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AMINOACIDURIA AND ORGANIC
ACIDURIA IN NEUROLOGY
DR. KOUSHIK MUKHERJEE
JUNIOR RESIDENT
CATABOLISM OF AMINO
ACID IN A GLANCE
WHEN TO SUSPECT IN
NEWBORNS
AMINO-ACIDURIA
PHENYL KETONURIA(PKU)
 Discovery of PKU- an important milestone in the
history of medicine
 Discovered by Asbjørn Føllin...
 Later Følling subsequently requested urine samples
from 430 intellectually impaired patients from a
number of local inst...
ABJORN FØLLING
The Egeland children
CLASSIC PKU
HYPERPHENYLALANINEMIA CAUSED BY
DEFICIENCY OF THE COFACTOR
TETRAHYDROBIOPTERIN
 In affected infants with plasma concentrations >20
mg/dL, excess phenylalanine is metabolized to
phenylketones (phenylpy...
 The exact mechanism of damage caused by
elevated levels of intracerebral phenylalanine
remains elusive.
 There have bee...
CLASSIC PKU
 Severe hyperphenylalaninemia (plasma phenylalanine
levels >20 mg/dL), if untreated, invariably results in th...
 Older untreated children become hyperactive with
autistic behaviors, including purposeless hand
movements, rhythmic rock...
NEONATAL DIAGNOSIS OF PKU
 Early diagnosis of PKU is important because the
disease is treatable by dietary means.
 Newbo...
NEONATAL SCREENING OF PKU
 Must be made within one month of birth, if mental
retardation is to be prevented.
 Screening ...
GUTHRIE TEST
TREATMENT OF CLASSIC PKU
Principles of treatment of PKU
 Treatment must begin during first 7-10 days of life to
prevent m...
 Avoiding low levels of phenylalanine in blood as it is
an essential amino acid and therefore is essential for
physical &...
MRI brain of a 27-year-old man who was screened at birth and
was found to have a borderline phenylalanine level.
HYPERPHENYLALANINEMIA CAUSED BY
DEFICIENCY OF THE COFACTOR
TETRAHYDROBIOPTERIN
 In 1-3% of infants with hyperphenylalanin...
 The clinical manifestations differ greatly from PKU.
 Neurologic symptoms often manifest in the first few
months of lif...
 The control of hyperphenylalaninemia is important
in patients with cofactor deficiency, because high
levels of phenylala...
TYROSINEMIA TYPE I (TYROSINOSIS,
HEREDITARY TYROSINEMIA)
 Caused by a deficiency of the enzyme
fumarylacetoacetate hydrol...
 Episodes of acute peripheral neuropathy
resembling acute porphyria occur in approximately
40% of affected children.
 Th...
 Diagnosis is usually established by demonstration
of elevated levels of succinylacetone in urine or
blood.
 A diet low ...
HOMOCYSTINURIA CAUSED BY CYSTATHIONINE
Β-SYNTHASE DEFICIENCY (CLASSIC
HOMOCYSTINURIA)
 most common inborn error of methio...
 Elevations of both methionine and homocystine (or
homocysteine) in body fluids are the diagnostic
laboratory findings.
...
HOMOCYSTINURIA CAUSED BY DEFECTS
IN METHYLCOBALAMIN FORMATION
 Methylcobalamin is the cofactor for the enzyme
methionine ...
 The presence of megaloblastic anemia
differentiates these defects from homocystinuria
due to methylenetetrahydrofolate r...
HOMOCYSTINURIA CAUSED BY DEFICIENCY OF
METHYLENETETRAHYDROFOLATE REDUCTASE
 This enzyme reduces 5,10-
methylenetetrahydro...
 Laboratory findings include moderate
homocystinemia and homocystinuria.
 The methionine concentration is low or low nor...
CYSTINURIA
 Occurs due to sulfite oxidase
deficiency(Molybdenum Cofactor Deficiency).
 The enzyme and or the cofactor de...
 The accumulation of sulfites in body fluids in this
condition causes the inhibition of antiquitin enzyme
which is necess...
HARTNUP DISORDER
 In this autosomal recessive disorder, named after
the first affected family, there is a defect in the
t...
 Mental development is usually normal
 Two individuals in the original kindred were
cognitively impaired. Episodic psych...
 Urinary excretion of proline, hydroxyproline, and
arginine remains normal. This finding differentiates
Hartnup disorder ...
ORGANIC ACIDURIA
 The term "organic acidemia" or "organic aciduria" (OA)
applies to a group of disorders characterized by the
excretion of...
