Biochemical Genetics 1 Flashcards
Aminoacidopathies, urea cycle disorders, and organic acidemias
How is phenylalanine hydroxylase deficiency detected on NBS
Tandem mass spec after 24hrs of age
Hyperphenylalanemia manifests as a time-dependent increase of Phe in the blood (false -‘s)
What is seen on brain MRI in 90% of individuals with PAH deficiency
progressive white matter dz on brain MRI even w/out evidence of neurologic deterioration
How is phenylalanine hydroxylase deficiency detected on biochemical analysis
Elevated Phe levels > 120umol/L with low Tyr levels; Normal BH4/Pterin levels
Not typically useful in dx bc PAH is a liver enzyme
Those with classic PKU have levels >1200umol/L
How is phenylalanine hydroxylase deficiency detected on single gene testing
Sequence analysis of PAH FIRST followed by gene-targeted del/sup
When should diet be initiated in relation to molecular genetic analysis for patients with phenylalanemia
Low Phe diet should be initiated prior to results of pterin or molecular genetic studies
What are the clinical features associated with classic PKU if left untreated
epilepsy, ID/behavior problems, Parkinson features (in adults), musty body odor, eczema, decreased skin/hair pigmentation, variable microcephaly, osteopenia, and B12 deficiency
What causes the distinct body odor and eczema in PKU
Excess Phe
What causes the decreased skin/hair pigmentation in PKU
Low Tyr
What are pathognomonic features associated with PKU
Musty/mousy body odor, Parkinson features in adults, decreased skin and hair pigmentation
What are the clinical features associated with hyperphenylalanemia if left untreated
Those with < or equal to 600Umol/L are not at increased risk for intellectual, neurological, and neuropsychiatric impairment than those without PAH deficiency
What are the molecular features associated with the PAH gene
less severe of the 2 variants determines dz severity
majority of the PVs in PAH are missense, nonsense, frameshift, and splice variants
PVs that confer the most severe phenotypes abolish PAH activity (null variants of various types
Missense variants typically retain some residual enzyme activity
What are some DD for PAH deficiency
BH4 deficiency: accounts for 2% of elevated Phe levels in most pops; will also have abnormal pterin levels in urine/blood (NOT SEEN IN PKU). Also have recurrent hyperthermia without infections, swallowing issues, hypersalivation
What is the treatment regimen for classic PKU
AVOID ASPARTAME
measurement of blood Phe levels weekly for the first yr of life, biweekly until 13yo, monthly thereafter
monitor Phe blood levels 2-3hrs after eating
Sapropterin (Kuvan): 30% decrease in Phe plasma aa analysis; majority with mild or moderate PKU may be responsive while up to 10% with classic PKU show a response
What is the treatment regimen for non-classic hyperphenylalanemia
experts believe dietary tx is unnecessary
<600umol/L and >360umol/L tx is controversial
<360umol/L and >120umol/L no tx
How is tyrosinemia type 1 detected on NBS
presence of succinylacetone from blood spot via tandem mass spec on NBS is pathognomonic
What do increased tyr or met levels in the blood suggest
Liver disease
Infants with type 1 tyrosinemia could have slightly elevated/normal blood levels when the first NBS is collected
Increased Tyr could be transient tyrosinemia in a newborn, tyrosinemia type 2/3, or other liver disease
Increased met could be liver dysfunction, defects in met metabolism, or homocystinuria
How is tyrosinemia type 1 detected on biochemical analysis
Increased succinylacetone, increased tyr, met, and phe; increased urinary conc. of tyr metabolites and S-ALA
How is tyrosinemia type 1 detected on single gene testing
Sequence analysis of FAH first, then gene-targeted del/dup analysis
What are the clinical features associated with tyrosinemia type 1
Severe liver involvement or later in in the first yr of life with liver dysfunction, significant renal involvement, odor of “boiled cabbage/ rotten mushrooms”, growth failure, neurologic crises, hepatocellular carcinoma, and rickets
When is the typical onset of tyrosinemia type 1
presents in young infants or within the first year of life
Describe the liver involvement associated with tyrosinemia type 1
Before age 6mo typically have acute liver failure which can progress to ascites (fluid buildup in the abdomen), jaundice, and gastrointestinal bleeding
