Biochemical Genetics 4

Question 1

What laboratory findings are consistent with the dx of SLO

Answer 1

Elevated serum concentration of 7-dehydrocholesterol (7-DHC)
Low serum concentration of cholesterol (total cholesterol does NOT identify all individuals with SLO bc total cholesterol can be in the normal range)

Question 2

How is the dx with SLO established

Answer 2

Biallelic PVs in DHCR7 (via sequence analysis then del dup)

Question 3

What clinical features are consistent with SLO

Answer 3

prenatal and postnatal growth restriction, microcephaly, moderate to severe ID, characteristic facial features (narrow forehead, epicanthal folds, ptosis, short nose with anteverted nares, short mandible with preservation of jaw width, nevus simplex, low set ears, redundant skin at nape of neck), cleft palate, abnormal gingivae, CHDs (increased incidence of atrioventricular canal defects), hypospadias, ambiguous genitalia, postaxial polydactyly, 2-3 toe syndactyly

poor suck, FTT, irritability, GERD, severe cholestasis, pyloric stenosis, Hirschsprung dz, sensory hyperreactivity, sleep cycle disturbance, self injurious behavior (hand biting/ head banging), ASD, temperament dysregulation, social and communication deficits, depression, abnormalities of myelination on neuroimaging, photosensitivity, 46,XY individuals with extreme under-virilization of the external genitalia resulting in female external genitalia

~25% with renal anomalies, cleft palate, oligo and polyodontia, enamel hypoplasia, ptosis, strabismus, optic atrophy, recurrent otitis media, adrenal insufficiency, low serum concentrations of testosterone

Question 4

What are the recommendations for tx of SLO

Answer 4

Tx low cholesterol and its precursors with cholesterol supplementation to: improve growth, reduce photosensitivity, increase nerve conduction velocity, improve tone, achieve ambulation, improve developmental cognitive and behavioral changes
feeding therapy, standard tx for GERD and Hirschsprung dz, melatonin or other hypnotic for sleep disturbances, ASM for epilepsy, orthopedics/PT/OT for hypotonia/hypertonia later in life, skin protection for photosensitivity, hearing aids, standard tx for: cleft palate, dental anomalies, cataracts, ptosis, and/or strabismus, CHDs, adrenal insufficiency and limb defects

Question 5

What should be considered about sex reassignment in SLO

Answer 5

Reassignment of sex of rearing for infants with a 46,XY karyotype and female genitalia may not always be appropriate bc most will have early death, and the process of sex reassignment can be highly disruptive to a family already coping with difficult issues

Question 6

What u/s findings are consistent with a dx of SLO

Answer 6

IUGR is the most common
major malformations of the brain, heart, kidneys, or limbs; ambiguous genitalia, especially female-appearing genitalia or severe hypospadias in an XY fetus
increased NT, cystic hygroma, nonimmune hydrops, cleft palate

Question 7

How is the dx of Niemann Pick type C established

Answer 7

multigene panel that includes NPC1, NPC2 and other genes of interest is most likely to identify the molecular cause
CMA using oligonucleotide or SNP arrays to detect genome-wide large deldups including NPC1/NPC2 that cannot be detected by sequence analysis

Question 8

What clinical features are associated with Niemann Pick C

Answer 8

slowly progressive LSD
perinatal period/infancy: hepatosplenomegaly, jaundice, pulmonary infiltrates, persistent ascites; many infants succumb at this stage
children: hypotonia, DD, ataxia, dysarthria, dysphagia, epileptic seizures, dystonia, gelastic cataplexy (laughing uncontrollably or having episodes of inappropriate laughter- injuries may occur), progressive dementia, insidiously progressive cognitive impairment
adults: present with apparent psychiatric illness

Question 9

What is the molecular pathogenesis and mechanism of dz for Niemann Pick type C

Answer 9

PVs in NPC1/NPC2 lead to dysfunction or complete loss of the NPC1/NPC2 proteins, the deficiency of which leads to accumulation in the lysosomes of multiple lipid cargoes, including unesterified cholesterol, glucosylceramide, and gangliosides

LOF

Question 10

What supportive laboratory findings are seen in pts with Familial lipoprotein lipase deficiency

