Metabolic Flashcards

Question

What are the biochemical defects in pyruvate metabolism disorders?

Answer 1

- **Pyruvate Dehydrogenase Complex Deficiency (PDHCD):** Deficiency of PDH complex → pyruvate cannot convert to acetyl-CoA → accumulates as lactate and alanine - **Pyruvate Carboxylase Deficiency:** Deficiency of pyruvate carboxylase → impaired conversion of pyruvate to oxaloacetate → disrupted gluconeogenesis and TCA cycle - **Lactic Acidosis due to Mitochondrial Disorders:** Defects in mitochondrial oxidative phosphorylation enzymes → pyruvate accumulates and is converted to lactate

Answer 2

- **Pyruvate Dehydrogenase Complex Deficiency (PDHCD):** Ketogenic diet (high fat, low carb), thiamine supplementation, dichloroacetate (experimental), supportive therapy - **Pyruvate Carboxylase Deficiency:** Biotin supplementation, glucose and bicarbonate support, avoid fasting, symptomatic management - **Lactic Acidosis due to Mitochondrial Disorders:** Supportive therapy, avoid fasting, cofactor/vitamin cocktails (e.g., thiamine, riboflavin, CoQ10), mitochondrial disease-specific therapies

Answer 3

- **Pyruvate Dehydrogenase Complex Deficiency (PDHCD):** Variable; some children survive into adulthood with supportive care, but neurologic outcomes are often poor - **Pyruvate Carboxylase Deficiency:** Poor in severe neonatal form; milder forms may have longer survival with dietary management - **Lactic Acidosis due to Mitochondrial Disorders:** Highly variable depending on specific mutation; prognosis ranges from early death to chronic multisystem disease

Answer 4

- **Phenylketonuria (PKU):** Autosomal recessive, PAH gene mutation - **Maple Syrup Urine Disease (MSUD):** Autosomal recessive, BCKDHA/B/C gene mutations - **Homocystinuria:** Autosomal recessive, CBS gene mutation (most common) - **Tyrosinemia Type I:** Autosomal recessive, FAH gene mutation - **Alkaptonuria:** Autosomal recessive, HGD gene mutation - **Cystinuria:** Autosomal recessive, SLC3A1 or SLC7A9 gene mutations - **Non-ketotic Hyperglycinemia:** Autosomal recessive, GLDC or AMT gene mutations

Answer 5

- **Phenylketonuria (PKU):** Intellectual disability, seizures, eczema, musty body odor, fair skin and hair - **Maple Syrup Urine Disease (MSUD):** Poor feeding, vomiting, lethargy, hypotonia or hypertonia, sweet maple syrup odor in urine, encephalopathy in neonates - **Homocystinuria:** Marfanoid habitus, lens dislocation (inferonasal), intellectual disability, thrombosis, osteoporosis - **Tyrosinemia Type I:** Failure to thrive, hepatomegaly, jaundice, renal tubular dysfunction, risk of hepatocellular carcinoma - **Alkaptonuria:** Dark urine on standing, ochronosis (bluish-black connective tissue pigmentation), arthritis - **Cystinuria:** Recurrent kidney stones, especially in childhood, no systemic illness - **Non-ketotic Hyperglycinemia:** Severe neonatal hypotonia, apnea, seizures, developmental delay, coma

Answer 6

- **Phenylketonuria (PKU):** ↑ Phenylalanine in plasma, ↓ tyrosine, positive newborn screening with tandem MS - **Maple Syrup Urine Disease (MSUD):** ↑ Branched-chain amino acids (leucine, isoleucine, valine), alloisoleucine (diagnostic), ketonuria, metabolic acidosis - **Homocystinuria:** ↑ Homocysteine and methionine in plasma, positive urinary cyanide-nitroprusside test - **Tyrosinemia Type I:** ↑ Tyrosine, ↑ succinylacetone (pathognomonic), elevated AFP, liver dysfunction labs - **Alkaptonuria:** ↑ Homogentisic acid in urine, urine darkens on standing or with alkali - **Cystinuria:** Positive urinary cyanide-nitroprusside test, hexagonal crystals in urine, ↑ cystine in urine - **Non-ketotic Hyperglycinemia:** ↑ Glycine in plasma and CSF, CSF/plasma glycine ratio >0.08, normal ammonia, no ketosis

Answer 7

- **Phenylketonuria (PKU):** Deficiency of phenylalanine hydroxylase → impaired conversion of phenylalanine to tyrosine - **Maple Syrup Urine Disease (MSUD):** Deficiency of branched-chain α-ketoacid dehydrogenase complex → impaired breakdown of leucine, isoleucine, valine - **Homocystinuria:** Deficiency of cystathionine β-synthase → impaired conversion of homocysteine to cystathionine - **Tyrosinemia Type I:** Deficiency of fumarylacetoacetate hydrolase → accumulation of toxic metabolites (succinylacetone) - **Alkaptonuria:** Deficiency of homogentisate oxidase → accumulation of homogentisic acid - **Cystinuria:** Defect in renal tubular reabsorption of cystine, lysine, ornithine, and arginine → ↑ urinary cystine - **Non-ketotic Hyperglycinemia:** Defect in glycine cleavage system → impaired glycine degradation

