Board review 11 27 2012
1 / 84

Inborn Errors of Metabolism - PowerPoint PPT Presentation

  • Uploaded on

Board Review 11/27/2012. Inborn Errors of Metabolism. Test Question. What topic should we do for December Board Review? Poisonings and Environmental Exposures Substance Abuse. Approach to Metabolic Disorders…. Inborn Errors of Metabolism. Acute Presentation Metabolic crisis

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about ' Inborn Errors of Metabolism' - gage-barnes

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Board review 11 27 2012

Board Review 11/27/2012

Inborn Errors of Metabolism

Test question
Test Question

What topic should we do for December Board Review?

  • Poisonings and Environmental Exposures

  • Substance Abuse

Inborn errors of metabolism
Inborn Errors of Metabolism

  • Acute Presentation

    • Metabolic crisis

    • Sudden onset of lethargy, vomiting, irritability, respiratory compromise, seizures, encephalopathy

    • Typically due to hyperammonemia, acidosis, ketosis, hypoglycemia

  • Chronic Presentation

    • Indolent course

    • Can affect multiple organ systems

      • CNS

      • Liver

      • Heart

      • Kidney

      • Muscle

      • Eye

    • Dysmorphic features

Typical acute metabolic crisis
Typical Acute Metabolic Crisis…

  • Appear normal at birth

    • Metabolic intermediate responsible for symptoms is removed by maternal placenta

  • Within days-months (rarely years) will develop a septic/shock-like picture

  • Acute onset: lethargy, vomiting, tachypnea (or apnea), irritability, seizures

  • Encephalopathic

  • Workup for infection/sepsis yields normal results

Question 1
Question #1

An infant who presented with vomiting is now lethargic and progressing to a comatose state. Mom says she just found out the newborn screen was abnormal. Which two tests are most important EMERGENTLY so that interventions may be started?

  • Potassium and brain MRI

  • WBC and ketones

  • Lactate and platelets

  • Glucose and ammonia

  • Cardiac stress test and glucose tolerance test

Lab workup
Lab Workup

  • Acidosis

    • pH <7.3, pCO2<30,bicarb <15

    • Can suggest:

      • Metabolic disorder

      • Infection

      • Dehydration

      • Intoxication

      • Anoxia

  • Elevated lactate

    • Measured on blood gas

    • Can suggest: hypoxia or poor perfusion (dehydration)

    • Metabolic disorders:

      • Glycogen storage disease

      • Pyruvate defect

      • Fructose 1,6 biphosphonate deficiency

      • Mitochondrial disease

Lab work up continued
Lab work up (continued)

  • Ketosis

    • Ketones are a normal part of physiology, but not when they generate acidosis

    • Organic acidemias

  • Hyperammonemia

    • Urea cycle defects

    • Organic acidemias

    • Fatty acid oxidation defects

  • Hypoglycemia

    • Hyperinsulinism

    • Liver failure

      • Glycogen storage disease, tyrosinemia, galactosemia, Niemann-Pick

    • Organic acidemias

    • Fatty acid oxidation defect

Question 2
Question #2

A 3 day old infant was initially vigorous at birth but now has poor feeding, tachypnea, and lethargy. Septic work-up is negative. Serum electrolytes, glucose, and lactate are normal. An ABG shows: pH 7.53, pCO2 20, HCO3 25. Serum ammonia level is 465mcmol/L (elevated). Urine ketones are negative. What is the most likely diagnosis?

  • Fatty acid oxidation defect

  • Urea cycle defect

  • Organic acidemia

  • Glycogen Storage Disease Type I

  • Renal tubular acidosis

Specific disorders
Specific Disorders

  • Urea Cycle Defects

  • Organic Acidemias

  • Amino Acid Disorders

  • Carbohydrate Disorders

  • Fatty Acid Oxidation Defects

Urea cycle defects1
Urea Cycle Defects

  • Classic presentation:

    • First few days of life: poor feeding, vomiting, tachypnea, lethargy  coma

  • Late onset:

    • Partial enzyme deficiencies

    • Recurrent vomiting, developmental delay, learning difficulties, seizures, brittle hair, protein intolerance

