Lysosomal storage disorders Flashcards
Enzyme of Gaucher disease?
Beta-glucocerebrosidase
AJ husband with brother dying of congenital condition in his early 40s. Which of the following does the husband have the highest risk to be a carrier?
A.Cystic fibrosis
B.Familial dysautonomia
C.Gaucher disease
D.Tay–Sachs disease
E.None of the above
C.Gaucher disease
What is the gene symbol for Gaucher disease?
GBA
Which one of the following assays is most likely be used to test the for Gaucher carrier status?
A.Chromosome microarray
B.Exome sequence analysis
C.Multiplex ligation-dependent probe amplification (MLPA)
D.Next-generation sequencing panel
E.Sanger sequence analysis
F.Target variant analysis
G.None of the above
F.Target variant analysis
Four variants, N370S, L444P, 84GG, and IVS2+1, account for approximately 90% of the pathogenic variants in Ashkenazi Jewish individuals with type 1 Gaucher disease.
Husband carrier of the L444P variant in GBA. Which one of the following genetic studies most likely is the next step in the conception planning workup for this couple?
A.Testing the husband for glucocerebrosidase enzyme activity B.Testing the husband with a sequence assay for GBA with reflex to deletion/duplication
C.Testing the wife for glucocerebrosidase enzyme activity
D.Testing the wife for the four common GBA pathogenic variants in Ashkenazi Jews
E.Testing the wife with a sequencing assay for GBA
F.None of the above
E.Testing the wife with a sequencing assay for GBA
What is the false negative rate for targeted Gaucher testing in an unaffected AJ individual with family history?
A.>99%
B.80%
C.45%
D.10%
E.<1%
D.10%
The four pathogenic variants (N370S, L444P, 84GG, and IVS2+1) in GBA account for approximately 90% of the Gaucher disease (GD)–causing alleles in the Ashkenazi Jewish population.
What is the false negative rate for targeted Gaucher testing in an unaffected non-Jewish individual with family history?
A.>99%
B.80%
C.45%
D.10%
E.<1%
C.45%
In non-Jewish populations, the same four alleles account for approximately 50%–60% of disease-causing alleles.
What is the most common pathogenic variant of GBA in a patient with hepatosplenomegaly and osteopenia?
A.84GG: c.84dupG(p.Leu29AlafsTer18)
B.IVS2+1G>A: c.115+1G>A
C.L444P: c.1448T>C(p.Leu483Pro)
D.N370S: c.1226A>G(p.Gly416Ser)
E.None of the above
D.N370S: c.1226A>G(p.Gly416Ser)
Individuals with at least one N370S allele do not develop primary neurological disease. However, the risk for Parkinson disease among individuals with GD is not precluded by the presence of an N370S allele.
What is the most common pathogenic variant of GBA in a patient with early adult seizures (GD types 2 and 3)?
A.84GG: c.84dupG(p.Leu29AlafsTer18)
B.IVS2+1G>A: c.115+1G>A
C.L444P: c.1448T>C(p.Leu483Pro)
D.N370S: c.1226A>G(p.Gly416Ser)
E.None of the above
C.L444P: c.1448T>C(p.Leu483Pro)
c.1448T>C(p.Leu483Pro) variant, historically called “L444P,” tend to have severe disease,
Prenatal testing shows GBA N370S. Which one of the following symptoms would the unborn baby most likely NOT have in postnatal life?
A.Anemia
B.Hepatosplenomegaly
C.Osteopenia
D.Seizure
E.None of the above
D.Seizure
Prenatal testing shows GBA L444P. Which one of the following symptoms would the unborn baby most likely NOT have in postnatal life?
A.Anemia
B.Arrhythmia
C.Hepatosplenomegaly
D.Osteopenia
E.Seizure
B.Arrhythmia
Prenatal testing shows GBA L444P. Which one of the following symptoms would the unborn baby most LIKELY have in postnatal life?
A.Arrhythmia
B.Developmental delay
C.Odd-smelling urine
D.Seizures
E.Sudden death
D.Seizures
Unaffected AJ couple in conception planning. What is the risk of the couple’s firstborn child having Gaucher disease?
A.1/54
B.1/108
C.3/288
D.1/144
E.None of the above
B.1/108 .
1 in 18 carrier in AJ
2/3 risk of being a carrier
2/3 x 1/18 x 1/4 = 1/108
Unaffected AJ couple in conception planning with two healthy boys. What is the risk of the couple’s next child having Gaucher disease?
