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Master Boards Review -- Biochem
Terms in this set (74)
NBS conditions detected from amino acids
PKU, MSUD, homocystinuria, citrullinemia, arginosuccinic aciduria, tyrosinemia type I
NBS conditions detected from fatty acids oxidation
MCAD, VLCAD, SCAD, MADD, CPT-2 deficiency, CACT deficiency, LCHAD/TFP deficiency
NBS conditions detected from organic acids
Glutaric acidemia type I, propionic acidemia, methylmalonic acidemia, isocaleric acidemia, 3-hyroxy-3-methyl glutaryl CoA lyase, 3-methylcrotonyl CoA carboxylase deficiency
NBS condition detected from sugars
Biochem tests and the types of conditions they detect
Plasma amino acids (aminoacidopathies), urine amino acids (disorders of amino acid transport), CSF (neurotransmitter disorders). Urine organic acids (organic acidemias, FAO). Plamsa Carnitine and acylcarnitine (FAO and organic acidemias
Disorders of amino acid metabolism
PKU and biopterin metabolism, tyrosinemia, MSUD, homocystinuria, glycine encephalopathy
Phenylalanine is converted to tyrosine by Phe hydroxylase. Caused by mutations in PAH (98%) or BH4 synthesis defects (2%). Plasma amino acids show elevated Phe (low tyrosine). Urine organic acids show phenylketones. Features: eczema, fair skin/hair, develop microcephaly, delays noted at 6 months. Low protein/low Phe diet. Monitor plasma amino acids (Phe/Tyr)
Tetrahydrobiopterin - an essential cofactor for AA hydroxylation (ie Phe hydroxylase). FU testing for PKU diagnosis is to measure urine pterins. If normal, it is PKU, if abnormal could be a defect of BH4 synthesis. Elevated phe levels w/o mutations in PAH can be cause my mutations in multiple genes. BH4 defects affects synth of multiple hydroxylases (Tyr and Trp).
BH4 deficiency Dx, Sx and Tx
Dx: urine pterins (neopterin and biopterin), DHPR activity in blood, neurotransmitter metabolites in CSF. Truncal hypotonia, hypertonia of extremities, dystonia, swallowing difficulties, myoclonic seizures (even with dietary phe control). Tx: BH4 supplements, DHPR if deficient, DOPA/Carbidopa and 5-OH trytophan. Normal diet
Tyrosinemia type 1
Liver problems (cirrhosis and liver cancer), boiled cabbage odor, rickets due to Fanconi syndrome, neuro crises. Dx: plasma amino acids elevated Tyr, succinylacetone in urine organic acids is diagnostic. Tx: low protein, low phe/tyr diet
Tyrosinemia type 2
photophobia or corneal erosions, hyperkeratotic plaques of palms and soles, ID in 50%. Dx: Plasma amino acids elevated Tyr. Tx: low protein, low phe/tyr diet
Accumulation of oxidized homogentisic acid in connective tissue causes arthritis and heart valve failure. Sx: pigmentation of sclera and ear cartilage, arthritis, heart disease later in life, urine darkens (black) on standing. Dx: homogenitisic acid in urine organic acids. Tx: NTBC w/ low tyr/phe diet
Deficiency of branched chain ketoacid dehydrogenase (BCKD). Leucine accumulation causes brain swelling. Sx: poor feeding, lethargy progresses to coma w/in 1 week of life. Dx: plasma amino acids elevated Leu (highest), Val, Ile. Urine organic acids: elevated KIC, KMV, KIV, 2-OH-isovalerate. Ketonuria. DNA analysis.
Sx untreated patients: ID, deep venous thrombosis, strokes, lens dislocation, long long bones, early eath, osteoporosis (Marfan look-alike). Most common form caused by cystathionine beta-synthase deficiency. Excesse homocysteine interferes w/ collage cross-linking. Plasma amino acids elevated methionine, presence of free homocystine. Total plasma homocysteine is very elevated.
Glycine encephalopathy (nonketotic hyperglycinemia)
Accumulation of large quantities of glycine in all body tissues. Defect in glycine cleavage system (GLDC, AMT, GCSH genes). Classic form manifests in first hours/days of life: progressive lethargy, hypotonia, myoclonic jerks, apnea, often death. Survivors develop ID and seizures. Hx hiccups before and after birth. Dx plasma amino acids (high glycine), CSF amino acids (elevated glycine). Not identified w/ NBS.
