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Pediatrics > Metabolics > Flashcards

Metabolics Flashcards

1
Q

What is the pathology of Pompe Disease?

A
  • Glycogen storage disease - Type II
  • AR disorder
  • Acid maltase deficiency which leads to glycogen build-up in the LYSOSOMES of cardiac, smooth muscle and skeletal muscles
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2
Q

What are the different forms of Pompe Disease?

A

• Infantile Pompe: uniformly lethal without enzyme replacement therapy. Generalized muscle weakness with a floppy appearance, neuropathic bulbar weakness, feeding difficulties, macroglossia, hepatomegaly and hypertrophic cardiomyopathy

• Late-onset Pompe: juvenile and adult-onset disease is characterized by a lack of severe cardiac involvement and a less-severe short-term prognosis. Slowly progressive proximal muscle weakness with truncal involvement and greater involvement of the lower limbs than the upper limbs, with the pelvic girdle, paraspinal muscles and diaphragm being the most affected. May also see lingual weakness, ptosis and dilatation of blood vessels like the basilar artery and the ascending aorta
initial symptoms are usually respiratory insufficiency manifested by somnolence, morning headache, orthopnea and exertional dyspnea

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3
Q

What tests are done to confirm Pompe Disease?

A
  • elevated serum CK, LDH and aspartate aminotransferase
  • CXR: cardiomegaly
  • ECG: high-voltage QRS, ventriculomegaly
  • ECHO may show LV outflow obstruction
  • muscle biopsy: will show vacuoles that stain positively for glycogen with high acid phosphatase
  • EMG: myopathic features with excessive electrical irritability of muscle fibers
  • Confirm with enzyme assay demonstrating deficient acid α-glucosidase, OR 2 pathogenic mutations in the GAA gene. Skin fibroblast assay is preferred over muscle biopsy
    • in infantile GSD Type II, urinary glucose tetrasaccharides are also useful (will be high) as is CVS and amniocentesis assays
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4
Q

What are the treatments available for Pompe Disease?

A
  • Enzyme replacement: recombinant human acid α-glucosidase (20 mg/kg every 2 wks)
  • High protein diet and exercise may be helpful
  • Nocturnal ventilatory support
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5
Q

What are 3 causes of hyperammonemia in a newborn?

A
  • Urea cycle defects: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), arginosuccinate synthetase OR lyase (AS< AL), arginase, n-acetylglutamate suynthetase (NAGS)
  • Organic acidemias: Propionic, MMA, isovaleric, B-ketothiolase def, multiple carboxylase def, MCADD, GLUT2, 3-hydroxy-3methylglutaric aciduria
  • Others: Lysinuric protein intolerance, hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome, transient hyperammonemia of newborn, congenital hyperinsulinism with hyperammonemia
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6
Q

How do you treat hyperammonemia?

A
  • NPO, stop feeds
  • IV fluid rehydration with D10W and lipids
  • Scavenging (acylation therapy) with benzoate sodium or phenylacetic acid
  • Arginine, citrulline and carnitine supplementation
  • Dialysis

Long term: High calorie, low protein diet +/- Liver transplant?

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7
Q

What is characteristic in the setting of a child with a urea cycle defect?

A

Respiratory alkylosis

means of distinguishing from organic acidemias

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8
Q

What tests should be ordered in a child with high ammonia?

A
  • serum Ammonia (serial measurements)
  • blood gas
  • serum lytes
  • Plasma AA (quantitative)
  • Urinary organic acids
  • For CPS vs. OTC, do urinary orotic acid level (HIGH in OTC, low in CPS/NAGS)
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9
Q

What is characteristic of lysosomal storage disorders?

A
  • Deficiency in lysosomal hydrolase leading to the intra-lysosomal accumulation of different substrates
  • Buildup leads to neurodegeneration, organomegaly, pulmonary infiltration or skeletal abnormalities
  • THINK - CHERRY RED SPOTS!
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10
Q

Describe features of Tay Sachs Disease?

A

• GM2 gangliosidase deficiency
• Accumulation of GM2 gangliosides in the CNS leads to loss of motor skills, increased startle, macrocephaly and seizures
• Infantile, juvenile and adult forms
More common in Ashkenazi Jews (carrier 1/25)

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11
Q

How does Tay Sachs differ from Sandhoff disease?

A
  • Both are GM2 ganglioside deficiencies
  • Tay Sachs: neurological deficits
  • Sandhoff: +/- HSM, cardiac involvement and bone abnormalities
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12
Q

What is the most common form of lysosomal storage disorder?

A

Gaucher disease!
• Multisystemic lipidosis with heme abnormalities, organomegaly and skeletal involvement
• Pathologic finding is Gaucher cells in the reticuloendothelial system
• Tx: enzyme replacement (beta-glucocerebrosidase deficiency)
• Diagnosis: skin/liver biopsy measuring glucocerebrosidase enzyme activity (affected individuals will have 0-15% of normal enzyme activity)

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13
Q

What are characteristic findings of Gaucher Disease?

