SINGLE-GENE DISORDERS WITH ATYPICAL INHERITANCE MCQs | MCQ Quiz | OmpathStudy Kenya

Question 1

What is the second most common genetic cause of mental retardation after Down syndrome?

Accepted Answer

Fragile X syndrome — Fragile X syndrome is the second most common genetic cause of mental retardation after Down syndrome, with a frequency of 1 in 1550 for affected males and 1 in 8000 for affected females.

Question 2

What is the normal number of CGG repeats in the FMR1 gene?

Accepted Answer

Around 29 — In the normal population, the number of CGG repeats in the FMR1 gene averages around 29, whereas affected persons have 200 to 4000 repeats (full mutations).

Question 3

What defines a premutation in fragile X syndrome?

Accepted Answer

52-200 CGG repeats — Premutations are characterized by 52 to 200 CGG repeats. Carrier males and females have premutations that can be converted to full mutations (200-4000 repeats) during oogenesis.

Question 4

During which process can premutations be converted to full mutations in fragile X syndrome?

Accepted Answer

Oogenesis only — During oogenesis (but not spermatogenesis), premutations can be converted to full mutations by further amplification of CGG repeats, which can then be transmitted to both sons and daughters.

Question 5

What is the only distinctive physical abnormality detected in at least 90% of postpubertal males with fragile X syndrome?

Accepted Answer

Macroorchidism — The only distinctive physical abnormality that can be detected in at least 90% of postpubertal males with fragile X syndrome is macroorchidism (large testicles).

Question 6

What phenomenon describes the worsening of clinical features with each successive generation in fragile X syndrome?

Accepted Answer

Anticipation — Anticipation refers to the phenomenon whereby clinical features worsen with each successive generation, as the mutation becomes increasingly deleterious as it is transmitted through generations.

Question 7

What percentage of carrier females with fragile X are affected (mentally retarded)?

Accepted Answer

30-50% — From 30% to 50% of carrier females are affected (mentally retarded), a number much higher than that for other X-linked recessive disorders, explained by inheritance of full mutations.

Question 8

What is the molecular basis for fragile X syndrome?

Accepted Answer

Silencing of FMRP due to methylation — When CGG repeats exceed 230, the DNA of the FMR1 gene becomes abnormally methylated, extending to the promoter region, resulting in transcriptional suppression and absence of FMRP.

Question 9

What is the function of FMRP (Familial Mental Retardation Protein)?

Accepted Answer

RNA-binding protein that regulates mRNA translation in synapses — FMRP is an RNA-binding protein transported from cytoplasm to nucleus, where it binds specific mRNAs and transports them to axons and dendrites, regulating translation at synapses.

Question 10

What condition affects approximately 30% of females carrying the fragile X premutation?

Accepted Answer

Premature ovarian failure before age 40 — Approximately 30% of females carrying the premutation have premature ovarian failure (before age 40), indicating that premutations are not benign though abnormalities are milder.

Question 11

What syndrome develops in approximately one-third of premutation-carrying males in their sixth decade?

Accepted Answer

Fragile X-associated tremor-ataxia — About one-third of premutation-carrying males exhibit fragile X-associated tremor-ataxia starting in their sixth decade, characterized by intention tremors and cerebellar ataxia, potentially progressing to parkinsonism.

Question 12

In Huntington disease, when does conversion from premutation to full mutation occur?

Accepted Answer

During spermatogenesis — Unlike fragile X syndrome where expansion occurs during oogenesis, in Huntington disease and some other trinucleotide repeat disorders, premutations are converted to full mutations during spermatogenesis.

Question 13

What type of mutation occurs when trinucleotide repeats affect coding regions?

Accepted Answer

Toxic gain of function — When mutations affect coding regions (like in Huntington disease), they give rise to misfolded proteins that interfere with normal protein function, called toxic gain-of-function mutations.

Question 14

What are diseases involving CAG repeat expansions in coding regions commonly called?

Accepted Answer

Polyglutamine diseases — Diseases involving CAG repeats that encode polyglutamine tracts are referred to as "polyglutamine diseases," which primarily affect the nervous system and feature accumulation of misfolded protein aggregates.

Question 15

Why does maternal inheritance occur in mitochondrial diseases?

Accepted Answer

Ova contain mitochondria while spermatozoa contain few or none — Ova contain mitochondria within their abundant cytoplasm, whereas spermatozoa contain few if any mitochondria. The mitochondrial DNA of the zygote is therefore derived entirely from the ovum.

Question 16

Which organs are most affected by mitochondrial diseases?

Accepted Answer

Skeletal muscle, heart, and brain — Because mitochondrial DNA encodes enzymes for oxidative phosphorylation, diseases from mitochondrial mutations affect organs most dependent on oxidative phosphorylation: skeletal muscle, heart, and brain.

Question 17

What is the prototypical mitochondrial disease?