Untreated, may die from liver failure w/in wks or mos of symptoms
Describe the renal involvement associated with tyrosinemia type 1
Renal tubular involvement beginning after 6mo, includes Fanconi syndrome (affects how the kidneys reabsorb certain essential substances causing increased urination, bone pain, muscle weakness), and renal tubular acidosis
Describe the neurological crises associated with tyrosinemia type 1
changes in mental status, abdominal pain, peripheral neuropathy (weakness, numbness and pain, usually in the hands and feet), and/or respiratory failure requiring mechanical ventilation
Describe the cancer risks associated with tyrosinemia type 1
Without nitisinone tx and low tyr diet, there are significantly increased risks of developing and succumbing to hepatocellular carcinoma
What are the molecular features associated with FAH
Targeted analysis for the p. Pro261Leu variant accounts for >99% in AJs
c.1062+5G>a (IV612+5 G>A) accounts for 88% of variants in the French Canadian pop
Pseudodeficiency alleles exist- leads to decreased FAH enzyme activity but adequate FAH mRNA
PVs (missense, nonsense, and splice site variants) result in LOF of FAH activity leading to cellular damage + apoptosis
What are some DD for tyrosinemia type 1
Tyrosinemia type 2: defect in tyrosine aminotransferase (TAT) with high levels of ONLY tyr; associated with painful, nonpruritic, and hyperkeratotic plaques on the soles and palms, ophthalmologic involvement, and DD
Tyrosinemia type 3: very rare and ill defined; deficiency of P-hydroxyphenylpyruvic acid dizoygenase; ID/ataxia, NO LIVER INVOLVEMENT, skin and ocular changes
Homocystinuria
Acute intermittent porphyria
What is the treatment regimen for tyrosinemia type 1
Respiratory support, fluid management, and blood products for bleeding in liver failure
Nitisinone (Orfadin): blocks the second step of the tyrosine degradation pathway and prevents FAA accumulation that would turn into succinylacetone
Low tyr diet: nitisinone increases blood concentrations of tyr, which can lead to tyr crystals forming in the cornea
Measure carnitine levels due to skeletal muscle weakness from renal tubular Fanconi anemia
Osteoporosis and rickets tx with 25-hydroxy-vitamin D, Ca++. and phosphate
When is liver transplantation appropriate for patients with tyrosinemia type 1
Those with severe liver failure at presentation and don’t respond to nitisinone tx
Have documented evidence of malignant changes in hepatic tissue
What kind of special genetic mechanism can occur in tyrosinemia
Gene reversion can occur (explains clinical variability in families/those w same genotype) in which the spontaneous self correction of a germline PV to the normal sequence occurs in somatic cell division
The “normal” cells have a selective growth advantage bc they are no longer at risk for apoptosis from the accumulation of FAA
How is maple syrup urine disease detected on NBS
Based on quantification of the ratios of (leu +isoleu) to ala and phe on dry blood spots
positive screen requires follow-up w quantitative plasma aa and alloisoleucine analyses
NEONATES WITH ISOLATED HYDROXYPROLINEMIA WILL SCREEN + BUT CONFIRMATORY AA ANALYSIS WILL ONLY SHOW INCREASED HYDROXYPROLINE
When should testing for MSUD begin
Immediately after positive NBS either by quantification of aa ratios or plasma AA/ alloisoleucine levels
How is MSUD detected on genetic testing
Identification of biallelic PVs in BCKDHA, BCKDHB, or DBT
Use of a multigene panel w/ del/dup is recommended
What are the clinical features associated with classic MSUD
Maple syrup odor in cerumen (earwax) after birth (~12hrs) and in urine @5-7do; acute metabolic intoxication (leucinosis) with risk for cerebral edema and death, and neurologic deterioration from net protein degradation by infection, sx, injury, psychological stress, iatrogenic essential aa deficiency, recurrent thrush infections
83-100% chance of anxiety, depression, or panic disorder by 35yo; 50% chance for ADHD
How is MSUD detected on biochemical testing
increased levels of BCAAs and alloisoleucine; urinary excretion of BCKDs and BCKAs in infants >48-72hrs old; ketonuria, absence of hypoglycemia/hyperammonemia
What does leucinosis cause in patients with MSUD
nausea, anorexia, altered consciousness, acute dystonia, ataxia
What does neurologic issues cause in patients with MSUD