A.1/54
B.1/108
C.1/216
D.1/417
E.1/1668
F.None of the above
C.1/216
1/18 x 1/3 (husband being a carrier ) x 1/4 = 1/216
prior (1/3)
conditional (1/4)
joint (1/6)
The molecular results revealed a compound heterozygous genotype, p.N370S/p.L444P, in GBA. Which one of the following symptoms would this patient most likely NOT develop in his lifetime due to Gaucher disease?
A.Hepatomegaly
B.Seizure
C.Splenomegaly
D.Thrombocytopenia
E.None of the above
B.Seizure
A molecular genetic test detects N370S/L444P variants in GBA, which confirms the diagnosis of Gaucher disease. For which one of the following diseases does this patient NOT have an increased risk?
A.Hepatocarcinoma
B.Melanoma
C.Multiple myeloma
D.Non-Hodgkin’s lymphoma
E.Osteosarcoma
F.Pancreatic cancer
G.Parkinson disease
H.None of the above
E.Osteosarcoma
The diagnosis of hexosaminidase A deficiency relies on the demonstration of which one of the following?
A.Deficiency of alpha-hexosaminidase B (HEX B) enzymatic activity
B.Deficiency of beta-hexosaminidase A (HEX A) enzymatic activity
C.Sequence analysis of HEXA with reflex to del/dup analysis
D.Sequence analysis of HEXB with reflex to del/dup analysis
E.Targeted HEXA mutation analysis
F.Targeted HEXB mutation analysis
B.Deficiency of beta-hexosaminidase A (HEX A) enzymatic activity
Tay–Sachs disease is caused by deficiency of which one of the following?
A.Beta-hexosaminidase A
B.Beta-hexosaminidase B
C.Beta-hexosaminidase A and B
D.Beta-galactosidase
E.Beta-glucocerebrosidase
A.Beta-hexosaminidase A
In which one of the following populations is the carrier frequency of Tay–Sachs disease relatively lower?
A.Ashkenazi Jewish
B.French Canadians
C.Louisiana Cajuns
D.Pennsylvania Amish
E.Mormons in Utah
E.Mormons in Utah
Which one of the following does NOT explain why Tay–Sachs disease has increased prevalence in the Ashkenazi Jewish population?
A.Bottleneck effect
B.Founder effect
C.Genetic drift
D.Heterozygous advantage
E.None of the above
D.Heterozygous advantage
Husband has decreased beta-hexosaminidase A (50%). Wife is Greek. Which one of the following studies is the most appropriate next step in the workup for this couple as a part of the prenatal care?
A.Order targeted HEXA pathogenic variant analysis for the husband.
B.Order targeted HEXA pathogenic variant analysis for the wife.
C.Order HEXA sequence analysis reflex to del/dup analysis for the husband.
D.Order HEXA sequence analysis reflex to del/dup analysis for the wife.
E.Test the wife for beta-hexosaminidase A (HEX A) enzymatic activity.
F.Test the unborn child for beta-hexosaminidase A (HEX A) enzymatic activity.
G.Wait for the child to be born, then test the child. H.No follow-up is necessary.
A.Order targeted HEXA pathogenic variant analysis for the husband.
two pseudodeficiency alleles (p.Arg247Trp and p.Arg249Trp) are not associated with neurological disease, but are associated with reduced degradation of the synthetic substrate when HEX A enzymatic activity is determined. The presence of one pseudodeficiency allele reduces HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside.
About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme–based testing are carriers of a pseudodeficiency allele. About 2% of Jewish individuals identified as heterozygotes by HEX A enzyme–based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele
A targeted HEXA pathogenic variant analysis confirms that the husband carries the p.Tyr427IlefsTer5 pathogenic variant. Wife is nonAJ. Which one of the following studies is the most appropriate next step in the workup for this couple as a part of prenatal care?
A.Order targeted HEXA pathogenic variant analysis for the unborn child.
B.Order targeted HEXA pathogenic variant analysis for the wife.
C.Order HEXA sequence analysis reflex to del/dup analysis for the unborn child.
D.Order HEXA sequence analysis reflex to del/dup analysis for the wife.
E.Test the wife for beta-hexosaminidase A (HEX A) enzymatic activity.