    • Failure to thrive

    • Precipitating cause for acute hyperammonemic encephalopathy

      • Infection, trauma, fasting, medications (glucocorticoids)

Urea cycle defects2
Urea Cycle Defects

  • Hyperammonemia WITHOUT acidosis

    • Usually have respiratory ALKALOSIS

    • No ketones

    • No hepatomegaly

  • Types:

    • Ornithinetranscarbamylase deficiency (X-linked)

    • Carbamoyl phosphate synthase deficiency (AR)

    • Citrullinemia (AR)

    • Argininosuccinicacidemia (AR)

    • Argininemia (AR) (arginase deficiency)

      • Does not present with hyperammonemia

      • Neurologic manifestations

Urea cycle defects3
Urea Cycle Defects

  • Diagnosis: plasma amino acid concentrations

    • Urine orotic acid value can help distinguish types

    • Enzyme analysis of tissue samples

  • Treatment:

    • Reduce ammonia! (more on this later)

      • Reduce protein intake

      • Avoid catabolism

    • Arginine supplements can be helpful

Specific disorders1
Specific Disorders

  • Urea Cycle Defects

  • Organic Acidemias

  • Amino Acid Disorders

  • Carbohydrate Disorders

  • Fatty Acid Oxidation Defects

Question 3
Question #3

A 2 day old newborn presents with feeding difficulties and lethargy. Septic work-up is negative and urine organic acid values suggest an organic acidemia. The following are lab values which could be seen on initial presentation EXCEPT:

  • Low pH

  • Hyperammonemia

  • Hyperglycemia

  • Elevated lactate

  • Ketones in the urine

Organic acidemias
Organic Acidemias

  • Organic acids are the intermediates in the catabolism (break down) of amino acids, lipids and other compounds

    • Products go to Krebs cycle  ATP

  • Specific enzyme deficiencies lead to characteristic urine organic acid profiles

Inborn errors of metabolism

Organic Acids Defects





Odd chain fatty acids





Propionyl CoA

Methylmalonyl CoA

Succinyl CoA

Krebs Cycle



Isovaleryl CoA



Acetyl CoA


Even chain fatty acids





Acetyl CoA

Glutaryl CoA

Crotonyl CoA

Organic acidemias1
Organic Acidemias

  • Important features

    • High anion gap metabolic acidosis

    • Ketosis

    • Elevated lactate

    • +/- hypoglycemia

    • +/- hyperammonemia

  • Typically presents in first few days of life with introduction of protein into diet

    • Irritable, poor feeding, lethargy  coma

Organic acidemias2
Organic Acidemias

  • Diagnosis: urine organic acids

    • Plasma acylcarnitine profile can help distinguish between types

  • Types (multiple!!)

    • Isovalericacidemia

      • Seizures, high incidence of infection, odor of sweaty feet

    • Propionicacidemia

    • Methlymalonicacidemia

      • May respond to vitamin B12

Urea cycle defects vs organic acidemias
Urea Cycle Defects vs Organic Acidemias



Specific disorders2
Specific Disorders

  • Urea Cycle Defects

  • Organic Acidemias

  • Amino Acid Disorders

  • Carbohydrate Disorders

  • Fatty Acid Oxidation Defects

Amino acid disorders
Amino Acid Disorders

  • Other disorders of amino acid catabolism

  • Similar clinical manifestations to organic acidemias

    • Diagnosed differently

    • Plasma amino acids (vs urine organic acids )

Phenylketonuria pku
Phenylketonuria (PKU)

  • Deficiency of enzyme that converts phenylalanine to tyrosine

  • Not typically seen due to newborn screening

  • Asymptomatic for a few months, then…

    • Severe vomiting, irritability, eczema, mousy odor of urine

    • Blond hair, blue eyes

  • Late signs: profound intellectual disability**

  • Pregnant woman not treated adequately:

    • Fetal risks: miscarriage, SGA, microcephaly, cardiac defects

  • Treatment: low phenylalanine diet (lifelong!**), frequent monitoring, dietary counseling, adequate tyrosine intake

Maple syrup urine disease
Maple Syrup Urine Disease

  • Deficiency of enzyme used to breakdown branched-chain amino acids

    • leucine, isoleucine, valine

  • Clinical signs:

