GeneticsGenetics

Robert W. Marion, M.DRobert W. Marion, M.D..Albert Einstein Col of Med/Albert Einstein Col of Med/

Children’s Hosp at MontefioreChildren’s Hosp at Montefiore

Question 1:

In the NICU, you’ve just examined a newborn with hypotonia and dysmorphic features that included epicanthal folds, upward slanting of the palpebral fissures, flat nasal bridge with anteverted nares and midface hypoplasia. Among the following, the medical complication that is MOST likely to present in the newborn period in this infant is:

A. atlantoaxial instabilityB. hypothyroidismC. leukemiaD. obstructive bowel diseaseE. seizures

Question 1: Preferred Response: DQuestion 1: Preferred Response: D

The baby has features of Down syndrome. He The baby has features of Down syndrome. He should be observed for:should be observed for: Obstructive gi tract abnormalitiesObstructive gi tract abnormalities (~10%) (~10%)

including duodenal atresia, annular pancreas, including duodenal atresia, annular pancreas, anal atresia, and TEF. anal atresia, and TEF.

Cardiac anomaliesCardiac anomalies (~40%) including ECCD. (~40%) including ECCD. ALL INFANTS WITH DS SHOULD HAVE ALL INFANTS WITH DS SHOULD HAVE ECHO-CARDIOGRAM BEFORE DISCHARGE ECHO-CARDIOGRAM BEFORE DISCHARGE FROM THE NURSERY!FROM THE NURSERY!

Polycythemia and leukemoid reactionPolycythemia and leukemoid reaction (which can look like leukemia but is self-(which can look like leukemia but is self-limited); ALL INFANTS WITH DS SHOULD limited); ALL INFANTS WITH DS SHOULD HAVE A CBC!HAVE A CBC!

Congenital hypothyroidismCongenital hypothyroidism (~1%) (~1%)

Question 1: Preferred Response: D (GI Question 1: Preferred Response: D (GI obstruction)obstruction)

Atlantoaxial instability, which can lead to Atlantoaxial instability, which can lead to compression of the cord, occurs in ~10%, but is compression of the cord, occurs in ~10%, but is not a problem in the newborn period. Neck films not a problem in the newborn period. Neck films (lateral in neutral, flexion and extension) should (lateral in neutral, flexion and extension) should be performed after age 3.be performed after age 3.

Pts with DS have a higher incidence of leukemia, Pts with DS have a higher incidence of leukemia, which approaches 1% (but is also not a problem which approaches 1% (but is also not a problem in the NB).in the NB).

Seizures occur in a small number of patients Seizures occur in a small number of patients with DS .with DS .

All patients with DS display cognitive All patients with DS display cognitive impairment, (most with IQs in the mod MR impairment, (most with IQs in the mod MR range). Early intervention to maximize range). Early intervention to maximize development in early childhood is recommended.development in early childhood is recommended.

HE SHOULD ALSO HAVE CHROMOSOME HE SHOULD ALSO HAVE CHROMOSOME TESTING:TESTING:

Question 2:

You tell the infant’s parents of your concern that their baby has Down syndrome. After the initial shock, the mother asks about her risk of having another child with a chromosomal abnormality.The statement that you are MOST likely to include in your discussion is that her risk:

A. can be estimated by determination of maternal serum alpha-fetoprotein in all future pregnanciesB. cannot be estimated until her infant's chromosome complement has been determinedC. is increased for Down syndrome, but not for any other chromosomal abnormalityD. is no greater than that of other women her ageE. is not increased until she reaches the age of 35

Question 2:Question 2: Preferred Response: BPreferred Response: B Following the clinical diagnosis of Down syndrome, it’s Following the clinical diagnosis of Down syndrome, it’s

essential to obtain a karyotype, which will provide essential to obtain a karyotype, which will provide information about parental risks in future pregnancies. information about parental risks in future pregnancies. In DS:In DS:

95% are due to trisomy 2195% are due to trisomy 21 (47,XY,+21 or (47,XY,+21 or 47,XX+21)47,XX+21)

3% are due to unbalanced Robertsonian 3% are due to unbalanced Robertsonian translocations involving an acrocentric translocations involving an acrocentric chromosomechromosome (13, 14,15, 21, or 22) ; ie: 46, XY, -14. t (13, 14,15, 21, or 22) ; ie: 46, XY, -14. t (14q21q) (14q21q)

2% are due to mosaicism2% are due to mosaicism

If the condition is caused by trisomy, the If the condition is caused by trisomy, the recurrence risk for any trisomy is 1%recurrence risk for any trisomy is 1%

Question 2:Question 2: Preferred Response: BPreferred Response: B

If the condition is due to an If the condition is due to an unbalanced unbalanced translocationtranslocation, it is necessary to do a karyotype , it is necessary to do a karyotype on the parents. In these cases:on the parents. In these cases:

2/3 are 2/3 are de novode novo (both parents have normal (both parents have normal karyotypes). RR is ~1%karyotypes). RR is ~1%

1/3 result from unbalanced segregation of a 1/3 result from unbalanced segregation of a balanced Robertsonian translocation in one balanced Robertsonian translocation in one of the parents.of the parents.

If mother is the translocation carrier (45,XX,-14,-21, If mother is the translocation carrier (45,XX,-14,-21, t(14q21q), RR=10-15% t(14q21q), RR=10-15%

If father is the translocation carrier (45,XY,-1`4,-If father is the translocation carrier (45,XY,-1`4,-21,t(14q21q), RR=2-5%. 21,t(14q21q), RR=2-5%.

If the balanced translocation involves one chromosome If the balanced translocation involves one chromosome 21 attached to the other (ie. 45,XY, -21,-21, t(21q21q), 21 attached to the other (ie. 45,XY, -21,-21, t(21q21q), all progeny will have Down syndrome!all progeny will have Down syndrome!