F.Test the unborn child for beta-hexosaminidase A (HEX A) enzymatic activity.
G.Wait for the child to be born, then test the child. H.No follow-up is necessary.
E.Test the wife for beta-hexosaminidase A (HEX A) enzymatic activity.
A targeted HEXA pathogenic variant analysis confirms that the husband carries the p.Tyr427IlefsTer5 pathogenic variant. A HEXA enzymatic activity study with leukocytes from the wife reveals that her enzymatic activity is also decreased to approximately 50%. Which one of the following studies is the most appropriate next step in the workup for this couple as a part of prenatal care?
A.Order targeted HEXA pathogenic variant analysis for the unborn child.
B.Order targeted HEXA pathogenic variant analysis for the wife.
C.Order HEXA sequence analysis reflex to del/dup analysis for the unborn child.
D.Order HEXA sequence analysis reflex to del/dup analysis for the wife.
E.Test the wife for beta-hexosaminidase A (HEX A) enzymatic activity.
F.Test the unborn child for beta-hexosaminidase A (HEX A) enzymatic activity.
G.Wait for the child to be born, then test the child.
H.No follow-up is necessary.
B.Order targeted HEXA pathogenic variant analysis for the wife.
A targeted HEXA pathogenic variant analysis confirms that the husband carries the p.Tyr427IlefsTer5 pathogenic variant. A HEX A enzymatic activity study with leukocytes from the nonAJ wife reveals that her enzyme activity is also decreased to approximately 50%. What is the chance that the wife is NOT a silent carrier of Tay–Sachs disease?
A.90%
B.50%
C.35%
D.10%
E.2%
C.35%
A targeted HEXA pathogenic variant analysis confirms that the husband carries the p.Tyr427IlefsTer5 pathogenic variant. A HEX A enzymatic activity study with leukocytes from the wife reveals that her enzyme activity is also decreased to approximately 50%. A targeted HEXA pathogenic variant analysis detects a variant, p.Arg247Trp, in the wife. Which one of the following most likely is the risk of the unborn child to develop Tay–Sachs disease?
A.<1%
B.25%
C.50%
D.67%
E.>99%
F.Cannot predict
G.None of the above
A.<1%
The HEXA gene variant p.Arg247Trp is a pseudodeficiency allele
Patient is French Canadian. Which one of the following pathogenic variants in the HEXA gene does the physician try to make sure is covered by the ordered test?
A.c.1073+G>A
B.c.1421+1G>C
C.p.Gly269Ser
D.p.Tyr427IlefsTer5
E.7.6-kb genomic deletion involving HEXA
F.None of the above
E.7.6-kb genomic deletion involving HEXA
The husband had a paternal uncle living in a psychiatric home without a clear diagnosis. A targeted molecular analysis confirmed that the wife is a carrier, but not the husband. The carrier frequency of TSD in Ashkenazi Jews is 1 in 30. If the detection rate of the molecular assay is 90% in Ashkenazi Jews, what is the residual risk of their first child having TSD?
A.1/291
B.1/582
C.1/1164
D.1/2328
E.None of the above
C.1/1164
Prior probability of carrier 1 in 30
Detection rate 90%
Conditional probability is 10% or 1 in 10
Joint probability is 1/300
Posterior probability is 1/291
1/291 x 1/4 = 1/1164
The HEX A enzyme study indicates that he is a carrier. However, the targeted molecular study with the six common variants in HEXA (p.Tyr427IlefsTer5, c.1421+1G>C, c.1274_1277dupTATC, p.Gly269Ser, p.Arg247Trp, and p.Arg249Trp) did not detect a pathogenic variant. What is the false negative rate of the targeted molecular study with the six common variants in HEXA?
A.90%
B.50%
C.35%
D.10%
E.5%
E.5%
Between 1 and 6% for HEXA
In adult-onset variant, which one of the following pathogenic variants in the HEXA gene would the patient most likely have?
A.c.1073+1G>A
B.c.1274_1277dupTATC(p.Tyr427IlefsTer5)
C.c.1421+1G>C
D.c.533G>A(p.Arg178His)
E.c.739C>T(p.Arg247Trp)
F.c.745C>T(p.Arg249Trp)
G.c.805G>A(p.Gly269Ser)
H.7.6-kb genomic deletion involving HEXA
I.Not sure
G.c.805G>A(p.Gly269Ser)
infantile - c.1073+1G>A
c.1274_1277dupTATC(p.Tyr427IlefsTer5)
c.1421+1G>C
19 mo Portuguese boy with leukodystrophic changes and cherry-red macula. A molecular analysis further confirmed the diagnosis by detection of two compound heterozygous pathogenic variants. Which one of the following pathogenic variants in the HEXA gene would the patient most likely have?