Answer 10

impaired clearance of chylomicrons from plasma causing the plasma to be milky in appearance
high plasma triglyceride concentrations regardless of fasting status

Question 11

How is the dx of Familial lipoprotein lipase deficiency established

Answer 11

biallelic PVs in LPL gene (sequence analysis then del/dup)
measurement of lipoprotein lipase enzyme activity but is not routinely available
most variants are in the highly conserved central homology region

Question 12

What are the clinical features of Familial lipoprotein lipase deficiency

Answer 12

starts in childhood; severity of symptoms correlate with the degree of chylomicronemia
episodes of abdominal pain (varying from mild to incapacitating), recurrent acute pancreatitis (rarely associated with total pancreatic necrosis and death), eruptive cutaneous xanthoma, hepatosplenomegaly

mild dementia, depression, memory loss can occur but are reversible

Question 13

Describe the recommended tx for a pt with Familial lipoprotein lipase deficiency

Answer 13

medical nutrition therapy: maintaining plasma triglyceride concentration, restriction of dietary fat
medium chain triglycerides may be used for cooking
pancreatitis caused by chylomicronemia syndrome is tx in a manner typical to other forms of pancreatitis

Question 14

What should be avoided in pts with Familial lipoprotein lipase deficiency

Answer 14

avoid agents that increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, glucocorticoids, SSRIs, and beta-adrenergic blocking agents is recommended
fish oil is contraindicated

Question 15

What are the clinical features associated with dysbetalipoproteinemia/familial dyslipidemia/hyperlipidemia

Answer 15

most pts are asymptomatic, mean are more affected (2:1 ratio); rarely occurs before adulthood or in premenopausal women
xanthomas of the eyelids, transient xanthomas on the palms, hepatomegaly, highly progressive atherosclerosis that can lead to premature cardiovascular dz

Question 16

Describe the molecular cause of dysbetalipoproteinemia/familial dyslipidemia/hyperlipidemia and how it is dx

Answer 16

results from mutations in the APOE gene encoding apolipoprotein E, a protein mediating the cellular uptake of triglyceride-rich lipoprotein remnants
dx based on evidence of abnormal lipoprotein profile with increased fasting serum concentrations of total cholesterol, triglycerides, and apolipoprotein B, and lowered HDL cholesterol

Question 17

Describe the tx for dysbetalipoproteinemia/familial dyslipidemia/hyperlipidemia

Answer 17

a diet poor in carbohydrates and saturated fat, exercise, and lipid-lowering drugs will lead to complete regression of the dz within a few months

w/out tx, 5-10x higher risk of premature and recurrent atherothrombotic events than the general population

Question 18

What laboratory findings are consistent with a dx of familial hypobetalipoproteinemia

Answer 18

low plasma total cholesterol level
low plasma LDL cholesterol level
low plasma apoB level
low plasma triglyceride level
high liver enzymes

Question 19

How is the dx of familial hypobetalipoproteinemia established

Answer 19

proband with either biallelic or heterozygous PVs in APOB (sequence analysis first, then del/dup)

Question 20

What clinical features are consistent with biallelic familial hypobetalipoproteinemia

Answer 20

may present from infancy through to adulthood
steatorrhea (fat in feces) is the primary gastro manifestation; Delayed growth trajectory, decreased bone mineral density, hepatomegaly, hepatic steatosis in childhood, steatohepatitis, fibrosis, irregularly spiculated RBCs (acanthocytosis), low-grade anemia, reticulocytosis, hyperbilirubinemia, hemolysis, vitamin K deficiency leading to easy bruising and prolonged bleeding, atypical pigmentation of the retina, loss of night vision and/or color vision, progressive loss of deep tendon reflexes, muscle pain or weakness, dysarthria, ataxia, broad-based gait, tremors

Question 21

What clinical features are consistent with heterozygous familial hypobetalipoproteinemia

Answer 21

typically asymptomatic with mild liver dysfunction and hepatic steatosis
5-10% develop relatively more severe nonalcoholic steatohepatitis
fatty liver is common w mild fat malabsorption in young adulthood; protection against atherosclerotic cardiovascular dz, lifelong reductions in serum LDL cholesterol concentrations

Question 22

What is the molecular pathogenesis for familial hypobetalipoproteinemia? Mechanism of dz?