    • First week of life: poor feeding, tachypnea with shallow breathing, profound lethargy, hypertonicity

    • Maple syrup smelling urine

    • Hypoglycemia, acidosis


  • Multiple subtypes

    • Type I: liver failure, kidney involvement, nerve problems

    • Type II: oculocutaneous

      • Corneal ulcerations leading to clouding, skin thickening on palms/soles

  • Treatment: low tyrosine and phenylalaine diet


  • Cystathioninesynthase deficiency  elevated methionine levels

  • 2 subtypes: Pyridoxine (B6) responsive and B6 resistant

    • Better IQ prognosis in responsive type

  • Clinical manifestations:

    • Ectopialentis (posterior), skeletal abnormalities (marfanoid), cognitive deficits, thromboembolic events

    • Light-colored skin, hair, eyes

  • Diagnosis: homocysteine in urine

  • Treatment: pyridoxine

    • If no response: diet high in cystine and low in methionine

Specific disorders3
Specific Disorders

  • Urea Cycle Defects

  • Organic Acidemias

  • Amino Acid Disorders

  • Carbohydrate Disorders

  • Fatty Acid Oxidation Defects


  • Deficiency of galactose-1-phosphate uridyltransferase

  • Appear normal until first meal

  • Develop poor feeding, failure to thrive, vomiting, lethargy, jaundice, abdominal distension, hepatomegaly

  • Labs:

    • Hypoglycemia

    • +Reducing substances in urine (non-glucose)

Inborn errors of metabolism

Galactose Metabolism



Breast milk, cow’s milk






galactose-1-P uridyltransferase






Question 4
Question #4

A 6 day old female who is breast fed is brought to the emergency room due to poor feeding, vomiting, hepatomegaly, and jaundice. You suspect galactosemia. Which of the following would support this diagnosis?

  • Blood culture positive for E. coli

  • Diabetic mother

  • Serum ammonia > 600 mcmol/L

  • Cherry red spot on retina

  • Microcephaly


  • Diagnosis: enzyme assay on RBCs

  • Complications: Liver disease (cirrhosis with portal hypertension/ascites), Gram-negative (E. coli) sepsis, cataracts, MR, speech delay, ovarian failure

    • Cataracts are reversible with diet change

    • Developmental and speech delays are common despite good dietary control**

  • Treatment: galactose free diet, ophthalmology and developmental follow-up

Question 5
Question #5

A 9 year old male is brought to the emergency room due to vomiting and lethargy shortly after a birthday party. PMHx is significant for FTT in late infancy which resolved without determination of a diagnosis. He had had several bouts of vomiting in the past, usually after consuming candy or soft drinks. Labs reveal elevated AST and ALT. What is the most likely diagnosis?

A. Hereditary fructose intolerance

B. Glycogen storage disease Type II

C. Fatty acid oxidation defect

D. Fabry disease

E. Zellweger syndrome

Hereditary fructose intolerance
Hereditary Fructose Intolerance

  • Deficiency in enzyme to break-down fructose (aldolase B)

  • Exposure to fructose results in vomiting, poor feeding; can see seizures in extreme cases

  • Continued exposure:

    • FTT, hepatomegaly, hypoglycemia, jaundice, renal dysfunction, liver failure, ascites

    • Labs: elevated liver transaminases, elevated direct bilirubin, clotting abnormalities

  • Diagnosis: enzyme assay from liver biopsy

  • Treatment: remove fructose from diet

Fructose 1 6 biphosphatase deficiency
Fructose-1,6-biphosphatase Deficiency

  • Enzyme converts FDP to F-6-P (part of gluconeogenesis)

  • Deficiency of this enzyme  when challenged with fructose, get buildup of FDP which inhibits gluconeogenesis decreased glucose production

  • Labs: hypoglycemia, lactic acidosis, ketosis

  • Hepatomegaly

  • Diagnosis: enzyme assay from liver biopsy

  • Treatment: remove fructose from diet, avoid fasting

Specific disorders4
Specific Disorders

  • Urea Cycle Defects

  • Organic Acidemias

  • Amino Acid Disorders

  • Carbohydrate Disorders

  • Fatty Acid Oxidation Defects

Fatty acid oxidation defects
Fatty acid oxidation defects

  • Multiple enzymatic reactions involved in the degradation of saturated fatty acids