A.c.1073+1G>A
B.c.1274_1277dupTATC(p.Tyr427IlefsTer5)
C.c.1421+1G>C
D.c.533G>A(p.Arg178His)
E.c.739C>T(p.Arg247Trp)
F.c.745C>T(p.Arg249Trp)
G.c.805G>A(p.Gly269Ser)
H.7.6-kb genomic deletion involving HEXA
I.Not sure
D.c.533G>A(p.Arg178His)
The c.1073+G>A, c.1274_1277dupTATC(p.Tyr427IlefsTer5), c.1421+1G>C, and c.533G>A(p.Arg178His) pathogenic variants are null alleles, which in the homozygous state or in compound heterozygosity are associated with Tay–Sachs disease (TSD).
The p.Arg178His pathogenic variant predominantly found in individuals of Portuguese background
The null allele, c.1073+1G>A is in about 10%–15% of individuals with Celtic, French Canadian (specifically
Infant parents AJ and French Canadian. Further confirmation was made by detection of two compound heterozygous pathogenic variants through molecular analysis. Which one of the following pathogenic variants in the HEXA gene would the patient most likely NOT have?
A.c.1073+1G>A B.c.1274_1277dupTATC(p.Tyr427IlefsTer5) C.c.1421+1G>C
D.c.805G>A(p.Gly269Ser)
E.7.6-kb genomic deletion involving HEXA
F.Not sure
D.c.805G>A(p.Gly269Ser) - adult onset
A lysosomal enzyme assay of the peripheral blood revealed that both β-hexosaminidases A and B isoenzyme were absent in the serum. Brain and spinal cord affected. Which one of the lysosomal disorders would the patient most likely have?
A.Gaucher disease
B.Niemann–Pick disease
C.Sandhoff disease
D.Tay–Sachs disease
E.None of the above
C.Sandhoff disease
Enzymatic assays were performed and revealed a deficiency of both hexosaminidases A and B, confirming the diagnosis of Sandhoff disease. A molecular study was ordered to further confirm the diagnosis and for family counseling. Which one of the following genes would most likely be tested to detect Sandhoff disease in this patient?
A.GBA
B.GM2A
C.HEXA
D.HEXB
E.SMPD1
D.HEXB
other - Pathogenic variants in the GM2A gene cause GM2-gangliosidosis, AB variant.
A sequence study for the HEXB gene was ordered to further confirm the diagnosis and for family counseling. A heterozygous pathogenic variant, c.619A>G (p.Ile207Val), was detected. Which one of following would most likely describe the pathogenesis of Sandhoff disease in this patient?
A.Dominant negative
B.Gain of function
C.Haploinsufficiency
D.Loss of function
E.None of the above
D.Loss of function
Creole population of northern Argentina; the Metis Indians in Saskatchewan, Canada; and people from Lebanon.
AJ preconception counseling with no FHx. Genetic counseling is done, and an Ashkenazi Jewish panel is offered. Which one of following is the most appropriate first step in the workup for this couple?
A.Test the husband immediately.
B.Test the wife immediately.
C.Test both the wife and the husband immediately. D.Perform a noninvasive prenatal test when the wife is pregnant.
E.Test the fetus with CVS when the wife is pregnant. F.Test the fetus with amniocentesis when the wife is pregnant.
G.None of the above.
B.Test the wife immediately.
X-linked conditions on the testing panel for which only females are screened.
AJ prenatal testing at 6 weeks counseling with no FHx. Genetic counseling is done, and an Ashkenazi Jewish panel is offered. Which one of following is the most appropriate first step in the workup for this couple?
A.Test the husband immediately.
B.Test the wife immediately.
C.Test both the wife and the husband immediately. D.Perform a noninvasive prenatal test when the wife is pregnant.
E.Test the fetus with CVS when the wife is pregnant. F.Test the fetus with amniocentesis when the wife is pregnant.
G.None of the above.
C.Test both the wife and the husband immediately.
If the woman is already pregnant, both partners must be screened simultaneously.
