Metabolic Sid Flashcards

Question

What is the "**EASY"** 2 part list for FAOD's ?

Answer 1

**_1. CHAIN:_** **Short**: SCAD **Medium:** MCAD **Long:** VLCAD **_2. MEMBRANE:_** **Plasma:** Carnitine uptake deficiency **Mitochondrion:** CPT1

Answer 2

**1. Blood:** **a. Basic:** CBC, Gluc (_hypoglycemia_), lytes, lactate and CPK, bld gas, ketones (_low_) b. **Liver**: _raised_ ALT, AST, PT, PTT & NH3 c. **metabolic:** plasma carnitine **+** acylcarnitine levels d. **Guthrie**: raised acylcarnitines in ﬁlter paper blood spots. 2. **Urine:** a. In fasting- elevated levels of mediumchain dicarboxylic acids b. Ketones c. MS analysis of Urine organic acids, acylglycine **3. Diagnosis** a. common **A985G mutation** b. measurement of **specific enzyme activity** c Plasma **acylcarnitine** and plasma **carnitine** (free and total) **4. Pathology:** a. Liver biopsy -steatosis The diagnosis of FAODs even b. postmortem for genetic counselling and evaluation of siblings

Answer 3

1. **iv 10% dextrose** (12-15 mg/kg/min ) to treat hypoglycemia+ suppress lipolysis as 2. **Avoid fasting \>10-12 hr.** 3. **Restricting dietary fat or treatment with carnitine is controversial.** Long-chain fat, however, needs to be restricted in severe long-chain FAODs and substituted by medium-chain triglycerides 4. **Hospital admission** is recommended for procedures that would require the patients to **take nothing orally for \>8 h**, especially if less than 1 year of age. 5. **Carnitine** is undisputedly effective in patients with carnitine transporter deficiency 6. **Liver transplantation** may be the ultimate consideration if there is **NO** evidence of **neurological disease or other systemic involvement** that may impair recovery and return to baseline function

Answer 4

**1. DEATH:** a. 25% of unrecognized patients may **die during their 1st attack** of illness. b. Often Hx **history of sibling death** due to unrecognized MCAD deﬁciency. **2. Brain injury:** **a.** +/- permanent brain injury **2" to hypoglycemia.** b. T**he prognosis for survivors without brain damage** is excellent because cognitive impairment or cardiomyopathy does not occur in MCAD deﬁciency. **3. Increasing age:** a. **Muscle pain and reduced exercise tolerance** may become evident with increasing age. b. **Fasting tolerance improves with age** and the risk of illness decreases.

Answer 5

1. **MCAD**- most common 2. **Very Long Chain Acyl CoA Dehydrogenase (VLCAD)** VLCAD 2nd most common, usually more severely affected than those with MCAD deﬁciency, presenting earlier in infancy and having more chronic problems with muscle weakness or episodes of muscle pain and rhabdomyolysis 3. Short-Chain Acyl CoA Dehydrogenase (**SCAD)** Deﬁciency - mild 4. Long-Chain 3-Hydroxyacyl CoA Dehydrogenase * *(LCHAD)**/Mitochondrial Trifunctional Protein (**TFP)** Deﬁciency- more severe than MCAD

Answer 6

**Deficiency** in the enzyme glucose-6-phosphatase, **Clinical**: (\> 3 mths..stretch out their feeds) Growth failure, poor feeding, episodes of ketotic hypoglycemia -fits, lethargy **Exam:** Course facies, cherubic, lethargic, hepatomegaly **Labs**: a. _Basic_: CBC - may have low ANC's b. _metabolic:_ Ketotic hypoglycemia, raised (lactic acid, uric acids, triglycerides) **Treatment:** **A. Acute decompensation management principles1.** 1. **ABCs** 2. **P****revent catabolism** - *(downstream hypoglycemia is more impt than upstream toxicity)* a. iv dextrose b. Treat inciting factor c. Monitor for acute complications/sequelae **B. Long term complications** Neutropenia and frequent infections malignant transformation of Hepatic adenomas Hypertension, and renal insufficiency. IBD **Long term treatment** 1. Frequent doses of cornstarch or continuous NGT 2. Education of parents for Sick day monitoring

Answer 7

**Defect** in the enzyme myophosphorylase. **Clinical** -(Onset -adolescence) 1. exercise induced muscle pain (followed by a “second wind” phenomenon in which the patient briefly feels better.) , exercise induced fatigue, and rhabdomyolysis. Myoglobinuria 2. renal injury can occur. **Blood:** 1. Raised CK concentrations following exercise. 2. muscle biopsy, which demonstrates deficient enzyme and glycogen within the myocytes. 3. DNA analysis of the PYGM gene- (no need biopsy). **Management:** 1. Avoidance of strenuous aerobic and isometric exercise 2. light aerobic activity as tolerated.

