APPROACH TO INBORN METABOLIC ERRORS
Dr. Seema Kapoor*
Associate Professor of Pediatrics, Maulana Azad Medical College Email: seemam@vsnl.com*
Why pursue metabolic diagnosis?
Inborn errors of metabolism are important diseases because they are severely debilitating. Often they can be treated effectively, if diagnosed early. Quick diagnosis may be difficult to make because presenting symptoms are protean, non-specific and may not be obvious. Diagnostic tests for metabolic disorders are sent away to specialty laboratories and results do not return promptly. Clinicians sometimes dismiss this category of diseases as being too rare to warrant committing aspects of these diseases to memory, though of mortality and morbidity. Diagnosis does not require extensive knowledge of biochemical pathways or of individual metabolic diseases. An understanding of the clinical manifestations of IEM's provides the basis for knowing when to consider the diagnosis. What is actually important is to "Keep them in mind".

In the United States, collectively they are estimated to affect 1 in 1400 to 1 in 5000 infants. In India out of the 24 million births annually, it is estimated that they would constitute 20,800 births.(1,2) As an important cause of developmental delay, they constitute approximately(5) 75% cases as per a tertiary hospital-based study(3).

When to suspect an IEM?
In common pediatric practice, one should identify the genetic red flags which may help an individual think 'genetically'. Although individually they may be rare, collectively every 1 in 1000 newborns has an inborn metabolic defect(3). A red flag should prompt testing, intervention, counseling, follow-up and referral by a metabolic specialist. Whehlan et al 4 have summarized these into an easily remembered mnemonic;

A red flag should prompt testing, intervention, counseling, follow-up and referral by a metabolic specialist.

Family GENES
F- Family history of consanguineous mating, multiple affected siblings or individuals in multiple generations and history of neonatal deaths should alert us to the possibility of IEM.

G- Groups of congenital anomalies or obvious dysmorphism: The disorders of energy metabolism that are active in fetal life may present with dysmorphism at birth. Smith-Lemli-Opitz syndrome is now known to be an inborn error of cholesterol synthesis. The other dysmorphic IEM's are enumerated in Table 2.

E- Extreme or exceptional presentation of common conditions. Examples of these are the situation where an infant presents with unusually severe reaction to infection or metabolic stress. For example a few infants with Maple syrup urine disease (MSUD) are asymptomatic at birth but a mild viral URI or gastroenteritis can precipitate severe dehydration and metabolic acidosis. Similarly severe intractable diarrhea in infancy should alert the pediatrician to the possibility of congenital chloride diarrhea or lactase, sucrase-isomaltase deficiency.

N- Neurologic symptoms. Infants with IEMs can present to the pediatrician with unexplained encephalopathy. Many neonates with less severe enzyme deficiencies present in infancy with vomiting, failure to thrive and encephalopathy. The presentation can also be fluctuating and episodic with mild neurological manifestations such as behavioral disturbances, headaches and coma with convulsions.

E- Extreme or unusual pathology. An important example is an infant with unusual smell of body or urine. The various odors are MSUD-Maple syrup (burnt sugar) ; Isovaleric academia & Glutaric Aciduria Type II - Sweaty feet; Phenylketonuria-mushy; or musty -Methyl crotonyl aciduria- tom car urine; Trimethylaminuria-rotting fish Tyrosinemia- Rancid or fishy odor.

S- Surprising lab values: Finding a low blood urea in a neonate with respiratory alkalosis in a symptomatic neonate may offer a clue to the diagnosis of urea cycle defect and may prompt the clinician to get ammonia estimation. Apart from these clues, it is important to remember that the first characteristic in suspecting these diseases is one of exclusion. The more common etiologies like sepsis and HIE, are quite common and therefore it is prudent to pursue these diagnosis. One important feature of IEM's is that both symptoms and signs may worsen after stress which may occur naturally after "infections" or produced by "milk feeding". Therefore one may suspect IEM in a child who may have a mild but persistent acidosis substantially after an acute infection is treated and the patient's hemodynamic status has normalized using the same corollary.

One important feature of IEM's is that both symptoms and signs may worsen after stress which may occur naturally after "infections" or produced by "milk feeding."

What are the clinical manifestations of a child with IEM?
The types of clinical presentation can be grouped in the following categories-

Neurologic manifestations - Neurologic manifestations may be in the form of unexplained encephalopathy, seizures, acute ataxia or an acute psychotic episode.