Answer 8

- **Phenylketonuria (PKU):** Low-phenylalanine diet for life, special medical formula, sapropterin (BH4) in responsive cases - **Maple Syrup Urine Disease (MSUD):** Restriction of branched-chain amino acids, special medical formula, thiamine in some forms, liver transplant in severe cases - **Homocystinuria:** Pyridoxine (B6) responsiveness testing, methionine restriction, betaine, folate, B12 supplements - **Tyrosinemia Type I:** NTBC (nitisinone) + tyrosine/phenylalanine restriction, liver transplant in advanced disease - **Alkaptonuria:** Low-protein diet, vitamin C, nitisinone (off-label), joint replacement for arthritis - **Cystinuria:** High fluid intake, urinary alkalinization (potassium citrate), thiol drugs (tiopronin, penicillamine) - **Non-ketotic Hyperglycinemia:** Sodium benzoate, dextromethorphan, ketogenic diet, supportive care

Answer 9

- **Phenylketonuria (PKU):** Excellent if treated early; untreated leads to severe intellectual disability - **Maple Syrup Urine Disease (MSUD):** Variable; good with early diagnosis and strict diet; risk of metabolic decompensation - **Homocystinuria:** Risk of thromboembolism and cognitive delay; improved outcome with early diagnosis and therapy - **Tyrosinemia Type I:** Poor without treatment; good with NTBC and dietary control; risk of HCC remains - **Alkaptonuria:** Benign in childhood; arthritis and ochronosis develop in adulthood - **Cystinuria:** Good with preventive measures; recurrent stones may cause renal complications - **Non-ketotic Hyperglycinemia:** Poor; most severe forms lead to profound disability or early death

Answer 10

- **Carbamoyl phosphate synthetase I (CPS1) deficiency:** Autosomal recessive - **Ornithine transcarbamylase (OTC) deficiency:** X-linked recessive - **Argininosuccinate synthetase (ASS1) deficiency / Citrullinemia Type I:** Autosomal recessive - **Argininosuccinate lyase (ASL) deficiency:** Autosomal recessive - **Arginase (ARG1) deficiency:** Autosomal recessive - **N-acetylglutamate synthase (NAGS) deficiency:** Autosomal recessive

Answer 11

- **CPS1 Deficiency:** Hyperammonemia in neonates, poor feeding, vomiting, lethargy, coma, respiratory alkalosis - **OTC Deficiency:** Most common UCD; affects males severely, females variably; hyperammonemia, encephalopathy, vomiting - **ASS1 Deficiency (Citrullinemia Type I):** Hyperammonemia, lethargy, seizures, elevated citrulline, hepatomegaly - **ASL Deficiency:** Hyperammonemia, trichorrhexis nodosa (hair defect), hepatomegaly, developmental delay - **Arginase Deficiency:** Progressive spasticity, seizures, developmental delay, milder/no hyperammonemia - **NAGS Deficiency:** Similar to CPS1 deficiency; neonatal hyperammonemia, often responsive to carglumic acid (Carbaglu)

Answer 12

- **CPS1 Deficiency:** Hyperammonemia, low citrulline, normal orotic acid - **OTC Deficiency:** Hyperammonemia, low citrulline, ↑ orotic acid (from excess carbamoyl phosphate) - **ASS1 Deficiency (Citrullinemia I):** Hyperammonemia, ↑ citrulline, normal/low argininosuccinate - **ASL Deficiency:** Hyperammonemia, ↑ argininosuccinate in plasma and urine - **Arginase Deficiency:** ↑ Arginine, mild or no hyperammonemia, ↑ urinary orotic acid - **NAGS Deficiency:** Hyperammonemia, low citrulline, low/normal orotic acid, response to carglumic acid

Answer 13

- **CPS1 Deficiency:** Deficiency of carbamoyl phosphate synthetase I → prevents ammonia incorporation into the urea cycle - **OTC Deficiency:** Deficiency of ornithine transcarbamylase → impaired conversion of carbamoyl phosphate + ornithine to citrulline - **ASS1 Deficiency (Citrullinemia I):** Deficiency of argininosuccinate synthetase → impaired formation of argininosuccinate from citrulline + aspartate - **ASL Deficiency:** Deficiency of argininosuccinate lyase → impaired conversion of argininosuccinate to arginine + fumarate - **Arginase Deficiency:** Deficiency of arginase → impaired conversion of arginine to urea + ornithine - **NAGS Deficiency:** Deficiency of N-acetylglutamate synthase → ↓ production of NAG, a required activator of CPS1

