Metabolic disorders

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Pediatric boards review of metabolic disorders

Galactosemia

Inheritance: AR
Type: galactose metabolism disorder
Defect: galactose-1-phosphate uridyl transferase deficiency
Presentation: G1P accumulates in kidney, liver & brain
--infants: liver dysfunction, jaundice, hepatomegaly, cataracts, e. coli sepsis
--long-term: ovarian failure, amenorrhea, DD, LD, speech disorder
Test: urine ketones are elevated, positive non-glucose reducing substances. Diagnose with flourescent spot test for GALT activity (Beutler)
Treatment: remove galactose from diet **note that cognitive effects (DD/speech delay) can persist despite treatment!

Maple Syrup Urine Disease

Inheritance: AR
Type: disorder of amino acid metabolism
Defect: branch chain alpha-ketoacid dehydrogenase complex (BCKD complex)
Presentation: CNS disease early in infancy, urine/hair/skin smells like maple syrup
Test: increased branch-chain AAs (leucine, isoleucine, valine)
Treatment: dietary control of branch-chain AAs

MCAD

Inheritance: AR
Type: fatty acid oxidation defect
Defect: medium chain acyl co-A dehydrogenase deficiency
Presentation: </= 2 yrs old, fasting-induced lethargy, hypoglycemia, seizure, coma (think of in cases of SIDS, reye syndrome)
Test: increased C8, C8:1, C10:1 esters - free serum carnitine can be low but not always
Treatment: IV glucose and bicarbonate. Avoid fasting.

Glycogen Storage Disease

Inheritance: AR except 2 types are XL
Type: disorder of carbohydrate metabolism
Defect: varies - results in glycogen accumulation in cytoplasm in most all disorders except Pompe disease where it accumulates in lysosomes
Presentation: divided into two groups based on impact: liver v. muscle
Test: urinary ketones increased, NO reducing substances
Treatment: supportive, prevent hypoglycemia
*8+ types on separate cards

Mucopolysaccharidoses

Inheritance: most AR except Hunters (XL)
Defect: lysosomal hydrolase enzymes resulting in accumulation of macromolecules in target organs, *notably increased Dermatan Sulfate levels
Presentation: > 1 yo, most with severe and disproportionate CNS involvement in triphasic pattern
*4 types on separate cards

Phenylketonuria

Inheritance: AR
Type: disorder of amino acid metabolism
Defect: phenylalanine hydroxylase enzyme (PAH): can't convert phenylalanine to tyrosine
Presentation: infant with vomiting, irritibility, eczamoid rash, mousy odor
Test: quantatative anaylsis of phenylalanine and tyrosine
Treatment: limit phenylalanine intake

Homocystinuria

Inheritance: AR
Type: disorder of amino acid metabolism
Defect: in cystathionine beta-synthetase enzyme
Presentation: marfanoid habitus, DD/MR,lens subluxation or dislocation down and medial, increased risk of thromboembolism in both arteries and veins
Test:elevated levels of hyomocystine
Treatment: large doses of pyridoxine (B6), diet low in methionine, betaine

Urea Cycle Defect

Inheritance: AR except OTC deficiency is XL
Type: intoxication
Defect: 6 main enzyme defects, ornithine transcarbamylase deficiency (OTC) is most common
Presentation: brain edema, lethargy, vomiting and confusion. Variable as more proximal defects result in more severe symptoms.
Test: RESPIRATORY ALKALOSIS, increased ammonia (in absence of liver dz), increased CSF glutamine and NO ketoacidosis, decreased plasma arginine.
--Citrulline low in proximal disorders
--OTC deficiency assoc w increased urinary orotic acid
Treatment: decrease dietary nitrogen intake, replace deficient AAs and push toward alternate pathways

Zellwegger Syndrome

Inheritance: AR
Type: peroxisomal biogenesis disorder
Defect: deficiency in multiple peroxisome functions
Presentation: birth 1 - 2 yrs old, loss of skills in progressive course. Characteristic facies: high forehead, epicanthal folds, broad-based nasal bridge, anteverted nares, micrognathia. Large anterior fontanelle, cataracts, pigmented retinopathy, hearing & vision loss, jaundice and calcific stippling of patella and epiphyses.
Test: abnormal VLCFAs

Menkes Disease

Inheritance: XL
Defect: defect in MNK gene -- impaired uptake of copper
Presentation: 2 - 3 mo, progressive neurologic deterioration, seizures, loss of milestones - subdural hematomas and retinal hemorrhages NOT d/t child abuse!
Test: clinical, low serum copper