CLINICAL APPROCH TO INFANTS WITH OA
CLINICAL MANIFESTATIONS OF OA
 The organic acidemias share many clinical similarities.
 A neonate affected with an organ...
 Methylmalonic aciduria, cblC variant, may present with
developmental delay, minor dysmorphology, and
hypotonia without a...
CLINICAL COURSE
 Individuals with organic acidemias have a greater
risk of infection and a higher incidence of
pancreatit...
DIAGNOSIS
 Acidosis: Serum bicarbonate lower than:
 22 mmol/L in individuals younger than age one
month
 17 mmol/L in n...
 Ketosis: A positive (not trace) urine dipstick for
ketones OR A urine organic acid profile containing
excess βhydroxybut...
 Abnormal liver function tests:
 Hypoglycemia: Serum glucose lower than:
 40 mg/dL in term and preterm infants
 60 mg/...
Clinical Findings in Organic Acidemias
DIAGNOSIS CONT…
 Gas chromatography/mass spectrometry
(GC/MS):
 Firstline diagnosis in the organic acidemias is urine
or...
 The urinary organic acid profile is nearly always
abnormal in the face of acute illness with
decompensation.
 However, ...
Metabolic Findings in Organic
Acidemias Caused by Abnormal
Amino Acid Catabolism
MANAGEMENT
 Many of the organic acidemias respond to
treatment, and in the neonate especially, early
diagnosis and prompt...
 Treatment strategies are:
 Dietary restriction of the precursor amino acids
 Use of adjunctive compounds to:
 Dispose...
MANAGEMENT OF ACUTE DECOMPENSATION
 Frequent episodes of decompensation can be
devastating to the central nervous system....
INDIVIDUAL ORGANIC ACIDURIAS
CLASSIC MAPLE SYRUP URINE DISEASE
 Decarboxylation of leucine, isoleucine, and valine is
accomplished by a complex enzyme...
 This form has the most severe clinical
manifestations.
 Affected infants who are normal at birth develop
poor feeding a...
 Cerebral edema may be present; convulsions occur
in most infants, and hypoglycemia is common.
 In contrast to most hypo...
 Diagnosis is often suspected because of the
peculiar odor of maple syrup found in urine, sweat,
and cerumen.
 It is usu...
 Neuroimaging during the acute state may show
cerebral edema, which is most prominent in the
cerebellum, dorsal brainstem...
T2-weighted MRI demonstrates elevated signal intensity of white matter
in the thalamus, globus pallidus, and posterior lim...
 Treatment of the acute state is aimed at hydration
and rapid removal of the branched-chain amino
acids and their metabol...
 Liver transplantation has been performed in a
number of patients with classic MSUD with
promising results. These childre...
ISOVALERIC ACIDEMIA
 This condition is caused by the deficiency of the enzyme
isovaleryl CoA dehydrogenase.
 Lethargy, c...
 Along with other supportive measures,as
isovalerylglycine has a high urinary clearance,
administration of glycine (250 m...
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
(MULTIPLE CARBOXYLASE DEFICIENCY NEONATAL
OR EARLY FORM)
 Infants with this rare au...
 If the condition remains untreated, generalized
erythematous rash with exfoliation and alopecia (partial
or total), fail...
 Treatment with biotin (10 mg/day orally) usually
results in an improvement in clinical manifestations
and may normalize ...
3-METHYLGLUTACONIC ACIDURIA TYPE III
(COSTEFF OPTIC ATROPHY SYNDROME)
 Clinical manifestations in these patients include
...
3-HYDROXY-3-METHYLGLUTARIC
ACIDURIA
 This condition is a result of a deficiency of HMG-
CoA lyase.This enzyme catalyzes t...
MEVALONIC ACIDURIA
 Mevalonic acid, an intermediate metabolite of
cholesterol synthesis, is converted to 5-
phosphomevalo...
PROPIONIC ACIDEMIA (PROPIONYL
COENZYME A CARBOXYLASE
DEFICIENCY)
 In the severe form of the condition, patients develop
s...
 Neuroimaging shows these abnormalities, which
usually occur after an episode of metabolic
decompensation, to be a result...
METHYLMALONIC ACIDEMIA
 Mental development and IQ of patients with
methylmalonic acidemia may remain within the
normal ra...
GLUTARIC ACIDURIA TYPE 1
 Glutaric aciduria type 1 (GA-1) is an autosomal
recessive disorder of lysine, hydroxylysine, an...
 MRI brain reveals frontotemporal atrophy, dilated sylvian fissures with open
opercula (arrow), diffuse hyperintense lesi...