AJ and Eastern European preconception counseling with no FHx. Genetic counseling is done, and an Ashkenazi Jewish panel is offered. Which one of following is the most appropriate first step in the workup for this couple?
A.Test the husband immediately.
B.Test the wife immediately.
C.Test both the wife and the husband immediately. D.Perform a noninvasive prenatal test when the wife is pregnant.
E.Test the fetus with CVS when the wife is pregnant. F.Test the fetus with amniocentesis when the wife is pregnant.
G.None of the above.
A.Test the husband immediately.
If only one partner is of a Jewish background, that partner should be screened first. If he or she is found to be a carrier of a specific disease(s), the other partner must be screened for that disease(s), if they want to know their risk for having a child with that disease(s).
18 mo boy with 2nd degree consanguinity and PAS negative lipid laden histiocytes. A lysosomal enzyme assay of peripheral blood revealed that acid sphingomyelinase (ASM) was absent in the serum. Which one of the lysosomal disorders would the patient most likely have?
A.Gaucher disease
B.Niemann–Pick disease
C.Sandhoff disease
D.Tay–Sachs disease
E.None of the above
B.Niemann–Pick disease
NPD type B is a nonneuronopathic type of acid sphingomyelinase (ASM) deficiency.
Which one of the following genes would most likely be tested for Niemann–Pick disease in this patient?
A.GBA
B.GM2A
C.HEXA
D.HEXB
E.SMPD1
E.SMPD1
SMPD1 and NPD1 are the genes associated with NPD. SMPD1 is associated with type A and type B NPD and NPC1 and NPC2 with type C NPD
The carrier frequency is 1 in 90 in the Ashkenazi Jewish population.
The prevalence is estimated to be 1 in 250,000 in the general population.
A multigene panel for lysosomal storage disorders detected a heterozygous pathogenic variant, c.1829_1831delGCC (p.Arg608Del), in SMPD1. Which one of the following would be the most cost-effective next step in the workup for this patient?
A.Diagnose the patient with Niemann–Pick disease and follow with appropriate treatment.
B.Diagnose the patient with acid sphingomyelinase deficiency and follow with appropriate treatment.
C.Perform deletion and duplication analysis of the genes in the multigene panel for lysosomal storage disorders.
D.Perform deletion and duplication analysis of the SMPD1 gene.
E.None of the above.
D.Perform deletion and duplication analysis of the SMPD1 gene.
In NPD type B, the variant p.Arg610del may account for almost 90% of pathogenic alleles in individuals from the Maghreb region of North Africa (i.e., Tunisia, Algeria, and Morocco), 100% of pathogenic alleles in Gran Canaria Island, and about 20%–30% of pathogenic variants in the United States.
c.1829_1831delGCC(p.Arg608Del)
c.416T>C(p.Leu139Pro)
c.592G>C(p.Ala198Pro)
c.1426C>T(p.Arg476Trp)
A 19 mo AJ girl with a diagnosis of Niemann–Pick disease type A. Which one of the following pathogenic variants in SMPD1 would the patient most likely have?
A.c.1493G>T(p.Arg498Leu)
B.c.1829_1831delGCC(p.Arg608Del) C.c.416T>C(p.Leu139Pro)
D.c.592G>C(p.Ala198Pro)
E.c.1426C>T(p.Arg476Trp)
F.None of the above
A.c.1493G>T(p.Arg498Leu)
In NPD type A, three variants (p.Arg498Leu, p.Leu304Pro, p.Phe333SerfsTer52) account for approximately 90% of pathogenic alleles in the Ashkenazi Jewish population.
p.L302P (Leu304Pro): This missense mutation is a common cause of NPD-A in the Ashkenazi Jewish population.
A lysosomal enzyme assay of peripheral blood revealed that galactocerebrosidase (GALC) enzyme activity was 2% of normal in leukocytes. Which one of the lysosomal disorders would the patient most likely have?
A.Gaucher disease
B.Krabbe disease
C.Niemann–Pick disease
D.Sandhoff disease
E.Tay–Sachs disease
F.None of the above
B.Krabbe disease
A molecular study was ordered to further confirm the diagnosis of Krabbe disease and for family counseling. Which one of the following genes would most likely be tested for Krabbe disease in this patient?