    • Release acetyl-CoAs and ketones which are used for energy production, especially during a FASTING state

    • The enzymes involved in breaking down fatty acids are specific to different fatty acid lengths

      • Short, medium, long, and very-long acyl-CoAdehydrogenases


      • Deficiency in any can lead to fatty acid oxidation defect

      • ALL are autosomal recessive

Fatty acid oxidation
Fatty acid oxidation



Fatty acids


  • Medium chain acylCoAdehydrogenase deficiency(MCAD) is most common defect

    • 25% risk of death with first episode

  • SCAD is typically benign


acetyl CoA


Krebs cycle

Question 6
Question #6

A 2 month old female becomes comatose after an upper respiratory illness. Which of the following lab findings would most suggest a disorder of fatty acid oxidation?

  • Hypoglycemia with metabolic alkalosis

  • Hypoglycemia with + ketonuria

  • Hyperglycemia with - ketonuria

  • Hyperglycemia with + ketonuria

  • Hypoglycemia with - ketonuria

Fatty acid oxidation defects1
Fatty acid oxidation defects

  • Key feature: Hypoketotic hypoglycemia

    • Reducing substances are also negative

    • +/- hyperammonemia

  • Typically presents after recent illness; period of fasting

  • Can be associated with hepatomegaly, liver disease, hypertrophic cardiomyopathy, arrhythmias, adult onset myopathy

    • Labs: glucose, electrolytes, ammonia level, LFTs, CPK, lactate, uric acid, urinalysis for myoglobinuria

  • Diagnosis: plasma acylcarnitine profile

    • +/- skin biopsy

Carnitine transport defects
Carnitine Transport Defects

  • Carnitine transports longer chain fatty acids in to the mitochondria for breakdown

    • Defects in the enzymes involved in this process can lead to similar symptoms of fatty acid oxidation defects

    • Hypoketotic hypoglycemia

    • Hepatomegaly, elevated transaminases, elevated ammonia

    • Seizures (secondary to hypoglycemia)

    • Can typically present in adulthood with muscle weakness, elevated CPK, myoglobinuria

  • Diagnosis: plasma acylcarnitine profile

    • +/- skin biopsy

General treatment principles
General Treatment Principles

  • Prompt recognition of possible inborn error of metabolism

    • Appropriate testing

    • Immediate interventions

  • Treat hypoglycemia with glucose infusions

  • Treat encephalopathy due to hyperammonemia

    • Sodium benzoate and sodium phenylacetate to remove ammonia

    • Emergent hemodialysis if level is > 600

    • Stop all protein intake if urea cycle defect or amino acid disorder suspected

      • Calories supplied with dextrose and intralipids

General treatment principles1
General Treatment Principles

  • Can give large doses of co-factors while waiting for specific lab tests to come back

    • Vit B12, thiamine, biotin, riboflavin, folic acid, carnitine

  • Once diagnosed

    • Dietary counseling

    • Genetic counseling

Question 7
Question #7

You are seeing a new 1 year old patient for developmental delay. Based on a positive family history, you are suspecting an inborn error of metabolism as the cause. What are you MOST likely to see on exam??

  • Lack of babbling but normal motor exam

  • Inability to sit alone or cruise but says 5-10 words

  • Poor babbling, inability to sit alone, no holding toys/objects in her hands

  • Normal development

  • You are worried about autism but nothing else

Clinical manifestations
Clinical Manifestations

  • Difficult to recognize and diagnose

  • Onset from birth to adulthood

  • Neurologic abnormalities

    • Developmental delay that is typically global

    • Seizures, often resistant to medications

    • Movement disorders

      • Dystonias

      • Choreas

    • Abnormal tone

    • Hearing loss

    • Blindness

    • Stroke should suggest homocystinuria or the mitochondrial disorder MELAS

Question 8
Question #8

You are convinced that a patient is suffering from a chronic inborn error of metabolism. Other than Genetics, who would you MOST likely consult first during your initial work-up.