Elevated ammonia DDx
Urea cycle defects, organic acidemias, FAO defects, sepsis.
Urea cycle defect. X-linked dominant inheritance. Presents shortly after birth in males w/ lethargy, coma, death. Dx plasma ammonia high, plasma amino acids high glutamine, citrulline can be low or normal (also high in CSF AA), urine orotic acids. Confirm w/ molecular testing of OTC gene. Female carriers: About 15% have symptoms (usually mild), typically have 5-30% enzyme activity in liver biopsies. Can become symptomatic during the peripartum period.
Urea cycle defects how to diagnose
Plasma amino acids: elevated glutamine and specific changes for each condition, citrulline very low is key for diagnosis for most conditions. Hyperammonemia. Urine orotic acid is elevated in most defect (not CPS-I or NAGS).
Urea cycle defect. Type I is ASA synthase deficiency, neonatal presentation (plasma amino acids citrulline very high). Type II is Citrin deficiency adult onset disorientation, restlessness, drowsiness, coma (plasma amino acids can normalize, severe hyperammonemia).
Fatty acid oxidation defects
Presents w/ fasting-induced hypoketotic hypoglycemia, liver failure, hyperammonemia (Reye syndrome), cardiomyopathy, myopathy, hypertonia, neuropathy, arrhythmia, rhabdomyolysis. Dx w/ plasma carnitine/acylcarnitine profile, urin organic acids during acute attack, free fatty acids, 3-OH fatty acids. Confirm w/ molecular study. Tx: avoid fasting, low fat diet, MCT oil (sometimes), carnitine, essential fatty acids.
Medium chain acylCoA dehydrogenase (MCAD) def
Most common FAO defect. Mutations in ACADM gene. Presents: fasting-induced hypoketotic hypoglycemia, coma, sudden death. Dx: plasma acylcarnitine profile (increased C6, C8, C1:1), urine organic acids (hexanolglycine present), DNA testing. ID by NBS using MS/MS
VLCAD def phenotypes
Very-long-chain acyl-CoA dehydrogenase. Three phenotypes: 1 early onset hypertrophic cardiomyopathy, high morbility/mortality, biventricular hypertrophy. 2 milder form w/ hypoketotic hypoglycemia, similar to MCAD def w/ increased LFTs, elevated CPK. 3 Stress-induced rhabdomyolysis resembling the muscle form of CPT2 def. Dx: Plasma acylcarnitine profile high C14:1-carnitine, but other abnormally high acylcarnitines are found (C14:0, C16:0, C16:1, C16:2, C18:1, C18:2.)
Long chain 3-OH-AcylCoA dehydrogenase (LCHAD) def
Presents: fasting-induced vomiting and hypoglycemia, hypotonia, cardiomyopathy, liver dysfunction, retinitis pigmentosa w/ time. Neuropathy and recurrent rhabdomyolysis. Lab: hypoketotic hypoglycemia, increased LFTs, increased CPK. Dx: urine organic acid 3-OH saturated and unsaturated fatty acids, dicarboxylic aciduria during attacks, abnormal acylcarnitines (not always), elevated 3-OH-fatty acids.
Enzyme defects for galactosemia
Galactose-1-phosphate-uridyltrasferase (GALT) deficiency (classic), Galactokinase (GALK) deficiency, Epimerase (GALE) deficiency
Classic galactosemia findings
Neonatal: Hepatocellular damage (jaundice, hepatomegaly), Food intolerance (vomiting, dirrhea, poor feeding), failure to thrive, sepsis, cataracts. Postnatal: ID (45%), speech delays, motor delays (tremor, poor coordination, ataxia), premature ovarian insufficiency (almost always, though age varies). If diagnosis is not made at birth liver disease and brain damage is severe. Tx: elimiation of gal from diet reverses growth failure, renal and hepatic dysfuction and cataracts. Even w/ dietary restrictions some dev delays.