Once a balanced translocation is found, other family Once a balanced translocation is found, other family members should be testedmembers should be tested

Question 3:

As long as you’re already in the nursery, you’re asked to see 3 infants with cleft lip and/or palate. The first has a left CL+P; exam is otherwise normal. You tell his parents that this is apparently an isolated birth defect. During counseling about their risk for having another affected child, the statement that you are MOST likely to include is that:A. because the defect is isolated, their risk is no greater than that of any other coupleB. Isolated cleft lip and palate is a multifactorial trait that has a 4% risk of recurrenceC. the recurrence risk can be estimated only after a chromosome analysis has been obtainedD. the risk is increased for future girls, but not boysE. the risk would be increased only if one of the parents had cleft lip and palate

Question 3: Preferred Response: BQuestion 3: Preferred Response: B Isolated CL+/-P is inherited as a multifactorial (MF) Isolated CL+/-P is inherited as a multifactorial (MF)

trait, caused by the interplay of genetic and trait, caused by the interplay of genetic and environmental factors. Disorders showing MF environmental factors. Disorders showing MF inheritance occur more commonly in individuals in a inheritance occur more commonly in individuals in a particular family than in the general population, but at particular family than in the general population, but at a lower rate than would be expected for single gene a lower rate than would be expected for single gene traits. RR for MF traits have been derived by analysis traits. RR for MF traits have been derived by analysis of many families that express the trait. For CL+/-P, of many families that express the trait. For CL+/-P, RR RR for a family in which neither parent is affected for a family in which neither parent is affected and only one child is affected is 2-5%.and only one child is affected is 2-5%.

MF inheritance is seen in many common birth defects MF inheritance is seen in many common birth defects (CHD, CDH, NTDs, pyloric stenosis, hypospadias, etc). (CHD, CDH, NTDs, pyloric stenosis, hypospadias, etc). In general, the In general, the RR for all of these disorders is RR for all of these disorders is between 2 and 5%.between 2 and 5%.

MF inheritance is also the cause of most disease of MF inheritance is also the cause of most disease of childhood and adulthood, ie. asthma, DM, childhood and adulthood, ie. asthma, DM, hypertension, cancer, autism, alcoholism, coronary hypertension, cancer, autism, alcoholism, coronary artery disease, etc.artery disease, etc.

Question 3: Preferred Response: BQuestion 3: Preferred Response: B RR of MF traits is altered by a # of factors, including RR of MF traits is altered by a # of factors, including

the number of family members who are affected. The the number of family members who are affected. The RR for subsequent sib of a child who has clubfoot is RR for subsequent sib of a child who has clubfoot is 3%. However, if one parent also had clubfoot, RR is 3%. However, if one parent also had clubfoot, RR is 10-15%.10-15%.

To provide accurate information about RR, a careful To provide accurate information about RR, a careful exam should be done to identify additional anomalies. exam should be done to identify additional anomalies. The possibility that the most obvious defect is part The possibility that the most obvious defect is part of a genetic syndrome, which may carry a higher risk, of a genetic syndrome, which may carry a higher risk, must be considered .must be considered .

In general, In general, chromosome analysis should be chromosome analysis should be obtained in pts with two or more major obtained in pts with two or more major abnormalitiesabnormalities (eg, clefting, congenital heart (eg, clefting, congenital heart disease) or disease) or one major anomaly and two or three one major anomaly and two or three minor defectsminor defects (eg, epicanthal folds, simian line). (eg, epicanthal folds, simian line). Accordingly, chromosome analysis would not be Accordingly, chromosome analysis would not be indicated for an infant with an isolated cleft lip and indicated for an infant with an isolated cleft lip and palate.palate.

Question 4

The next baby you see in the nursery, a boy, has bilateral CL+P. Further exam reveals scalp defect in the parietooccipital region, microphthalmia, cryptorchidism, a cardiac murmur and polydactyly. Of the following, the MOST likely underlying condition is:A. holoprosencephaly sequenceB. retinoic acid embryopathyC. trisomy 13D. trisomy 18E. valproate embryopathy

Question 4: Preferred Response: CQuestion 4: Preferred Response: C

As noted in the last question, CL+/-P can occur in As noted in the last question, CL+/-P can occur in isolation or as part of a multiple malformation isolation or as part of a multiple malformation syndrome. Syndromes (groups of malformations syndrome. Syndromes (groups of malformations caused by a single identifiable etiology) can occur caused by a single identifiable etiology) can occur due to a chromosomal abnormality, a single gene due to a chromosomal abnormality, a single gene mutation, or as the result of exposure to a mutation, or as the result of exposure to a teratogen. In the present patient, the pattern of teratogen. In the present patient, the pattern of findings is most consistent with findings is most consistent with trisomy 13.trisomy 13.

Trisomy 13 (47,XX or Y,+13) occurs in 1 in 5-Trisomy 13 (47,XX or Y,+13) occurs in 1 in 5-10,000 liveborns. Most affected infants die in the 10,000 liveborns. Most affected infants die in the newborn period; 5% survive to 6 months.newborn period; 5% survive to 6 months.

It is associated with advanced maternal age. It is associated with advanced maternal age. Associated features include holoprosencephaly, Associated features include holoprosencephaly, severe MR; microcephaly; microphthalmia; severe MR; microcephaly; microphthalmia; coloboma; CL+/-P; ear anomalies; coloboma; CL+/-P; ear anomalies; distinctive distinctive scalp defects in the occipital area;scalp defects in the occipital area; CHD; CHD; postaxial polydactyly and cryptorchidism in males. postaxial polydactyly and cryptorchidism in males.

Question 4: Preferred Response: CQuestion 4: Preferred Response: C Peripheral blood karyotypePeripheral blood karyotype should be should be

performed to document dx and help provide performed to document dx and help provide genetic counseling about future risks. In genetic counseling about future risks. In particular, it’s important to determine if the child particular, it’s important to determine if the child has a translocation inherited from one parent has a translocation inherited from one parent which would increase the RR (see previous case).which would increase the RR (see previous case).

Fetal valproate syndrome results in CHD, NTDs Fetal valproate syndrome results in CHD, NTDs and unusual facial features (narrow bifrontal and unusual facial features (narrow bifrontal diameter, high forehead and epicanthi) as well as diameter, high forehead and epicanthi) as well as limb defects. limb defects.

Retinoic acid embryopathy results in facial Retinoic acid embryopathy results in facial asymmetry, microtia or anotia, & CHD. asymmetry, microtia or anotia, & CHD.

Trisomy 18 is characterized by growth deficiency, Trisomy 18 is characterized by growth deficiency, prominent occiput, low-set ears, micrognathia, prominent occiput, low-set ears, micrognathia, clenched hand, and structural defects of the heart clenched hand, and structural defects of the heart and kidney. Microphthalmia and clefting are and kidney. Microphthalmia and clefting are notnot prominent featuresprominent features..