Acute metabolic encephalopathy (Small Molecule Disease) -
Acute encephalopathy due to a metabolic disorder usually results from accumulation in the brain, to a critical level, of a small diffusible metabolite or precursor (e.g. ammonia) or from deficiency of an essential product (adenosine triphosphate) or form a defective transport process (e.g. carnitine). These disorders are therefore also called as small molecule diseases. Most of these metabolites cross the placenta and are cleared by the mother and affected infants are normal at birth. Such infants are discharged from the postnatal wards to return later with poor feeding, vomiting, lethargy, irritability and seizures which is the limited repertoire of a neonatal presentation, cerebral edema frequently sets in and follows a relentless course. The interval period may be hours to days to weeks. It is important to carry out first line investigations and find out if metabolic acidosis is present with accompanying tachypnea. Pyridoxine dependency, urea cycle enzyme defects and maple syrup urine disease may present without accompanying acidosis. Refractory seizures especially in utero seizures may be seen in nonketotic hyperglycinemia (NKH). An important key to NKH may be the presence of motor automatisms. Molybdenum cofactor deficiency may also present with refractory seizures and key to the diagnosis is obtained by a low plasma urate. Certain disorders may be difficult to diagnosis due to special CSF sample required for neurotransmitter levels. Folinic acid responsive seizures and Pyridoxal phosphate deficiency may also be difficult to diagnose. Acute encephalopathy in the older child is frequently due to fatty acid oxidation defects, urea cycle defects specially OTC deficiency which may be unmasked, mitochondrial encephalopathy, creatine deficiency syndrome and late onset forms of MMA and thiamine responsive intermittent MSUD. A pneumonic to be remembered
in acute encephalopathy is GELAK which spells for glucose, electrolytes, lactate, ammonium and ketones.

A pneumonic to be remembered in acute encephalopathy is GELAK which spells for glucose, electrolytes, lactate, ammonium and ketones.

Hypoglycemia may present as acute encephalopathy. The frequent causes are prematurity, intrauterine growth retardation, maternal diabetes mellitus and sepsis. It is generally not difficult to control and the underlying cause is usually obvious. Nevertheless otherwise unexplained severe and/or persistent hypoglycemia should be investigated for an underlying metabolic cause. It is important to decipher where the hypoglycemia is ketotic or hypoketotic. Hypoketotic hypoglycemia is due to over utilization of glucose whereas ketotic is due to underproduction. Over utilization can be due to hyperinsulinism or fatty acid oxidation defects (FAOD). Hyperinsulinism should be suspected with recurrent, severe hypoglycemia occurring after a short fasting period, or if high concentrations are required (>12 mg/kg/min). A clue to the presence of hyperinsulinism is a Free Fatty Acid/3 Hydroxybutyrate ratio of user than three, whereas in fatty acid oxidation defects it is more than three. In the newborn FAOD may present with acute encephalopathy between 24 to 72 hours of age. The most common defect in fatty acid oxidation with an incidence of 1/10000 of 20,000 births is MACD deficiency. Up to one quarter of cases, first present in the newborn period with fasting hypoglycemia, a small but important proportion of sudden infant deaths can also result from defects in fatty acid oxidation and this group of disorders must be excluded if there is history of SIDS or near miss SIDS. When hypocalcaemia is associated with metabolic acidosis, it suggests a defect in gluconeogenesis or an organic academia (GSD type I or fructose 6 biphosphatase deficiency). When ketosis is associated with hypoglycemia MSUD should be considered. The combination of cholestatic jaundice and hypoglycemia should prompt one to think of pituitary insufficiency or FAOD.

It is important to decipher where the hypoglycemia is ketotic or hypoketotic?

Metabolic encephalopathy may be associated with elevated blood ammonia and this is a clinical emergency as ammonia is a potent neurotoxin. Hyperammonemia can be primary due to a urea cycle enzyme defect (UCED) with usually presents in the first week of life. The commonest disorder is an X-linked OTC deficiency. Secondary hyperammonemia may be observed due to suppression of intermediary metabolism in organic acidemias and FAOD. A clue to the presence of hyperammonemia is mild respiratory alkalosis due to stimulation of the respiratory centre by ammonium. It is important to differentiate this from transient hyperammonemia in the newborn which usually occurs in premature or LBW infants often in the presence of pulmonary disease. The onset of hyperammonemia is within 24 hrs of birth and elevation up to 2500 mol/l can be seen. Typically the plasma glutamine: ammonium ratio is less than 1.6 whereas for urea cycle defects it is more than 1.6. An approach to hyperammonemia is depicted in the algorithm.