Answer 14

- **General Measures:** Protein-restricted diet, avoidance of catabolism, IV glucose and lipids in crisis, dialysis in acute hyperammonemia - **Ammonia Scavengers:** Sodium benzoate, sodium phenylacetate/phenylbutyrate for nitrogen excretion - **Arginine Supplementation:** For most UCDs except arginase deficiency - **Citrulline Supplementation:** For OTC and CPS1 deficiency to help bypass the block - **Carglumic Acid (Carbaglu):** Used in NAGS deficiency to activate CPS1 - **Liver Transplant:** Considered in severe or recurrent hyperammonemia cases

Answer 15

- **CPS1 Deficiency:** Poor if untreated; early treatment can improve survival but neurodevelopmental delay is common - **OTC Deficiency:** Variable; severe in males with neonatal onset, better in late-onset or female carriers with early management - **ASS1 Deficiency (Citrullinemia I):** Good if diagnosed early and managed aggressively; risk of decompensation persists - **ASL Deficiency:** Variable; developmental delays common; better with early treatment - **Arginase Deficiency:** Less severe hyperammonemia; progressive neurological dysfunction if untreated - **NAGS Deficiency:** Excellent prognosis with early diagnosis and carglumic acid therapy

Answer 16

- **Methylmalonic Acidemia (MMA):** Autosomal recessive, MUT gene or cobalamin metabolism genes (cblA, cblB, cblC) - **Propionic Acidemia (PA):** Autosomal recessive, PCCA or PCCB gene mutations - **Isovaleric Acidemia (IVA):** Autosomal recessive, IVD gene mutation - **Glutaric Acidemia Type I (GA-I):** Autosomal recessive, GCDH gene mutation - **3-Methylcrotonyl-CoA Carboxylase Deficiency (3-MCC):** Autosomal recessive, MCCC1 or MCCC2 gene mutations - **Multiple Carboxylase Deficiency (MCD):** Autosomal recessive, either holocarboxylase synthetase or biotinidase gene mutations

Answer 17

- **Methylmalonic Acidemia (MMA):** Poor feeding, vomiting, hypotonia, lethargy, metabolic acidosis, hyperammonemia, failure to thrive - **Propionic Acidemia (PA):** Similar to MMA; severe metabolic acidosis, neutropenia, cardiomyopathy, hyperammonemia - **Isovaleric Acidemia (IVA):** Sweaty feet odor, vomiting, lethargy, seizures, metabolic acidosis, risk of coma - **Glutaric Acidemia Type I (GA-I):** Macrocephaly, dystonia, neurologic regression, subdural hematomas mimicking abuse - **3-Methylcrotonyl-CoA Carboxylase Deficiency (3-MCC):** Hypoglycemia, lethargy, hypotonia, can be asymptomatic in newborn screen - **Multiple Carboxylase Deficiency (MCD):** Vomiting, hypotonia, rash, alopecia, seizures; early onset (holocarboxylase), late onset (biotinidase)

Answer 18

- **Methylmalonic Acidemia (MMA):** Metabolic acidosis with increased anion gap, ketonuria, hyperammonemia, ↑ methylmalonic acid in urine/plasma - **Propionic Acidemia (PA):** Similar to MMA; ↑ propionic acid, ↑ glycine, metabolic acidosis, neutropenia, hyperammonemia - **Isovaleric Acidemia (IVA):** Metabolic acidosis, ↑ isovalerylglycine and isovalerylcarnitine (C5) in urine/plasma, ketonuria - **Glutaric Acidemia Type I (GA-I):** ↑ glutaric acid, ↑ 3-hydroxyglutaric acid, normal ammonia, metabolic acidosis - **3-Methylcrotonyl-CoA Carboxylase Deficiency (3-MCC):** ↑ 3-methylcrotonylglycine, ↑ C5-OH carnitine on newborn screen - **Multiple Carboxylase Deficiency (MCD):** Metabolic acidosis, ↑ lactate, ↑ organic acids (3-hydroxyisovaleric acid, others), low biotinidase activity in late-onset form

Answer 19

- **Methylmalonic Acidemia (MMA):** Deficiency of methylmalonyl-CoA mutase or defect in cobalamin metabolism → impaired conversion of methylmalonyl-CoA to succinyl-CoA - **Propionic Acidemia (PA):** Deficiency of propionyl-CoA carboxylase → impaired conversion of propionyl-CoA to methylmalonyl-CoA - **Isovaleric Acidemia (IVA):** Deficiency of isovaleryl-CoA dehydrogenase → accumulation of isovaleryl-CoA and its toxic metabolites - **Glutaric Acidemia Type I (GA-I):** Deficiency of glutaryl-CoA dehydrogenase → accumulation of glutaric acid and 3-hydroxyglutaric acid - **3-Methylcrotonyl-CoA Carboxylase Deficiency (3-MCC):** Deficiency in 3-methylcrotonyl-CoA carboxylase → impaired leucine catabolism - **Multiple Carboxylase Deficiency (MCD):** Deficiency in either holocarboxylase synthetase or biotinidase → impaired biotin recycling and function of biotin-dependent carboxylases