Accepted Answer

Leber hereditary optic neuropathy — Leber hereditary optic neuropathy is the prototypical mitochondrial disorder, manifesting as progressive bilateral loss of central vision leading to blindness.

Question 18

What is genomic imprinting?

Accepted Answer

Differential inactivation of genes during gametogenesis — Genomic imprinting is an epigenetic process whereby certain genes are differentially inactivated during paternal and maternal gametogenesis, creating functional differences between maternal and paternal gene copies.

Question 19

What molecular mechanism is associated with genomic imprinting?

Accepted Answer

Methylation of gene promoter — At the molecular level, imprinting is associated with methylation of the gene promoter, as well as histone protein modifications, which silence the gene.

Question 20

What chromosomal region is deleted in both Prader-Willi and Angelman syndromes?

Accepted Answer

Chromosome 15q11-q13 — Both Prader-Willi and Angelman syndromes involve deletion of band q12 in the long arm of chromosome 15 (15q11-q13), but the parent of origin differs.

Question 21

In Prader-Willi syndrome, which parental chromosome is deleted?

Accepted Answer

Paternal — In Prader-Willi syndrome, the deletion affects the paternally derived chromosome 15 in all cases, demonstrating parent-of-origin effects on gene function.

Question 22

What clinical features characterize Prader-Willi syndrome?

Accepted Answer

Mental retardation, obesity, small hands/feet, hypogonadism — Prader-Willi syndrome is characterized by mental retardation, short stature, hypotonia, obesity, small hands and feet, and hypogonadism.

Question 23

In Angelman syndrome, which parental chromosome is deleted?

Accepted Answer

Maternal — In Angelman syndrome, the deletion affects the maternally derived chromosome 15, in contrast to Prader-Willi syndrome where the paternal chromosome is deleted.

Question 24

What clinical features characterize Angelman syndrome?

Accepted Answer

Mental retardation, ataxic gait, seizures, inappropriate laughter — Angelman syndrome patients are mentally retarded and present with ataxic gait, seizures, and inappropriate laughter, giving rise to the name "happy puppet syndrome."

Question 25

What is uniparental disomy?

Accepted Answer

Inheritance of both chromosomes of a pair from one parent — Uniparental disomy is the inheritance of both chromosomes of a pair from one parent. In Prader-Willi syndrome, this can occur when both copies of chromosome 15 are from the mother.

Question 26

What gene is responsible for Angelman syndrome?

Accepted Answer

UBE3A — The Angelman syndrome gene is UBE3A, which encodes a ligase in the ubiquitin-proteasome proteolytic pathway and is expressed primarily from the maternal allele in specific brain regions.

Question 27

What does maternal imprinting mean?

Accepted Answer

The maternal allele is inactivated — Maternal imprinting refers to transcriptional silencing of the maternal allele, whereas paternal imprinting means the paternal allele is inactivated.

Question 28

How many CGG repeats define a full mutation in fragile X syndrome?

Accepted Answer

200-4000 — Full mutations in fragile X syndrome are characterized by 200 to 4000 CGG repeats, which arise through expansion of premutations (52-200 repeats).

Question 29

Why can Prader-Willi syndrome result from maternal uniparental disomy of chromosome 15?

Accepted Answer

Patient lacks functional genes from nonimprinted paternal chromosome — Maternal uniparental disomy means the patient has both copies from the mother and lacks functional genes from the nonimprinted paternal chromosome 15, resulting in the same effect as paternal deletion.

Question 30

Approximately how many diseases are now known to be caused by trinucleotide repeat mutations?

Accepted Answer

About 40 — About 40 diseases are now known to be caused by trinucleotide repeat mutations, and all disorders discovered so far are associated with neurodegenerative changes.

Question 31

What percentage of Prader-Willi syndrome cases show an interstitial deletion detectable by standard cytogenetics?

Accepted Answer

60-75% — In 60% to 75% of Prader-Willi syndrome cases, an interstitial deletion of band q12 in chromosome 15—del(15)(q11;q13)—can be detected. Many others have smaller deletions detectable by FISH.

Question 32

Which technique can detect smaller deletions in Prader-Willi syndrome not visible by standard cytogenetics?

Accepted Answer

FISH analysis — In patients without detectable cytogenetic abnormality, FISH (Fluorescence In Situ Hybridization) analysis can reveal smaller deletions within the same chromosomal region.

Question 33

Where is FMRP most highly expressed in normal tissues?

Accepted Answer

Brain and testis — FMRP is widely expressed in normal tissues, but higher levels are found in the brain and the testis, which correlates with the clinical manifestations of fragile X syndrome.

Question 34

What is the original diagnostic method that gave fragile X syndrome its name?

Accepted Answer

Culturing cells in folate-deficient medium showing X chromosome discontinuity — The syndrome gets its name from culturing patient cells in folate-deficient medium, which revealed a discontinuity of staining or constriction in the long arm of the X chromosome. This method is now replaced by DNA-based analysis.