Question 5:

The next baby you visit in the nursery has a CP and retro-gnathia, but no other anomalies. Of the following, the MOST serious complication that may occur in the first 72 hours of this child's life is:A. acute otitis media requiring antibiotic treatmentB. congestive heart failureC. difficulties with breastfeedingD. upper airway obstruction with oxygen desaturationE. worsening airway obstruction when placed in the prone position

Question 5: Preferred Response: DQuestion 5: Preferred Response: D

Pierre-Robin malformation sequence (Pierre-Robin malformation sequence (PRMS) PRMS) is characterized by: is characterized by: (1) micrognathia, (2) (1) micrognathia, (2) glossoptosisglossoptosis; and (; and (3) U-shaped cleft of the 3) U-shaped cleft of the palatepalate. The initial event in the sequence is . The initial event in the sequence is failure of mandibular growth in the 1failure of mandibular growth in the 1stst trimester. trimester. This results in displacement of the tongue & This results in displacement of the tongue & failure of the palatal shelves to close, causing failure of the palatal shelves to close, causing the U-shaped cleft. the U-shaped cleft.

PRMS may occur in isolation or as part of a PRMS may occur in isolation or as part of a syndrome (ie. Stickler, VCF, and CHARGE syndrome (ie. Stickler, VCF, and CHARGE syndromes).syndromes).

In infants, the glossoptosis may occlude the In infants, the glossoptosis may occlude the airway, especially when they are supine. airway, especially when they are supine. Obstructive apneaObstructive apnea with desaturation is by with desaturation is by far the most serious complication that may far the most serious complication that may develop within the first days of life. Such develop within the first days of life. Such obstruction may be severe enough to cause obstruction may be severe enough to cause ischemic encephalopathy.ischemic encephalopathy.

Question 5: Preferred Response: DQuestion 5: Preferred Response: D Feeding difficulties are common in children with Feeding difficulties are common in children with

PRMS. Posterior displacement of the tongue and PRMS. Posterior displacement of the tongue and the cleft may contribute to a poor suck. In most the cleft may contribute to a poor suck. In most cases, though, oral feeding, including cases, though, oral feeding, including breastfeeding, is successful. Although OM is breastfeeding, is successful. Although OM is quite common among children who have cleft quite common among children who have cleft palate, it typically does not cause problems in palate, it typically does not cause problems in early infancy.early infancy.

PRMS is a medical emergency in the PRMS is a medical emergency in the newborn!newborn! The infant should be placed in The infant should be placed in the prone position, which allows the tongue the prone position, which allows the tongue to fall forward, relieving the obstruction. to fall forward, relieving the obstruction. But this is only a temporary measure: But this is only a temporary measure: definitive treatment is essential to assure definitive treatment is essential to assure that the airway remains open. Placement of that the airway remains open. Placement of a nasopharyngeal tube should occur, a nasopharyngeal tube should occur, followed by surgical management.followed by surgical management.

Question 6:

As long as you’re already in the nursery, the resident asks you to see a newborn who has some unusual features. Born by C/S because of breech presentation, the baby has a deformed cranium, torticollis, facial asymmetry, a dislocated right hip, and bilateral clubfeet. Findings on the remainder of the physical examination are normal. Of the following, the MOST likely cause of this infant's abnormalities isA. a chromosomal abnormalityB. a malformation syndromeC. an underlying CNS defectD. exposure to a teratogen in uteroE. intrauterine compression

Question 6: Preferred Response: Question 6: Preferred Response: EE

Malformations Malformations are abnormalities of form or are abnormalities of form or function that are caused by alterations in the function that are caused by alterations in the tissue primordia that forms a structure; as such, tissue primordia that forms a structure; as such, malformations occur in the 1st trimester, range malformations occur in the 1st trimester, range from mild to severe, and often require surgical from mild to severe, and often require surgical correction. They occur in ~3% of newborns.correction. They occur in ~3% of newborns.

Deformations Deformations result from abnormal external result from abnormal external forces acting on normal tissue. Unlike forces acting on normal tissue. Unlike malformations, they develop after the 1st malformations, they develop after the 1st trimester, are often mild, & usually improve trimester, are often mild, & usually improve spontaneously once the external force has been spontaneously once the external force has been removed. 1-2% of neonates have 1 or more removed. 1-2% of neonates have 1 or more deformations.deformations.

Question 6: Preferred Response: EQuestion 6: Preferred Response: E

The infant described has multiple features The infant described has multiple features suggestive of a suggestive of a deformation sequence due to deformation sequence due to intrauterine compressionintrauterine compression. The most important . The most important factor contributing to deformation is factor contributing to deformation is restriction of restriction of fetal movementfetal movement caused by mechanical forces, caused by mechanical forces, malformations, or functional abnormalities. malformations, or functional abnormalities. However, mechanical causes are most common. However, mechanical causes are most common. Frequently, > 1 deformations are present because Frequently, > 1 deformations are present because the mechanical force exerts an adverse effect on the mechanical force exerts an adverse effect on multiple body parts. 1/3 of all deformations occur in multiple body parts. 1/3 of all deformations occur in infants who present in the breech position.infants who present in the breech position.

A chromosomal abnormality or teratogen exposure A chromosomal abnormality or teratogen exposure associated with the multiple defects described for associated with the multiple defects described for this infant would be expected to cause this infant would be expected to cause malformations of internal organ systems as well as malformations of internal organ systems as well as external findings external findings

Question 7:You’re in Spina Bifida Clinic. Your first patient is an infant recently D/C’d from the NICU after having her myelomeningocele closed and a VP shunt placed. She has typical problems of an infant with an L2 lesion: hydrocephalus, dislocated hips, club feet and paraplegia. Her parents are concerned about recurrence in future pregnancies. Of the following, the statement you are MOST likely to make is that their RRA. depends on the family's ethnic backgroundB. depends on the location of the defect along the neural axisC. is increased only if the defect is part of a genetic syndromeD. is the same as that for any other coupleE. will be reduced if the mother takes periconceptional folate supplementation

Question 7: Preferred Response: EQuestion 7: Preferred Response: E NTDs result from failure of the neural tube to close prior NTDs result from failure of the neural tube to close prior

to the 27th postconceptional day. Closure proceeds from to the 27th postconceptional day. Closure proceeds from mid-cervical area caudally and rostrally. Anterior closure mid-cervical area caudally and rostrally. Anterior closure defects result in anencephaly; posterior defects result in defects result in anencephaly; posterior defects result in meningocele or myelomeningocele..meningocele or myelomeningocele..

Before 1990, NTDs occurred in 1 in 1,000 births. Etiology Before 1990, NTDs occurred in 1 in 1,000 births. Etiology is hetero- geneous, including chromosome anomalies is hetero- geneous, including chromosome anomalies (trisomy 18), single gene defects (Meckel-Gruber), and (trisomy 18), single gene defects (Meckel-Gruber), and teratogenic exposures (Valproic acid). teratogenic exposures (Valproic acid).