Answer 20

- **General Management:** Emergency protocol for metabolic crises (IV glucose, lipids, stop protein intake, dialysis if needed) - **Diet:** Protein restriction (especially leucine, valine, isoleucine), specialized metabolic formulas - **Carnitine Supplementation:** To promote excretion of toxic metabolites (especially in IVA, MMA, PA) - **Antibiotics:** Oral metronidazole may reduce gut propionate-producing bacteria (MMA, PA) - **Biotin:** High-dose for Multiple Carboxylase Deficiency (especially late-onset/biotinidase form) - **Hydration & Electrolyte Balance:** Especially during decompensations - **Liver Transplantation:** Considered in MMA and PA with recurrent decompensations

Answer 21

- **Methylmalonic Acidemia (MMA):** Variable; frequent metabolic crises, risk of neurologic damage, chronic kidney disease, improved with early transplant - **Propionic Acidemia (PA):** Severe in neonates, risk of cardiomyopathy, cognitive delay, better prognosis with liver transplant and strict management - **Isovaleric Acidemia (IVA):** Better prognosis with early detection and management; crises can be fatal without treatment - **Glutaric Acidemia Type I (GA-I):** Risk of irreversible neurologic damage in infancy; better outcomes with early diagnosis and low-lysine diet - **3-Methylcrotonyl-CoA Carboxylase Deficiency (3-MCC):** Often asymptomatic if detected via newborn screening; mild to moderate course - **Multiple Carboxylase Deficiency (MCD):** Excellent prognosis with early biotin therapy; severe if untreated

Answer 22

- **MCAD Deficiency:** Autosomal recessive, ACADM gene mutation - **VLCAD Deficiency:** Autosomal recessive, ACADVL gene mutation - **LCHAD Deficiency:** Autosomal recessive, HADHA gene mutation - **Carnitine Transporter Defect:** Autosomal recessive, SLC22A5 gene mutation - **CPT I Deficiency:** Autosomal recessive, CPT1A gene mutation - **CPT II Deficiency:** Autosomal recessive, CPT2 gene mutation - **MADD (Glutaric Acidemia Type II):** Autosomal recessive, ETFA, ETFB, or ETFDH gene mutations

Answer 23

- **MCAD Deficiency:** Fasting-induced hypoketotic hypoglycemia, vomiting, lethargy, seizures, sudden death - **VLCAD Deficiency:** Neonatal cardiomyopathy, hypoglycemia, hepatomegaly, later-onset myopathy with rhabdomyolysis - **LCHAD Deficiency:** Hypoketotic hypoglycemia, liver dysfunction, retinal abnormalities, peripheral neuropathy, maternal HELLP syndrome - **Carnitine Transporter Defect:** Hypoglycemia, hepatomegaly, muscle weakness, low plasma carnitine - **CPT I Deficiency:** Hypoketotic hypoglycemia, hepatomegaly, elevated free carnitine - **CPT II Deficiency:** Muscle pain, rhabdomyolysis, myoglobinuria after exercise or fasting - **MADD (GA II):** Severe neonatal: hypotonia, metabolic acidosis, hepatomegaly; Milder late-onset: muscle weakness, fatigue

Answer 24

- **MCAD Deficiency:** Hypoglycemia with low ketones, ↑ C8, C6, C10:1 acylcarnitines - **VLCAD Deficiency:** ↑ C14:1 and C14:2 acylcarnitines, hypoglycemia, metabolic acidosis - **LCHAD Deficiency:** Hypoglycemia, ↑ C16-OH and C18:1-OH acylcarnitines, elevated liver enzymes - **Carnitine Transporter Defect:** Very low free and total carnitine in plasma - **CPT I Deficiency:** ↑ Free carnitine, ↓ acylcarnitine (esp. long-chain species), hypoketotic hypoglycemia - **CPT II Deficiency:** ↑ C16 and C18:1 acylcarnitines during rhabdomyolysis episodes - **MADD (GA II):** ↑ Multiple acylcarnitines, organic acids in urine (e.g., glutaric, ethylmalonic, isovaleric)