A clue to the presence of hyperammonemia is mild respiratory alkalosis due to stimulation of the respiratory centre by ammonium.

Acute Encephalopathy may be accompanied with disorder of acid-base status. A persistent metabolic acidosis with normal tissue perfusion may suggest an underlying organic acidosis, a defect of pyruvate metabolism or of the mitochondrial respiratory chain. Congenital Lactic acidosis also constitute an overwhelmingly large group.

Lactate estimation is fraught with pre-analytical errors and a persistently high lactate > 2.0 mmol/L is considered significant. A rise in CSF lactate is pathognomonic of a metabolic defect, if meningitis is excluded. In some cases, only CSF lactate may be elevated. A normal blood and CSF lactate in an acutely sick newborn effectively excludes a mitochondrial respiratory chain disorder. Lactic acidosis is frequent seen secondary to circulatory failure severe systemic disease and is also seen with pyruvate metabolism defects and Electron Transport Chain defects. Secondary Lactic acidosis is commonly seen with defects in gluconeogenesis. Lactic acidosis occurring as a sequel of hypoxemia gets corrected easily and exists with a normal Lactate: Pyruvate ratio.

A rise in CSF lactate is pathognomonic of a metabolic defect, if meningitis is excluded.
Lactate: Pyruvate ratio. Defects in the enzymes that link glycolysis with the citric acid cycle, such as pyruvate dehydrogenase (PDH) or pyruvate carboxylase (PC) on enzymopathies are usually associated with severe impairment of neurologic function. A clue to the presence is an elevated citrulline level in cases with PC deficiency.

Lactic acidosis occurring as a sequel of hypoxemia gets corrected easily and exists with a normal Lactate: Pyruvate ratio.

Organic Acidosis result from an a defect in an enzyme that normally degrades an organic acid and result in accumulation of that anion, often producing acidosis. The major difference between organic acidemias and aminoacidopathies is the severe metabolic acidosis. In addition to encephalopathy, these patients have moderate to severe hyperammonemia as a result of secondary inhibition of urea cycle by accumulating organic acids and hypoglycemia. Bone marrow suppression with pancytopenia is commonly observed and hence the association with sepsis. These following pointers may help us in diagnosis:
  1. Metabolic acidosis may imply the patient has a small molecule disease.
  2. Hypoglycemia without ketones may imply that patient has a disorder of fatty acid oxidation.
  3. Organomegaly with coarse features may imply that patient has a storage disorder.
  4. Organomegaly without coarse features may imply that patient has a storage or a non-storage disease.
  5. Hyperammonemia can also accompany organic acidemias and mitochondrial disorders due to suppression of the urea cycle by toxic metabolites along with primary urea cycle defects.
  6. Pancytopenias commonly accompany organic acidemias and can predispose to sepsis and hence may defy the principle of parsimony or the KISS principle "keep it simple, stupid" suggesting that both can co-exist and frequently do. However these rules of thumb are only starting possibilities. Therefore small molecule diseases may cause hepatomegaly and large molecule disease can cause acidosis.

Chronic Encephalopathy or Episodic illness

Chronic hyperammonemia in an infant may present with cyclical vomiting, faddy eating (high protein intolerance), behavioural changes and neurologic deficits (e.g., spastic diplegia as in arginase deficiency). There should be a high threshold for suspicion of hyperammonemia in patients whose neurologic status deteriorates for no apparent cause. One of the common presentations is the one with "overwhelming metabolic coma" which is the combination of cerebral and hepatic failure in the presence of lactic academia with or without hyperammonemia. This syndrome complex is often called Reye's like illness (Fulminant hepatoencephalopathy). The disease is often biphasic, with the first phase consisting of a trivial viral disorder from which the patient seems to be recover uneventfully. The second phase that of encephalopathy, is almost always heralded by persistent, unrelenting vomiting lasting for several hours to 1 day. Progressive disturbance in the level of consciousness soon follows, reaching varying degrees of severity in a rostrocaudal fashion. An early stage of lethargy and confusion in some patients progresses stereotypically to delirium, dystonic (decorticate/decerebrate) coma, and finally herniation of the brain stem. In the 1980s, a number of diseases were discovered that could mimic RS clinically (vomiting and encephalopathy), biochemically (abnormal liver enzymes and elevated blood ammonia), and pathologically (microvesicular steatosis of the liver). The list of diseases that could mimic RS became quite extensive and has been reported in the setting of several small molecule diseases, most of which involve impairment of mitochondrial function. A modified score can help decipher the probable etiology of the Reyes like illness and is depicted in Figure 2. It is noteworthy that salicylic acid, the use of which was associated with Reye's epidemiologic analysis of the syndrome, can uncouple oxidative phosphorylation. The most important of these mimickers of RS are the metabolic disorders, especially the MCADs, long-chain acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase deficiencies