Newborn Screen Test

Covered:
1) defects causing intoxication/energy metabolism defects
--amino acid defects
--fatty acid oxidation defects
--galactosemia
--biotinidase deficiency
2) non-metabolic disorders
--hemoglobinopathies
--endocrine disorders: CAH, congenital hypothyroidism
--cystic fibrosis

X-linked adrenoleukodystrophy

Inheritance: XL
Type: peroxisomal disorder
Defect: single-function peroxisomal disorder - results in accumulation of VLCFAs in white matter of CNS and adrenal cortex
Presentation: Peak sx 7yo (3 - 15), sx mimic ADHD, ataxia, visual defecits and seizures - rapidly progressive
Test: look for elevated plasma VLCFA levels, esp C26:0

Hereditary fructose intolerance

Inheritance: AR
Type: fructose metabolism disorder
Defect: fuctose 1,6-bisphosphate aldolase
Presentation: like galactosemia but later onset when exposure to fructose/sucrose (juice, sweetened cereal): jaundice, hepatomegaly, vomiting, lethargy, seizures, irritibility. Can p/w proximal renal tubule syndrome
Test: fructose as urinary-reducing substance during episode
Treatment: rid diet of sucrose, fructose and sorbitol

Type I glycogen storage disease: von Gierke Disease

Inheritance: AR
Type: glycogen storage disease (affect liver)
Defect: Glucose-6-phosphatase/Translocase Deficiency
Presentation: 2 types, Ib p/w neutropenia or neutrophil defects and increased bacterial infections.
3 - 4 mo with hepatomegaly, FTT and seizures
Test: hypoglycemia, lactoacidosis, hyperuricemia, hyperlipidemia. Dx with gene analysis

Type III glycogen storage disease: Limit Dextrinosis

Inheritance: AR
Type: glycogen storage disease (affect liver)
Defect: Debrancher Deficiency
Presentation: hepatomegaly, hypoglycemia, short stature, skeletal defects and cardiomyopathy. 3 types - variable
Test: urine ketones, NO reducing substances

Type IV glycogen storage disease: Amylopectinosis, Andersen disease

Inheritance: AR
Type: glycogen storage disease (affect liver)
Defect: brnaching enzyme deficiency
Presentation: cirrhosis of liver, hepatomegaly, FTT in first 18mo, death by 5yo
Test: urine ketones, NO reducing substances

Type VI glycogen storage disease: Hers Disease

Inheritance: AR
Type: glycogen storage disease (affect liver)
Defect: liver phosphorylase deficiency
Presentation: rare, benign with hepatomegaly and growth retardation in childhood
Test: urinary ketones, NO reducing substances

Type IX glycogen storage disease

Inheritance: 4 types: 2 AR, 2 XL
Type: glycogen storage disease (affect liver)
Defect: liver phosphorylase kinase deficiency
Presentation: variable based on type: hepatomegaly, growth retardation, muscle hypotonia, cirrhosis, muscle cramps, myoglobinuria on exercise, progressive muscle weakness/atrophy
Test: urinary ketones, NO reducing substances

Type 0 glycogen storage disease

Inheritance: AR
Type: glycogen storage disease (affect liver)
Defect: glycogen synthase deficiency result in decreased glycogen stores
Presentation: infants with early morning drowsiness, sometimes seizures with hypoglycemia and hyperketonemia. NO hepatomegaly
Test: urinary ketones, NO reducing substances
Treatment: frequent feedings, cornstarch

Type XI glycogen storage disease: Fanconi-Bickel Syndrome

Inheritance: AR
Type: glycogen storage disease (affect liver)
Defect: GLUT2 gene (think of in consanguineous parents)
Presentation: <1yo with proximal tubule renal dysfunction, increased glycogen in liver and kidney, FTT, rickets, hepatomegaly, poor height attainment
Test: urinary ketones

Type V glycogen storage disease: McArdle Disease

Inheritance: AR
Type: glycogen storage disease (affect muscle)
Defect: muscle phosphorylase deficiency
Presentation: presents older (20s - 30s), sx of exercise-induced muscle cramps and intolerance, burgandy-colored urine after exercise d/t rhabdo; glucose consumption pre-exercise can HELP symptoms (opposite of Type VII)
Test: increased CPK at rest and with exercise, increaed NH4 after exercise