Answer 22

ApoB is essential for the formation of intestinally derived chylomicrons and hepatically derived very low-density lipoprotein and their metabolites, including LDL
mutated apoB is unable to be incorporated and secreted as a component of a lipoprotein particle, resulting in low levels of LDL cholesterol, and accumulation of fat in the liver

LOF; rarely missense variants (these are associated with familial HYPERlipidemia)

Question 23

How is the dx of Menkes dz established

Answer 23

most commonly established with a hemizygous PV in ATP7A or heterozygous PV in females OR by additional biochemical studies
sequence (80%) analysis then del/dup(20%)
plasma and CSF catecholamine analysis are distinctively abnormal

Question 24

What are the clinical features associated with classic Menkes dz

Answer 24

neurodegeneration and FTT commencing at 2-3mo; age of dx is usually between 4-8mo; if untx, pass away between 7mo-3.5yrs
loss of early developmental milestones, hypotonia, seizures, changes to hair (short, sparse, coarse, twisted, often lightly pigmented), jowly appearance of face; transient hypoglycemia, prolonged jaundice, persistent temp instability, vascular tortuosity, neck masses, bladder diverticula, gastric polyps, subdural hematomas, cerebrovascular accidents; cerebral and cerebellar atrophy, ventriculomegaly, delayed myelination, wormian bones, “corkscrew” appearance of cerebral vessels

Question 25

What are the recommended evals following dx of Menkes

Answer 25

neurologic eval (brain imaging, consider EEG, assess for autonomic dysfunction) developmental assessment: eval for early intervention/special ed and/or PT/OT/speech therapy gastro/nutrition/feeding team eval pelvic u/s for bladder function assess for recurrent pneumonias via chest radiographs

Question 26

What is the recommended tx for Menkes

Answer 26

early tx with subcutaneous injections of copper histidinate, ideally within 4wks of birth; often enhances survival and improves quality of neurodevelopmental outcome some infants may not show significant improvement vitamin C supplementation is ineffective

Question 27

What is the molecular pathogenesis, mechanism of dz, and lab considerations for Menkes

Answer 27

protein encoded by ATP7A transports copper across the cell membrane and is critical for copper homeostasis Loss of copper transport function deep intronic variants may be difficult to detect by commercial molecular dx labs

Question 28

How is the dx of Wilson disease established

Answer 28

using clinical, biochemical, and molecular genetic findings based on the dx scoring system Kayser-Fleisher rings: 2pts Neuro manifestations: 2pts (severe); 1pt (mild) serum ceruloplasmin 1pt (low); 2pts (very low) coombs-negative hemolytic anemia: 1pt biallelic PV identified: 4pts one PV identified: 1pt *also takes into account lab values* greater than or equal to 4pts, dx is established; less than or equal to 2pts, dx is unlikely

Question 29

How is the dx of Wilson disease established through molecular testing

Answer 29

sequence analysis of ATP7B first then gene targeted del/dup targeted analysis can be performed FIRST in individuals from pops with known founder variants (AJ, canary islands, Druze, Sardinia)

Question 30

What are the clinical features associated with Wilson dz

Answer 30

manifest in individuals ages 3yo-older than 70yo as hepatic, neurologic, psychiatric, or hematologic disturbances phenotypic expression varies even within families "classic triad": liver dz, movement disorder, Kayser-Fleisher ring liver dz in children and younger adults, recurrent jaundice, hepatitis-like illness, autoimmune hepatitis, hepatic failure, chronic liver dz, fatty liver movement disorders or rigid dystonia, irreversible brain damage on brain imaging; depression is common hemolytic anemia with hemolysis Kayser-Fleisher rings from copper deposition, kidney involvement, arthritis, reduced bone mineral density, pancreatitis, cardiomyopathy, cardiac arrhythmias, rhabdo of skeletal muscle, sunflower cataracts

