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
How is the dx of Wilson disease established through molecular testing
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)
What are the clinical features associated with Wilson dz
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
What are the clinical features associated with TREATED Wilson disease
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
What is the recommended tx for Wilson dz
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
What is the molecular pathogenesis and lab considerations for Wilson dz
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
What are some laboratory findings associated with a dx of Hemochromatosis
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)
How is the dx of Hemochromatosis established
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
What are the features associated with clinical Hemochromatosis
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
What are the features associated with biochemical Hemochromatosis? Non-penetrant?
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
What factors influence the penetrance of Hemochromatosis
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
What tx is recommended for Hemochromatosis
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
What is the recommended surveillance for Hemochromatosis
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
What should pts with Hemochromatosis avoid
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
What genetic counseling considerations need to take place for pts with Hemochromatosis
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
What is the molecular pathogenesis and mechanism of disease of Hemochromatosis
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
How is the dx of AIP established
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
Describe the biochemical testing that is necessary for dx of AIP
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
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?
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
What are the clinical features associated with active (symptomatic) AIP
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
What are the clinical features associated with high excreter AIP
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
What are the clinical features associated with asymptomatic and latent AIP
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
Describe the penetrance of AIP
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
What is the recommended tx for someone with AIP
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
Can predictive testing be done in minors for AIP
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
What biochemical findings are consistent with a dx of Familial porphyria cutanea tarda
increased urine or plasma total porphyrins
predominant uroporphyrin and hepatocarboxylporphyrin in urine
pink appearing urine that is bright pink under UV light
How is the dx of Familial porphyria cutanea tarda established
elevated porphyrins in the urine and a heterozygous PV in UROD (sequence then del/dup)
What are the clinical features associated with Familial porphyria cutanea tarda
skin fragility, chronic blistering over sun-exposed areas, elevation in aminotransferases, increased iron stores, varying degrees of fibrosis, photosensitivity, facial hypertrichosis, hyperpigmentation, pseudoscleroderma
What is the pathophyis of Familial porphyria cutanea tarda? Susceptibility factors that lead to dz?
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
How is the dx of PMM2-CDG established
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
What are the typical presentations and stages seen in PMM2-CDG
hydrops fetalis at the severe end, infantile multisystem presentation, late-infantile and childhood ataxia-intellectual disability stage, and an adult stable disability stage
What are the clinical features associated with infantile multisystem presentation PMM2-CDG
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)
What are the clinical features associated with late-infantile and childhood ataxia-ID stage of PMM2-CDG
between 3-10yrs
hypotonia, ataxia, children are usually extroverted and cheerful, seizures, stroke-like episodes, thoracic deformities, kyphoscoliosis, progressive peripheral neuropathy, ID
What are the clinical features associated with adult stable disability stage of PMM2-CDG
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
What are the clinical features of Lesch-Nyhan syndrome
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
What is the recommended tx for someone with Lesch-Nyhan syndrome
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
What are some clinical features that are indicative of BH4 deficiency
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
What type of testing can clarify a dx of PKU or BH4 deficiency
a BH4 loading test, in which infants suspected for BH4 deficiency are given BH4
molecular testing
What is the tx recommendation for pts with BH4 deficiency
oral doses of synthetic BH4, L-DOPA for life as supplemental therapy for neurotransmitter precursors
How is the dx of trimethylaminuria established
excretes in urine more than 10% of total trimethylamine as the free amine AND
biallelic PVs in FMO3
What clinical features are associated with trimethylaminuria
fishy odor resulting from excess excretion of trimethylamine
bullying can also occur due to the odor
How is trimethylaminuria tx
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
What kind of condition is Batten dz, what is the inheritance, and what are some of the broad features
LSD, juvenile form of neuronal ceroid lipofuscinoses, progressive problems with vision, movement, cognition with onset in childhood
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