Isolated NTDs exhibit MF inheritance. RR is 2-4%; such Isolated NTDs exhibit MF inheritance. RR is 2-4%; such couples should be offered prenatal monitoring in future couples should be offered prenatal monitoring in future pregnancies.pregnancies.

Isolated NTDs are more common in individuals from the Isolated NTDs are more common in individuals from the British Isles and less common in Asians; in NA, births of British Isles and less common in Asians; in NA, births of infants with NTDs cluster in the late fall and early winter. infants with NTDs cluster in the late fall and early winter. This has led to the discovery that This has led to the discovery that periconceptual folic periconceptual folic acid supplementation can decrease the risk of having acid supplementation can decrease the risk of having a child with NTD by 70%.a child with NTD by 70%. This diminution in risk exists This diminution in risk exists for both women who have had a previous affected child as for both women who have had a previous affected child as well as those who have not had an affected child. well as those who have not had an affected child.

Question 7: Preferred Response: EQuestion 7: Preferred Response: E It has been hypothesized that FA prevents It has been hypothesized that FA prevents

NTDs by stimulating certain enzymes (eg, NTDs by stimulating certain enzymes (eg, methionine synthetase) that otherwise are methionine synthetase) that otherwise are present in reduced levels in susceptible present in reduced levels in susceptible women. women.

It’s recommended that all women take FA: It’s recommended that all women take FA: women who’ve had a previously affected child women who’ve had a previously affected child are given a dose of 4 mg/day; all others are given a dose of 4 mg/day; all others receive 0.4 mg/day.receive 0.4 mg/day.

RR in families does not depend significantly RR in families does not depend significantly upon the ethnic group. The location of the upon the ethnic group. The location of the defect along the neural axis also does not defect along the neural axis also does not influence RR. If the NTD is part of a influence RR. If the NTD is part of a syndrome, the specific RR for the syndrome syndrome, the specific RR for the syndrome should be discussed.should be discussed.

Question 8:While in Spina Bifida Clinic, you are visited by a 42 y.o. G1P0 who is in her 16th week of pregnancy. She is concerned about the possibility of her child having myelomeningocele. Of the following, the MOST useful diagnostic evaluation isA. amniocentesisB. chorionic villus samplingC. cordocentesisD. fetal ultrasonographyE. maternal alpha-fetoprotein screening

Question 8: Preferred Response: DQuestion 8: Preferred Response: D

Fetal sonography performed between 12 & 24 Fetal sonography performed between 12 & 24 weeks of pregnancy is most useful for detection weeks of pregnancy is most useful for detection of structural anomalies such as NTDs.of structural anomalies such as NTDs. Its Its sensitivity & specificity can be substantially improved sensitivity & specificity can be substantially improved if performed by an experienced sonographer. It’s if performed by an experienced sonographer. It’s noninvasive, safe, & accurate in experienced hands. noninvasive, safe, & accurate in experienced hands. Advantages of early fetal sonography include Advantages of early fetal sonography include improved dx of multiple gestation and accurate improved dx of multiple gestation and accurate dating of the pregnancy. dating of the pregnancy.

Although levels of AFP in amniotic fluid are Although levels of AFP in amniotic fluid are increased in the fetus who has open NTDs, this test increased in the fetus who has open NTDs, this test has limited sensitivity & specificity for the dx of a has limited sensitivity & specificity for the dx of a myelomeningocele. Early amnio (between 12 & 14 myelomeningocele. Early amnio (between 12 & 14 weeks) is most useful for detecting fetal chromosomal weeks) is most useful for detecting fetal chromosomal abnormalities (ie trisomy 21) & genetic defects . abnormalities (ie trisomy 21) & genetic defects .

Question 8:Question 8: Preferred Response: DPreferred Response: D

CVS, which entails biopsy of the placenta CVS, which entails biopsy of the placenta between 8 & 11 wks, is between 8 & 11 wks, is not usefulnot useful for for diagnosing NTDs. It’s most helpful for diagnosing NTDs. It’s most helpful for detecting cytogenetic abnormalities, but it detecting cytogenetic abnormalities, but it is an invasive procedure and has risks.is an invasive procedure and has risks.

Cordocentesis (aspiration of fetal blood by Cordocentesis (aspiration of fetal blood by puncture of the umbilical cord) is puncture of the umbilical cord) is not not usefuluseful for the diagnosis of NTDs. It can for the diagnosis of NTDs. It can aid in diagnosing conditions such as aid in diagnosing conditions such as coagulation disorders, blood cell coagulation disorders, blood cell abnormalities, and congenital infections abnormalities, and congenital infections such as toxoplasmosis. This invasive such as toxoplasmosis. This invasive procedure has a great many risks.procedure has a great many risks.

We’ll discuss maternal serum AFP We’ll discuss maternal serum AFP screening in the next question:screening in the next question:

Question 9:

At the end of Spina Bifida Clinic, you are talking to a group of residents about NTDs. You explain that when the fetus has an open NTD, elevated levels of maternal serum alphafetoprotein (MSAFP) can be seen during the 16th-18th weeks of pregnancy. Of the following, your discussion is MOST likely to include the statement that:A. chromosomal disorders can also cause high levels of MSAFPB. further tests are required to confirm the diagnosis of an NTDC. levels of AFP in maternal serum and amniotic fluid have similar specificityD. the majority of birth defects cause elevated levels of MSAFPE. the presence of multiple fetuses will not affect the interpretation of MSAFP levels

Question 9: Question 9: Preferred Response: BPreferred Response: B AFP, the fetal equivalent of albumin, is produced only AFP, the fetal equivalent of albumin, is produced only

during fetal life; thereafter, AFP is found only in the during fetal life; thereafter, AFP is found only in the serum of pregnant women and adults with liver disease serum of pregnant women and adults with liver disease (hepatoma).(hepatoma).

Since the 1960s, an association between NTDs & Since the 1960s, an association between NTDs & elevated levels of AF-AFP has been noted. The defect in elevated levels of AF-AFP has been noted. The defect in the fetal skin causes AFP to pass between the fetal the fetal skin causes AFP to pass between the fetal circulation and the amniotic fluid. Elevated AF-AFP circulation and the amniotic fluid. Elevated AF-AFP levels also occur in fetuses with omphalocele, levels also occur in fetuses with omphalocele, gastroschisis, bladder exstrophy, cystic hygroma, as well gastroschisis, bladder exstrophy, cystic hygroma, as well as in multiple gestations, impending fetal death, etc.as in multiple gestations, impending fetal death, etc.

