Inborn errors of metabolism









  • Unexpected and unexplained clinical deterioration in a previously healthy infant or child is an important clue to the presence of an inborn error of metabolism (IEM).



  • Loss of previously attained developmental milestones during childhood is an important clue to the presence of a neurodegenerative disorder, such as lysosomal storage disease.



  • Blood glucose less than 40 mg/dL is distinctly unusual after the first 24 hours of life, particularly in infants who have started feeding, and should be thoroughly investigated.



  • Laboratory evaluation for IEM should be undertaken in any child with a suggestive clinical history regardless of the results of newborn screening. A normal newborn screen, although perhaps reassuring, does not rule out the possibility of an IEM.



  • With catastrophic illness in a previously well child without signs of any particular IEM, the “shotgun” diagnostic evaluation should minimally include plasma amino acid analysis, plasma acylcarnitine profile, and urine organic acid analysis by gas chromatograph–mass spectrometry.



Metabolism can be defined as the sum of all biochemical processes that convert food to smaller molecules and energy for the purposes of structure and function. An inborn error of metabolism (IEM) is an inherited deficiency of any critical step in metabolism. Although genetic deficiency of catalytic enzymes in intermediary metabolic pathways is the classic paradigm for IEM, the pathophysiology of metabolic disorders may involve abnormalities of any number of cellular processes, including transmembrane transport, cell signaling, cell differentiation and development, energy production, and others. Many IEMs are individually rare, although a few—including phenylketonuria (PKU) and medium-chain acyl-coenzyme A (acyl-CoA) dehydrogenase deficiency (MCADD), a defect in fatty acid oxidation—exhibit a population incidence approaching 1:10,000 live births. Specific IEMs may be more common in certain ethnic groups with a history of relative reproductive isolation. Collectively, the population incidence of all IEMs may approach 1:1500 live births, depending on how broadly IEM is defined. Many IEMs are associated with catastrophic illness necessitating advanced life support. Although IEM may present rarely within the professional lifetime of the average medical practitioner, critically ill children with IEM will not be uncommon visitors to the pediatric intensive care unit, especially in a tertiary care center.


Other textbooks on the diagnosis and treatment of IEM provide an exhaustive list of known disorders. , Rather than recapitulate an encyclopedia of possible diseases, this chapter presents a diagnostic rationale based on specific clinical symptom complexes that are likely to occur in the critically ill child. Algorithms for the differential diagnosis of specific clinical scenarios are provided in support of this rationale. Symptoms often begin during early infancy in the biochemically most severe IEM. Naturally, these IEMs with neonatal onset are the focus of the discussion in this chapter. However, “milder” or late-onset variants of virtually every IEM have been described with onset of symptoms occurring at all ages, even during adulthood. Some IEMs uniformly present after the neonatal period; age of symptom onset (late infancy, childhood, or adulthood) often is an important clue to the specific diagnosis. The clinical presentation, diagnostic workup, and treatment of neonatal onset disorders provide a paradigm for the evaluation and management of possible IEMs in a child of any age.