Question 31

What are the clinical features associated with TREATED Wilson disease

Answer 31

lifelong oral pharmacotherapy and dietary copper restriction individuals that are "asymptomatic", "clinically asymptomatic", symptomatic with liver dz are all expected to do well with lifelong tx individuals with Wilson dz with neurologic or psychiatric manifestations mostly stabilize but neuro findings may not respond to medical tx, with acceleration of neuro involvement or development of new manifestations

Question 32

What is the recommended tx for Wilson dz

Answer 32

goal of therapy is to institute tx with chelating agents as soon as possible in those who are asymptomatic, clinically asymptomatic, or symptomatic (tx is LIFELONG) for individuals who have more advanced liver dz or develop liver failure, eval for liver transplant should be considered copper chelating agents that increase urinary excretion of copper are the first-line tx for persons with symptomatic Wilson dz; D-penicillamine, Trientine Zinc interferes with absorption of copper from the GI tract restriction of foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, and nuts) orthotopic liver transplant is reserved for individuals who do not respond to medical therapy or cannot tolerate it bc of serious side effects

Question 33

What is the molecular pathogenesis and lab considerations for Wilson dz

Answer 33

gene is expressed mostly in the liver and kidneys tissue damage occurs after excessive copper accumulation resulting from lack of copper transport from the liver. Even when no transporter function is present, accumulation of copper occurs over several yrs include promoter variants in comprehensive ATP7B testing

Question 34

What are some laboratory findings associated with a dx of Hemochromatosis

Answer 34

elevated transferrin saturation (indicator of increased recycling of iron and increased risk for iron overload) elevated serum ferritin concentration higher Hb, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV)

Question 35

How is the dx of Hemochromatosis established

Answer 35

HFE HC is established in most persons with characteristic laboratory and/or clinical features by identification of HFE p.Cys282Tyr homozygosity (most do not have clinical HC; a significant proportion have biochemical HC) penetrance of other common genotypes is markedly lower than that of p.Cys282Tyr homozygosity *Targeted analysis for p.Cys282Tyr and p.His63Asp should be considered first for individuals with N European ancestry

Question 36

What are the features associated with clinical Hemochromatosis

Answer 36

absorb increased iron from a normal diet via small intestine mucosa, excessive free parenchymal iron, cause target organ injury and, potentially, organ failure usually appear between 40-60yo in males and after menopause in females arthropathy of the metacarpophalangeal joints, DM, elevated serum concentrations of hepatic transaminases, and progressive skin pigmentation; weakness, chronic fatigue, abdominal pain, weight loss, joint stiffness, pain liver dz: hepatomegaly, cirrhosis, portal HTN, primary liver ca (hepatocellular carcinoma, cholangiocarcinoma) and end-stage liver dz hypogonadotropic hypogonadism congestive heart failure and/or cardiac arrythmias in 15% individuals dx and tx have a normal life expectancy; if not, 10-30% risk of primary liver ca if untx

Question 37

What are the features associated with biochemical Hemochromatosis? Non-penetrant?

Answer 37

elevated transferrin saturation and serum ferritin concentration in the absence of clinical features of iron overload; 70-95% are asymptomatic nonpenetrant: normal serum ferritin concentration at dx and is usually associated with lack of development of clinical or lab features of iron overload

Question 38

What factors influence the penetrance of Hemochromatosis

Answer 38

some environmental factors modify penetrance: increased dietary consumption of heme iron was associated with higher serum ferritin levels consumption of more than two alcoholic drinks per day (HC is often associated with chronic alcoholism) viral hepatitis accelerate liver injury in persons with HFE HC proportion of females with clinical HC is lower than that of males

Question 39

What tx is recommended for Hemochromatosis

Answer 39

therapeutic phlebotomy is the standard of care for individuals who have either only biochemical evidence of iron overload or clinical manifestations of iron overload. it is a simple, inexpensive, safe, and effective way to remove excess iron some people, especially females, tolerate phlebotomy poorly; Anemia is NOT characteristic of HC on avg., males require removal of 2x as many units of blood to achieve iron depletion as females erythrocyapheresis is an effective and safe alternative to phlebotomy therapy for individuals iron chelation therapy to achieve iron depletion is a tx alternative for individuals who have an elevated serum ferritin concentration and concomitant symptoms of anemia