Since 1970s, the association between these defects and Since 1970s, the association between these defects and elevated levels of MSAFP was also noted. Measuring elevated levels of MSAFP was also noted. Measuring MSAFP between the 16MSAFP between the 16thth and 22 and 22ndnd week of gestation has week of gestation has become a standard become a standard screeningscreening test throughout the test throughout the world. world.

As noted above, an elevated MSAFP level is As noted above, an elevated MSAFP level is not not pathognomonic for exposed neural tissue. It is not, pathognomonic for exposed neural tissue. It is not, however, elevated with most birth defects. And however, elevated with most birth defects. And trisomy trisomy 13, 18 and 21 are all associated with an MSAFP 13, 18 and 21 are all associated with an MSAFP level that is less than expectedlevel that is less than expected. .

Question 9: Question 9: Preferred Response: BPreferred Response: B A positive MSAFP requires confirmatory A positive MSAFP requires confirmatory

testing, including sonogram (to verify testing, including sonogram (to verify dates and identify defects) and dates and identify defects) and amniocentesis (for chromosome analysis or amniocentesis (for chromosome analysis or acetylcholinesterase activity).acetylcholinesterase activity).

The concentration of AFP in the maternal The concentration of AFP in the maternal serum is an order of magnitude serum is an order of magnitude lower lower than than that in the amniotic fluid; thus, it is more that in the amniotic fluid; thus, it is more difficult to measure. difficult to measure.

The development and refinement of The development and refinement of obstetric sono-graphy has led some obstetric sono-graphy has led some authorities to question whether this might authorities to question whether this might be an adequate screening tool for NTDs. be an adequate screening tool for NTDs. However, ultrasonography will fail to However, ultrasonography will fail to detect some flat or low detect some flat or low myelomeningoceles. myelomeningoceles.

Question 10:

In genetics clinic, you’re seeing a 5 y.o. who hasmultiple café au lait spots and axillary freckling. Slitlamp ophthalmic exam reveals the presence of Lisch nodules,confirming the diagnosis of neurofibromatosis. Of the following, the MOST appropriate statement about the potential for the development of tumors in this child is that:A.acoustic neuromas are common and annual screening with MRI is indicatedB. all patients with NF-1 eventually develop plexiform

neurofibromasC. annual urinary catecholamine screening for the

presence of pheochromocytoma is indicatedD. cutaneous neurofibromas usually do not appear

until preadolescenceE. the overall lifetime risk for the development of

malignancy is 50%

Question 10: Preferred Response: DQuestion 10: Preferred Response: D

This child has features of NF-1. Diagnosis of NF-1 This child has features of NF-1. Diagnosis of NF-1 is made on the basis of having two of the is made on the basis of having two of the following 7 criteria: following 7 criteria: Café au lait spotsCafé au lait spots: 6 or more of >0.5 cm in : 6 or more of >0.5 cm in

diameter for prepubertal children or >1.5 cm diameter for prepubertal children or >1.5 cm post pubertallypost pubertally

Axillary and/or inguinal frecklesAxillary and/or inguinal freckles Neurofibromas:Neurofibromas: 2 or more, or 1 plexiform 2 or more, or 1 plexiform Optic gliomaOptic glioma Lisch nodulesLisch nodules Skeletal abnormalitiesSkeletal abnormalities, including scoliosis, , including scoliosis,

pseudarthrosis, sphenoid wing dysplasiapseudarthrosis, sphenoid wing dysplasia Family historyFamily history of a 1 of a 1stst degree relative with degree relative with

NF-1, diagnosed using these criteria.NF-1, diagnosed using these criteria.

Question 10: Preferred Response: DQuestion 10: Preferred Response: D NF-1 is an autosomal dominant disorder NF-1 is an autosomal dominant disorder

and one of the most common single-gene and one of the most common single-gene defects. defects. The gene, NF-1, which is on The gene, NF-1, which is on

chromosome 17, produces chromosome 17, produces neurofibronin, an inhibitor of nerve neurofibronin, an inhibitor of nerve growth factor.growth factor.

The gene is huge, one of the largest in The gene is huge, one of the largest in the human genome; there are no the human genome; there are no “common mutations.” As such, “common mutations.” As such, molecular diagnosis depends on molecular diagnosis depends on sequencing the entire gene, a strategy sequencing the entire gene, a strategy that is not practical. that is not practical.

In about half of cases, the condition In about half of cases, the condition occurs as a spontaneous mutation. occurs as a spontaneous mutation.

Question 10: Preferred Response: DQuestion 10: Preferred Response: D Other tumors in NF-1 include: Other tumors in NF-1 include:

Plexiform NFs: evident by age 2; undergo Plexiform NFs: evident by age 2; undergo sarcomatous change in ~5% of cases; present a sarcomatous change in ~5% of cases; present a surgical challenge because of their extensive vascular surgical challenge because of their extensive vascular supply. supply.

CNS tumors: ie. optic gliomas, occur in 2-3% CNS tumors: ie. optic gliomas, occur in 2-3% Overall,Overall, lifetime risk for the development of a lifetime risk for the development of a

malignancy in patientsmalignancy in patients who have NF-1 is who have NF-1 is ~5%~5% ((NOT 50%!).NOT 50%!).

Acoustic neuromas are a prominent feature of Acoustic neuromas are a prominent feature of NF-2NF-2. They are bilateral in ~ 85% of patients . They are bilateral in ~ 85% of patients and unilateral in ~6%. In NF-2, cutaneous and unilateral in ~6%. In NF-2, cutaneous findings are not as prominent.findings are not as prominent.

Pheochromocytoma is a rare tumor in NF-1 Pheochromocytoma is a rare tumor in NF-1 (<1% of patients), but it is common in patients (<1% of patients), but it is common in patients who have von Hippel-Lindau disease.who have von Hippel-Lindau disease.

Question 11: The next patient in clinic is the mother of a 13-mo-old boy recently diagnosed with factor VIII deficiency hemophilia. The woman is in the 1st trimester of her 2nd pregnancy, and is interested in knowing if prenatal diagnosis is available. Of the following, the statement about prenatal diagnosis that you are MOST likely to include in your discussion is that:

A. factors VIII and IX deficiency hemophilia can be dx’d prenatally in over 95% of familiesB. factors VIII and IX deficiency hemophilia can be dx’d prenatally only in 20% of familiesC. neither type of hemophilia can be dx’d prenatallyD. only factor IX deficiency hemophilia can be dx’d prenatallyE. only factor VIII def. hemophilia can be dx’d prenatally

Question 11:Question 11: Preferred Preferred Response: AResponse: A

Molecular technology allows us to Molecular technology allows us to prenatally diagnose mutations leading to prenatally diagnose mutations leading to Factor XIII and Factor IX hemophilia Factor XIII and Factor IX hemophilia in in > 95% of families> 95% of families. The genes for both . The genes for both diseases are located near the end of Xq.diseases are located near the end of Xq.