Classic galactosemia labs/diagnosis
Dx by GALT enzyme activity:
G/G is <1.5 u/gHgb
D/G is 3-9 u/gHgb
Normal is 14.7-25.4 u/gHgb
DNA testing: GALT panel to detect variants
Q188R is classic variant
N341D is Duarte
GALT deficiency genotypes
1 D variant reduces enzyme activity 25%
1 G mutation reduces enzyme activity 50%
Enzyme activity of 0% is severe and 25% uncertain clinical impact.
N/G carrier 50%;
D/D 50%; D/N 75%;
D/G 25%; G/G 0%;
Pompe disease (glycogen storage disease type 2) cause
Deficiency of alpha-glucosidase. Accumulation of glycogen in tissues, primarily skeletal and cardiac muscle. Behaves as a lysosomal storage disorder rather than a glycogen storage disease (alpha-glucosidase is localized w/in lysosomes and deficiency results in intralysosomal accumulation of glycogen).
Dx based on clinical presentation, enzyme assay on blood spot, DNA analysis. Tx: supportive care, enzyme replacement therapy, investigational gene therapy.
Pompe disease presentation
Infantile: onset within 1 year of life, cardiomegaly/myopathy, organomegaly, hypotonia, delays or respiratory sx due to heart failure, macroglossia, hepatomegaly due to heart failure not glycogen storage, death by 1 year.
Juvenile: onset 3-15 yrs, weakness, skeletal muscle affected (not heart), slowly progressive, respiratory failure/death by 20 years..
Adult (muscular): onset >15 years, weakness, slowly progressive proximal myopathy, may require respiratory support at night.
Other sx childhood/adulthood onset: variable progression, morning headache, resp insuff, gait abnormality, daytime somnolence, shortness of breath/sleep apnea, scapular winging, scoliosis, low back pain, muscle weakness
Disorder of biotin recycling.
Profound: <10% enzyme activity, seizures, hypotonia, ataxia, DD, skin rash, alopecia, vision/hearing loss, infections, resp distress/apnea can occur.
Partial: 10-30% activity, typically asymptomatic, may show sx when stressed. Onset ranges from several weeks to several years. Most symptomatic pt have metabolic ketolactic acidosis and organic aciduria. Tx: Biotin supp. is very effective
Biotinidase Deficiency Dx and testing strategy
Enzyme testing in serum is common screening method, normal range 3.5 - 13.8 U/L. Control sample is important. Very low (<0.5) w/ control likely profound. Low (~1-2) w/ control possibly partial. Screening: virtually 100% detection using colorimetric test for biotinidase activity (NBS). False positives in premature infants, jaundice or sample in plastic before drying (heat). 5 common mutations or DNA sequencing (99% sensitivity) for confirmation of dx. Testing strategy: start w/ enzyme assay, if low repeat, then consider DNA testing.
Deficiency of hypoxanthine-guanine-phosphoribosyl transferase (HPRT gene). X-linked. High degree of heterogeneity. 95% detection rate for mutations. Carrier females are asymptomatic. Characteristics: hyperuricemia (orange crystals in urine), self-mutilative behavior, choreoathetosis, spasticity, ID, involuntary movements, dystonia. Normal at birth, delays start at 6-12 months. Speech is difficult to understand. Most do not walk. Lifespan 20-30 years. Dx by high uric acid levels in serum and urine.
Partial deficiency of hypoxanthine-guanine-phosphoribosyl transferase (HPRT). Assoc w/ hyperuricemia, but no central nervous system manifestations. Causes uric acid crystalluria, nephrolithiasis, obstructive uropathy, gouty arthritis. Intermediate form: neuro disability ranging from minor clumsiness to debilitating motor dysfuction (spasticity, hyperreflexia) in assoc w/ hyperuricemia
Caused by adenosine deaminase (ADA) deficiency. Purine nucelotides and deoxynucleotides accumulate and are toxic for B and T cells. Absence of any immune response. Tx: recombinant ADA, antibiotics, antivirals, immunoglobulins. Outcome: autism, brain damage, seizures.
Mito are inherited only from the egg (maternal origin/inheritance). Pt mutations are usually inherited, gross mutations (like Pearson syndrome) are usually de novo. Heteroplasmy: Coexistance of normal and mutant mtDNA. Threshold effect of accumulation of mutation. Some tissues may specifically affected -- mito segregation.