Question 40

What is the recommended surveillance for Hemochromatosis

Answer 40

iron measures (serum transferrin and ferritin): q3-4mo for clinical, 6-12 for biochemical joint radiographs for arthropathy DM assessment for those with diabetes q6-12mo, liver enzymes and function tests serum FSH and LH, testosterone, and estradiol for hypogonadotropic hypogonadism EKG/echo annually

Question 41

What should pts with Hemochromatosis avoid

Answer 41

medicinal iron and nutritional supplements containing iron excessive alcohol intake daily ingestion of supplemental vitamin C consumption of uncooked seafood which increased risk of infection for microorganisms that thrive in conditions with excess iron

Question 42

What genetic counseling considerations need to take place for pts with Hemochromatosis

Answer 42

low clinical penetrance; Pseudodominance (occurrence of AR disorder in 2 generations of a family without consanguinity) has been observed and is attributed to the high prevalence of the p.Cys282Tyr phenotype in ppl of European ancestry molecular genetic testing based pop screening for HFE HC is not recommended bc penetrance is low and natural hx of untx individuals cannot be predicted; BIOCHEMICAL based screening of males of European descent >30yo may be considered prenatal testing is NOT typically performed since it is an adult onset treatable disorder with low clinical penetrance

Question 43

What is the molecular pathogenesis and mechanism of disease of Hemochromatosis

Answer 43

HFE allele p.Cys282Tyr disrupts a disulfide bond and alters the conformation of HFE; consequently, hepatocytes lose the capability to upregulate hepcidin, the master regulator or iron metabolism LOF

Question 44

How is the dx of AIP established

Answer 44

when the dx of an AIP attack is suspected based on clinical findings, begin with biochemical testing when a multigene panel or genomic test (sequence analysis then deldup) has identified an HMBS PV, confirm the dx of AIP w biochemical testing to determine the concentration of PBG in the urine. Molecular genetic testing is NOT enough to dx active (symptomatic) AIP bc the relatively high prevalence of HMBS PVs in the general pop and the low penetrance can lead to misdiagnosis of AIP

Question 45

Describe the biochemical testing that is necessary for dx of AIP

Answer 45

An increased urinary PBG concentration is essential to establish an unequivocal dx of an acute porphyria attack biochemical confirmation that the increased urinary PBG concentration is caused by AIP and not another acute porphyria requires evidence that: total fecal porphyrin concentration is normal and plasma porphyrin fluorescence emission is normal

Question 46

What are the classifications of AIP? What are the criteria for an individual who is heterozygous for a HMBS PV to be categorized in each of these groups?

Answer 46

based on clinical hx (number of attacks) and urine PBG to creatinine ratio Active (symptomatic) AIP: 1 or more attacks in the last 2yrs symptomatic high excreter: chronic porphyria related manifestations during the last 2yrs AND a urine PBG to creatinine ratio greater than 4x the normal asymptomatic high excreter: no porphyria related manifestations during the last 2yrs AND a urine PBG to creatinine ratio greater than 4x the normal asymptomatic AIP: 1 or more porphyria related attacks in the past but has had no acute porphyria related manifestations during the last two years AND a urine PBG to creatinine ratio less than 4x the normal latent AIP: no acute porphyria related manifestations ADN urine PBG-creatinine ratio less than 4x the normal

Question 47

What are the clinical features associated with active (symptomatic) AIP

Answer 47

more common in women than men, onset in the second or third decade affected individuals may recover from acute porphyria attacks within ds but recovery from severe attacks that are not promptly recognized and tx may take wks or months significantly increased urinary PBG concentration and 2 or more of the clinical manifestations of an acute porphyria attack for more than 24hrs severe abdominal pain; back, buttock, or limb pain; nausea, vomiting, constipation, diarrhea, abdominal distention, tachycardia, HTN, urinary retention, incontinence, dysuria, peripheral neuropathy, muscle weakness, respiratory failure, anxiety, insomnia, irritability, mild cognitive impairment, aberrant behavior, hallucinations, confusion, impaired consciousness, seizures, brain MRI changes, hyponatremia ; significant risk of hepatocellular carcinoma 50yrs or older, chronic kidney dz attacks may be precipitated by: prescribed and recreational drugs, endocrine factors (mainly reproductive hormones; there is a higher risk for pregnancy-induced HTN disorder, gestational diabetes, and infants with IUGR), fasting (inadequate caloric intake), stress including recurrent illnesses, infections, alcoholic stress, and sx