Hemophilia occurs in ~1 in 5,000 Hemophilia occurs in ~1 in 5,000 individuals in the general population, individuals in the general population, with 80-85% of patients having factor with 80-85% of patients having factor VIII deficiency hemophilia (hemophilia A) VIII deficiency hemophilia (hemophilia A) and 10-15% having factor IX deficiency and 10-15% having factor IX deficiency (hemophilia B). Neither disorder has (hemophilia B). Neither disorder has apparent racial or ethnic predilection.apparent racial or ethnic predilection.

Question 11:Question 11: Preferred Response: APreferred Response: A

The factor VIII gene is larger, more complex, and The factor VIII gene is larger, more complex, and has a strong predisposition to spontaneous has a strong predisposition to spontaneous mutation:mutation: ~1/3 of affected individuals have no family history and ~1/3 of affected individuals have no family history and

appear to represent new mutations. appear to represent new mutations. >200 mutations have been identified, the most >200 mutations have been identified, the most

common being an inversion in the tip of Xq which common being an inversion in the tip of Xq which accounts for ~45% of cases of severe hemophilia A and accounts for ~45% of cases of severe hemophilia A and always is associated with the severe form of the always is associated with the severe form of the disease. disease.

Other mutations account for the remaining cases of Other mutations account for the remaining cases of severe disease and most cases of moderate or mild severe disease and most cases of moderate or mild disease.disease.

The factor IX gene is considerably smaller and The factor IX gene is considerably smaller and less complex. >400 mutations have been less complex. >400 mutations have been identified. Because the gene is smaller, DNA identified. Because the gene is smaller, DNA sequencing can be employed to identify sequencing can be employed to identify mutations and can be used for carrier detection mutations and can be used for carrier detection and prenatal dx. There is a and prenatal dx. There is a very low rate of very low rate of spontaneous mutation, so the family history spontaneous mutation, so the family history almost always is positive.almost always is positive.

It’s lunch time in Clinic. Time for some quickies:

Of the following, the findings that are MOST suggestive of the dx of Prader-Willi syndrome are:

A. gigantism and visceromegalyB. hyperactivity and ataxic movementsC. hypocalcemia and a congenital heart defectD. MR and macroorchidismE. obesity and small hands and feet

The answer is EThe answer is E AA describes Beckwith Wiedemann describes Beckwith Wiedemann

syndromesyndrome BB describes Angelman syndrome describes Angelman syndrome CC describes diGeorge (aka velocardiofacial, describes diGeorge (aka velocardiofacial,

Shprintzen, or 22q11.2 deletion syndrome)Shprintzen, or 22q11.2 deletion syndrome) D D describes Fragile X syndromedescribes Fragile X syndrome Children with PWS have a characteristic Children with PWS have a characteristic

history:history: Hypotonia in infancy, with poor sucking and FTTHypotonia in infancy, with poor sucking and FTT Improvement in muscle tone by age 1 yearImprovement in muscle tone by age 1 year Development of a voracious, insatiable appetiteDevelopment of a voracious, insatiable appetite Development of obesity and related problemsDevelopment of obesity and related problems

PWS results from deficiency of the PWS results from deficiency of the gene product of the SNRPN gene. gene product of the SNRPN gene. SNRPN (15q11) is SNRPN (15q11) is only expressed only expressed in the chromosome 15 inherited in the chromosome 15 inherited from the fatherfrom the father. Thus, . Thus, PWS PWS results when a copy of paternal results when a copy of paternal chromosome 15 is missingchromosome 15 is missing. This . This can be caused by:can be caused by:

Deletion of pat 15q11.2 (seen in 60-Deletion of pat 15q11.2 (seen in 60-70%): 70%): Use FISH to diagnoseUse FISH to diagnose

Maternal uniparental disomy of Maternal uniparental disomy of chromosome 15 (yielding two copies of chromosome 15 (yielding two copies of maternal chromosome 15 and no maternal chromosome 15 and no copies of paternal chromosome 15) copies of paternal chromosome 15) (seen in 20%)(seen in 20%)

Another quickie:

All of the following are associated with Williams syndrome EXCEPT

A. “Cocktail party” personalityB. HypercalcemiaC. Supravalvular aortic stenosisD. Short philtrumE. Mental retardation

The answer is DThe answer is D WS is caused by WS is caused by

deletion of 7q11.2 (use deletion of 7q11.2 (use FISH to make diagnosis)FISH to make diagnosis)

Occurs in 1 in 5,000 Occurs in 1 in 5,000 birthsbirths

Features include all Features include all those listed in question those listed in question except for short except for short philtrum (which is seen philtrum (which is seen in fetal alcohol in fetal alcohol syndrome).syndrome).

Heart disease occurs in Heart disease occurs in 80%, with SVAS in 67%80%, with SVAS in 67%

A third quickie:

Noonan syndrome is characterized by each of the following EXCEPT

A. Autosomal recessive inheritanceB. Short statureC. Pulmonic stenosisD. Webbed neckE. Low set ears

The answer is AThe answer is A Noonan syndrome is usually caused by Noonan syndrome is usually caused by

a mutation in the a mutation in the PTPN11 PTPN11 gene on gene on chromosome 12.chromosome 12.

Occurs in 1 in 10,000 birthsOccurs in 1 in 10,000 births Features include all those listed in Features include all those listed in

question except for AR inheritancequestion except for AR inheritance 50% also have Factor 11 deficiency 50% also have Factor 11 deficiency

causing prolonged PTT.causing prolonged PTT.

Yet another:

A child is born with esophageal atresia. Other associated abnormalities might include all of the following EXCEPT

A. Cardiac defect such as VSDB. Absence of the left radiusC. Renal malformationsD. HemivertebraE. Cataracts

The answer is EThe answer is E Esophageal atresia, occurring alone or as part Esophageal atresia, occurring alone or as part

of a TEF, can be isolated or part of a syndrome of a TEF, can be isolated or part of a syndrome or association. The most common association is or association. The most common association is VACTERL.VACTERL.

Association: a group of malformations that Association: a group of malformations that occur more commonly together than would be occur more commonly together than would be expected by chance, but for which no etiology expected by chance, but for which no etiology can be identified.can be identified.