GC issues with mtDNA mutations
Phenotype predictions based on genotype of a single tissue are generally unreliable except for individuals w/ high levels of mtDNA mutations. For new mtDNA mutations, the absence of a mutation in blood does not exclude presence in other tissues. Prenatal testing: accurate phenotype predictions are not possible, prognosis can only be predicted if fetus is essentially homoplasmic for a highly pathogenic mtDNA mutation.
Lactic acidosis ddx
Metabolic causes: disorders of the respiratory chain, pyruvate dehydrogenase or carboxylase deficiency, glycogen storage diseases, defects of gluconeogenesis, organic acidemias, disorders of biotin metabolism, fatty acid oxidation disorders. Many other secondary causes that are much more common than metabolic
Hearing loss >50% of cases, ataxia, stroke-like episodes, peripheral neuropathy, myopathy, ocular findings.
Disorders caused by abnormal mtDNA: Leigh syndrome, NARP (Neurogenic muscle weakness, ataxia, retinitis pigmentosa), MELAS (Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), MERRF.
mtDNA deletion syndromes: kearns-sayre, chronic progressive external ophthalmoplegia, maternally inherited diabetes mellitus and deafness, Pearson syndrome.
Disorders of intergenomic communication: Mito DNA deletion syndrome - Alpers disease (progressive infantile poliodystropy), MNGIE (Mitochondrial neuorgastrointestinal encephalopathy syndrome), progressive external ophthalmoplegia
Spongy degeneration and vascular proliferation in the brain. Present w/in 2 yrs w/ feeding problems, dev delays, hypotonia. Followed by loss of dev skills, external ophthalmoplegia, optic atrophy, seizures, episodes of apnea. Periods of recovery then decline w/ fever/infections. Progressive decline to death w/in a few years of onset.
Inheritance: Caused by mutations in mtDNA in about 30% of cases. Other nDNA cases have AR or X-linked inheritance.
Dx: suspected from clinical presentation and characteristic MRI findings. Confirm w/ DNA testing (caused by mutations in nDNA and mtDNA) or characteristic changes to skeletal muscle.
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
Progressive neuro disorder onset 2-10 yrs. Repeated headaches, recurrent vomiting, seizures following neuro deficits resembling strokes. Easily fatigue, short stature, sensorineural hearing loss over time. Abnormal brain imaging at time of attacks. Lactic acidosis, ketonuria, increased excretion of hexanoylglycine and suberylglycine. Muscle biopsy shows ragged red fibers (common in mito disorders) that stain positive for cytochrome c oxidase. Blood vessels stain positive fro succinyl dehydrogenase. Most cases are caused by mutations in the mitochondrially encoded leucine tRNA (mutations in other tRNAs also noted). Mutations may be found in blood, but in several cases, muscle biopsy is needed to confirm or exclude the dx.
Neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP)
Presents in late-childhood or adults: dev delay, seizures, dementia, retinitis pigmentosa, ataxia, sensory neuropathy, proximal weakness. Abnormal brain imaging (atrophy of cerebellum). Caused by mutations in mitrochondrial ATPase6 gene which also causes Leigh syndrome when present w/ higher degree of heteroplasmy.
Mitochondrial neuorgastrointestinal encephalopathy syndrome (MNGIE)
Multisystem disorder clinically characterized by onset between 2nd and 5th decades of life. Ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, thin body habitus, peripheral neuropathy and myopathy. Caused by mutation in gene encoding thymidine phophorylase (TYMP). Can be assoc w/ renal tubulopathy. Accumulation of deoxyuridine, a substrate of thymidine phosphorylase.
mtDNA deletion syndrome. Sideroblastic anemia and exocrine pancreas dysfunction. Usually fatal in infantcy. Mutations are usually more abundant in blood than other tissues. Classic dyad: sideroblastic anemia and exocrine pancreatic dysfunction. Bone marrow: ringed sideroblasts, vacuolization of erythroid and myeloid precursors. Pt develop progressive liver failure and intractable metabolic acidosis and usually die in infancy. Survivors go on to Kearns-Sayre syndrome. Very rare.
mtDNA deletion syndrome. Multisystem, onset before 20yrs, pigmentary retinopathy, PEO. At least one of the following: cardiac conduction block, cerebrospinal fluid protein concertration high, cerebellar ataxia. Onset usually in childhood.