 Therapy consists in carnitine supplementation to
remove glutaric acid, a diet restricted in amino
acids capable of produ...
THANK YOU………..
Aminoaciduria and organic aciduria in neurology
Aminoaciduria and organic aciduria in neurology
Aminoaciduria and organic aciduria in neurology
Aminoaciduria and organic aciduria in neurology
Aminoaciduria and organic aciduria in neurology
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Aminoaciduria and organic aciduria in neurology

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aminoaciduria and organic aciduria are considered as important disorder in the group of inborn error of metabolism.

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Aminoaciduria and organic aciduria in neurology

  1. 1. AMINOACIDURIA AND ORGANIC ACIDURIA IN NEUROLOGY DR. KOUSHIK MUKHERJEE JUNIOR RESIDENT
  2. 2. CATABOLISM OF AMINO ACID IN A GLANCE
  3. 3. WHEN TO SUSPECT IN NEWBORNS
  4. 4. AMINO-ACIDURIA
  5. 5. PHENYL KETONURIA(PKU)  Discovery of PKU- an important milestone in the history of medicine  Discovered by Asbjørn Følling, one of the first Norwegian physicians to apply chemical methods to the study of medicine.  In 1934, the parents,Borgny and Harry Egeland of two intellectually impaired children approached Følling to ascertain whether the strange musty odour of her children’s urine might be related to their intellectual impairment.  He analysed their urine specimen and found phenylpyruvic acid in their urine.
  6. 6.  Later Følling subsequently requested urine samples from 430 intellectually impaired patients from a number of local institutions.  These eight individuals all presented with a mild complexion (often with eczema), stooping figure with broad shoulders, a spastic gait, and severe intellectual impairment.  Family studies of the affected individuals led to the suggestion of an inherited recessive autosomal trait.  Dr Følling published his findings and suggested the name ‘imbecillitas phenylpyruvica’ relating the intellectual impairment to the excreted substance,thereafter renamed ‘phenylketonuria
  7. 7. ABJORN FØLLING The Egeland children
  8. 8. CLASSIC PKU
  9. 9. HYPERPHENYLALANINEMIA CAUSED BY DEFICIENCY OF THE COFACTOR TETRAHYDROBIOPTERIN
  10. 10.  In affected infants with plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate) that are excreted in the urine, giving rise to the term phenylketonuria (PKU).  The term hyperphenylalaninemia implies lower plasma levels (<20 mg/dL) of phenylalanine.  The brain is the main organ affected by hyperphenylalaninemia. The CNS damage in affected patients is caused by the elevated concentration of phenylalanine in brain tissue. The high blood levels of phenylalanine in PKU saturate the transport system across the blood–brain barrier causing inhibition of the cerebral uptake of other large neutral amino acids such as tyrosine and tryptophan.
  11. 11.  The exact mechanism of damage caused by elevated levels of intracerebral phenylalanine remains elusive.  There have been a few adults with classic PKU and normal intelligence who have never been treated with a phenylalanine-restricted diet. Phenylalanine content of the brain in these individuals was found to be close to that of normal subjects when studied by magnetic resonance spectroscopy (MRS).
  12. 12. CLASSIC PKU  Severe hyperphenylalaninemia (plasma phenylalanine levels >20 mg/dL), if untreated, invariably results in the development of signs and symptoms of classic PKU.  The affected infant is normal at birth. Profound intellectual disability develops gradually if the infant remains untreated. Cognitive delay may not be evident for the first few months.  In untreated patients, 50-70% will have an IQ below 35, and 88-90% will have an IQ below 65. Only 2-5% of untreated patients will have normal intelligence.  Many patients require institutional care if the condition remains untreated. Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom.
  13. 13.  Older untreated children become hyperactive with autistic behaviors, including purposeless hand movements, rhythmic rocking, and athetosis.  Neurologic signs include seizures (approximately 25%), spasticity, hyperreflexia, and tremors.  Diagnosis is through new born screening in developed countries.  In developing countries identification of phenylketones in the urine by ferric chloride may offer a simple test for diagnosis of infants with developmental and neurologic abnormalities.
  14. 14. NEONATAL DIAGNOSIS OF PKU  Early diagnosis of PKU is important because the disease is treatable by dietary means.  Newborn with PKU frequently has normal blood levels of phenylalanine (PA) at birth  As the mother clears increased blood PA in her fetus through placenta. So, test performed at birth may show false –ve results.  PA begins to be elevated when newborn takes milk (containing proteins) for at least 24 hours  Accordingly, feeding with milk for 48 hours is sufficient to raise the newborn blood PA to levels that can be used for diagnosis.