Features of VACTERL include:Features of VACTERL include: Vertebral anomaliesVertebral anomalies Anal anomalies (imperforate, stenotic, etc)Anal anomalies (imperforate, stenotic, etc) Cardiac anomalies (VSD, ASD most common)Cardiac anomalies (VSD, ASD most common) Tracheo-Esophageal FistulaTracheo-Esophageal Fistula Renal anomaliesRenal anomalies Limb anomalies (specifically radial ray Limb anomalies (specifically radial ray

defects)defects)

Last one:

Which of the following is typical of Ehlers Danlos syndrome?

A. OsteoporosisB. Hypotrichosis C. Large head and short extremitiesD. Joint laxityE. Progressive neurologic and ophthalmologic problems

The answer is DThe answer is D Osteoporosis Osteoporosis is seen in osteogenesis imperfecta.is seen in osteogenesis imperfecta. Hypotrichosis Hypotrichosis occurs in anhidrotic ectodermal occurs in anhidrotic ectodermal

dysplasia.dysplasia. Large head and short extremities Large head and short extremities describes describes

achondroplasia.achondroplasia. Ehlers Danlos Ehlers Danlos is a disorder of collagen that leads to:is a disorder of collagen that leads to:

Joint laxityJoint laxity Spontaneous joint dislocationSpontaneous joint dislocation Hyperelastic skinHyperelastic skin Poor scar formation (“cigarette paper” scars)Poor scar formation (“cigarette paper” scars) Easy bruisabilityEasy bruisability

OKAY, LUNCH IS OKAY, LUNCH IS OVEROVER

TIME TO GO TO TIME TO GO TO METABOLIC CLINIC:METABOLIC CLINIC:

1st Patient in Metabolic Clinic: The parents of a 2 y.o. boy with Tay-Sachs disease (TSD) (hexosaminidase A deficiency) ask you about the availability of prenatal testing during their next pregnancy. Of the following, the MOST appropriate statement to include in your counseling is that:A. prenatal dx should be considered only after testing each parent to determine carrier statusB. testing can be performed on chorionic villus cells obtained as early as 10 weeks of pregnancyC. testing is possible only if the parents' mutations in the hexosaminidase gene are knownD. the results of prenatal diagnostic testing for TSD are considered investigationalE. their risk of having another similarly affected child is no greater than that of any other couple

Preferred Response: BPreferred Response: B TSD, an AR inborn error of metabolism, results from deficiency TSD, an AR inborn error of metabolism, results from deficiency

of HexA, a lysosomal enzyme. Parents of an affected child are of HexA, a lysosomal enzyme. Parents of an affected child are obligate carriersobligate carriers and together, have a RR of 25% for and together, have a RR of 25% for subsequent pregnancies. subsequent pregnancies.

HexA activity can be measured in fetal cells obtained by CVS, HexA activity can be measured in fetal cells obtained by CVS, performed as early as 10 weeks gestation, or via amnio (14-16 performed as early as 10 weeks gestation, or via amnio (14-16 weeks).weeks).

Carrier frequency for TSD is highest in Ashkenazi Jews and Carrier frequency for TSD is highest in Ashkenazi Jews and French Canadians, although the mutation can occur in any French Canadians, although the mutation can occur in any ethnic group. Among Ashkenazim, the carrier frequency is ~1 ethnic group. Among Ashkenazim, the carrier frequency is ~1 in 25. in 25.

Screening programs to identify carriers have been conducted Screening programs to identify carriers have been conducted since the 1970s. These programs, relying on the measurement since the 1970s. These programs, relying on the measurement of hex activity in serum or isolated leukocytes, have virtually of hex activity in serum or isolated leukocytes, have virtually eradicated the disease among this population. In the past 10 eradicated the disease among this population. In the past 10 years most infants dx’d with TSD have been non-Jewish or have years most infants dx’d with TSD have been non-Jewish or have had one Jewish and one non-Jewish parent. Thus, screening of had one Jewish and one non-Jewish parent. Thus, screening of couples in whom one member is Ashkenazi Jewish is couples in whom one member is Ashkenazi Jewish is recommended.recommended.

Preferred Response: BPreferred Response: B Deficiency of HexA activity results in Deficiency of HexA activity results in

accumulation of GM2 gangliosides in the CNS, accumulation of GM2 gangliosides in the CNS, liver, and spleen. Following a 6 to 9 month liver, and spleen. Following a 6 to 9 month period of normal development, affected infants period of normal development, affected infants present with hypotonia, apathy, developmental present with hypotonia, apathy, developmental delay, and an exaggerated startle response. delay, and an exaggerated startle response. Exam reveals a Exam reveals a cherry red spotcherry red spot in the in the maculae, which represents lipid accumulation maculae, which represents lipid accumulation in the ganglion cells (cherry red spots are also in the ganglion cells (cherry red spots are also seen in Type I GM1 gangliosidosis and seen in Type I GM1 gangliosidosis and Niemann-Pick disease). Macrocephaly is Niemann-Pick disease). Macrocephaly is common after age 1. The disease progresses common after age 1. The disease progresses rapidly, with death occurring by 5 years.rapidly, with death occurring by 5 years.

The genes encoding HexA has been mapped, The genes encoding HexA has been mapped, and specific mutations have been identified, and specific mutations have been identified, including several that are common among including several that are common among Ashkenazim. Ashkenazim.

Next Pt. in Metab Clinic:You’re seeing a 3 y.o. with Hunter syndrome (MPS-2) for F/U. His parents tell you the boy’s newborn brother has just been dx’d with this same disorder, and they’ve heard that bone marrow transplant-ation can “cure” the baby of his condition. Of the following, the statement you are MOST likely to include in a discussion of transplantation for Hunter syndrome and other inborn errors of metabolism is thatA. family members who are carriers of the disorder cannot be donorsB. infections are less common than in patients who have a hematologic disorderC. it is contraindicated in disorders that include adverse neurologic symptomsD. it never has been successful in the treatment of enzyme deficiency disordersE. successful transplantation may halt disease progression for some disorders

Preferred Response: EPreferred Response: E Organ & bone marrow transplantation (BMT) Organ & bone marrow transplantation (BMT)

may halt progression of some metabolic may halt progression of some metabolic disorders. Because more effective disorders. Because more effective immunosuppressants have been developed & immunosuppressants have been developed & there are no other effective treatment there are no other effective treatment strategies, BMT has been used increasingly. strategies, BMT has been used increasingly. Each case must be considered individually and Each case must be considered individually and parents must be provided with detailed info parents must be provided with detailed info about associated morbidity and mortality to about associated morbidity and mortality to permit them to make an informed decision.permit them to make an informed decision.