There should be high threshold for suspicion of diplegia as in arginase deficiency. There should be a high threshold for suspicion of hyperammonemia in patients whose neurologic status deteriorates for no apparent cause.

Modified Reye's Syndrome Score:

Findings

Points

Clearly defined prodrome

Yes = 2, No = 0, Not recorded = 1

Vomiting

Moderate-severe = 2, Minimal = 1, No = 0

Serum ALT/AST

Not recorded = 1, >3 x normal = 3, <3 x normal = 2

Plasma ammonia

Not raised = 2, Not measured >> 1, >3 x normal = 3

Cerebrospinal fluid S3 x normal = 2, Not raised = 0, Not measured = 1
WBC, <8 x 10*/L, WBC, >8 x 10 9, Not examined, bloody tap. or not recorded = 1

Hepatic pathology

Macroscopic fatty, no histology = 1, Panlobular microvesicular far = 3, Typical or suggestive of RS = 2, No histology = 0

Investigations of alternate diagnosis

Done = 2, Not done = 0

One of more atypical features (family history, recurrence, unusual presentation such as sudden death)

If present = 2



Score: 14-17 pts = portable RS; 11-13 pts = possible RS; 11-13 pts = possible RS; 9-10 pts = unlikely RS; 0-8 pts = excluded RS. ALT, alanine aminotransferase; AST, aspartate aminotransferase; WBC, white blood cells.

Developmental Delay:

This is the most important cause of referral to a metabolic specialist in infancy. The infant may present to you with extraneurologic signs when it becomes easy to identify the cause. Presence of alopecia, skin rash and hypotonia may suggest Biotinidase deficiency, whereas presence of inverted nipples, lipodystrophy and peau-de-orange skin may suggest carbohydrate deficient glycoprotein syndromes.

Developmental delay may present with specific neurological signs such as dyskinesias, dystonia, parkinsonism and choreoathetosis. Dystonia can involve all muscle groups such as tongue, facio-oropharyngeal and visceral musculature. Parkinsonism in an infant results in hypokinesis, drooling, swallowing difficulty, sweating, pinpoint pupils, oculogyric spasms and blank facies with relative preservation of smile. These extrapyramidal signs may suggest the possibility of disorders of biopterin synthesis, 4-hydroxybutraryic aciduria and early onset Pelizaeus-Merzbacher syndrome.

Few inborn metabolic errors may present with insidious onset developmental arrest, poor feeding, hypotonia, some degree of ataxia and frequent autistic features. For example, classic untreated Phenylketonuria may present at 3-12 months of age with hypsarrhythmia and autistic features, while 3-hydroxybutaric aciduria and mevalonic aciduria along with adenylosuccinase deficiency may present with frequent autistic features. So if autism co-exists with failure to thrive and hypotonia, there is a case to investigate the infant for IEM's. Most of the large molecule disorders present as neurodegenerative disorders involving white and grey matter.

So if Autism co-exists with failure to thrive and hypotonia, there is a case to investigate the infant for IEM


Large Molecule Disease

The hallmark of large molecule disease is the storage of large molecules in tissue or body fluids. These tend to cause dementia, epilepsy, movement disorders, gradual blindness and spasticity, in the case of leucodystrophies. What constitutes large molecules is arbitrary; however in general, the dysfunctional molecules have a structural, membrane, receptor or other function in cells but are not directly involved in intermediary energy metabolism and removal of acid or nitrogen. Because these disorders produce their symptoms in tandem with gradual accumulation of the stored material, these conditions present at varying intervals after birth.