cognitive impairment, hyperactivity, sleep disturbances, hallucinations, mood swings, focal dystonia, choreoathetosis, and ataxia
What is the single strongest predictor of neurocognitive disability in patients with MSUD
Prolonged neonatal encephalopathy (lethargy, intermittent apnea, opisthotonus, “fencing and bicycling” movement) between 4/5do
What features are associated with iatrogenic essential aa deficiency in patients with MSUD
Anemia, hair loss, growth failure, due to chronic deficiency of leucine, isoleucine, and valine
What clinical features are associated with intermediate MSUD
may have maple syrup smell in neonatal period and abnormal labs
present with feeding issues, poor growth, DD in infancy or later with apparent nonsyndromic ID (majority are caught on NBS)
tolerate more leucine and require less nutritional support
What is the residual enzyme activity associated with MSUD
3-30%
What clinical features are associated with intermittent MSUD
tolerate normal leucine intake, typically normal or mildly elevated BCAAs
MAY ESCAPE DETECTION ON NBS
During infections/physiological stress, can develop all features of classic MSUD
What is the mechanism of disease in patients with MSUD
caused by decreased activity of BCKD, a multi-enzyme complex in the mitochondria
skeletal muscle is the major site of transamination and oxidation of BCAAs
BCKD is expressed in the brain
mechanism of dz is decreased function or LOF
What are the molecular features of MSUD
BCKDHA has PV missense in 3’UTR; DBT has PV missense in 3’UTR which are higher than expected
Notable PVs include c.548G>C in BCKDHB a founder variant in the AJ pop; c.1196C>G in DBT a founder variant in the Malay pop
BCKDHA accounts for 45% of PVs, BCKDHB accounts for 35% of PVs; DBT accounts for 20% of PVs
What are some DD for MSUD
Need to exclude: birth asphyxia, hypoglycemia, status epilepticus (seizures >5min), meningitis, and encephalitis
Urea cycle defects
Hyperketosis syndromes
Glycine encephalopathy
Propionic acidemia/isolated methylmalonic acidemia
What are pathognomonic findings of MSUD that sets it apart from other similar conditions
Unique for odor and + urine dinitrophenylhydrazine test
What is the treatment regimen for MSUD
requires supervision of metabolic dietitian (age appropriate tolerance of leu, iso, val, AND avoiding deficiencies of essential aas, fatty acids, and micronutrients)
Dietary indiscretion causes elevated BCAAs but RARELY results in encephalopathy and acute decompensation (lethargy, encephalopathy, seizures, or progressive coma should be managed with generous caloric support in a hospital)
Orthotopic liver transplants
Plasma levels should be:
Leu 150-300umol/L
Iso ~= to Leu
Val at LEAST 2X >Leu
When should MSUD tx begin if the syndrome is suspected
IMMEDIATELY
What does an orthotopic liver do for a patient with MSUD
metabolic “cure” for classic MSUD
does not reverse cognitive disability but may arrest progression of neurocognitive impairment
What considerations are needed for individuals who are pregnant and have MSUD
Pregnancy possible for pts with classic MSUD
Increased Leu in pregnant person likely teratogenic
Keep mat levels of BCAAs b/wn 150-300umol/L for safe delivery
Postpartum is dangerous for mom – refer to metabolic center
How is the dx of nonketotic hyperglycemia established using laboratory findings
Isolated elevation of levels of glycine in plasma and CSF (obtained simultaneously) by quantitative aa analysis
abnormal CSF to glycine ratio (elevation of CSF glycine is more important than the ratio)
Urine organic acid profile is expected to be normal
What findings on brain MRI would be suspicious for nonketotic hyperglycemia
most consistent abnormalities noted on diffusion weighted imaging in the first 3mo of life
ALL INFANTS with diffuse restriction of white matter that can recede after 3mo but can be recognized elsewhere between 3-14mo
The corpus callosum can be thin and shortened but is NOT absent
Small group of infants develop hydrocephalus
Atrophy present in older individuals with severe NKH
How is the dx of nonketotic hyperglycemia established using genetic testing
Biallelic PVs in GLDC, AMT, and (proposed to be involved) GCSH
A multigene panel including the above that also includes del/dup analysis is recommended
What does the analysis of the glycine cleavage enzyme system (GCS) entail for the dx of NKH? How much enzyme activity do these individuals have? Those with variants in the AMT gene?
