemble the findings in this case, but the appearance of macrophages is different: they contain many small vacuoles. Tay-Sachs disease involves a deficiency of hexosaminidase A and is associated with severe mental retardation and death before 10 years of age.