These can be classified as lysosomal, peroxisomal or golgi apparatus disorders. The lysosomal storage diseases are a group of which over forty disorders are currently known that result from defects in lysosomal function. Lysosomes are cytoplasmic organelles that contain enzymes (specifically, acid hydrolases) that break macromolecules down to peptides, amino acids, monosaccharides, nucleic acids and fatty acids. The lysosomal storage diseases are classified by the nature of the primary stored material involved, and can be broadly broken into the following: lipid storage disorders (including Gaucher's and Niemann-Pick diseases); gangliosidosis (including Tay-Sachs disease); leukodystrophies; mucopolysaccharidoses; glycoprotein storage disorders and mucolipidoses.


Peroxisomal disorders:
are characterized by dysfunction of the peroxisome. They bridge the category of small molecule disease and large molecule disease. They cause fluid accumulation of unmetabolized long chain fatty acids in the plasma, but these are not stored in fixed intracellular concentrations as large molecule disease. Therefore the most efficient screening test is to measure long and very long chain fatty acids in the plasma. These diseases tend to present with signs of central with or without peripheral myelin dysfunction. In the neonatal presentations liver, heart and skeletal systems can be involved. Examples include Zellweger, neonatal Refsum and Neonatal ALD.

Golgi apparatus disorders: Also represented currently by the congenital disorders of glycosylation. These are characterized by defective glycosylation of proteins in the golgi apparatus. The proteins are normal but they are glycosylated insufficiently so that their function, transport and survival is impaired. A diagnosis can therefore be obtained by measuring the "hypoglycosylated forms of serum transferrin". Examples include Phosphomannomutase deficiency.

Non-neurological manifestations


Cardiac Failure or cardiomyopathy
Cardiomyopathies with presentation in infancy frequently have a genetic basis. Both Hypertrophic and dilated Cardiomyopathies are associated with inborn errors of metabolism. The presentation in the infant can be in the form of either features of failure or heart block and rhythm disturbances. Figure 3 describes the approach in a child with cardiac manifestations. Long chain fatty oxidation disorder may present with cardiomyopathy, cardiac arrhythmias and cardiac arrest. Cardiomyopathy may be the presenting feature of mitochondrial, respiratory chain, Barth syndromes, Carbohydrate deficiency syndromes, and glycogen storage disease type IV (GSD). It may therefore be necessary to check for lactate, 3-methylglutaconic levels and ammonia levels in children with cardiomyopathy of unidentified origin, if the clinical picture suggests. These glutaconic acids or dicarboxylic acids are a result of ö oxidation of these fatty acids.

Figure 3. Algorithm to a child with cardiac manifestations


CARDIAC MANIFESTATION
Jaundice and liver failure: Hepatocellular dysfunction is also seen in sepsis which accompanies IEM's and the involvement of non-hepatic tissues and organs is often significant. The secondary metabolic consequences of hepatocellular failure are often difficult to distinguish from primary metabolic disturbances causing liver disease. Causes of failure early in life are galactosemia, Tyrosinemia Type I, FAOD, a 1 antitrypsin deficiency, GSD IV, peroxisomal disorder, mtDNA depletion syndrome, CDG syndromes and Niemann Pick C. Liver failure later in life may be due to GSD III, Gaucher's Type III, Niemann Pick type C, Wilson's disorder, Cholesterol Ester Storage Disease. The renal fanconi syndrome may accompany liver failure.

Dysmorphologic Presentation: Contrary to the clinical pearls which suggested that malformations imply chromosomal defects, the discovery of Smith-Lemli-Opitz syndrome lead to the theory of "Metabolic Dysplasia" whereby the presence in the fetus of a toxic metabolite or the absence of a useful metabolite can cause abnormality of organogenesis. The following table depicts syndromes associated with dysmorphic and other presentations.