requires analysis of a liver bx, usually obtained by sx endoscopy as a wedge bx or at autopsy
Vast majority have no detectable GCS activity
Those w defects in AMT tend to have GCS activity up to 25% of normal values
What are the clinical features associated with severe NKH
No developmental progress and intractable epilepsy
Never make developmental gains, some will regain few skills
Spontaneous bottle feeding, looking, and smiling when tx with benzoate (around 3-4mo they can lose these skills)
Before 6mo, develop progressive spasticity and cortical blindness
increasingly difficult to tx seizures in the 1st yr; EEG with multifocal spikes
scoliosis/hip dislocation; occasionally can have cleft palate, clubfeet, secondary microcephaly
Recurrent and long episodes of unexplained severe crying
What type of condition is NKH? What is the life expectancy?
Inborn error of metabolism resulting in accumulation of large quantities of glycine in all body tissues including the brain
Typically will pass away within the first few weeks of life, but can live up to 3-5yo
What are the clinical features associated with attenuated NKH
variable developmental progress with treatable or no epilepsy (relatively easy to tx with benzoate or dextromethorphan alone)
Hyperactivity common, can be severe
Many have choreic movements
Intermittent episodes of lethargy triggered by fever and infection
Can have poor, intermediate, or good outcomes
What are the clinical features associated with poor attenuated NKH
developmental quotient <20 with epilepsy
Manifestations between attenuated and severe forms
Learn how to grasp objects, usually able to sit, have limited interaction with some signs
What are the clinical features associated with intermediate attenuated NKH
developmental quotient 20-50 with easily treatable or no epilepsy
walk and communicate with some speech and sign language
grasp items and eat independently
choreatic movements and pronounced ADHD
What are the clinical features associated with good attenuated NKH
Developmental Quotient >50 with no epilepsy
make substantial developmental progress
half do not present with symptoms until after 3mo
have ADHD; episodes of severe lethargy with infections
What percent of infants with neonatal onset NKH have the severe form? The attenuated form?
85%; 15%
What percent of infants with infantile onset NKH have the severe form? The attenuated form?
defined as greater than 2 weeks
50%; 50%
What percent of infants with late onset NKH have the severe form? The attenuated form?
defined as onset >3mo
all have attenuated NKH
What is the neonatal presentation of NKH
progressive lethargy into profound coma and marked hypotonia in the first hours to days of life
80% of infants ventilatory drive slows, leading to prolonged apnea and often death (20% maintain spontaneous ventilation)
Majority of infants regain spontaneous respiration within the first three wks of life, some show spontaneous improvement in alertness in the first mo of life
Myoclonic jerks and hiccups are often a sign of epilepsy
initial EEG often shows a burst suppression pattern
What is the infantile presentation of NKH
hx of hypotonia early one, present with DD and infantile-onset seizures that can be mild or increasingly difficult to tx
What is the late presentation of NKH
rare, associated with the attenuated form, involves DD and possible mild seizures
Is there intrafamilial variability for nonketotic hyperglycemia
No, the phenotype of severe vs attenuated NKH is consistent within families
What are the prognostic predictors for dx of severe NKH
presence of a very thin and shortened corpus callosum
Presence of hydrocephalus
development of clear pyramidal tract signs (hyperreflexia, weakness, spasticity, and a Babinski sign) before 6mo
cleft palate and clubfeet when present
persistent burst suppression pattern
What are the prognostic predictors for dx of attenuated NKH
glycine/creatine ratio is higher in severe than in attenuated NKH
presence of choreatic movements
What are some of the differential diagnoses for nonketotic hyperglycemia
GCS cofactor deficiencies (pyridoxine dependent epilepsy)
Abnormal regulation of GCS (intracellular cobalamin metabolism)
Glycine transport defects (GLYT1 encephalopathy)
Inhibition of GCS activity (organic acidemias- will have abnormal urine organic acids)
What is the management for patients with nonketotic hyperglycemia
MRI of the brain in neonates (brain atrophy in severe form)
EEG
Developmental assessment
Neurologic assessment
Orthopedic eval
Pulmonary eval
Ophthalmologic assessment
GI eval
What are the current treatment methods for severe NKH