  • Orthopedics

  • ENT

  • Urology

  • Heme/Onc

  • Ophthalmology

Work up

  • Thorough developmental history and assessment

  • If a metabolic disorder is suspected, initial work-up could include…

    • Glucose, pH, lactate, ammonia level

    • Plasma amino acids and urine organic acids

    • VLCFA and acylcarnitine profile

    • Urinary mucopolysaccharides and oligosaccharides

    • MRI of the brain

    • Skeletal survey

      • May uncover dysostosis multiplex (seen in lysosomal storage diseases)

    • Ophthalmologic examination

Work up1

  • Results of the initial history and physical exam should guide which tests can be added or eliminated

  • Positive results on the initial screening will typically lead to further, more specific testing

    • DNA analysis

      • For diagnosis

      • For genetic counseling

    • Enzyme assays

    • Liver biopsy

    • Etc…but this would be guided by a friendly Dr. Marble 

Question 9
Question #9

A 3 month old female is found to have hepatomegaly on routine exam. She is asymptomatic. Lab testing shows hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia and elevated AST and ALT. Which type of disorder do you suspect?

  • Glycogen storage disorder

  • Mitochondrial disorder

  • Lysosomal storage disorder

  • Peroxisomal disorder

  • Wilson’s Disease

Specific disorders5
Specific Disorders

  • Glycogen Storage Disorders

  • Peroxisomal Disorders and Lipoprotein Disorders

  • Lysosomal Disorders

  • Mitochondrial Disorders

Glycogen storage diseases
Glycogen Storage Diseases

  • Hypoglycemia with hepatomegalysuggests a GSD.

  • Often present when an infant begins sleeping through the night…which results in “prolonged fasting.”

  • Helpful labs include…

    • Glucose

    • Uric acid

    • Lactic acis

    • LFTs

    • Lipids

  • A liver biopsy is often necessary, but DNA testing is becoming more readily available

Inborn errors of metabolism


Krebs cycle

  • Glycogen is a storage form of glucose:

  • Liver glycogen releases glucose into the circulation

  • Muscle glycogen is used locally

Lactic acidosis

Acetyl CoA


Glucose – 1- P

Malonyl CoA


Stimulates fatty acid synthesis and inhibits fatty acid breakdown



Pentose phosphate shunt


Glucose – 6- P


GSD types 1a and 1b




Glut 2



Von gierke disease gsd 1
Von Gierke Disease (GSD 1)

  • Autosomal recessive deficiency of hepatic glucose-6-phosphatase

  • Clinical manifestations

    • Hypoglycemia with lactic acidosis during fasting

    • Distended abdomen (due to large liver)

    • Doll-like or cherubic face

    • Poor growth

    • Seizures secondary to low glucose

    • Increased TG and cholesterol

  • Treatment

    • Infusion of glucose continuously, especially at night until 2

    • Cornstarch after 2yo

    • Frequent meals and snacks

    • Allopurinol if uric acid too high

    • Liver transplant (LATER)

Von gierke disease gsd 11
Von Gierke Disease (GSD 1)

  • Long-term complications

    • Sub-optimal growth velocity and short stature in adulthood

    • Delayed puberty in poorly-controlled disease

    • Hepatomegaly, renomegaly

    • Nephrocalcinosis

    • Impaired platelet function…bleeding tendency and epistaxis

    • Hepatic adenomas

      • Intrahepatic hemorrhage

      • Malignant transformation

    • Osteoporosis

    • Rickets and anemia

    • PCOS

Pompe disease gsd 2
Pompe Disease (GSD 2)