A
  • HSM
  • Erlenmeyer flask appearance of long bones
  • Type 1: presents with clinical and radiographic bone disease, including bone pain, pathologic fractures, subchondral joint collapse, osteopenia, focal sclerotic or lytic lesions, and osteonecrosis. Also presents with hepatosplenomegaly, anemia, thrombocytopenia and lung disease
  • Type 2 and 3: will have neurological findings i.e. Pyramidal signs (opisthotonus, head retroflexion, spasticity and trismus), cognitive impairment, oculomotor apraxia, seizures, and progressive myoclonic epilepsy
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14
Q

What is Fabry Disease?

A
  • Lysosomal storage disease
  • X-linked
  • +pain, kidney dz/proteinuria, cardiac, angiokeratoma
  • corneal clouding
  • metachromatic leukodystrophy
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15
Q

What are some features of Krabbe Disease?

A
  • Lysosomal storage disease
  • aka globoid leukodystrophy
  • AR
  • Results from white matter accumulation of built up substrate, affects peripheral and central myelin
  • Neurodegeneration, seizures, blindness
  • No treatment; death in infancy
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16
Q

At what age do children with Neimann Pick Disease tend to expire?

A
  • 2-3 years
  • Lysosomal Storage Disease
  • Fatal disorder of infancy characterized by FTT, HSM and rapidly progressive neurodegenerative course
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17
Q

An infant presents with failure to thrive, jaundice, hepatomegaly, hypoglycemia, poor feeding and vomiting and nuclear cataracts. What diagnosis should be considered? What are they at increased risk for?

A

Galactosemia

At increased risk for E. coli neonatal sepsis and pseudotumour cerebri

18
Q

What is the pathology in galactosemia?

A
  • Deficiency in galactose-1-phosphate uridyl transferase.
  • Two main forms; classic (complete or near complete deficiency) and partial.
  • The infant, exposed to formula/EBM is unable to metabolize galactose-1-phosphate, leading to accumulation andinjury to the kidney, liver and brain
19
Q

How is galactosemia diagnosed?

A
  • Demonstration of a reducing substance in several urine specimens collected while the patient is receiving human milk, cow’s milk or any lactose containing formula
  • May also perform direct enzyme assay using erythrocytes using non-radioactive UV and HPLC
20
Q

Under what circumstances can you suggest Soy formula over other milk and milk alternatives?

A

• Galactosemia (AR)

21
Q

What are the long term effects/sequelae in galactosemia?

A
  • Learning disabilities
  • Speech delays
  • Premature ovarian insufficiency
  • Cataracts (can regress overtime)
22
Q

How many types of muccopolysaccharidosis are there?

A

7

1-4, 6-8; no type 5

23
Q

Features of Hurler’s Disease (MPS 1)

A
  • Coarse facial features, corneal clouding, large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia (spade-like hands)
  • Short stature
  • Developmental delay/Intellectual disability
  • Hepatosplenomegaly
  • Acute cardiomyopathy
  • Valvular heart disease with incompetence of MV and AV, narrowing of coronary arteries occurs
  • Recurrent URI and ear infections, noisy breathing, persistent copious nasal discharge
  • OSA
  • Combined conductive and neurosensory hearing loss, enlarged tongue
  • Progressive ventricular enlargement with increased intracranial pressure caused by communicating hydrocephalus also occurs
  • Glaucoma, and retinal degeneration
  • Umbilical and inguinal hernias
24
Q

Treatment for Hurler’s Disease

A

• HSCT
(improve growth, HSM, facial features, improve hearing and amend the natural history of cardiac and respiratory involvement)
• Enzyme replacement therapy with laronidase

25
Q

What is the most common peroxisomal disorder?

A

• X-linked adrenoleukodystrophy

26
Q

What is the pathology of x-linked adrenoleukodystrophy?

A
  • gene defect leads to deficient peroxisomal degradation of fatty acids leading to the accumulation of VLCFA
  • leads to progressive dysfunction of the central and peripheral nervous system white matter and damage to the adrenal cortex
  • characteristic defects in neuronal migration, micronodular cirrhosis of the liver, renal cysts, chondrodysplasia punctata, sensorineural hearing loss, retinopathy, congenital heart defects, dysmorphic features
27
Q

Describe classic neurologic pathology in x-linked adrenoleukodystrophy

A
  • age of onset between 4-8 years
  • most common initial sx = hyperactivity (often mistaken for ADHD), worsening school performance in a child who had previously been a good student
  • impaired auditory discrimination, tone perception is preserved
  • impaired spatial orientation
  • disturbances of vision, ataxia, poor handwriting, strabismus
  • seizures
  • fmhx of male relative affected
28
Q

What is the pathogenesis of Zellweger Sydrome?

A
  • AR condition that leads to disruption of the entire complex of peroxisome
  • hypotonia, high forehead with flat facies, large fontanelles and hepatomegaly
  • high serum iron level
  • growth deficiency
  • glaucoma
  • cryptorchidism
  • hypertrophied pylorus
  • breech presentation
29
Q

What must be done for a child who screens and tests positive for biotin deficiency?