Glycine-lowering therapy is not effective in improving the affected individuals development, even when initiated at birth (does however decrease frequency and severity of seizures)
Improves attentiveness and resolves neonatal apnea
What are the current treatment methods for attenuated NKH
Reduction of plasma concentration of glycine tx with sodium benzoate (improves alertness, reduces or eliminates episodic lethargy, and may also improve behavior) and blockade of NMDA receptors
Early, aggressive tx of children with PVs associated with residual GCS activity who are likely to develop attenuated NKH resulted in improved neurodevelopmental outcome and reduced propensity for epilepsy
Why is a glycine-restricted diet not necessarily indicated in the tx of patients with NKH
contribution of dietary glycine is small compared to the excess in endogenous glycine synthesis versus endogenous catabolism of glycine
been associated with protein malnutrition
What are the agents to avoid in a patient with NKH
Valproate- it raises blood and CSF glycine concentrations and may increase seizure frequency
Vigabatrin resulted in rapid loss of function of the glycine cleavage enzyme system
What is the mechanism of disease for Nonketotic hyperglycemia
Loss of function. Residual enzyme activity correlates with the outcome of the dz
What are some molecular considerations when taking into account the diagnosis of NKH
GLDC analysis is complicated by the presence of a processed full-length pseudogene with 98% homology to the true gene
20% of pathogenic GLDC variants are large deletions as a result of nonallelic homologous recombination of Alu repeats
How is the diagnosis of homocystinuria made biochemically
total homocysteine levels above 100 umol/L when accompanied by high or borderline high methionine makes the dx very likely
ENZYME ACTIVITY TESITNG IS NO LONGER AVAILABLE IN THE US
How is the dx of homocystinuria made on NBS
Detected in SOME affected individuals
screens for hyperMETHIONINEMIA using tandem mass spec
If initial result exceeds cutoff of methionine, follow up testing is required: 1. repeat dried blood specimen OR 2. quantitative plasma aa analysis and analysis of plasma total homocysteine (dependent on screening program recommendation)
Since NBS is for methionine and not homocysteine, other causes of elevated total homocysteine may not be detected bc the methionine level in these disorders is reduced or normal
What are the MAJOR clinical findings of homocystinuria
Ectopia lentis and/or severe myopia
Skeletal abnormalities (excessive height, long narrow limbs (dolichostenomelia), scoliosis, pectus excavatum)
Thromboembolism (vascular abnormalities)
DD/ID
NO JOINT HYPERMOBILITY (SPECIFIC TO MARFAN)
How is the diagnosis of homocystinuria made with molecular genetic testing
Sequence analysis of CBS FIRST then gene-targeted del/dup analysis if only one or no PVs is found
Targeted analysis is performed only in the Qatari pop in which a single PV (p.Arg336Cys, c.1006C>T) is present in 93% of the pop
What type of challenge testing is required immediately after dx of homocystinuria
Pyridoxine (B6) challenge test
Affected individual (in the neonate or beyond) is given 100mg of pyridoxine daily for two consecutive days, concentrations of plasma total homocysteine and aas are measured in 48hrs after the first dose
Reduction of 30% or more in plasma total homocysteine and/or plasma methionine concentration suggests B6 responsiveness
What are the clinical characteristics of homocystinuria
B6-responsive pts typically have milder presentations than non-responsive individuals (BUT NOT ALWAYS)
Myopia followed by ectopia lentis (after one yo but before 8yo)
Tall and slender, marfanoid habitus, prone to osteoporosis
Scoliosis, high-arched palate, arachnodactyly, pes cavus, pectus excavatum or carinatum, genu valgum (knock knees)
Thromboembolism is the major cause of morbidity and early death (problems typically appear in young adults)
DD is often the first abnormal sign in individuals with homocystinuria
Seizures in 21% of individuals
Psychiatric problems (personality disorder, anxiety, depression, OCD, psychotic episodes
Hypopigmentation of the hair and skin, malar flush, livedo reticularis (skin to appear reddish-violet and blotchy, forming a net-like pattern), and pancreatitis
What are the genotype-phenotype correlations in homocystinuria
presence of a single p.Gly307Ser allele predicts B6 non-responsiveness
presence of a single p.Ile278Thr allele usually predicts B6 responsiveness
In what populations is homocystinuria most commonly present
- Qatar
- Norway
- Germany
- Ireland
What are some of the differential diagnoses associated with homocystinuria
Marfan
Tyrosinemia type 1 or galactosemia (secondary hypermethioninemia)