Answer 8

1. Lysosomal storage diseases USMLE dirty https://www.youtube.com/watch?v=7udUG8KkN\_E

Answer 9

**Genetics:** X Linked recessive **Males:** late childhood/early adolescence **Female** heterozygotes in adolescence/adulthood. **1. Skin: acroparesthesias** (painful hands and feet) , reduced sweating, angiokeratomas **2. Gastro: recurrent abdominal pain.** 3. **Renal**: _proteinuria + renal failure_**..**dialysis & transplant.( if untreated) (Females-renal failure 10 years)later than males, 4. early **arthrosclerosis and stroke, and cardiac hypertrophy.** **Diagnosis:** 1. **low agalactosidase** enzyme activity in males. 2. DNA testing esp in females (near-normal enzyme activity. **Treatment:** ERT is available for treatment.

Answer 10

**Pathogenesis:** accumulation of glucocerebroside in the liver, spleen, and bone marrow. More common in individuals of Ashkenazi Jewish decent. **Clinical**: M 1. **Marrow obliteration and splenic sequestration/hepatosplenomegaly** - anemia, thrombocytopenia & bone paindue to , , and . The brain is not affected, although Parkinsonism has been recently shown to be associated with Gaucher disease. **2. Neuropathic variants (types 2 and 3)** Type 2 is- rapid, and severe neurodegeneration in childhood Type 3 ocular + neuromotor dysfunction severe visceral signs **Treatment:** ERT and substrate inhibitors are available for treatment.

Answer 11

1. Niemann Pick has hepatomegaly and Tay Sachs does not 2. Both have cherry red spots on macula

Answer 12

Has **Globoid** cells, like the **Krabbe** is out of this **world** Enzyme: galactosylceramidase. Buildup: **Clinical**: (infantile neurodegeneration). Infants present in the 1. 1. **Neuro:** increasing muscle tone, irritability, fits, vision loss, and developmental regression,2. Recurrent **fevers** without source can been seen.The infant develops with **Diagnosis:** 1. is by enzyme assay or DNA analysis. 2. CSF protein elevated **Progx/Management****:** 1. Death 2. HSCT with mixed results.

Answer 13

**1. MPS 1 (Hurler syndrome )** - progressive * Enzyme: L-Iduronate* * Buildup: Dermatan Sulphate* a. Corneal clouding, coarse facial features, hepatosplenomegaly, bony deformity, and developmental regression. **Progx:** **1.** Without treatment - fatal. 2. ERTand HSCT effective 2. **MPS II (Hunter syndrome) -** *X marks the sport (Xlinked and no cataract)...rifle against the skin/"derm"* * Enzyme: Iduronate Sulphatase* * Buildup: Dermatan Sulphate* **Clinical:** similar to MPS I but no corneal clouding. MPS I and II Both **Hurler and Hurlers** have milder forms without developmental regression that are amenable to ERT, which does not cross the blood-brain barrier.

Answer 14

**Pathophysio:** 1.**deficiency** in the enzyme b-hexosaminidase A. **accumulation**- sphingolipid GM2 ganglioside 2. more common in Ashkenazi Jews **Diagnosis:** a. _DNA analysis -HEXA gene_ b. _enzyme assay of b-hexosaminidase A_ in leukocytes. **Clinical: (early** infancy**)** 1. **Neuro**: with weakness, startle reflex ++, Myoclonic jerks and developmental regression , macrocephaly+, seizures, spasticity, unresponsiveness+ 2. **Eye**: cherry red spots on the maculae, vision loss, Visceromegaly **Progx/Management:** **1.** no effective treatment , fatal by age 4 years. 2. Carrier screening reduced the incidence in Ashkenazi Jews.