Type VII glycogen storage disease: Tarui Disease

Inheritance: AR
Type: glycogen storage disease (affect muscle)
Defect: muscle phoshpofructokinase deficiency
Presentation: rare - fatigue and pain with exercise, occurs in childhood. Assoc w hemolysis, deposition of amylopectin-like glycogen in muscles, exercise intolerance is WORSE after carb-heavy meal (opposite of Type V)
Test: elevated uric acid levels common

Type II glycogen storage disease: Pompe Disease

Inheritance: AR
Type: lysosomal storage defect/glycogen storage disease
Defect: Acid alpha-1,4 glucosidase deficiency
Presentation: d/t glycogen build-up in lysosomes. 3 forms, infantile, juvenile and adult forms. Infantile assoc with cardiac involvement. All w proximal muscle weakness
Test: elevated CPK, AST, LDH. Diagnose w muscle biopsy
Treatment: enzyme replacement, high-protein diet, nocturnal ventilatory support

Hurler Syndrome

Inheritance: AR
Type: Mucopolysaccharidosis (Type I)
Defect: in gene coding for alpha-L-iduronidase
Presentation: varies - coarse facial features, mid-face hypoplasia, large tongue, frequent URIs, umbilical/inguinal hernias, OFC > 95th%ile w communicating hydrocephalus, atlantoaxial subluxation, bone abnormalities, eye problems
Test: see bone & eye probs (ie corneal clouding)
Treatment: enzyme replacement

Hunter Syndrome

Inheritance: XLR
Type: Mucopolysaccharidosis (Type II)
Defect: in gene coding for iduronate-2-sulfatase
Presentation: mostly males, variable: LD, ADD, challenging behavior, seizures, middle ear disease, hernias, coarse facial features, diarrhea, joint stiffness, HSM, nodular rash around scapulae/extensor surfaces is pathognomonic but rare in kids
Treatment: enzyme replacement

San Filippo Syndrome

Inheritance: AR
Type: Mucopolysaccharidosis (Type III)
Defect: inability to catabolize heparin sulfate
Presentation: severe CNS involvement (triphasic), from DD with URIs, diarrhea, sleep disturbance to challenging behavior (hyperactivity, aggression, no sense of danger),progress to death in 20s d/t swallowing dysfunction and progressive vegetative state

Morquio Syndrome

Inheritance: AR
Type: Mucopolysaccharidosis (Type IV)
Defect: deficiency in galactose-6-sulfatase resulting in defective degradation of keratin sulfate
Presentation: short-trunk dwarfism, fine corneal deposits, skeletal dysplasia, normal intelligence. Odontoid dysplasia is universal and most severe manifestation

Maternal PKU

NOT defect in infant, but results from exposure to toxins in utero:
decreased growth, microcephaly, MR< congenital heart defects and can look like FAS

Niemann Pick disease

Inheritance: AR
Type: sphingolipidoses
Defect: routing of cholesterol esters within and through the lysosome
Presentation: 3 - 5 yo w ataxia, HSM, poor school function, poor fine motor skills, cataplexy and narcolepsy are common
Test: intralysosomal accumulation of unesterified cholesterol in fibroblasts

Tay-Sachs disease

Inheritance: AR
Type: sphingolipidoses
Defect: abnormal storage of lipids
Presentation: axial and extremity hypotonia, hyperreflexia, cherry red macula, macrocephaly, seizures with auditory stimuli, juvenile/adult form more common in Ashkenazi Jews

Gaucher Disease T1

Inheritance: AR
Type: sphingolipidoses
Defect: deficiency of lysosomal glucocerebrosidase
Presentation: most common lysosomal storage disease (most common Jewish genetic disease): non-CNS disease with only visceral involvement, incidental splenomegaly. 3 types which vary in terms of neuro sx, but all have hepatosplenomegaly (**note - this is the ONLY storage disease where the spleen is bigger than the liver!), bone lesions/fx, anemia and lung dz, "ink spots" on abdomen
Test: screen for 5 most common mutations Treat: enzyme infusion

Fabry Disease

Inheritance: XLR
Type: sphingolipidosis
Defect: lipid storage
Presentation: hypohidrosis, pain crises with heat exposure, angiokeratomata, multi-organ involvement
Test: urine casts and maltese crosses, deficiency lysosomal alpha-galactosidase in plasma, leukocytes or skin fibroblasts
Treatment: carbamazepine, gabapentin for symptom relief, enzyme replacement therapy

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