Answer 25

- **MCAD Deficiency:** Deficiency of medium-chain acyl-CoA dehydrogenase → impaired β-oxidation of medium-chain fatty acids - **VLCAD Deficiency:** Deficiency of very long-chain acyl-CoA dehydrogenase → blocked oxidation of long-chain fatty acids - **LCHAD Deficiency:** Deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase (part of mitochondrial trifunctional protein) - **Carnitine Transporter Defect:** Impaired carnitine uptake into cells → blocks fatty acid entry into mitochondria - **CPT I Deficiency:** Deficiency of carnitine palmitoyltransferase I → impaired formation of acylcarnitine at outer mitochondrial membrane - **CPT II Deficiency:** Deficiency of carnitine palmitoyltransferase II → impaired reconversion of acylcarnitine to acyl-CoA inside mitochondria - **MADD (GA II):** Deficiency in ETF or ETFDH → impaired electron transfer in multiple acyl-CoA dehydrogenase reactions

Answer 26

- **General Principles:** Avoid fasting, ensure frequent feeding with high-carbohydrate meals - **MCAD/VLCAD/LCHAD:** Emergency glucose infusion during illness, avoid prolonged fasting, medium-chain triglyceride (MCT) supplementation (in LCHAD) - **Carnitine Transporter Defect:** Lifelong oral carnitine supplementation - **CPT I Deficiency:** High-carbohydrate, low-fat diet, avoid fasting - **CPT II Deficiency:** Avoid prolonged exercise, stress; glucose support during crises - **MADD (GA II):** Riboflavin supplementation (in riboflavin-responsive forms), dietary fat/protein restriction, carnitine - **All FAODs:** Monitor carnitine and acylcarnitine profiles regularly

Answer 27

- **MCAD Deficiency:** Excellent with early diagnosis and avoidance of fasting; sudden death if untreated - **VLCAD Deficiency:** Variable; neonatal cardiomyopathy form has high mortality, later-onset myopathy form has better outcome - **LCHAD Deficiency:** Risk of chronic complications (retinopathy, neuropathy); early diagnosis improves outcomes - **Carnitine Transporter Defect:** Good with early carnitine supplementation; cardiomyopathy and death if untreated - **CPT I Deficiency:** Favorable if managed early; metabolic crises possible if fasting not avoided - **CPT II Deficiency:** Myopathic form usually benign with management; recurrent rhabdomyolysis if noncompliant - **MADD (GA II):** Severe neonatal form often fatal; late-onset riboflavin-responsive form has good prognosis

Answer 28

- **Zellweger Spectrum Disorders (ZSD):** Autosomal recessive; mutations in PEX genes (e.g., PEX1, PEX6) - **X-linked Adrenoleukodystrophy (X-ALD):** X-linked recessive; ABCD1 gene mutation - **Refsum Disease (Adult):** Autosomal recessive; PHYH or PEX7 gene mutations - **Rhizomelic Chondrodysplasia Punctata (RCDP):** Autosomal recessive; PEX7, GNPAT, AGPS gene mutations - **Acatalasemia:** Autosomal recessive; CAT gene mutation - **Primary Hyperoxaluria Type I:** Autosomal recessive; AGXT gene mutation (peroxisomal enzyme defect)

Answer 29

- **Zellweger Spectrum Disorders (ZSD):** Hypotonia, craniofacial dysmorphism, seizures, liver dysfunction, developmental delay, sensorineural hearing loss - **X-linked Adrenoleukodystrophy (X-ALD):** Behavioral changes, spasticity, vision and hearing loss, adrenal insufficiency, neurologic regression in childhood form - **Refsum Disease (Adult):** Retinitis pigmentosa, anosmia, peripheral neuropathy, ataxia, ichthyosis, cardiac conduction defects - **RCDP:** Severe growth retardation, shortening of proximal limbs (rhizomelia), stippled epiphyses, cataracts, intellectual disability - **Acatalasemia:** Often asymptomatic; may develop oral ulcers, gangrene - **Primary Hyperoxaluria Type I:** Recurrent nephrolithiasis, nephrocalcinosis, progressive renal failure

Answer 30

- **Zellweger Spectrum Disorders (ZSD):** ↑ Very long-chain fatty acids (VLCFAs), ↑ phytanic acid, ↑ bile acid intermediates, ↓ plasmalogens - **X-linked Adrenoleukodystrophy (X-ALD):** ↑ VLCFAs (C24:0, C26:0) in plasma, abnormal MRI with white matter demyelination - **Refsum Disease:** ↑ Phytanic acid in plasma, normal VLCFAs, abnormal alpha-oxidation of fatty acids - **RCDP:** ↓ Plasmalogens in erythrocyte membranes, ↑ phytanic acid (in type 1), radiographic chondrodysplasia punctata - **Acatalasemia:** Absent/low catalase activity in blood or fibroblasts - **Primary Hyperoxaluria Type I:** ↑ Urinary oxalate, ↑ glycolate; kidney ultrasound shows nephrocalcinosis