A.GALC
B.GBA
C.GM2A
D.HEXA
E.HEXB
F.SMPD1
A.GALC
The physician ordered a molecular study for GALC, and the result was positive. Which one of the following would most likely be the finding of the molecular study in this patient?
A.Compound heterozygosity for a 30kb deletion and c.857G>A(p.Gly286asp)
B.Heterozygosity for c.857G>A(p.Gly286asp) C.Homozygosity for a 30-kb deletion
D.Homozygosity for c.857G>A(p.Gly286asp)
E.Negative
F.None of the above
C.Homozygosity for a 30-kb deletion
45% of infantile Krabbe
Three other pathogenic variants associated with the infantile phenotype, c.1586C>T(p.Thr529Met), c.1700A>C(p.Tyr567Ser), and c.1472delA(p.Lys491ArgfsTer62), make up another 15% of the mutant alleles in individuals of European ancestry
Urine examination revealed an increased amount of heparan sulfate and dermatan sulfate. Lysosomal enzyme study revealed absence of α-L-iduronidase. Which one of the lysosomal disorders would the patient most likely have?
A.Hunter syndrome
B.Hurler syndrome
C.Krabbe disease
D.Niemann–Pick disease
E.Sanfilippo syndrome
F.None of the above
B.Hurler syndrome (mucopolysaccharidosis II)
Sanfilippo syndrome (mucopolysaccharidosis III) is associated with a deficiency in one of the enzymes needed to break down the glycosaminoglycan heparan sulfate. - α-N-acetylglucosaminidase (NAGLU) gene mutations.
17 mo boy with coarse facial features, hepatosplenomegaly and skeletal dysplasia. The urinary glycosaminoglycan (GAG) was elevated. A lysosomal enzyme study revealed absence of α-L-iduronidase enzyme activity in leukocytes. A molecular study was ordered to further confirm the diagnosis of Hurler syndrome and for family counseling. Which one of the following genes would most likely be tested for Hurler syndrome in this patient?
A.GALC
B.HEXA
C.IDS
D.IDUA
E.None of the above
D.IDUA
Hurler mucopolysaccharidosis type I
IDS- Hunter syndrome mucopolysaccharidosis type II
Sanfilippo syndrome (mucopolysaccharidosis III) - SGSH, NAGLU, HGSNAT, and GNS gene mutations
2 yr old with ID, hepatosplenomegaly and respiratory infections. Lysosomal enzyme study revealed absence of iduronate 2-sulfatase (I2S) enzyme activity in leukocytes. Which one of the lysosomal disorders would the patient most likely have?
A.Hunter syndrome
B.Hurler syndrome
C.Krabbe disease
D.Niemann–Pick disease
E.Sanfilippo syndrome
F.None of the above
A.Hunter syndrome
A molecular study was ordered to further confirm the diagnosis of Hunter syndrome and for family counseling. Which one of the following genes would most likely be tested for Hunter syndrome in this patient?
A.GALC
B.HEXA
C.IDS
D.IDUA
E.None of the above
C.IDS
iduronate-2-sulfatase (I2S).
Pregnant mother with an affected child with Hunter syndrome, older unaffected child. Which one of the following would most likely describe the estimated risk of the unborn boy developing the same condition?
A.>99%
B.1/2
C.1/4
D.Up to 1%.
E.Not predictable
F.None of the above
B.1/2
Hunter X-linked carrier so
Urine analysis showed the presence of glycosaminoglycans (GAGs). His serum alkaline phosphatase level was increased to 539IU/L. Lysosomal enzyme study revealed absence of iduronate 2-sulfatase (I2S) enzyme activity in the white blood cells. The patient was diagnosed with Hunter syndrome. A Sanger sequencing analysis of IDS did not detect pathogenic variants. The reflex deletion/duplication study also did not detect pathogenic imbalances. Which one of the following would most likely explain the molecular results in this patient?
A.A promoter variant missed by Sanger sequencing
B.A translocation involving IDS
C.Unequal recombination between IDS and IDSP1 D.Wrong diagnosis
E.None of the above
C.Unequal recombination between IDS and IDSP1
heparan and dermatan sulfate (two forms of glysosaminoglycans, or GAGs) in lysosomes,
The IDS gene consists of nine exons and spans about 24kb of genomic DNA. An IDS pseudogene, IDSP1, is located about 25kb telomeric to IDS. Homologous regions shared by IDS and IDSP1 predispose to unequal recombination events, leading to complex rearrangements and sometimes large deletions
Sequence analysis may detect 82% of pathogenic variants within IDS. Gene-targeted deletion/duplication analysis detects 9% of patients. Complex rearrangements, resulting from recombination with the IDSP1 pseudogene or from other processes, may be seen in 9% of patients.