  15. 15. NEONATAL SCREENING OF PKU  Must be made within one month of birth, if mental retardation is to be prevented.  Screening program for neonate (6 –14 days of life) using Guthrie test is performed: - A disk of a filter paper containing blood from a heel prick is placed on plates impregnated with a microorganism, Bacillus subtilis, which requires phenylalanine for growth, the only source being the blood spot. - The growth of the organism is a positive test.  Test has to be confirmed by measuring blood phenylalanine
  16. 16. GUTHRIE TEST
  17. 17. TREATMENT OF CLASSIC PKU Principles of treatment of PKU  Treatment must begin during first 7-10 days of life to prevent mental retardation. .  Treatment aims at maintaining blood phenylalanine levels close to normal range.  Treatment should be continued for many years (at least till age of 8) as high blood levels of phenylalanine between 4 – 8 years leads to mental retardation. However, life-long treatment by diet restriction of phenylalanine is preferred
  18. 18.  Avoiding low levels of phenylalanine in blood as it is an essential amino acid and therefore is essential for physical & mental growth.  Tyrosine is must be supplied in diet as it cannot be synthesized from phenylalanine in cases of PKU Protocol of treatment:  By feeding synthetic amino acid preparations low in phenylalanine  Supplemented with some natural foods such as vegetables, fruits & certain cereals selected for their low phenylalanine content & rich in tyrosine.
  19. 19. MRI brain of a 27-year-old man who was screened at birth and was found to have a borderline phenylalanine level.
  20. 20. HYPERPHENYLALANINEMIA CAUSED BY DEFICIENCY OF THE COFACTOR TETRAHYDROBIOPTERIN  In 1-3% of infants with hyperphenylalaninemia, the defect resides in 1 of the enzymes necessary for production or recycling of the cofactor BH4.  If these infants are misdiagnosed as having PKU, they may deteriorate neurologically despite adequate control of plasma phenylalanine.  More than half of the reported patients have had a deficiency of 6-pyruvoyltetrahydropterin synthase.  Patients with hyperphenylalaninemia as a result of BH4 deficiency also manifest neurologic findings related to deficiencies of the neurotransmitters dopamine and serotonin.
  21. 21.  The clinical manifestations differ greatly from PKU.  Neurologic symptoms often manifest in the first few months of life and include extrapyramidal signs (choreoathetotic or dystonic limb movements, axial and truncal hypotonia, hypokinesia), feeding difficulties, and autonomic abnormalities. Intellectual disability, seizures, hypersalivation, and swallowing difficulties are also seen.  The symptoms are usually progressive and often have a marked diurnal fluctuation.  Diagnosd by Measurement of neopterin (oxidative product of dihydroneopterin triphosphate) and biopterin (oxidative product of dihydrobiopterin and BH4) in body fluids, especially urine and BH4 loading test.
  22. 22.  The control of hyperphenylalaninemia is important in patients with cofactor deficiency, because high levels of phenylalanine cause intellectual disability and also interfere with the transport of neurotransmitter precursors (tyrosine, tryptophan) into the brain. Plasma phenylalanine should be maintained as close to normal as possible (<6 mg/dL). This can be achieved by oral supplementation of BH4 (5-20 mg/kg/day).  Lifelong supplementation with neurotransmitter precursors such as l-dopa and 5- hydroxytryptophan, along with carbidopa to inhibit degradation of l-dopa before it enters the CNS, is necessary in most of these patients even when treatment with BH4 normalizes plasma levels of phenylalanine.
  23. 23. TYROSINEMIA TYPE I (TYROSINOSIS, HEREDITARY TYROSINEMIA)  Caused by a deficiency of the enzyme fumarylacetoacetate hydrolase.  Organ damage is believed to result from accumulation of metabolites of tyrosine degradation, especially fumarylacetoacetate and succinylacetone.  An acute hepatic crisis commonly heralds the onset of the disease and is usually precipitated by an intercurrent illness that produces a catabolic state.  Renal involvement is manifested as a Fanconi-like syndrome with hyperphosphaturia, hypophosphatemia, normal anion gap metabolic acidosis, and vitamin D– resistant rickets. Nephromegaly and nephrocalcinosis may be present on ultrasound examination. Glomerular failure may occur in adolescents and older patients.