Answer 31

- **ZSD:** Generalized peroxisome biogenesis defect due to PEX gene mutations → impaired β-oxidation of VLCFAs, synthesis of plasmalogens - **X-ALD:** Defective peroxisomal membrane transporter (ABCD1) → impaired import of VLCFAs for degradation - **Refsum Disease:** Deficiency of phytanoyl-CoA hydroxylase or impaired alpha-oxidation pathway → accumulation of phytanic acid - **RCDP:** Defects in plasmalogen biosynthesis enzymes (PEX7, GNPAT, AGPS) → disrupted membrane lipid formation - **Acatalasemia:** Catalase enzyme deficiency → impaired breakdown of hydrogen peroxide in peroxisomes - **Primary Hyperoxaluria Type I:** Deficiency of alanine-glyoxylate aminotransferase (AGT) → overproduction of oxalate in peroxisomes

Answer 32

- **ZSD:** Supportive care; manage feeding, seizures, hearing aids; liver transplant not curative - **X-ALD:** Hematopoietic stem cell transplant (HSCT) in early cerebral form; adrenal hormone replacement; gene therapy (investigational) - **Refsum Disease:** Dietary restriction of phytanic acid (avoid dairy, ruminant fat, certain fish); plasmapheresis in acute cases - **RCDP:** Supportive management, physical therapy, manage cataracts and respiratory infections - **Acatalasemia:** Good hygiene, avoid oral trauma; no specific treatment needed in mild cases - **Primary Hyperoxaluria Type I:** High fluid intake, pyridoxine (vitamin B6), dialysis, combined liver-kidney transplant in advanced disease

Answer 33

- **ZSD:** Poor prognosis; most infants die within first year due to liver failure or respiratory complications - **X-ALD:** Childhood cerebral form rapidly progressive if untreated; adrenal form manageable with steroid replacement; adult AMN form progresses slowly - **Refsum Disease:** Good prognosis with dietary management; vision and neurologic symptoms may persist - **RCDP:** Poor prognosis; many infants die in early life due to respiratory complications, severe developmental delay - **Acatalasemia:** Excellent prognosis; generally benign if no secondary infections - **Primary Hyperoxaluria Type I:** Variable; without early treatment leads to ESRD; transplant improves survival

Answer 34

- **MPS I (Hurler):** Autosomal recessive, IDUA gene - **MPS II (Hunter):** X-linked recessive, IDS gene - **MPS III (Sanfilippo A-D):** Autosomal recessive, multiple genes (SGSH, NAGLU, HGSNAT, GNS) - **MPS IV (Morquio A, B):** Autosomal recessive, GALNS or GLB1 - **MPS VI (Maroteaux-Lamy):** Autosomal recessive, ARSB gene - **MPS VII (Sly):** Autosomal recessive, GUSB gene - **Gaucher Disease:** Autosomal recessive, GBA gene - **Tay-Sachs Disease:** Autosomal recessive, HEXA gene - **Niemann-Pick A/B:** Autosomal recessive, SMPD1 gene - **Niemann-Pick C:** Autosomal recessive, NPC1/2 gene - **Pompe Disease:** Autosomal recessive, GAA gene - **Fabry Disease:** X-linked recessive, GLA gene - **Metachromatic Leukodystrophy:** Autosomal recessive, ARSA gene - **Krabbe Disease:** Autosomal recessive, GALC gene - **GM1 Gangliosidosis:** Autosomal recessive, GLB1 gene

Answer 35

- **MPS I (Hurler):** Coarse facies, hepatosplenomegaly, corneal clouding, developmental delay, skeletal dysplasia - **MPS II (Hunter):** Similar to Hurler but no corneal clouding, aggressive behavior, X-linked inheritance - **MPS III (Sanfilippo):** Severe CNS involvement, hyperactivity, sleep disturbances, rapid neurodegeneration - **MPS IV (Morquio):** Severe skeletal dysplasia, short stature, normal intelligence - **MPS VI (Maroteaux-Lamy):** Skeletal changes, corneal clouding, cardiac disease, normal intellect - **Gaucher Disease:** Hepatosplenomegaly, bone crises, anemia, thrombocytopenia; Type 2/3 have CNS involvement - **Tay-Sachs:** Progressive neurodegeneration, hyperacusis, cherry-red macula, no hepatosplenomegaly - **Niemann-Pick A/B:** A: neurodegeneration + hepatosplenomegaly; B: visceral symptoms only - **Niemann-Pick C:** Vertical gaze palsy, ataxia, hepatosplenomegaly, psychiatric symptoms - **Pompe Disease:** Hypotonia, cardiomegaly, macroglossia, respiratory failure - **Fabry Disease:** Pain crises, angiokeratomas, hypohidrosis, renal and cardiac involvement - **MLD:** Progressive motor and cognitive decline, hypotonia, peripheral neuropathy - **Krabbe Disease:** Irritability, spasticity, optic atrophy, developmental regression - **GM1 Gangliosidosis:** Coarse facies, hepatosplenomegaly, neurodegeneration, cherry-red spot