Question 48

What are the clinical features associated with high excreter AIP

Answer 48

symptomatic: permanently high urinary PBG concentration; condition usually occurs after an acute porphyria attack and can persist for many yrs asymptomatic: permanently high urinary PBG concentration and has had no porphyria related manifestations

Question 49

What are the clinical features associated with asymptomatic and latent AIP

Answer 49

asymptomatic: refers to a person who has had one or more acute porphyria attacks in the past but has had no acute porphyria related manifestations during the last 2yrs latent: refers to someone who is a carrier who has never experienced acute porphyria related manifestations and does not have significantly elevated urinary PBG concentration

Question 50

Describe the penetrance of AIP

Answer 50

Higher in heterozygous family members of an individual who either has symptomatic or asymptomatic acute porphyria or is a high excreter than in heterozygotes in the general population

Question 51

What is the recommended tx for someone with AIP

Answer 51

Tx intercurrent infections and other diseases promptly high carbohydrate intake IV human hemin (Pahematin) is most effective for sporadic acute neurovisceral attacks which may be lifesaving if given early when neuronal damage is still reversible Givlaari is a subcutaneously delivered RNA interference therapeutic designed to reduce urinary excretion of PBG liver transplant is curative ovulation suppression therapy has been used for women with recurrent menstrual cycle related acute neurovisceral attacks prophylactic hemin infusion is also possible pain relief meds need to be evaluated so as to not cause an attack

Question 52

Can predictive testing be done in minors for AIP

Answer 52

children in families with AIP should be offered testing with appropriate consent from parents or guardians to provide advice/education on avoidance of precipitating factors and ensure rapid dx with prompt tx should an attack occur in adolescence

Question 53

What biochemical findings are consistent with a dx of Familial porphyria cutanea tarda

Answer 53

increased urine or plasma total porphyrins predominant uroporphyrin and hepatocarboxylporphyrin in urine pink appearing urine that is bright pink under UV light

Question 54

How is the dx of Familial porphyria cutanea tarda established

Answer 54

elevated porphyrins in the urine and a heterozygous PV in UROD (sequence then del/dup)

Question 55

What are the clinical features associated with Familial porphyria cutanea tarda

Answer 55

skin fragility, chronic blistering over sun-exposed areas, elevation in aminotransferases, increased iron stores, varying degrees of fibrosis, photosensitivity, facial hypertrichosis, hyperpigmentation, pseudoscleroderma

Question 56

What is the pathophyis of Familial porphyria cutanea tarda? Susceptibility factors that lead to dz?

Answer 56

development of symptoms require BOTH heterozygosity for a UROD PV that results in ~50% reduction of UROD enzyme AND the presence of other susceptibility factors that generate an inhibitor that reduces UROD activity to less than 20% of normal activity risk factors that influence dz susceptibility: HFE PVs, secondary iron overload (iron deficiency is protective), excessive alcohol consumption, tobacco use, oral estrogen use, estrogen mimetics/antagonists (tamoxifen), toxins that significantly induce cytochrome P450 enzymes, ESKD, Hep C infection, HIV infection

Question 57

How is the dx of PMM2-CDG established

Answer 57

biallelic PVs in PMM2 identified on molecular testing OR low levels of phosphomannomutase 2 (PMM2) enzyme activity PMM2-enzyme activity in fibroblasts and leukocytes is typically 0-10% of normal

Question 58

What are the typical presentations and stages seen in PMM2-CDG

Answer 58

hydrops fetalis at the severe end, infantile multisystem presentation, late-infantile and childhood ataxia-intellectual disability stage, and an adult stable disability stage

Question 59

What are the clinical features associated with infantile multisystem presentation PMM2-CDG