Peroxisome function, types of disorders, testing strategy
Function of peroxisomes: beta oxidation of VLCFA and biosynthesis of etherlipids (ie plasmalogens).
1 - disorders of peroxisome biogenesis, Zellweger syndrome spectrum, import sequence is abnormal;
2 - Single peroxisomal enzyme/transporter deficiencies, X-linke adrenoleukodystrophy (most common).
Testing starts with VLCFA/plasmalogens, then enzyme/ complementation/ DNA testing. Plasmalogens function in myelin, heart muscle and platelet aggregation is activated by a plasmalogen.
Peroxisome biogenesis disorder. Genes: PEX1,2,3,5,6,10,12,13,14,16,19,26. Spectrum includes zellweger syndrome most severe, neonatal adrenoleukodystrophy (NALD), infantile refsum disease (IRD) lease severe. Newborn: hypotonia, poor feeding, facial features similar to Down syndrome, neonatal seizures. May have cornial clouding, congenital cataracts and glaucoma. Liver may be enlarged. Renal cysts. Bony stippling of the patellae and other long bones. Older children: retinal dystrophy, sensorineural hearing loss, dev delay w/ hypotonia, liver dysfunction. Death in first year, usually no dev progress. NALD and IRD course is variable: can be very hypotonic, some learn to walk/talk, often slowly progressive.
Neonatal adrenoleukodystrophy (NALD)
Usually not dysmorphic, severe hypotonia, convulsions, absent grasp reflexes, little spontaneous movements at birth. Demylination of CNS, other brain abnormalities. Can survive to late infancy.
Infantile Refsum Disease (IRD)
Can present later in life (2-7yrs). Enlarged liver, cog impairment, sensorineural deafness, pigmented retina, anosmia, dysmorphic features. Accumulation of phytanic acid that results in lamellar structures in liver that look like plant chloroplasts (seen on US). Phytanic acid is also increased in Refsum disease so this can be also called infantile Refsum disease. Can survive into 20s.
X-linked adrenoleukodystrophy (X-ALD)
Peroxisome condition. Adrenoleukodystrophy protein (ALDP) encoded by ABCD1 gene on X chromosome. Primarily affects boys.
Childhood cerebral form (35%): onset 6-12 years, 90% w/ adrenal insufficiency. Rapid progression of neuro disturbances: Hyperactive, visually inattentive, increased tone in lower extremities, 4+ patellar reflexes, spastic gait, no organomegaly, darkly pigmented areas in areas not exposed to sunlight.
Adrenomyeloneuropathy (AMN) (50%): spastic paraparesis and sphincter dysfunction, onset 2-5th decade, 2/3 w/ adrenal insufficiency. Other phenotypes (15%): addison disease only, adult onset cerebral involvement, dementia.
Female heterozygotes 50% w/ mild AMN-like symptoms.
Types of lysosomal storage disorders and examples
Sphingolipidoses: Gaucher, Niemann-Pick
Mucopolysaccharidoses: Hurler, Hunter, Sanfilippo, Morquio
Mucolipidoses: I-cell disease
Mucolipidosis II (I-cell disease)
Severe mutations in GNPTA gene that reduce ptase activity to 2%. Char: psychomotor retardation, skeletal abnormalitites, coarse features. Dx at birth and death by 10yrs.
Mutations in GNPTAB that decrease acitivty to 2-15% of normal result in MIIIA aka Pseudo-hurler polydystrophy. Milder phenotype w/ later time of dx and longer life. For MPS IIIA/B/C Plasma lysosomal acid hydrolase levels greatly elevated, impaired targeting of newly synthesized acid hydrolases to lysosomes.
Mutations in GNPTG gene lead to the most mild phenotype. Plasma lysosomal acid hydrolase levels greatly elevated, impaired targeting of newly synthesized acid hydrolases to lysosomes.
X-linked lysosomal storage disorders
Fabry syndrome, MPSII (hunter syndrome)
Gaucher disease cause, subtypes and Dx
Deficiency of beta-glucocerebrosidase. Generally one mild mutation is assoc w/ non-neuronopathic form.
Type 1 Non-neuronopathic: onset any age, prevalent in Ash jew.