Answer 36

- **MPS Disorders:** ↑ Urinary glycosaminoglycans (GAGs); enzyme assay confirms specific deficiency - **Gaucher Disease:** ↓ β-glucocerebrosidase in leukocytes; bone marrow shows Gaucher cells (lipid-laden macrophages) - **Tay-Sachs Disease:** ↓ Hexosaminidase A in leukocytes or fibroblasts - **Niemann-Pick A/B:** ↓ Acid sphingomyelinase; foamy histiocytes in marrow - **Niemann-Pick C:** Positive filipin staining of fibroblasts; impaired cholesterol esterification - **Pompe Disease:** ↓ Acid α-glucosidase activity in blood or fibroblasts; ↑ CK, LDH - **Fabry Disease:** ↓ α-galactosidase A activity; elevated plasma/urine globotriaosylceramide (Gb3) - **MLD:** ↓ Arylsulfatase A activity in leukocytes - **Krabbe Disease:** ↓ Galactocerebrosidase (GALC); PAS-positive globoid cells in white matter - **GM1 Gangliosidosis:** ↓ β-galactosidase in leukocytes or fibroblasts

Answer 37

- **MPS I (Hurler):** Deficiency of α-L-iduronidase → accumulation of dermatan and heparan sulfate - **MPS II (Hunter):** Deficiency of iduronate sulfatase → accumulation of dermatan and heparan sulfate - **Gaucher Disease:** Deficiency of β-glucocerebrosidase → accumulation of glucocerebroside - **Tay-Sachs:** Deficiency of Hexosaminidase A → accumulation of GM2 ganglioside - **Niemann-Pick A/B:** Deficiency of acid sphingomyelinase → accumulation of sphingomyelin - **Niemann-Pick C:** Impaired cholesterol trafficking due to NPC1/2 defects → accumulation of unesterified cholesterol - **Pompe Disease:** Deficiency of acid α-glucosidase (GAA) → glycogen accumulation in lysosomes - **Fabry Disease:** Deficiency of α-galactosidase A → accumulation of globotriaosylceramide (Gb3) - **MLD:** Deficiency of arylsulfatase A → accumulation of sulfatides - **Krabbe Disease:** Deficiency of galactocerebrosidase (GALC) → accumulation of galactocerebroside and psychosine - **GM1 Gangliosidosis:** Deficiency of β-galactosidase → accumulation of GM1 ganglioside

Answer 38

- **MPS I (Hurler):** Hematopoietic stem cell transplant (HSCT), enzyme replacement therapy (ERT: laronidase) - **MPS II (Hunter):** Enzyme replacement therapy (idursulfase); no HSCT benefit - **Gaucher Disease:** ERT (imiglucerase, velaglucerase, taliglucerase), substrate reduction therapy (SRT) - **Tay-Sachs:** Supportive only; no effective disease-modifying therapy - **Niemann-Pick A/B:** Supportive for type A; ERT in trials for type B - **Niemann-Pick C:** Miglustat (substrate reduction therapy), supportive care - **Pompe Disease:** Enzyme replacement therapy (alglucosidase alfa) - **Fabry Disease:** ERT (agalsidase alfa/beta), chaperone therapy (migalastat), renal/cardiac monitoring - **MLD:** HSCT in pre-symptomatic or early disease; gene therapy (experimental) - **Krabbe Disease:** HSCT in early-onset before symptom onset; supportive after onset - **GM1 Gangliosidosis:** Supportive care; ERT and gene therapy in development

Answer 39

- **MPS I (Hurler):** Poor if untreated; HSCT improves survival and neurodevelopment if early - **MPS II (Hunter):** Variable; severe forms lead to early death, milder forms compatible with adulthood - **Gaucher Disease:** Type 1 has good prognosis with ERT; Type 2 fatal in infancy; Type 3 intermediate - **Tay-Sachs:** Infantile form fatal by age 4–5 years; juvenile and adult forms progress slowly - **Niemann-Pick A/B:** Type A fatal by age 3; Type B variable with survival into adulthood - **Niemann-Pick C:** Progressive neurologic decline; average survival into adolescence or early adulthood - **Pompe Disease:** Infantile form fatal without ERT; late-onset form has variable course - **Fabry Disease:** Variable; renal, cardiac, and cerebrovascular morbidity; improved with ERT - **MLD:** Infantile form rapidly fatal; late-onset slower but progressive - **Krabbe Disease:** Early-onset rapidly fatal; HSCT may improve survival if pre-symptomatic - **GM1 Gangliosidosis:** Infantile form fatal in early childhood; later forms slower progression