Arylsulfatase A enzyme activity in leukocytes decreased to 5.3% of normal in a patient with, hypocalcemia, dysmyelination or demyelination and metachromatic leukodystrophy. Which one of the lysosomal disorders would the patient most likely have?
A.Hunter syndrome
B.Hurler syndrome
C.Metachromatic leukodystrophy
D.X-linked adrenoleukodystrophy
E.Zellweger syndrome spectrum disorders
F.None of the above
C.Metachromatic leukodystrophy
Which one of the following genes would most likely be tested for metachromatic leukodystrophy in this patient?
A.ABCD1
B.ARSA
C.IDS
D.IDUA
E.PEX1
F.None of the above
B.ARSA
Which one of the following explains why development of an NBS test for MLD is a challenge?
A.Instability of the enzyme in dried blood spots B.Widespread occurrence of pseudodeficiency alleles C.Lack of available urine samples from NBS programs D.All of the above
E.None of the above
D.All of the above
sulfatides in urine
Which one of the genes would most likely NOT be included in the carrier panel for Ashkenazi Jews?
A.CFTR
B.GBA
C.HEXA
D.SMPD1
E.SMPD2
E.SMPD2
SMPD2 associated with type C of NPD would most likely NOT be included in the carrier panel for Ashkenazi Jews.
Which one of the following genes would most likely NOT be included in the carrier panel for Ashkenazi Jews?
A.ASPA
B.ELP1 (IKBKAP)
C.GLA
D.MEFV
E.None of the above
C.GLA
The carrier frequency of familial dysautonomia in Ashkenazi Jews is approximately 1 in 31. ELP1 (IKBKAP) is the only gene in which pathogenic variants cause familial dysautonomia;
Mediterranean fever in Ashkenazi Jews is approximately 1 in 13. MEFV is the only gene in which pathogenic variants cause familial
Electron microscopy studies showed typical zebra bodies. His serum α-galactosidase A (α-Gal A) enzyme activity was <1% of normal. Which one of the lysosomal disorders would the patient most likely have?
A.Fabry disease
B.Farber disease
C.Hunter syndrome
D.Hurler syndrome
E.Pompe disease
F.None of the above
A.Fabry disease
Plasma and urine samples, which were taken after admission, showed a significant decrease in GLA level (3.5 AgalU; normal in male, >15.0 AgalU), and a significant increase in the globotriaosylceramide (GL3) level (plasma 9.1g/mL [reference range, 3.9–9.9]), urine 5.11g/mgCr (reference range, 0.01–0.9).Which one of the following genes would most likely be tested for Fabry disease in this patient?
A.ABCD1
B.ARSA
C.GBA
D.GLA
E.None of the above
D.GLA
Biochemical confirmation of the clinical and histological diagnoses of Fabry disease was made by determining the leukocyte α-Gal A activity, which was totally deficient. Subsequently, a molecular assay for the GLA gene was ordered to confirm the diagnosis. Which one of the following molecular assays would most likely be used as a first-tier test to detect pathogenic variants for Fabry disease in this patient?
A.Chromosome microarray (CMA)
B.Multiplex ligation-dependent probe amplification (MLPA)
C.Next-generation sequencing (NGS)
D.Sanger sequencing
E.Target variant analysis of the founder pathogenic variants
F.None of the above
D.Sanger sequencing
More than 800 GLA pathogenic variants have been identified,
In a study of the Taiwan Chinese population, an unexpectedly high prevalence of the cardiac-variant Fabry-causing pathogenic variant c.640–801G>A (also known as IVS4+919G>A and c.639+919G>A) was found among newborns
1 in 50,000 to 1 in 117,000 males.
Targeted analysis for the IVS4+919G>A pathogenic variant can be performed first in individuals of Chinese ancestry with atypical presentation. Targeted analysis for the p.Ala143Pro pathogenic variant can be performed first in individuals from Nova Scotia (incidence 1 in 15,000)
Neonate with cardiac hypertrophy. The blood acid alpha-glucosidase (GAA) enzyme activity was 0.1pmol/punch/h (normal range, 2.88–89.02). Which one of the following lysosomal disorders would the patient most likely have?