Sometimes, BMT is undertaken to provide a Sometimes, BMT is undertaken to provide a source of enzyme that’s not produced in source of enzyme that’s not produced in sufficient quantities. For example, it’s been used sufficient quantities. For example, it’s been used successfully in pts with ADA deficiency. successfully in pts with ADA deficiency. Sometimes, organ tx replaces an organ that’s Sometimes, organ tx replaces an organ that’s been damaged by the disease process (ie liver been damaged by the disease process (ie liver tx. in alpha-1-antitrypsin deficiency, and renal tx tx. in alpha-1-antitrypsin deficiency, and renal tx in cystinosis).in cystinosis).

Preferred Response: EPreferred Response: E BMT in pts with inherited metabolic disorders carries the BMT in pts with inherited metabolic disorders carries the

same risks as when performed for other indications. Risks same risks as when performed for other indications. Risks include: infection; graft-versus-host disease; and rejection. include: infection; graft-versus-host disease; and rejection. Identifying a histocompatible donor frequently requires Identifying a histocompatible donor frequently requires that a donor from within the family be considered. that a donor from within the family be considered. Because most inherited metabolic disorders are Because most inherited metabolic disorders are transmitted as AR traits, the parents of affected children transmitted as AR traits, the parents of affected children are obligate carriers, and unaffected siblings have 2/3 are obligate carriers, and unaffected siblings have 2/3 chance of being carriers.chance of being carriers.

Carriers are acceptable donors.Carriers are acceptable donors. Because BMT is associated with high rates of morbidity Because BMT is associated with high rates of morbidity

and mortality, selection of appropriate candidates is and mortality, selection of appropriate candidates is important. In particular, there has been controversy over important. In particular, there has been controversy over whether patients with metabolic disorders that include whether patients with metabolic disorders that include neurologic symptoms should be candidates. Recent studies neurologic symptoms should be candidates. Recent studies with Hurler patients (MPS-IH) indicate that BMT can be with Hurler patients (MPS-IH) indicate that BMT can be beneficial despite the presence of adverse neurologic beneficial despite the presence of adverse neurologic symptoms. Particularly when the diagnosis is made early symptoms. Particularly when the diagnosis is made early and the transplantation is carried out shortly thereafter, and the transplantation is carried out shortly thereafter, improved neurologic function and increased survival have improved neurologic function and increased survival have been reported.been reported.

Next Pt. in Metab Clinic:You are called down to the ED to see a previously healthy 2 y.o. boy who was brought to the ED by his mother, who reported that he has had a cold and fever for the past 2 days. He has been taking only small amounts of juice and no solid foods. When she tried to arouse him after his nap today, he was lethargic and unresponsive. Results of laboratory studies include a glucose concentration of 40 mg/dL, an ammonia level of 200 mcg/dL, and an arterial blood pH of 7.4.At this time, the MOST important study to obtain isA. plasma acylcarnitine profileB. plasma insulin levelsC. serum acetylsalicylic acid concentrationD. urine and stool porphyrinsE. urine organic acids

Preferred Response: APreferred Response: A

This presentation is typical of a fatty acid oxidation This presentation is typical of a fatty acid oxidation defects, AR traits that represent defects in defects, AR traits that represent defects in mitochondrial beta-oxidation of fatty acids (MBOFA) & mitochondrial beta-oxidation of fatty acids (MBOFA) & include defects in include defects in plasma membrane carnitine plasma membrane carnitine transport; carnitine palmityl transferase I and II transport; carnitine palmityl transferase I and II deficiency (CPTI, CPTII); & long-chain, medium-deficiency (CPTI, CPTII); & long-chain, medium-chain, and short-chain acyl CoA dehydrogenase chain, and short-chain acyl CoA dehydrogenase deficiencies. deficiencies.

MCAD (medium-chain acyl CoA dehydrogenase MCAD (medium-chain acyl CoA dehydrogenase deficiency) is most common. Pts usually present by 2 deficiency) is most common. Pts usually present by 2 with lethargy after fasting, associated with a URI or with lethargy after fasting, associated with a URI or AGE. When ill, lab findings include hypoketotic AGE. When ill, lab findings include hypoketotic hypoglycemia and hyperammonemia. Definitive dx hypoglycemia and hyperammonemia. Definitive dx requires a plasma acylcarnitine profile. Dx is complex; requires a plasma acylcarnitine profile. Dx is complex; consult with a biochemical geneticist.consult with a biochemical geneticist.

MBOFA includes > 20 steps & requires metab of MBOFA includes > 20 steps & requires metab of carnitine for transport of LCFA into mitochondria. carnitine for transport of LCFA into mitochondria. Because MBOFA for production of energy is only Because MBOFA for production of energy is only required during fasting, clinical manifestations may not required during fasting, clinical manifestations may not become apparent (heterogeneity)become apparent (heterogeneity)

Preferred Response: APreferred Response: A Between episodes of illness, affected pts are normal. Between episodes of illness, affected pts are normal.

Unfortunately, the 1st episode may result in death and is Unfortunately, the 1st episode may result in death and is frequently mis-dx’d as Reye syndrome or SIDS. Correct dx frequently mis-dx’d as Reye syndrome or SIDS. Correct dx is essential for both proper Rx and genetic counseling. is essential for both proper Rx and genetic counseling. Treatment includes avoidance of fasting, carnitine Treatment includes avoidance of fasting, carnitine supplementation, and dextrose during acute episodes. supplementation, and dextrose during acute episodes.

Molecular diagnosis of MCAD is available; > 90% of mutant Molecular diagnosis of MCAD is available; > 90% of mutant alleles are accounted for by a single point mutation in the alleles are accounted for by a single point mutation in the MCAD gene.MCAD gene.

Wrong answers:Wrong answers: An organic acidemia should be suspected in pts presenting with An organic acidemia should be suspected in pts presenting with

hypoglycemia and hyperammonemia in the presence of metabolic hypoglycemia and hyperammonemia in the presence of metabolic acidosis.acidosis.

Plasma insulin levels should be obtained in a child suspected of Plasma insulin levels should be obtained in a child suspected of having hyperinsulinemia, which may cause hypoglycemia but usually having hyperinsulinemia, which may cause hypoglycemia but usually is not associated with hyperammonemia. is not associated with hyperammonemia.

Urine and stool porphyrin analysis is useful in the diagnosis of the Urine and stool porphyrin analysis is useful in the diagnosis of the porphyrias, porphyrias,

Acetylsalicylic acid poisoning usually presents with hyperventilation Acetylsalicylic acid poisoning usually presents with hyperventilation and dehydration, but hyperammonemia is not typical.and dehydration, but hyperammonemia is not typical.

GENETICS CLINIC IS OVER.

NOW COMES MILLER TIME!