Answer 40

- **Leigh Syndrome:** Mitochondrial or autosomal recessive (SURF1, NDUFS1, etc.) - **MELAS:** Mitochondrial inheritance; most commonly m.3243A>G in MT-TL1 - **MERRF:** Mitochondrial inheritance; typically m.8344A>G in MT-TK - **NARP:** Mitochondrial inheritance; MT-ATP6 gene mutation - **Kearns-Sayre Syndrome:** Sporadic large mtDNA deletions; mitochondrial inheritance - **Pearson Syndrome:** Sporadic mtDNA deletions; mitochondrial inheritance - **Alpers-Huttenlocher Syndrome:** Autosomal recessive; POLG gene mutation - **LHON:** Mitochondrial inheritance; mutations in ND1, ND4, ND6 genes

Answer 41

- **Leigh Syndrome:** Progressive neurodegeneration, hypotonia, brainstem dysfunction, lactic acidosis, respiratory failure - **MELAS:** Stroke-like episodes, seizures, lactic acidosis, hearing loss, short stature, diabetes - **MERRF:** Myoclonus, epilepsy, ataxia, muscle weakness, ragged red fibers on biopsy - **NARP:** Neuropathy, ataxia, retinitis pigmentosa, cognitive decline - **Kearns-Sayre Syndrome:** Ophthalmoplegia, pigmentary retinopathy, heart block, short stature, cerebellar signs - **Pearson Syndrome:** Sideroblastic anemia, pancreatic dysfunction, failure to thrive in infancy - **Alpers-Huttenlocher Syndrome:** Developmental regression, intractable seizures, liver failure - **LHON:** Painless subacute bilateral vision loss, typically in young adult males

Answer 42

- **Common Findings:** Elevated lactate and pyruvate in blood and CSF; increased lactate-to-pyruvate ratio - **Muscle Biopsy:** Ragged red fibers (Gomori trichrome stain); abnormal mitochondrial morphology - **Neuroimaging (e.g. MELAS, Leigh):** Symmetric basal ganglia lesions, stroke-like cortical changes not respecting vascular territories - **Urine Organic Acids:** Elevated lactate, Krebs cycle intermediates - **CSF Studies:** Elevated lactate, low glucose in some cases - **Enzyme Analysis:** Deficiency in respiratory chain complexes (I, III, IV) - **mtDNA Testing:** Point mutations (e.g. m.3243A>G in MELAS) or deletions (e.g. KSS, Pearson)

Answer 43

- **Leigh Syndrome:** Defects in mitochondrial respiratory chain complexes (I, IV), SURF1, PDH complex deficiency - **MELAS:** Mutation in mitochondrial tRNA (MT-TL1); impaired oxidative phosphorylation and ATP production - **MERRF:** Mutation in mitochondrial tRNA (MT-TK); impaired mitochondrial protein synthesis and ATP generation - **NARP:** Mutation in MT-ATP6 gene; defective ATP synthase (Complex V) function - **Kearns-Sayre Syndrome:** Large mtDNA deletions; multiple enzyme complex deficiencies (I, III, IV) - **Pearson Syndrome:** mtDNA deletions; defective hematopoiesis and oxidative phosphorylation - **Alpers-Huttenlocher Syndrome:** POLG mutation; mtDNA depletion, defective replication and repair - **LHON:** Mutations in mitochondrial ND1/ND4/ND6 genes; defective Complex I

Answer 44

- **Leigh Syndrome:** Supportive care; CoQ10, thiamine, biotin; treat underlying defect if possible (e.g., PDH deficiency) - **MELAS:** Arginine for stroke-like episodes, CoQ10, L-carnitine, antioxidants (vitamin C, E), seizure control - **MERRF:** Seizure control, CoQ10, L-carnitine, B vitamins; avoid valproate - **NARP:** Supportive care, manage neuropathy and vision loss - **Kearns-Sayre Syndrome:** Pacemaker for heart block, hormone replacement for endocrinopathies, CoQ10 - **Pearson Syndrome:** Transfusions, pancreatic enzyme replacement, bone marrow transplant (not curative) - **Alpers-Huttenlocher Syndrome:** Avoid valproate (risk of liver failure), manage seizures, supportive care - **LHON:** Idebenone (CoQ10 analog), gene therapy trials, visual aids, genetic counseling

Answer 45

- **Leigh Syndrome:** Poor prognosis; most patients die in early childhood due to respiratory failure - **MELAS:** Progressive course with recurrent strokes, hearing loss, and dementia; variable survival into adulthood - **MERRF:** Variable; progressive neuromuscular deterioration, epilepsy, and ataxia - **NARP:** Variable severity; more severe mutations may present earlier and progress faster - **Kearns-Sayre Syndrome:** Progressive multisystem involvement; risk of sudden cardiac death if untreated - **Pearson Syndrome:** Often fatal in infancy; survivors may develop KSS phenotype later - **Alpers-Huttenlocher Syndrome:** Severe progressive encephalopathy; early childhood mortality common - **LHON:** Visual prognosis poor; minimal improvement; systemic involvement rare but possible

Metabolic Flashcards

(69 cards)