A.Fabry disease
B.Farber disease
C.Hunter syndrome
D.Hurler syndrome
E.Pompe disease
F.None of the above
E.Pompe disease
Neonate with cardiomegaly. Dried blood spots were sent to assess alpha-glucosidase (GAA) activity, and results in the diagnostic range of Pompe disease were obtained at 7 days of life (0.9μmol/L/h [reference range, 1.35–6.0 at pH 3.8]). A molecular study was ordered to confirm the diagnosis. Which one of the following genes would most likely be tested for Pompe disease in this patient?
A.ASPA
B.ELP1 (IKBKAP)
C.GAA
D.GLA
E.MEFV
F.None of the above
C.GAA
22 yo with progressive limb weakness and low alpha-glucosidase. Which one of the following molecular assays would most likely be used as a first-tier test to detect pathogenic variants for late-onset Pompe disease in this patient?
A.Chromosome microarray (CMA)
B.Multiplex ligation-dependent probe amplification (MLPA)
C.Next-generation sequencing (NGS)
D.Sanger sequencing
E.Target variant analysis of the founder pathogenic variants
F.None of the above
D.Sanger sequencing
Infant dysmorphic features, light hair color, thrombocytopenia, hyperbilirubinemia, cranial synostosis, hepatomegaly, ASD, PDA and short humerus and femurs. Laboratory studies revealed elevated levels of multiple plasma and leukocyte lysosomal hydrolases in serum. He passed away at 5 weeks of age. Which one of the following lysosomal disorders would the patient most likely have?
A.Canavan disease
B.Fabry disease
C.Farber disease
D.I-cell disease
E.Pompe disease
F.None of the above
D.I-cell disease
N-acetylglucosamine-1-phosphotransferase. GNPTA
Nearly all lysosomal hydrolases are elevated in the plasma and bodily fluids of affected individuals because of the failure of targeting lysosomal acid hydrolases to the lysosomes.
Which one of the following molecular assays would most likely be used as a first-tier test to detect pathogenic variants for I-cell disease in this patient?
A.Chromosomal microarray (CMA)
B.Multiplex ligation-dependent probe amplification (MLPA)
C.Next-generation sequencing (NGS)
D.Sanger sequencing
E.Target variant analysis of the founder pathogenic variants
F.None of the above
D.Sanger sequencing
Several dozen pathogenic variants in all 21 exons of the GNPTA gene are known.
A genetic study was also ordered to confirm the diagnosis of a patient with a cherry-red macula who refused a skin biopsy. Which one of molecular assays would be most likely used as a first-tier test in this patient?
A.Chromosomal microarray (CMA)
B.Multiplex ligation-dependent probe amplification (MLPA)
C.Next-generation sequencing (NGS)
D.Sanger sequencing
E.Target variant analysis of the founder pathogenic variants
F.None of the above
C.Next-generation sequencing (NGS)
- many underlying diseases possible
Fabry disease and Hunter syndrome have a(n) _________________ inheritance pattern
X-linked
Name the 6 (of over 50) lysosomal storage disorders with enzyme replacement therapy
- Fabry
- Gaucher type I (1991 -1st)
- Pompe disease
- Hurler syndrome
- Hunter disease
- Maroteaux-Lamy syndrome
_______ and __________ are more prevalent among AJ population
Gaucher and Tay-sachs
_____________ is more frequent among Scandinavians and Russions
Hurler syndrome
What metabolic (in addition to vascular) diseases are associated with a cherry-red macula (degeneration of ganglion cells and exposure of underlying choroid)?
1.Sandhoff disease
2. galactosialidosis
3. GM1 gangliosidosis
4. GM2 gangliosidosis
5. Goldberg syndrome
6. metachromatic leukodystrophy
7. Niemann–Pick disease types A, B, C, and D
8. Farber lipogranulomatosis
9. multiple sulfatase deficiency
10. Gaucher disease
11. poisoning (dapsone)
12. Wolman disease
13. sialidosis type I.
Gaucher disease children who are compound heterozygotes for the c.84dupG(p.Leu29AlafsTer18) variant, also 84GG (historically called “N370S”), or c.115+1G>A (historically called “IVS2+1G>A”) tend to have a subacute disease course with progressive ______________ involvement and death in the first to second decade.
pulmonary
