Biochemical Genetics 4 Flashcards
Cholesterol synthesis disorders, dyslipidemias, heavy metals and heme, glycosylation, creatine, nucleic acids, and peptide disorders
What laboratory findings are consistent with the dx of SLO
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)
How is the dx with SLO established
Biallelic PVs in DHCR7 (via sequence analysis then del dup)
What clinical features are consistent with SLO
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
What are the recommendations for tx of SLO
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
What should be considered about sex reassignment in SLO
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
What u/s findings are consistent with a dx of SLO
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
How is the dx of Niemann Pick type C established
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
What clinical features are associated with Niemann Pick C
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
What is the molecular pathogenesis and mechanism of dz for Niemann Pick type C
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
What supportive laboratory findings are seen in pts with Familial lipoprotein lipase deficiency
impaired clearance of chylomicrons from plasma causing the plasma to be milky in appearance
high plasma triglyceride concentrations regardless of fasting status
How is the dx of Familial lipoprotein lipase deficiency established
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
What are the clinical features of Familial lipoprotein lipase deficiency
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
Describe the recommended tx for a pt with Familial lipoprotein lipase deficiency
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
What should be avoided in pts with Familial lipoprotein lipase deficiency
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
What are the clinical features associated with dysbetalipoproteinemia/familial dyslipidemia/hyperlipidemia
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
Describe the molecular cause of dysbetalipoproteinemia/familial dyslipidemia/hyperlipidemia and how it is dx
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
Describe the tx for dysbetalipoproteinemia/familial dyslipidemia/hyperlipidemia
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
What laboratory findings are consistent with a dx of familial hypobetalipoproteinemia
low plasma total cholesterol level
low plasma LDL cholesterol level
low plasma apoB level
low plasma triglyceride level
high liver enzymes
How is the dx of familial hypobetalipoproteinemia established
proband with either biallelic or heterozygous PVs in APOB (sequence analysis first, then del/dup)
What clinical features are consistent with biallelic familial hypobetalipoproteinemia
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
What clinical features are consistent with heterozygous familial hypobetalipoproteinemia
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
What is the molecular pathogenesis for familial hypobetalipoproteinemia? Mechanism of dz?
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)
How is the dx of Menkes dz established
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
What are the clinical features associated with classic Menkes dz
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
What are the recommended evals following dx of Menkes
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
What is the recommended tx for Menkes
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
What is the molecular pathogenesis, mechanism of dz, and lab considerations for Menkes
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
How is the dx of Wilson disease established
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