Pathophysiology of inborn errors of metabolism


Under the classic paradigm, an IEM is associated with deficiency of a specific protein, often a catalytic enzyme, involved in a critical metabolic pathway ( Fig. 81.1 ). This deficiency leads to a block in the pathway and the accumulation of the enzyme substrate. In this model, three distinct pathogenic mechanisms represent possible proximate causes of the symptoms associated with an IEM. The specific pathogenic mechanism involved in any given IEM dictates the appropriate treatment strategy. First, accumulation of the substrate may lead to toxic effects at very high levels; successful therapy requires effective elimination of the substrate or a method to block its toxic effects. An example for this mechanism is PKU, in which elevated phenylalanine levels adversely affect neuronal development, and the reduction of tissue phenylalanine content through dietary phenylalanine restriction largely prevents the major clinical features of PKU. Second, deficiency of the reaction product, should it be a critically important metabolite, may lead to disease. Supplementation with the essential metabolite, if possible, may cure the disease. Biotin is a required cofactor for four distinct carboxylase enzymes. Deficiency of free biotin develops in the face of genetic biotinidase deficiency and leads to symptoms of multiple carboxylase deficiency. Supplementation with oral biotin completely prevents the clinical manifestations of biotinidase deficiency. The final pathogenic mechanism involves the conversion of the enzyme substrate, through normally quiescent alternative pathways, to toxic secondary metabolites. Elimination or decreased production of these secondary metabolites may improve disease symptoms. For example, tyrosinemia type I (fumarylacetoacetate hydrolase [FAH] deficiency) is associated with recurrent attacks of abdominal pain and paresthesias reminiscent of acute intermittent porphyria. The accumulating substrate, fumarylacetoacetic acid, is converted through secondary pathways to succinylacetone. Succinylacetone, in turn, inhibits the heme synthetic pathway and causes porphyria-like symptoms. Pharmacologic inhibition of the tyrosine catabolic pathway proximal to the block at FAH decreases the production of fumarylacetoacetic acid and succinylacetone, alleviating the pathology associated with these toxic compounds.




• Fig. 81.1


Inborn error of metabolism paradigm. Normally, in a given step of intermediate metabolism with intact enzymatic activity, the substrate A is efficiently converted to the product B. In an inborn error of metabolism, a deficiency of enzyme activity may lead to excessive accumulation of the substrate; critical deficiency of the product; or production of an alternative, potentially toxic metabolite C through normally quiescent pathways.


Inheritance of inborn errors of metabolism


IEMs are heritable disorders. The majority of diseases are inherited in an autosomal recessive pattern, yielding a 25% recurrence risk in future offspring. The gene defects associated with several IEMs are located on the X chromosome. These IEMs, such as ornithine transcarbamoylase deficiency and glycerol kinase deficiency, are inherited in an X-linked pattern. These IEMs are most severe in males, but carrier females may be symptomatic, although usually with less severe or late-onset disease as a result of skewed X chromosome inactivation. Mutations for several mitochondrial disorders are found on mitochondrial DNA (mtDNA). Because mtDNA is exclusively passed from mothers to their offspring, these IEMs exhibit a maternal inheritance pattern but often with variable penetrance and expressivity. Prenatal diagnosis is possible for many IEMs. In addition to allowing for appropriate medical therapy, the timely diagnosis of an IEM in a sick infant or child is important for genetic counseling purposes.


Signs and symptoms of inborn errors of metabolism


Clinical signs and symptoms frequently associated with IEMs are listed in Box 81.1 . The symptom repertoire of the critically ill infant is limited, and the clinical presentation of metabolic disorders often is nonspecific. It is for this reason that the diagnosis of an IEM may be easily missed. To maintain maximum diagnostic sensitivity for IEMs, the clinician must maintain a high level of suspicion and be willing to initiate screening metabolic laboratory studies with little provocation ( Box 81.2 ). As was true for appendectomies in the era prior to the advent of ultrasound-based diagnosis of appendicitis, a certain number of nondiagnostic metabolic laboratory workups in sick children must be performed to ensure ascertainment of individuals with inherited metabolic disorders. In particular, IEM should be a strong diagnostic consideration in any neonate who has become catastrophically ill following a period of normalcy. This presentation may be clinically indistinguishable from bacterial or viral sepsis; the nonspecific supportive therapy provided to potentially septic infants (fluid and glucose administration) may alleviate the symptoms and mask the presence of an IEM. Diagnostic metabolic laboratory studies are most likely to provide definitive information if performed on clinical samples obtained at initial presentation and before any therapy is initiated. Failure to obtain the necessary specimens at this time may cause the clinician to miss an important diagnostic window of opportunity. Many children with an IEM have been saved initially by intensive but nonspecific treatment but then suffered clinical relapse or even death in the absence of the correct diagnosis. Certainly, the possibility of an IEM should be considered in any child for whom the clinical picture suggests sepsis but the laboratory evaluation for sepsis is negative. Unfortunately, bacterial sepsis is often a complicating factor in critically ill children with an IEM. For example, Escherichia coli infection (including pyelonephritis, bacteremia, or meningitis) is frequently detected at presentation in infants with galactosemia. The astute clinician remains ever vigilant for the signs and symptoms that may suggest an inherited metabolic disorder.