Question 35

What is the chromosomal location of the FMR1 gene?

Accepted Answer

Xq27.3 — The FMR1 gene maps to Xq27.3 on the long arm of the X chromosome, and mutations in this gene result in fragile X syndrome.

Question 36

Can mothers transmit mitochondrial DNA to their sons?

Accepted Answer

Yes, to both sons and daughters — Mothers transmit mitochondrial genes to all their offspring, both male and female; however, only daughters (not sons) transmit the DNA further to their progeny.

Question 37

What is the net effect of having genes from the nonimprinted paternal chromosome 15 in Prader-Willi syndrome?

Accepted Answer

No functional genes available since maternal copies are imprinted — Genes on the maternal chromosome 15 are imprinted (silenced), so the only functional alleles come from the paternal chromosome. Loss of these leads to Prader-Willi syndrome.

Question 38

What happens when the number of trinucleotide repeats exceeds approximately 230 in the FMR1 gene?

Accepted Answer

DNA becomes abnormally methylated — When CGG repeats exceed approximately 230, the DNA of the entire 5' region becomes abnormally methylated, extending to the promoter region, resulting in transcriptional suppression.

Question 39

In trinucleotide repeat disorders affecting noncoding regions, what is the typical outcome?

Accepted Answer

Loss of function due to suppressed protein synthesis — When mutations affect noncoding regions (like in fragile X syndrome), there is loss of function since protein synthesis is suppressed, in contrast to coding region mutations that cause toxic gain of function.

Question 40

What common feature is seen in polyglutamine diseases?

Accepted Answer

Accumulation of misfolded proteins in cytoplasmic aggregates — Accumulation of misfolded proteins in aggregates within the cytoplasm is a common feature of polyglutamine diseases resulting from CAG repeat expansions in coding regions.

Question 41

Why is Prader-Willi syndrome thought to result from loss of multiple genes rather than a single gene?

Accepted Answer

Several genes in the region are lost, unlike Angelman which involves one gene — Prader-Willi syndrome, unlike Angelman syndrome, probably is caused by loss of function of several genes located on chromosome 15 between q11 and q13, which are still being fully characterized.

Question 42

When is imprinting established?

Accepted Answer

In ovum or sperm and then stably transmitted to all somatic cells — Imprinting occurs in ovum or sperm (during gametogenesis) and is then stably transmitted to all somatic cells derived from the zygote.

Question 43

What type of disorders are predominantly associated with trinucleotide repeat mutations?

Accepted Answer

Neurodegenerative disorders — All trinucleotide repeat disorders discovered so far are associated with neurodegenerative changes, affecting primarily the nervous system.

Question 44

In normal individuals, which regions of the brain primarily express UBE3A from the maternal allele?

Accepted Answer

Specific regions of the brain — UBE3A is expressed primarily from the maternal allele in specific regions of the normal brain. In Angelman syndrome, UBE3A is not expressed in these areas, causing neurologic manifestations.

Question 45

What is the threshold number of CGG repeats above which abnormal methylation occurs in fragile X syndrome?

Accepted Answer

Approximately 230 — When the number of trinucleotide repeats in the FMR1 gene exceeds approximately 230, the DNA of the entire 5' region becomes abnormally methylated, leading to gene silencing.

Question 46

What is the role of FMRP-mRNA complexes in synapses?

Accepted Answer

Regulating translation of specific mRNAs — In synapses, FMRP-mRNA complexes perform critical roles in regulating the translation of specific mRNAs. The absence of this finely coordinated shuttle function underlies fragile X syndrome.

Question 47

What distinguishes the clinical presentation of males versus females with fragile X syndrome?

Accepted Answer

Males have moderate to severe mental retardation; 30-50% of carrier females are affected — Clinically affected males have moderate to severe mental retardation, while 30-50% of carrier females are affected (mentally retarded), much higher than typical X-linked recessive disorders.

Question 48

What happens during the conversion of premutation to full mutation in fragile X syndrome?

Accepted Answer

Further amplification of CGG repeats occurs — During oogenesis, premutations (52-200 repeats) can be converted to full mutations (200-4000 repeats) by further amplification of the CGG repeats.

Question 49

Why do Prader-Willi and Angelman syndromes demonstrate "parent-of-origin" effects?

Accepted Answer

Different genes are imprinted on maternal versus paternal chromosomes — These syndromes demonstrate parent-of-origin effects because different genes within the same region are imprinted on maternal versus paternal chromosomes, so deletion of maternal or paternal chromosome 15 produces distinct clinical syndromes.

SINGLE-GENE DISORDERS WITH ATYPICAL INHERITANCE MCQs | MCQ Quiz | OmpathStudy Kenya

Questions, Answers & Explanations