  • Deficiency in lysosomal breakdown of glycogen

  • Clinical manifestations

    • Infant 1 month or younger

    • Normal at birth but becomes floppy

      • Hypotonia with muscles “hard” on exam

    • Failure to thrive

    • Large liver and macroglossia

    • Progressive cardiomyopathy

  • Eventually, death is due to respiratory failure

Specific disorders6
Specific Disorders

  • Glycogen Storage Disorders

  • Peroxisomal Disorders and Lipoprotein Disorders

  • Lysosomal Disorders

  • Mitochondrial Disorders

Peroxisomal disorders
Peroxisomal Disorders

  • Peroxisomes: organelles involved in the beta-oxidation of VLCFA

  • Peroxisomal biogenesis disorders

    • ZellwegerSydrome = most severe

      • High forehead, flat occiput, Large anterior fontanelle

      • Epicanthal folds, Broad nasal bridge, anteverted nostrils

      • Micrognathia

      • Brain defects, seizures, severe intellectual disability

      • Liver disease, adrenal insufficiency, renal abnormalities

      • Death in first year of life

    • Refsum Disease, Adrenoleukodystrophy

  • Mutations of individual enzymes

Peroxisomal disorders1
Peroxisomal Disorders

Lipoprotein disorders
Lipoprotein Disorders

  • Familial hypercholesterolemia

    • Autosomal dominant

    • Deficiency of LDL receptors

    • Xanthomas after age 10 years

    • NOT associated with obesity

  • Congenital lipodystrophy

    • Adipose tissue resistant to insulin

    • Newborn that is thin AND long

  • Farber’s disease

    • Skin nodules and painful joints noted in 1st week of life

    • Cherry red spot on retina

Lipoprotein disorders1
Lipoprotein Disorders

  • Wolman Disease

    • Due to defective lipoprotein metabolism

    • Triglyceride and cholesterol esters deposited in body tissues

      • Serum levels are normal!

    • FTT, hepatosplenomegaly

    • Calcified and enlarged adrenal gland

Wilson s disease
Wilson’s Disease

  • Autosomal recessive disorder of copper transport

  • Accumulation of copper in tissues, mainly the liver and brain

  • Low serum ceruloplasmin

  • Also affects the eyes and the kidney

    • Visual deficits do NOT occur

  • Clinical manifestations

    • Liver deterioration

      • Jaundice

      • Hepatomegaly

    • Neurologic deterioration

  • Diagnosed by liver biopsy!

Menkes kinky hair syndrome
Menkes Kinky Hair Syndrome

  • X-linked recessive disorder of copper transport

  • Copper is poorly distributed to cells in the body

    • Accumulates in some tissues…small intestine and kidney

    • Brain and other tissues have unusually LOW levels

  • Low serum copper and ceruloplasmin

  • Clinical manifestations

    • Usually manifests in infancy

    • Brittle, colorless, twisted hairs

    • Seizures, dev’t delay, MR, hypotonia

Question 10
Question #10

  • Your patient had apparently normal development for the first 6 months of life but begins to slow down. She was able to sit unassisted by 1 year. She was very socially interactive and could grasp objects. She gradually lost her ability to sit and grasp objects, became less interactive, lost interest in eating, and became emaciated. She had splenomegaly. Ophthalmology exam revealed a cherry red spot macula. What family of disorders do you suspect MOST?

  • Glycogen storage disorder

  • Mitochondrial disorder

  • Lysosomal storage disorder

  • Organic acidemia

  • Urea cycle defect

Specific disorders7
Specific Disorders

  • Glycogen Storage Disorders

  • Peroxisomal Disorders and Lipoprotein Disorders

  • Lysosomal Disorders

  • Mitochondrial Disorders

Lysosomal disorders
Lysosomal Disorders

  • Lysosomes are organelles that degrade complex molecules to their building blocks.

  • Deficient enzymes result in the accumulation and storage of intermediates.

  • 3 different groups depending on type of glycoprotein involved

    • Mucopolysaccharidoses

    • Oligosaccharidoses

    • Sphingolipidoses

  • Labs

    • Urine mucopolysaccharides

    • Urine oligosaccharide

    • Enzyme assay

    • DNA (for genetic counseling and to rule out pseudoalleles)

Question 11
Question #11

  • A 14 month old female presented with developmental delay to your clinic. She was reportedly normal at birth but at 8 months was noted to have mild kyphosis when sitting. Late in infancy, the parents noticed gradual changes in craniofacial features including thickening of the eyebrows, large tongue, prominence of forehead. The patient hand been pulling to stand but lost this ability and seemed to be regressing in overall development. On exam, you notice a scaphocephalic head shape, frontal bossing, relatively thick eyebrows, cloudy cornea and stiff elbows. Which type of lysosomal disorder is MOST likely?