• BOX 81.1

Signs and Symptoms of Inborn Errors of Metabolism





  • Acute illness after period of normal behavior and feeding (hours to weeks)



  • Recurrent decompensation with fasting, intercurrent illness, or specific food ingestion



  • Unusual body odor



  • Persistent or recurrent vomiting



  • Failure to thrive



  • Apnea or tachypnea



  • Jaundice



  • Hepatomegaly or liver dysfunction



  • Lethargy or coma



  • Sepsis



  • Unexplained hemorrhage or strokes



  • Developmental delay with unknown etiology



  • Developmental regression



  • Seizures, especially if seizures are intractable



  • Hypotonia



  • Chronic movement disorder (ataxia, dystonia, choreoathetosis)



  • Family history of unexplained death or current illness in siblings



  • Parental consanguinity




• BOX 81.2

Screening Metabolic Laboratory Studies for Children With Suspected Inborn Errors of Metabolism





  • Plasma amino acid analysis: minimum 2 mL blood in a heparin tube



  • Plasma acylcarnitine profile: minimum 2 mL blood in a heparin tube



  • Urine organic acid analysis



  • Urine screening—qualitative mucopolysaccharide screening: minimum 10 mL urine




Recurrent episodes of vomiting and dehydration in response to fasting or intercurrent illness are an important clue to an IEM in older infants and children. Feeding difficulties and failure to thrive are common chronic complications. Children with unexplained hypotonia, developmental delay, or movement disorder should be evaluated for a possible IEM. Inherited neurodegenerative disorders, such as the lysosomal storage diseases, stereotypically cause developmental regression—specifically, loss of previously attained developmental milestones. Several IEMs are associated with major physical anomalies ( Table 81.1 ). When present, these anomalies are exceedingly valuable in suggesting a specific diagnosis and directing the diagnostic evaluation. More commonly, the child with an IEM is morphologically normal, and the presenting symptoms are nonspecific. The clinician must then rely on screening laboratory tests to evaluate the potential for IEMs.



TABLE 81.1

Physical Anomalies Associated With Inborn Errors of Metabolism

































Dysmorphic facial features


  • Peroxisomal disorders



  • Glutaric aciduria type II



  • Smith-Lemli-Opitz syndrome



  • Menkes syndrome



  • Lysosomal storage disorders

Structural brain anomalies


  • Glutaric aciduria type II (cortical cysts)



  • Pyruvate dehydrogenase deficiency (cortical cysts, agenesis of the corpus callosum)



  • Glycosylation disorders (cerebellar agenesis)

Macrocephaly


  • Glutaric aciduria type I (with subdural effusions)



  • Canavan disease



  • Alexander disease

Cataracts


  • Galactosemia



  • Peroxisomal disorders



  • Mitochondrial disorders



  • Lowe syndrome

Lens dislocation


  • Homocystinuria



  • Sulfite oxidase deficiency



  • Molybdenum cofactor deficiency

Pigmentary retinopathy


  • Peroxisomal disorders



  • Lysosomal storage disorders (cherry red spots)



  • Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency



  • Mitochondrial disorders

Renal cysts


  • Glutaric aciduria type II



  • Peroxisomal disorders



  • Mitochondrial disorders

Ambiguous genitalia


  • Congenital adrenal hyperplasia



  • Smith-Lemli-Opitz syndrome

Skeletal abnormalities


  • Menkes disease



  • Homocystinuria



  • Peroxisomal disorders



  • Lysosomal storage diseases

Hair or skin abnormalities


  • Menkes disease



  • Holocarboxylase synthetase deficiency



  • Biotinidase deficiency



  • Argininosuccinic aciduria



  • Phenylketonuria



Laboratory evaluation of suspected inborn errors of metabolism


Abnormal results of routine laboratory studies may provide clues to the presence and type of IEM ( eTable 81.2 ). Highly informative but sometimes subtle laboratory abnormalities are often overlooked, especially in a busy intensive care unit or hospital ward. For instance, a clinically relevant newborn screening result may have been sent to the primary care provider or birth hospital but not efficiently communicated to the intensive care unit in a different hospital, where the now critically ill infant has been admitted. It is imperative to verify the infant’s screening results with the primary care provider or newborn screening laboratory. Calculation of the anion gap, another example of a routine and highly informative result, is key to the differential diagnosis of metabolic acidosis (see also Chapter 72 ). Absence of urine ketones in hypoglycemic children older than 2 weeks strongly suggests impaired ketogenesis as a consequence of either hyperinsulinism or fatty acid oxidation disorder. On the other hand, fatty acid oxidation and ketogenesis are incompletely developed in neonates. The presence of ketones in urine of infants younger than 2 weeks is unusual, even during fasting or hypoglycemia, and suggests the presence of an unusual ketoacid, such as those excreted in maple syrup disease or the organic acidemias. Ketoacids, organic acids, and sugars such as galactose or fructose increase urine specific gravity. Urine specific gravity greater than 1.020 in any neonate or in well-hydrated older children suggests the unexpected presence of an osmotically active substance. Routine urinalysis at many hospitals may not include use of the Clinitest to detect reducing substances. Urine Chemstrips use a colorimetric glucose oxidase-based method to specifically detect glucose. This test does not react with any other sugar (galactose or fructose). However, some bedside blood glucose monitoring systems do react with galactose or fructose; inappropriately elevated capillary blood “glucose” accompanied by a normal venous glucose as measured by chemistry analyzer suggests the presence of a sugar other than glucose in the blood. A comatose infant with a blood urea nitrogen level below the limits of detection may have an inherited defect in the urea cycle. Blood ammonia measurement is crucial to confirming that suspicion. Failure to check the blood ammonia level has caused missed diagnoses, failure to appropriately treat hyperammonemia, and morbidity and mortality in comatose infants with urea cycle disorders or organic acidemias. Finally, bacterial sepsis and meningitis are more common causes of severe lethargy and coma in infants than are IEMs, but bacterial infection may also be a complicating feature in severely ill infants with an IEM. Infants with galactosemia, for example, are particularly prone to pyelonephritis, bacteremia, sepsis, or meningitis, often with E. coli , as noted previously. Antibiotic therapy without diagnosis and specific treatment of the underlying disorder may be useful in the short term but does not mitigate long-term IEM-specific effects.



eTABLE 81.2

Initial Laboratory Evaluation of Suspected Inborn Errors of Metabolism
















































Laboratory Test Abnormality Disorder
Complete blood count


  • Neutropenia



  • Macrocytic anemia



  • Pancytopenia




  • Organic acidemias



  • Glycogenosis type 1b



  • Cobalamin processing defects



  • Congenital lactic acidoses

Serum electrolytes Metabolic acidosis


  • Glycogenoses



  • Organic acidemias



  • FAO disorders



  • MSUD



  • Congenital lactic acidoses

Blood gas


  • Metabolic acidosis



  • Metabolic alkalosis




  • Same as above



  • Urea cycle disorders

BUN Low or undetectable BUN (with hyperammonemia) Urea cycle disorders
Transaminases (ALT, AST) Liver dysfunction (check CPK to exclude elevated ALT/AST from primary muscle disease)