A
  • avoidance of raw eggs (avidin binds and makes biotin less bioavailable)
  • biotin supplementation 5-10 mg/day
  • sensorineural hearing loss screen (note: biotin supplementation will halt but not reverse hearing loss)
  • ophthalmology screening
30
Q

What features on history would make you suspicious for a congenital disorder of glycosylation?

A
  • CNS (hypotonia and ataxia, muscle atrophy, decreased DTR, toe-walking)
  • Ocular movement defects
  • Coagulation abnormalities (stroke-like episodes due to reduced antithrombin II and protein C/S, factors VII, IX, XI and XIII)
  • GI symptoms (protein-losing enteropathy)
  • Retinitis pigmentosa
  • Growth failure
  • Skeletal abnormalities (contractures, kyphosis, pectus carinatum)
31
Q

What is the pathologic process in fatty acid oxidation disorders?

A

During periods of fasting, the body switches from carbohydrate metabolism to primarily fat metabolism
○ Important for skeletal muscles
○ Fatty acids are the preferred substrate for the heart
○ in FAODs, ketone bodies cannot be oxidized by the liver, but are exported to the brain, resulting in metabolic accumulation and features of vomiting, lethargy, rapidly progressing to coma, seizures or shock, cardiorespiratory collapse and/or SIDS

32
Q

What distinguishes Homocystinuria from Marfan Syndrome?

A
  • both are associated with lens dislocation however, dislocation is upward in MS and downward in homocystinuria
  • Homocystinuria is inherited as an autosomal recessive disorder, Marfan disease is autosomal dominant
  • Rigid joints are seen in homocystinuria rather than the hyperextensible joints in MS
  • Homocystinuria is a vaso-occlusive rather than a vaso-dilatory disease as in MS
  • 40% will be responsive to B6 supplementation, no effect in MS
33
Q

What is the diagnostic criteria for homocystinuria?

A
  • presence of elevate methionine and homocystine in serum and urine
  • Gold standard: enzyme assay from liver biopsy or cultured fibroblasts
34
Q

What are the important components of “critical sample”?

A
  • blood gas
  • insulin
  • TSH
  • beta-hydroxybuterate
  • free fatty acids
  • acylcarnitines
  • lactate
  • ammonia
  • urine organic acids
  • cortisol
  • ACTH
  • IGF-1
  • urine ketones
35
Q

What are the features of McArdle Disease?

A

Glycogen storage disease type V
• “Second wind” phenomenon
• symptoms caused by:
1) Brief exercise of great intensity (i.e. sprinting or carrying heavy loads)
2) Less intense but sustained activity (i.e. climbing stairs)
• moderate exercise (i.e. walking) can be performed by most patients for long periods
• exercise-induced myoglobinuria (caused by rhabdomyolysis)

36
Q

What kind of disorder is Niemann-Pick disease?

A

Lysosomal storage disorder

37
Q

Which amino acids are affected in the most common organic acidemias?

A

Leucine, isoleucine and valine (maple syrup urine disease)

• note: will have acidosis, ketones, no skin manifestations and characteristic odour of maple syrup

38
Q

Characteristic features of Phenylalanine hydroxylase deficiency?

A
  • Developmental and intellectual delay
  • Lighter complexion than unaffected siblings
  • Microcephaly
  • Unpleasant or musty odour
  • Growth retardation
  • Neurological changes: seizures (¬25%), spasticity, hyperreflexia, tremors
  • Hyperactive with autistic behaviours, including purposeless hand movements, rhythmic rocking, and athetosis
39
Q

Should phenylalanine be completely restricted from the diet of those children with PKU?

A

• No, it must be given in small quantities to prevent tyrosine protein deficiency and complications such as anorexia, FTT, rashes, anemia and diarrhea

40
Q

What is the pathological process in porphyria?

A
  • Disruption of the heme biosynthesis pathway within the liver and bone marrow, resulting in accumulation of heme-intermediaries
  • Leads to abdominal pain (cramping, ileus, abdominal distension, N/V, constipation), tachycardia, sympathetic overactivity (HTN, restlessness, coarse or fine tremors, excessive sweating), porphyric neuropathy, proximal muscle weakness of the UE then LE, blindness, numbness, paresthesias, seizures, anxiety, insomnia, depression, disorientation, hallucinations, and paranoia
41
Q

Treatment of acute intermittent porphyria?

A
  • IV hemin

* carbohydrate loading for mild attacks

42
Q

Features of Tyrosinemia

A

• Tyrosinemia Type 1 - Hepatorenal form (“1 belly”)

- Liver failure with synthetic dysfunction; conjugated jaundice, coagulopathy, cirrhosis
- Kidney: proximal renal tubular dysfunction leading to hypophosphatemic rickets
- GI: failure to thrive
- Neuro: paresthesias, seizures, paralysis

Treatment: Dietary restriction of tyrosine and phenylalaine +/- liver transplant

• Tyrosinemia Type 2 - oculocutaneous form (“2 eyes”)

- Eyes: photophobia, decreased tear production, corneal ulceration
- Skin: crusted,  hyperkeratotic lesions on palms and soles
- Neurologic: seizures, behavioural abnormalities, developmental delay

Treatment: Dietary restriction of tyrosine and phenylalaine +/- liver transplant

Pediatrics (27 decks)

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