Answer 59

feeding issues, faltering growth, DD, seizures, ocular manifestations, dysmorphic features, multivisceral involvement, hypotonia, hyporeflexia, strabismus, retinitis pigmentosa, congenital cardiac anomalies, HCM, osteopenia from infancy ~20% of affected infants die within the first yr of life with a severe neurologic-multivisceral course (faltering growth, vomiting, intractable hypoalbuminemia, severe edema throughout the body, pericardial effusion, renal hyperechogenicity, renal cysts, nephrotic syndrome, hepatic fibrosis, multiorgan failure)

Question 60

What are the clinical features associated with late-infantile and childhood ataxia-ID stage of PMM2-CDG

Answer 60

between 3-10yrs hypotonia, ataxia, children are usually extroverted and cheerful, seizures, stroke-like episodes, thoracic deformities, kyphoscoliosis, progressive peripheral neuropathy, ID

Question 61

What are the clinical features associated with adult stable disability stage of PMM2-CDG

Answer 61

demonstrate stable ID progressive peripheral neuropathy, cerebellar ataxia, dysarthria, dysmetria, women w hypogonadotropic hypogonadism, hyperprolactinemia, insulin resistance, renal microcysts on renal u/s, Dandy-Walker malformations, small white matter cysts

Question 62

What are the clinical features of Lesch-Nyhan syndrome

Answer 62

asymptomatic at birth with normal prenatal growth and development, hyperuricemia present at birth (orange colored crystals in the diaper) crystalluria, urolithiasis, nephrolithiasis, gout, juvenile arthritis, neurological features by 4mo (hypotonia, DD, recurrent vomiting, extrapyramidal signs, dystonia, dependent on a wheelchair, choreoathetosis, dysarthria, dysphagia, and opisthotonus, cognitive impairment), self-injurious behaviors (self-mutilation causing profound disfigurement, head-banging, limb-banging, eye-poking), megaloblastic anemia pts rarely make their 30s, death usually due to respiratory failure and infections like pneumonia

Question 63

What is the recommended tx for someone with Lesch-Nyhan syndrome

Answer 63

allopurinol: mainstay tx for hyperuricemia but does not have any effect on neurodevelopmental and cognitive outcomes tx with L-DOPA for increased dystonia and hyperactivity S-adenosyl methionine with an anti-psychotic like risperidone for dystonia and self-injurious behaviors physical rehab

Question 64

What are some clinical features that are indicative of BH4 deficiency

Answer 64

usually present within the first 6mo of life and can be detected on NBS FTT, microcephaly, seizures, swallowing difficulties, truncal hypotonia, limb hypertonia, bradykinesia, chorea, athetosis, opisthotonos, developmental delays, psychomotor delay progressive neurologic dysfunction, dystonia, recurrent hyperthermia

Question 65

What type of testing can clarify a dx of PKU or BH4 deficiency

Answer 65

a BH4 loading test, in which infants suspected for BH4 deficiency are given BH4 molecular testing

Question 66

What is the tx recommendation for pts with BH4 deficiency

Answer 66

oral doses of synthetic BH4, L-DOPA for life as supplemental therapy for neurotransmitter precursors

Question 67

How is the dx of trimethylaminuria established

Answer 67

excretes in urine more than 10% of total trimethylamine as the free amine AND biallelic PVs in FMO3

Question 68

What clinical features are associated with trimethylaminuria

Answer 68

fishy odor resulting from excess excretion of trimethylamine bullying can also occur due to the odor

Question 69

How is trimethylaminuria tx

Answer 69

restriction of dietary trimethylamine and its precursors avoid foods rich in choline: eggs, liver, kidney, peas, beans, peanuts, soya products, brussels sprouts, broccoli, cabbage, cauliflower, rapeseed products; HOWEVER, choline is necessary in fetus and young infant for nerve and brain development so it should not be over-restricted trimethylamine N-oxide: avoid seafood avoid milk from wheat-fed cows supplements of riboflavin may help maximize residual FMO3 enzyme activity

Question 70

What kind of condition is Batten dz, what is the inheritance, and what are some of the broad features

Answer 70

LSD, juvenile form of neuronal ceroid lipofuscinoses, progressive problems with vision, movement, cognition with onset in childhood AR