  • Galactosemia



  • Fructosemia



  • Tyrosinemia



  • α 1 -Antitrypsin deficiency



  • FAO disorders



  • Organic acidemias




    • Glycogenoses



    • Congenital lactic acidosis




  • Mitochondrial disorders



  • Congenital disorders of glycosylation

Total and direct bilirubin Hyperbilirubinemia


  • Galactosemia



  • Fructosemia



  • Tyrosinemia



  • α 1 -Antitrypsin deficiency



  • Congenital lactic acidosis



  • Citrin deficiency



  • Bile acid synthesis defects

Serum uric acid Hyperuricemia


  • Glycogenoses



  • Purine disorders

Blood ammonia Hyperammonemia


  • Urea cycle disorders



  • FAO disorders



  • Organic acidemias

Blood lactate Lactic acidemia


  • Congenital lactic acidoses



  • Glycogenoses



  • Fructosemia



  • Gluconeogenesis disorders




  • Urinalysis




    • Odor



    • Color



    • pH



    • Specific gravity



    • Ketones



    • Reducing substances





  • Unusual odor



  • Inappropriately high specific gravity due to metabolites



  • Ketosis



  • Positive reducing substances




  • PKU, MSUD, organic acidemias



  • Organic acidemias, galactosemia, fructosemia



  • MSUD, organic acidemias



  • Galactosemia, fructosemia


ALT, Alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; CK, creatine phosphokinase; FAO, fatty acid oxidation; MSUD, maple syrup urine disease; PKU, phenylketonuria.


Suspicion of an IEM based on clinical and routine laboratory findings should initiate specialized biochemical testing ( Table 81.3 ). In the case of severely ill infants or when the clinical suspicion of an IEM is very high, consultation with a biochemical geneticist, even if only by phone, is strongly advised to help direct the laboratory investigation and initial therapy. When the clinical presentation is nonspecific—that is, catastrophic illness in a previously well child without signs of any particular IEM—the “shotgun” diagnostic evaluation should minimally include plasma amino acid analysis, urine organic acid analysis by gas chromatography–mass spectrometry, and a plasma acylcarnitine profile. Although diagnostic laboratories in the United States must meet Clinical Laboratory Improvement Amendment requirements and often are accredited by the College of American Pathologists, the testing methodologies used, the quality of diagnostic testing for IEMs, and—more problematically—the availability of laboratory-associated consultants with experience in the diagnosis and treatment of IEMs vary widely among laboratories. Although the ability of clinicians to direct clinical specimens toward specific diagnostic laboratories may be inhibited by contractual arrangements between the hospital and large referral laboratories, the critically ill patient is best served by diagnostic evaluation carried out in a timely manner by an experienced biochemical genetics laboratory, with laboratory staff available by phone for expert consultation on interpretation of test results.



TABLE 81.3

Biochemical Genetic Laboratory Studies




















































































Specimen Test Disorder
Blood Plasma amino acid analysis Aminoacidopathies
Plasma carnitine Organic acidemias
FAO disorders
Plasma acylcarnitine profile Organic acidemias
FAO disorders
Carbohydrate deficient transferrin testing Congenital disorders of glycosylation
Urine Metabolic screen



  • Ketones

Organic acidemias



  • Reducing substances

Galactosemia, fructosemia



  • Mucopolysaccharide screen

Mucopolysaccharidoses
Organic acid analysis Organic acidemias
FAO disorders
Acylglycine profile Organic acidemias
FAO disorders
Quantitative mucopolysaccharide measurement and electrophoresis Mucopolysaccharidoses
Qualitative sulfites (Sulfitest) or quantitative sulfocysteine Sulfite oxidase deficiency
Molybdenum cofactor deficiency
Quantitative succinylacetone Tyrosinemia type 1
Quantitative purines Purine synthesis disorders
Urine α-aminoadipic acid semialdehyde Pyridoxine-responsive seizures

FAO, Fatty acid oxidation.