  • Mucopolysaccharidoses

  • Sphingolipidoses


  • Normal at birth but progressive in nature.

  • Neurologic involvement

    • Regression and loss of milestones

    • Intellectual disabilities

  • Hepatosplenomegaly

  • Skeletal manifestations

    • Coarsened facial features

    • Joint involvement

    • Short stature

    • Dysostosis multiplex…due to accumulation of glycosaminoglycans in the chondrocytes

  • Diagnosed by enzyme assay


  • AKA Lipid Storage Diseases

  • Clinical features that are present in different diseases

    • Hepatosplenomegaly

    • Normal development followed by neurologic regression

    • Demyelination

    • Normal urine glycosaminoglycans and oligosaccharides

    • Cherry red spot on ophthalmologic exam

Gaucher disease
Gaucher Disease

  • Clinical findings

    • Organomegaly

    • Bone pain

    • Easy bruisability

    • Short stature

    • Thrombocytopenia

    • X-ray

      • Osteosclerosis and lytic lesions

  • Infantile Gaucher Disease

    • Decreased beta glucosidase activity

    • Child in 1st or 2nd year of life with proressive HSM and CNS deterioration

Tay sachs
Tay Sachs

  • Autosomal recessive deficiency of hexosaminidase A, which breaks down GM2 ganglioside

  • High incidence in Ashkenazi Jews (1/30 is carrier)

  • Presentation

    • Normal development through the first 3-6 months 

    • Development of nonspecific signs like lethargy and hypotonia, mild weakness, myotonic jerks 

    • Continued deterioration including blindness and seizures 

    • Death by age 5

    • Exaggerated startle reflex to loud noise

    • Reduced visual attentiveness and abnormal eye movements

    • Macrocephaly

    • Cherry red spot on retina

  • Management is primarily supportive

    • Adequate nutrition

    • Airway protection

    • Controlling seizures

Other sphingolipidoses
Other Sphingolipidoses

  • Fabry Disease

    • Orange-colored skin lesions

    • Opacities of the eye

    • Vascular disease of the kidney, heart, and brain

  • Krabbe Disease

    • Demyelination Disorder

    • Progressive neurologic degeneration

    • Death by age 2 years

  • Niemann-Pick

    • Cherry red spot

    • CNS deterioration

    • Hepatosplenomegaly*

Question 12
Question #12

  • Which of the following classes of disorders is mostly MATERNALLY inherited?

  • Glycogen storage diseases

  • Urea cycle defects

  • Amino acid disorders

  • Mitochondrial disorders

  • Sphinogolipidoses

Specific disorders8
Specific Disorders

  • Glycogen Storage Disorders

  • Peroxisomal Disorders and Lipoprotein Disorders

  • Lysosomal Disorders

  • Mitochondrial Disorders

Mitochondrial disorders
Mitochondrial Disorders

  • Mitochondria are involved in

    • Fatty acid oxidation, including carnitine transport, urea cycle, citric acid cycle

    • *Energy production pathway of oxidative phosphorylation

  • Mitochondria have their own DNA that encodes proteins; all are derived from the ovum, so these disorders are MATERNALLY inherited!!

  • Mitochondria harboring mutations are less able to produce energy

    • Clinic symptoms become apparent when energy production is low

    • Brain, liver, and kidney are more susceptible to disease


  • Symptoms of hypoglycemia usually within the first hours/days of life

    • Poor feeding

    • Lethargy

    • Jitteriness

    • Hypotonia

  • Macrosomia

    • Height, weight, HC typically 95% or greater

    • Due to stimulation of IGF1 receptors

  • Persistent hypoglycemia

  • Inappropriately high insulin and C-peptide in the setting of hypoglycemia

  • NO ketonuria

    • Insulin decreases lipolysis and ketogenesis


  • Refractory hypoglycemia is major clue to diagnosis

    • Despite oral feedings glucose remains low

    • IV dextrose required but may NOT always work

    • Glucagon can sometimes correct the low glucose

    • Diazoxide

      • Decreases insulin secretion

      • Stimulates cortisol release

      • Often the “drug of choice” for refractory hypoglycemia*

Yay we re done thanks

YAY! We’re done Thanks!!!