What is the recommended treatment for individuals with homocystinuria
methionine restricted diet continued indefinitely. A methionine free aa formula supplying the other aas is provided
Folate and vitamin B12 optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease the plasma homocysteine concentration
Tx with betaine provides an alternate remethylation pathway to covert excess homocysteine and methionine may help to prevent thrombosis
What is the recommended surveillance for patients with homocystinuria
Infants should be monitored monthly for the fist six months of life and bimonthly until age 1yr, then every 3mo until age 3yrs
Semiannual monitoring through the remainder of childhood and annual monitoring in adolescence and adulthood are indicated
Regular ophthalmology assessments
DXA scans should be performed q3-5yrs to monitor for osteoporosis
What agents/circumstances should individuals with homocystinuria avoid
Oral contraceptives increase coagulability and should be avoided in females
Sx should also be avoided if possible bc increase in plasma homocysteine concentrations elevates the risk of a thromboembolic event
What is the pregnancy management for patients with homocystinuria
Prophylactic anticoagulation in the third tri and post partum recommended (low molecular weight heparin), low dose aspirin
does NOT appear to have teratogenic effects on a fetus
What is a counseling consideration that must be addressed with the parents of a patient with homocystinuria
It is possible (though unlikely) that a parent has classic homocystinuria but has remained asymptomatic (high clinical variability of the condition), it is appropriate to perform an exam and plasma homocysteine and aa analysis in both parents (affected women at increased risk for thromboembolic events during pregnancy
What are the type of PVs seen in patients with homocystinuria
Most often missense variants, some nonsense; the rest are various in/dels, and splice variants
Where are the two most common variants found in patients with homocystinuria
p.Gly307Ser and p.Ile278Thr are found in exon 8
p.Gly307Ser is the leading cause of homocystinuria in Ireland (71% of PVs)
p.Arg336Cys is present in 93% of affected individuals in the Qatari pop
How do the urea cycle disorders occur and what are they
group of rare disorder affected the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine
failure to break down nitrogen results in the abnormal accumulation of nitrogen (in the form of ammonia) in the blood
What are the signs and symptoms of severe neonatal onset NAGS (N-acetylglutamate synthetase deficiency)
refusal to eat and poor feeding habits, progressive lethargy, recurrent vomiting, diarrhea, irritability, and hepatosplenomegaly
Seizures, confusion, respiratory distress, and cerebral edema
in some cases, may progress to coma due to high levels of ammonia in the blood (resulting in neurological abnormalities including DD, learning disabilities, ID)
What are the signs and symptoms of late onset NAGS (N-acetylglutamate synthetase deficiency)
failure to thrive, poor growth, avoidance of protein from diet, ataxia, lethargy, vomiting, hypotonia
Can still experience hyperammonemic coma and life threatening complications
When do the symptoms of NAGS start in the severe neonatal form and what causes the symptoms
occur within 24-72hrs after birth
caused by accumulation of ammonia in the blood (nitrogen is a waste product of protein metabolism)
When do the symptoms of NAGS start in the late onset form
Occurs later in infancy or childhood or even adulthood in some cases
What causes NAGS and what is the function of the defective enzyme
biallelic mutations in NAGS
NAGS is an activator of another enzyme of the urea cycle (carbamyl phosphate synthetase (CPS))
What are some differential diagnoses for NAGS
Other urea cycle disorders
Reye syndrome: liver failure, encephalopathy, hypoglycemia, hyperammonia, occurs following a viral infection
Organic acidemias (affect the urea cycle as a secondary phenomenon)
What are some common clinical features among all urea cycle disorders
lack of appetite, vomiting, drowsiness, seizures, and/or coma
hepatosplenomegaly in some cases
in severe cases, life threatening complications may result
What are the common clinical features among all organic acidemias
hypotonia, poor feeding, lethargy, vomiting, and seizures
can progress to coma and life-threatening complications
What characteristic biochemical/laboratory findings should be indicative of a NAGS diagnosis
excessive amounts of ammonia in the blood (can also indicate other disorders like organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders)
URINARY ORGANIC ACIDS SHOULD BE NORMAL