The specific clinical presentation or specific screening laboratory findings may direct the intensivist or biochemical geneticist to order other more specialized metabolic tests (see Table 81.4 ). These analyses may provide diagnostic confirmation for specific disorders and supportive evidence alone for others. For several IEMs, confirmation of diagnosis may require enzyme activity analysis in tissue (red blood cells, lymphocytes, cultured skin fibroblasts, liver, or skeletal muscle depending on the specific disorder in question) or molecular DNA testing for a specific gene defect. In general, these tertiary tests—which are often difficult, labor intensive, and expensive—should be ordered following consultation with a biochemical geneticist. In some instances, confirmatory diagnostic biochemical or molecular tests are available only through specialized research laboratories. Molecular DNA analysis has become a prevalent and powerful weapon in the arsenal of available diagnostic tools. Whole exome sequencing—that is, DNA sequencing of all regions of the genome known to code functional proteins, using high-throughput DNA sequencing platforms—has proven utility in the diagnosis of complex phenotypes. Biochemical testing, which is more rapidly accomplished than DNA sequencing in most clinical laboratories and which is necessary to confirm the pathogenicity of sequence variants detected by molecular DNA analysis, remains vital to the process of disease diagnosis and treatment management.



TABLE 81.4

Emergency Treatment of Suspected Inborn Error of Metabolism


































Goal Action
Suppress toxic metabolite production Discontinue oral feedings
Correct fluid imbalance and electrolyte abnormalities Appropriate intravenous fluid management
Correct hypoglycemia IV dextrose-containing fluid infusion
Correct metabolic acidosis


  • IV hydration if pH >7.2



  • Add IV bicarbonate if pH <7.2



  • Sodium bicarbonate (1 mEq/mL solution), 1 mEq/kg IV push at <1 mEq/min



  • May repeat × 3 until pH >7.2; maximum dose 7 mEq/kg/24 h

Correct hyperammonemia


  • Suppress protein catabolism



  • Hemodialysis

Treat infection Appropriate infectious disease laboratory evaluation and antibiotic therapy
Suppress protein and lipid catabolism


  • Infuse D 10 ½NS at 1.5–2 × maintenance rate



  • Add insulin infusion if hyperglycemic



  • If severe, unrelenting acidosis, consider growth hormone or testosterone therapy to promote anabolism.

Empiric cofactor administration


  • L -carnitine, 25–50 mg/kg q6h IV if organic acidemia suspected or cardiomyopathy present.



  • B vitamin complex, 100 mg each vitamin every day



  • Vitamin B 12 , 1 mg IM × 1 if macrocytic anemia

Maintain nutritional status (if without enteral feeds × 2 days and without diagnosis of a specific IEM)


  • Enteral feeds or parenteral hyperalimentation to include the following:




    • Protein, 0.5 g/kg/day only



    • Lipid, 20% of total energy intake



    • Carbohydrate to provide at least the minimum necessary energy intake



IEM, Inborn error of metabolism; IM, intramuscularly IV, intravenous.


Postmortem evaluation of a child with suspected inborn errors of metabolism


Some IEMs, particularly those exacerbated by fasting, may present as sudden infant death. For many IEMs, acute metabolic compensation may be rapid and lethal despite intensive medical intervention. The time after clinical presentation but prior to death may be insufficient to execute an adequate metabolic evaluation. Disease diagnosis is still possible postmortem and is important for fully understanding the cause of death and determining recurrence risk in the family. A protocol for postmortem evaluation of an infant or child with suspected IEM is provided in eBox 81.3 . Many of the biochemical genetic analyses recommended for acutely ill children are still valid on postmortem specimens. Valuable information may be learned from amino acid, carnitine, and acylcarnitine analyses in blood and from metabolic screening and organic acid analysis in urine ( eBox 81.4 ). However, collection of blood and urine may not be possible postmortem, especially if the autopsy is performed many hours after death. In these instances, metabolic testing may be obtained on alternative specimens, such as vitreous humor or bile. In the event that screening biochemical studies suggest a specific diagnosis, disease confirmation by enzyme analysis in tissue is highly desirable. Many enzymes can be assayed in cultured fibroblasts; viable fibroblasts may be cultured from skin or Achilles tendon samples obtained as late as 24 hours after death. Biopsies of other organs may be necessary for analysis of certain other enzymes. Muscle, liver, and kidney specimens may be obtained postmortem for enzymatic analysis, but most enzymatic activities in solid organs deteriorate rapidly following death. Collection of specimens as soon as possible after death is critical for valid enzyme analyses.