Answer 15

**1. MPS III (Sanfilippo syndrome)** (neurodegenerative condition) a. slow developmental regression, with death \< 20 yr b. visceral and bony manifestations - less prominent c. behavioral, attention issues before motor and cognitive regression. 2. **MPS IV differs by..** - severe bony involvement and short stature. 3. **MPS VI** is very similar to **MPS I (Hurlers)** but never has developmental regression.

Answer 16

The peroxisome is a cellular organelle with disparate functions, including oxidation of very long-chain fatty acids (VLCFAs).

Answer 17

**Cause:** near or complete absence of peroxisomes. **Clinical**: 1. **Neuro: _d_**_ysmorphic_ facial characteristics, _seizures_, _hypotonia_ ++, and _hearing and vision deficits._ 2. _liver disease,_ characteristic _bone_ involvement, **Diagnosis:** 1. screening by _plasma VLCFA analysis_ **2. Radiology**: MRI brain brain - _leukodystrophy_ -Abn myelination **Progx:** fatal in infancy.

Answer 18

**Cause**: _X-linked condition_ from deficiency in peroxisomal oxidation of VLCFAs. * *Clinical**: _(school-age boys)_ 1. developmental regression, _new-onset spasticity_ 2. adrenal failure (acumulation in adrenal glands) **Diagnosis:** 1. screening by plasma VLCFA analysis **2. MRI**: white matter disease, **Management:** HSCT may halt progression

Answer 19

**Cause**: 1. multisystemic conditions from mutations in the mitochondrial genome or nuclear genes required for mitochondrial function 2. Genetics: a. ***Point mutations*** in the _mitochondrial genome_ are transmitted via **maternal inheritance,** **b. *deletions or duplications*** in the mitochondrial genome are usually sporadic c. ***mutations*** in _nuclear genes_ required for mitochondrial function are inherited in a mendelian pattern, usually autosomal recessive. 3. most important functions is the production of cellular energy in the form of ATP via the respiratory chain - affect **brain, skeletal and cardiac muscles, and the eye.** **Diagnosis:** 1. Muscle biopsymay show ragged red fibers on lightmicroscopy. 2. next-generation DNA sequencing of multigene panels for nuclear gene mutations, sequencing of the mitochondrial genome, and specific assays of muscle respiratory chain activity.

Answer 20

**1. MELAS (**mitochondrial encephalomyopathy, lactic acid, and strokelike episodes**)** **Cause:** _maternally_ inherited mutation in the mitochondrial tRNA for leucine. **Clinical**: (adolescence) **1. Neuro:** recurrent strokelike episodes (hemiparesis or other focal neurologic signs (posteriortemporal, parietal, and occipital lobes) 2. A**t least 2 of the following**: _seizures_ (focal or generalized), dementia, recurrent migraine headaches, and vomiting....and headaches 3. **Lactic** acidosis, **ragged red fibers** (RRF), orboth **4. Other**: diabetes mellitus a. _Muscle_: exercise intolerance, myopathy, ophthalmoplegia, b. b. _eyes_: pigmentary retinopathy, c. _Cardiac_: hypertrophic or dilated cardiomyopathy, cardiac conduction defects, d. Sensory: deafness, cortical blindness, f. endocrinopathy(diabetes mellitus), and proximal renal tubular dysfunction, g. development: delayed motor and cognitive development, short stature. **2. Kearns-Sayre syndrome** ( **Cause**: _sporadic_, noninherited partial deletions of the mitochondrial genome **Clinical:** **Neuro:** progressive external ophthalmoplegia * *Cardiac:** conduction abnormalities, cardiomyopathy * *Metabolic**: Common features include , lactic acidosis, and . 3. **Leigh syndrome (**Respiratory chain disorders) **Genetics:** _autosomal recessive pattern_ and are related to mutations in nuclear genes important for assembly, maintenance, or production of the respiratory chain (but may also be maternally inherited due to mitochondrial point mutations). **Clinical**: (infancy) **Neuro:** hypotonia, muscle weakness, global developmental delays, and seizures. **Metabolic**: lactic acidosis, **Diagnosis**: Neuroimaging may show basal ganglia lesions consistent with **Leigh syndrome**

Answer 21

Hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade **glycosaminoglycans**- GAG’s (acid mucopolysaccharides). The most common subtype is MPS-III, followed by MPS-I and MPS-II.

Answer 22

**Primary prevention** through genetic counseling and **Tertiary prevention** to avoid or treat complications: Respiratory, cardiovascular, hearing loss, carpal tunnel syndrome, spinal cord compression, hydrocephalus

Answer 23

Approved for MPS I, MPS II, and MPS VI.