Type 2 Neuronopathic: acute, onset in infancy, live 2-3 years, Strabismus, retroflexion of the neck, cortical thumbs, viceromegaly, failure to thrive, cachexia (skin and bone only)
Type 3 Neuronopathic: chronic onset in infancy/childhood, Severe early onset, progressive dev delay, oculomotor apraxia (cannot move eyes in meaningful way), anemia, thrombocytopenia, massive visceral enlargement, bone disease.
Dx: Enzyme assay where typical adult pt is 10-30% of normal and children w/ severe form have 10% activity. Residual activity is not always a good predictor of severity. Biochem assay of glucocerebrosidase activity. DNA analysis.
Gaucher disease type 1 features, incidence
Type 1 most common, ERT available for type 1 only.
Enz deficiency leads to macrophage engorgement. Onset in first/second decade (may present infancy to adulthood). Early onset more aggressive, variable progression, can be life threatening.
Child: growth delay, anemia, thrombocytopenia, hepatospenomegaly, anemia, growth retardation, bruising/bleeding, fatigue, abdominal pain.
Adult: bone crisis, pathologic fracture, collapsed vertebrae, osteonecrosis/osteopeia, erlenmeyer flask deformity.
Incidence 1:60,000. 1:450 in AJ
Fabry disease cause
Alpha-galactosidase A deficiency. Lipids accumulate in cells. X-linked recessive, Occurs in males w/ <1% enzyme activity. Cardiac and renal forms rarely found in men w/ <1% enzyme activity. Females can manifest symptoms (X inactivation), 25% of pt. Dx: enzyme activity is gold standard. DNA test is gold standard to detect female carriers.Tx: supportive care and enzyme replacement therapy for >16yrs. Gene GLA.
Fabry disease manifestations
Onset childhood/adolescence. Life threatening, death due to renal, cardiac, cerebrovascular complications. Average life expectancy 50yrs.
Small vessel injury, early ischemic stroke, recurrent fever as child, corneal/lenticular opacities, psych manifestations, heat/cold intolerance, progressive renal/end organ failure. Later onset of kidney disease/failure, CNS disease (stroke), cardiac diease later in life. End stage renal disease is most frequent cause of death among males w/o tx.
Cardiac: left ventricular hypertrophy/cardiomyopathy, coronary artery disease, conduction abnormalities, etc., most common cause death w/ tx
Angiokeratomas: clusters of punctate, dark red lesions on skin.
Acroparesthesia: burning, pain and discomfort of hands and feet, usually first sx around 4-5 yrs. Unresponsive to narcotic analgesics.
Almost always dx in adulthood, manifestations are age-specific and change over time. Death usually in 4th to 5th decade of life.
Cause: accumulation of glycosaminoglycans (GAGs). Incidence of all MPS combined: 1/25,000. Severe conditions: onset w/in 2 years, death before adulthood. Glycosaminoglycans are excreted in urine. Tx: no effective cure, some therapies are promising. ERT approved for MPS I, II and VI. Bone marrow transplant shown successful for MPS I, II and VI (risky). MPS type IV aka Maroteaux-Lamy syndrome.
Mucopolysaccharidosis I (MPS I) Hurler syndrome
Hurler. Alpha-L-iduronidase enzyme deficiency. Severe form onset 6months, lifespan <10yrs. Attenuated form onset 3-8yrs, normal lifespan. Often life threatening.
Coarse facial features, macroglossia, Macrocephaly, Chronic rhinitis/otitis, obstructive airway disease, umbilical/inguinal hernia, skeletal deformities, short stature, carpal tunnel syndrome, dev delay, cornial clouding, hearing loss, cardio disease, hepatosplenomegaly, joint stiffness.
Dx: clinical presentation, dysostosis multiplex by Xrays, urinary glucosaminoglycans, enzyme assay, then DNA.
Tx: supportive care, hematopoietic stem cell transplant, enzyme replacement therapy
Incidence 1:100,000, AR inheritance
MPS I pulmonary / CNS / Caridiac disease
Pulmonary disease: caused by GAG storage in lung, airway epithelium and bone. Decreased pulmonary function, restrictive lung disease due to small ribcage and stiff joints. Decreased diaphragmatic excursion due to hepatomegaly. Frequent infections w/ thick secreations, resp insufficiency. CNS: caused by GAG storage in neurons, macrophages and meninges. Causes ID, cummunicating hydrocephalus, headaches. Cardiac: Caused by GAG storage in heart valves, coronary arteries and aorta. Causes valve disease, pulmonary hypertension w/ right heart failure, cardiomyopathy, coronary artery/vascular disease, congestive heart failure.