Table: 1

Dysmorphism

Cataract

Severe
Hypotonia

Cardiac
Disease

Jaundice

Peroxisomal diseases

Lowe's
syndrome

Peroxisomal diseases

Disorders of
Fatty acid
Oxidation

Galactosemia

Lysosomal diseases

Zellweger syndrome

Non Ketotic
Hyper glycinemia

Pompe's
disease

Alfa-1-
Antitrypsin deficiency

Disorders of
cholesterol synthesis

Galactosemia

Congenital lactic acidosis

Respiratory chain
Disorders

Respiratory
chain disorders

Carbohydrate
Deficient glycoprotein syndromes (CDG)

CDG
syndromes

CDG
syndromes

CDG
syndromes

Neonatal
Haemo chromatosis

Congenital lactic acidosis

Cockayne syndrome

 

Congenital
Hyper insulinism

Tyrosinemia
Type I

Glutaric
Aciduria II

Hypo parathyroidism

 

 

Niemann Pick
Type

3-Hydroxyisobutryl Coenzyme
A deacylase deficiency

 

 

GSD Type IV and
Heart Specific Phosphorylase Kinase

Disorders of
fatty acid oxidation



Conditions in which IEM's are not thought of in Infancy:

Macrocytic or Nondegenerative anemia: Apart from inherited disorders of folate and cobalamin metabolism, other inherited disorders may present with macrocytic anemia. Clue to the presence of disorders of folate and B12 metabolism may be obtained from additional findings of homocysteinemia, homocysteinuria and low plasma methionine. Additional finding of methylmalonic aciduria points to inborn error of Vitamin B12 metabolism. Orotic aciduria is another important differential diagnosis with increased orotic acid excretion in urine due to deficiency of Uridine monophosphate synthetase deficiency. Pearson syndrome may present with refractory sideroblastic anemia, vacuolation of marrow precursors and chronic diarrhea.

Complex of Chronic diarrhea with failure to thrive, poor feeding and anorexia and hypotonia. This symptom complex is most commonly seen in our country with malnutrition. In the absence of a suggestive dietary history, this may be seen with pancytopenia in Schwachmann syndrome. Abetalipoproteinemia in early infancy may present with anorexia, failure to thrive and steatorrhea without retinal and neurologic manifestations which appear after 5 years of age. Lysinuric protein intolerance may present with neutropenia and recurrent attacks of hyperammonemia.

Interstitial Pneumonia: This is usually mistaken for a 'viral pneumonia' especially when a child presents with intercurrent illness. Pulmonary infiltrates are a constant finding in Farber Lipogranulomatosis and Neiman Pick Type A.

Renal Fanconi Syndrome: Apart from distal and Proximal RTA, Fanconi may be seen in a male neonate with Lowe's syndrome. A presentation like severe Vitamin D Dependent Rickets may be seen with renal tubulopathy in Tyrosinosis Type 1 and Respiratory chain disorders. One disease that presents in infancy is Bickel- Fanconi Syndrome which presents with hepatomegaly, doll-like facies, failure to thrive, tubulopathy and vitamin D unresponsive rickets in association with moderate hyperlactic acidemia.

Conclusions and Directions:
  1. The conception that malformations imply large chromosomal defects generated by virtue of the fact that large DNA disruption leads to affection of many enzymes and structural proteins is incorrect as confirmed in the case of Smith Lemli Opitz disease.
  2. It is generally advised that the blood spot for metabolic disease should be taken after the child has been fed as disorders like Phenylketonuria and branched chain aminoacidopathy (MSUD) exhibit increased excretion of their unmetabolized products after protein loading from the milk. But for disorders of fatty acid oxidation fasting is the best stressor, hence samples should be obtained both in the fasting and unfed state.
  3. It is often taught that a neurometabolic disease should not be suspected till a child has regression of milestones but the presentation can be one of delay, intermittent ataxia or symptoms after a triggering episode like GA type 1.
  4. The Occam principle or the KISS principle may not always hold true.
  5. Though individually rare these disorders are of significant incidence and though it is prudent to think of common things first, it is equally important to think "Metabolically".

References:
  1. Kumta NB. Inborn errors of metabolism (IEM) - An Indian perspective. Indian J Pediatr 2005;72(4):325-332.
  2. Verma IC. Burden of genetic diseases in India. Indian J Pediatr 2000;67(12):893-898.
  3. ICMR collaborating centres and central coordinating unit. Multicentric study on the genetic causes of mental retardation in India. Indian J Med Res (B) 1991;94:161-169.
  4. Whelan AJ, Ball S, Best L, Best RG, Echiverri SC, Ganschow P, Hopkin RJ, Mayefsky J, Stallworth J. Genetic red flags: clues to thinking genetically in primary care practice. Prim Care. 2004;31(3):497-508.
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