Answer 24

Reduces organomegally, improves growth, joint mobility, and physical endurance. - reduces sleep apnea and urinary GAG excretion. - do not cross BBB, so only for mild CNS problems involvement. - start enzymes before BMT for extra CNS problems How do you manage enzyme and BMT Rx? - Enzyme and BMT Rx useful in Hunter disease, MPS VI

Answer 25

Reduces organomegally, improves growth, joint mobility, and physical endurance. - reduces **sleep apnea** and urinary GAG excretion. - **do not cross BBB, so only for mild CNS problems** involvement. - start enzymes before BMT for extra CNS problems How do you manage enzyme and BMT Rx? - Enzyme and BMT Rx useful in Hunter disease, MPS VI

Answer 26

Works for MPS I, II, and VI (Maroteaux-Lamy disease (MPS VI)

Answer 27

**General:** - increased life expectancy, growth better, - joint stiffness, facial appearance, hepatosplenomegaly - Enzyme activity in serum and urinary GAG excretion normalize. **Resp/heart:**heart disease, upper airway obstruction, OSA **Neuro:** - Prevents CNS degeneration but does NOT correct it - improves communicating hydrocephalus, and hearing loss. - target young kids, severe MPS I, anticipated CNS probs, BMT \< 2 yr, baseline IQ \>70. Not correct: skeletal and eye problems **Risks:death** or 1’ graft failure ≈30% of the patients.

Answer 28

**Basic:** **a.** CBC **-** prolonged metabolic stress may lead to pancytopenia b. Septic work up - b cultures, urine, LP and CXR **Elect:** - low urea if UCD raised if organic acidemia) - N anion gap if UCD (raised if organic acidemia) maybe hypoglycemia **Blood gas:** If UCD initial alkalosis...later +/- acidosis Iforganic acidemia acidosis **LFT's:** NH3 raised in UCD and organic acidemia Raised transaminases and bilirubin if liver failure

Answer 29

**Blood:** a. aminoacids + organic acids + carnitine and acyl carnitine b. _genetics testing_ - mutation analysis important for future pregancies and siblings **Urine:** organic acids + orotic acid

Answer 30

This is why organic acidemias result in high NH3 levels

Answer 31

**Heart-** Short PR interval and high QRS waves

Answer 32

1. Triglycerides are broken up by lipolysis to the **Glycerol** back bone and **free fatty acids** (short, medium and long chain) 2. Carnitine is essential for metabolism of **fatty acids-**long chain 3. **B oxidation** is needed to break the **f**atty acids into acetyl CoA and to feed the Krebs cycle

Answer 33

**1. Early infantile type:** AR trait **Cause:** deficient activity of β-galactosidase, a lysosomal enzyme encoded by a gene on **Accumulation of:** GM1 gangliosides in the lysosomes CNS and visceral/liver cells, **Clinical:** **Neuro:** Developmental delay then GTC seizures, 50% of macular cherry red spot **Liver/skin;** hepatosplenomegaly, edema, angiokeratoma Skeletal: anterior beaking of the vertebrae, enlargement of the sella turcica thickening of the calvarium, are present. **Face**: low-set ears, frontal bossing, a depressed nasal bridge, and long philtrum. Up to **Progx:** \> 1 yr most -blind and deaf, CNS impairment++ Death by 3-4 yr of age. 2. Onset of **late infantile GM1** -1 and 3 years.(***Type II GM1 gangliosidosis )*** Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech. **3. The juvenile-onset form of GM1 gangliosidosis** (***Type II GM1 gangliosidosis )*** **Neuro**: ataxia, dysarthria, Low IQ, and spasticity. Deterioration may survive through the 4th decade of life. No hepatomegaly, facial abnormalities, norskeletal features seen in type 1 disease. 4. Onset of **adult GM1 i**s between ages 3 and 30. **muscle atrophy, CNS problem**s - severe and progress at a slower rate than in other forms of the disorder, **corneal** clouding in some patients, and dystonia (sustained muscle contractions that cause twisting and repetitive movements or abnormal postures). **Angiokeratomas** lower part of the trunk of the body. **Most** patients have a normal size liver and spleen. **Prenatal diagnosis** is possible by measurement of Acid Beta Galactosidase in cultured amniotic cells.