• eBOX 81.3

Modified from Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr . 2001;138(Suppl 1):S21–S29.

Postmortem Biochemical Genetic Evaluation


To be performed on any deceased infant <1 year old for which the cause of death is not apparent or any child with suspected IEM. Analyses are most reliable if obtained within 6 hours after death.



  • 1.

    Contact newborn screening laboratory for results of neonatal screening.


  • 2.

    Obtain a 3-mm punch biopsy of skin or Achilles tendon for fibroblast culture.



    • A.

      Prepare skin with chlorhexidine (Hibiclens) or alcohol. Do not use Betadine because it may inhibit fibroblast growth.


    • B.

      Use sterile technique.


    • C.

      Store biopsy specimen in sterile RPMI culture media (if available) at room temperature. May be stored in sterile nonbacteriostatic saline for up to 24 hours prior to culture if culture media are not readily available.


    • D.

      Send to cytogenetics or biochemical genetics laboratory for culture, possible enzyme analyses, and frozen storage.



  • 3.

    Collect blood via cardiac puncture (<5 mL per tube).



    • A.

      One red top tube at room temperature. Collect and store serum at −70°C.



      • I.

        Comprehensive metabolic panel (potassium, lipids, uric acid may not be accurate postmortem)


      • II.

        If hypoglycemic, insulin, growth hormone, and cortisol levels



    • B.

      One green top (sodium heparin) at room temperature. Collect and store plasma at −70°C.



      • I.

        Plasma amino acid analysis


      • II.

        Plasma carnitine levels


      • III.

        Plasma acylcarnitine profile



    • C.

      One green top (sodium heparin) at room temperature for cytogenetic (karyotype) analysis.


    • D.

      If storage disorder suspected, one green top (sodium heparin) at 4°C (wet ice) for leukocyte isolation and diagnostic enzyme analyses.


    • E.

      One lavender top (EDTA) tube at room temperature for complete blood count.


    • F.

      One yellow top (ACD) tube for DNA isolation and possible mutation analysis.


    • G.

      If infant <1 year old, spot whole blood onto newborn screening filter paper card for repeat screen.


    • H.

      Blood lactate and ammonia may not be accurate postmortem.



  • 4.

    Collect urine (10–20 mL) by suprapubic tap or by swabbing the bladder interior with cotton swab.



    • A.

      Urinalysis


    • B.

      Urine-reducing substances


    • C.

      Urine organic acid analysis


    • D.

      If storage disorder suspected, quantitative urine mucopolysaccharide and oligosaccharide analysis



  • 5.

    If urine is unobtainable, organic acid analysis may be performed on vitreous humor collected by needle aspiration from an eye. Freeze vitreous humor at −70°C.


  • 6.

    If blood is unobtainable, collect bile (2–3 mL) via puncture of the gallbladder for acylcarnitine profile. Store at −20°C.


  • 7.

    Collect several biopsies (2 g each) from skeletal muscle, cardiac muscle, kidney, and liver.



    • A.

      For routine histology, biopsies should be submitted fresh to the pathology laboratory.


    • B.

      For enzyme analyses, biopsies should be wrapped in aluminum foil, placed in a labeled small specimen container, and immediately frozen in liquid nitrogen. Store at −70°C.




ACD, Acid citrate dextrose; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic acid; RPMI, *Roswell Park Memorial Institute.

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