Mild form of Hurler. From mild to severe: MPS I Scheie -- MPS I Hurler-Scheie -- MPS I Hurler
Hunter syndrome (MPS II)
Iduronate sulphatase deficiency. X-linked inheritance, de novo rate 33%. Athropathy, dysostosis multiplex, macrocephaly, coarse facial features, carpal tunel. Delayed milestones, intellectual disability, seizures, sleep apnea, behavioral issues. Cardiac diease, progressive airway obstruction, hoarse voice, short stature, conductive/sensorineural hearing loss. Severe form onset 2-4yrs, dystosis multiplex, organomegaly, corneal clouding, ID, death by 10yrs. Attenuated form (non-CNS) slightly later onset, survival into adulthood, normal intelligence, short stature. Tx: enzyme replacement therapy, hematopoietic stem cell transplantation. Mutations to IDS gene
Diagnosis: 1 - Urine analysis of GAGs for presence of heparan and dermatan sulfate (MPS 1 and 2). 2 - Measure I2S in plasma, leukocytes or fibroblasts (deficiency = Hunter)
Sanfilippo syndrome (MPS III)
Missing one of 4 enzymes that breakdown heparan sulfate (forms A, B, C, D). Material builds in brain stopping normal development and causing hyperactivity, sleep disorders, loss of speech, dementia and typically death before adulthood. Form A: Present 2-3yrs, progressive intellectual deterioration. Some are short but less severe physical changes than hurler/hunter. Little difference among the four types. A few cases of B live healthy into early adult life. Dx: most pt have heparan sulfate in urine. Enzyme assay for all 4 forms needed. Tx: genistein (inhibits GAG synthesis).
Morquio disease (MPS IV)
MPS IVA: distinctive skeletal abnormalities, corneal clouding, odontoid hypoplasia. N-acetylgalactosamine 6-sulfatase deficiency. MPS IVB: presentation same as MPS IVA, enzyme deficiency is beta-galactoside. Multisystem including appearance (coarse facial features, macrocephaly), eyes, ears, nose, throat (corneal clouding), mouth/teeth (large tongue), Airway/respiration , heart (valvular disease, cardiomyopathy), abdomen (hepatospenomegaly), bones/joints, brain/nerves.
Other features: Profound psychomotor retardation and ophtho symptoms in first year of life, sitting is delayed and most unable to walk, strabismus, retinal degeneration. Carrier freq 1/122 among AJ. Gene MCOLN1
Elevated cholesterol and LDL cholesterol. AD inheritance. Heterozygotes have 2x normal cholesterol level (350-550 mg/dL). Xantomas in 20s and coronary atherosclerosis after 30 years, die in 50s. Men have 50% chance of MI by age 60.
Homozygotes have severe hypercholesterolemia (650-1000 mg/dL), dev xantomas by 4yrs, usually arcus cornea and myocardial infaction by age 20yrs. Tx LDL apheresis, liver transplant. Dx skin biopsy measure LDL receptor activity, DNA testing
FH is cuased by mutations in the LDL receptor. There is a correlation between residual receptor activity and cardio disease mortality.
Criteria to evaluate disorders for NBS
Condition: morbidity, mortality, natural history, epidemiology. Test: reliability, precision, clinical validity, confirmatory testing. Treatment: Availability, effectiveness, medical expertise. Screening program: effectiveness, benefits, cost, quality assurance, fu, outcome monitoring.
Considerations for interpretation of NBS results
Age at collection for use of appropriate cut-offs. Birth weight. Transfusion status. Medication. Diet. Use appropriate cut-offs from "normal" population evaluatingn age/weight related changes. Also evaluate values from affected population for making appropriate cut-offs. IV hyperalimentation causes elevated amino acids, acylcarnitines (Dextrose) and low free carnitine (if carnitine is not added to hyperal solutions there will be very low conc of free carnitine)
Congenital adrenal hyperplasia
Inadequate cortisol production results from enzymatic deficiency, prevents feedback inhibition of ACTH. Chronic ACTH stimulation produces adrenal hyperplasia.
Gene: 21-hydroxylase, psudogene and exons with high homology make testing difficult.
5-8% of all CAH pt have 11-hydroxylase deficiency
Two forms for classic 21-hydroxylase deficiency:
1-salt wasters: 60-70% of all affected children, adrenal crisis
2-simple virilizing form: precocious puberty
Both: Ambiguous genitalia (virilized newborn female).
Prenatal tx: dexamethasone, complications latrogenic Cushings in mother and unknown longterm outcomes
Tx: glucocorticoid (cortisol) replacement therapy, mineralcorticoid replacement therapy in salt-losing forms.
NBS: Measure 17-OH progesterone ELISA. 2nd tier: measure 17-hydroxyprogesterone (17-OHP) after extraction w/ organic solvents, simultaneous measurement of androstenedione and cortisol and calc ratio of (androstenedione+17-OHP)/cortisol.
Defect of urinary dibasic amino acid transport. Elevated urinary excretion of cystine, lysine, arginine, ornithine. Present: kidney stones, urinary tract infection, pain, hematuria, normal mentality. Genes: SLC3A1, SLC7A9.
Type 1: fully recessive. Heterozygotes have normal excretion of cystine and dibasic aa. Mutations to rBAT (SLC3A1).
Types 2 and 3: incomplete recessive form. Heterozygotes excrete cystine and dibasic aa at levels greater than normal. Mutations in b0+AT (SLC7A9)
Dx: plasma and urine aa (High cystine, arginine, lysine, ornithine, glycine), with decreased reabsorption of cystine. Quant reabsorption studies sometimes needed.
Tx: Stones prevented by dilution in larger urine volumes.
Most common forms are AD inheritance with very reduced penetrance and rare de novo mutations.
Deficiency of enzymes involved in heme biosynthetic pathway. AD or AR except porphyria cutanea tarda (PCT) where there is a sporadic (PCT I) and an inherited (PCT II) form.
Triggers: Drugs such as barbiturates, tranquilizers, birth control pills, sedatives. Chemicals, fasting, smoking, alcohol (esp heavy), infections, excess iron, emotional/physical stress, mentrual hormones, exposure to sun.
X-linked sideroblastic anemia
Acquired or inherited. Inherited form is due to ALAS2 deficiency. Acquired is due to alcohol use, chemotherapy, etc. Hypochromic anemia w/ incresed serum conc of iron. Bone marrow contains erythrocite precursors w/ iron-laden mitochondria around nucleus. Progressive iron accumulation leads to organ damage.
Porphyria cutanea tarda (PCT)
AD inheritance, significantly reduced penetrance
Most frequent type of porphyria. Decreased uroporhyringogen decarboxylase (URO-D) activity. Inherited AD. Tx: phlebotomy, low-dose chloroquine.
F-PCT: familial (hereditary) variant. 50% normal enzyme activity and other factors are needed for symptoms. 25% of all cases of PCT
S-PCT: sporadic variant, approx 70% of PCT. Enzymatic def is only in liver, no mutations in URO-D gene. Assoc w/ 1+ risk factors including (homozygosity of C282Y mutation HFE, hepatitis C, alcohol abuse, use of medical estrogens).
Present: skin fragility on dorsal side of hands, blistering on all sun-exposed areas. Blisters rupture, heal slowly, then form thick eschars, then hyperpigmented patches. Facial hypertrichosis is common esp in children and women. Scleroderma-like skin changes develop in light exposed areas in some pt.
Dx: Total porphyrin content in plasma is elevated. If plasma porphyrins are elevated, the urinary porphyrin profile can provide the dx. Measure URO-D activity in red blood cells or DNA testing confirmes F-PCT.
Acute Intermittent Porphyria
Half-normal activity of enzyme HMBS.
Presentation: life-threatening neurovisceral attacks of severe abdominal pain, nausea, vomiting, tachycardia, hypertension.
Most have 1 or a few attacks, about 5% have recurrent attacks. Usually occur after puberty, more common in women than men.
Most people w/ mutations in HMBS have no attacks.
AD inheritance. 1% de novo.
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