  24. 24.  Episodes of acute peripheral neuropathy resembling acute porphyria occur in approximately 40% of affected children.  These crises, often triggered by a minor infection, are characterized by severe pain, often in the legs, associated with extensor hypertonia of the neck and trunk, vomiting, paralytic ileus, and, occasionally, self-induced injuries of the tongue or buccal mucosa.  Marked weakness and paralysis occur in about 30% of episodes, which may lead to respiratory failure requiring mechanical ventilation.  Crises typically last 1-7 days but recuperation from paralytic crises can require weeks to months
  25. 25.  Diagnosis is usually established by demonstration of elevated levels of succinylacetone in urine or blood.  A diet low in phenylalanine and tyrosine can slow but does not halt the progression of the condition. The treatment of choice is nitisinone, which inhibits tyrosine degradation at 4-HPPD .This treatment prevents acute hepatic and neurologic crises.
  26. 26. HOMOCYSTINURIA CAUSED BY CYSTATHIONINE Β-SYNTHASE DEFICIENCY (CLASSIC HOMOCYSTINURIA)  most common inborn error of methionine metabolism.  The diagnosis is usually made after 3 yr of age, when subluxation of the ocular lens (ectopia lentis) occurs.  Progressive intellectual disability is common.  Psychiatric and behavioral disorders have been observed in more than 50% of affected patients.  Convulsions occur in approximately 20% of patients.  Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age.
  27. 27.  Elevations of both methionine and homocystine (or homocysteine) in body fluids are the diagnostic laboratory findings.  Freshly voided urine should be tested for homocystine because this compound is unstable and may disappear as the urine is stored.  Treatment with high doses of vitamin B6 (200- 1,000 mg/24 hr) causes dramatic improvement in most patients who are responsive to this therapy.  Restriction of methionine intake in conjunction with cysteine supplementation is recommended for patients who are unresponsive to vitamin B6.
  28. 28. HOMOCYSTINURIA CAUSED BY DEFECTS IN METHYLCOBALAMIN FORMATION  Methylcobalamin is the cofactor for the enzyme methionine synthase, which catalyzes remethylation of homocysteine to methionine.  The clinical manifestations are similar in patients with all of these defects. Vomiting, poor feeding, failure to thrive, lethargy, hypotonia, seizures, and developmental delay may occur in the first few months of life.  Laboratory findings include megaloblastic anemia, homocystinuria, and hypomethioninemia.
  29. 29.  The presence of megaloblastic anemia differentiates these defects from homocystinuria due to methylenetetrahydrofolate reductase deficiency  Treatment with vitamin B12 in the form of hydroxycobalamin (1-2 mg/24 hr) is used to correct the clinical and biochemical findings.  Results vary among both diseases and sibships
  30. 30. HOMOCYSTINURIA CAUSED BY DEFICIENCY OF METHYLENETETRAHYDROFOLATE REDUCTASE  This enzyme reduces 5,10- methylenetetrahydrofolate to form 5- methyltetrahydrofolate, which provides the methyl group needed for remethylation of homocysteine to methionine.  Clinical findings vary from apnea, seizure, microcephaly, coma, and death to developmental delay, ataxia, and motor abnormalities or even psychiatric manifestations.  Premature vascular disease or peripheral neuropathy has been reported as the only manifestation of this enzyme deficiency in some patients.
  31. 31.  Laboratory findings include moderate homocystinemia and homocystinuria.  The methionine concentration is low or low normal. This finding differentiates this condition from classic homocystinuria caused by cystathionine β-synthase deficiency.  Absence of megaloblastic anemia distinguishes this condition from homocystinuria caused by methylcobalamin formation.  Treatment of severe MTHFR deficiency with a combination of folic acid, vitamin B6, vitamin B12, methionine supplementation, and betaine has been tried. Of these, early treatment with betaine seems to have the most beneficial effect
  32. 32. CYSTINURIA  Occurs due to sulfite oxidase deficiency(Molybdenum Cofactor Deficiency).  The enzyme and or the cofactor deficiencies produce identical clinical manifestations.  Refusal to feed, vomiting, severe intractable seizures (tonic, clonic, myoclonic), cortical atrophy with subcortical multicystic lesions, and severe developmental delay may develop within a few weeks after birth.
  33. 33.  The accumulation of sulfites in body fluids in this condition causes the inhibition of antiquitin enzyme which is necessary for conversion of α-aminoadipic semialdehyde to α-aminoadipic acid; the resultant accumulation of α-aminoadipic semialdehyde and its cyclic form P6C causes the inactivation of pyridoxal-5-phosphate (active form of vitamin B6) and, hence, the vitamin B6–dependent epilepsy.  These children excrete large amounts of sulfite, thiosulfate, S-sulfocysteine, xanthine, and hypoxanthine in their urine.  No effective treatment is available; large doses of vitamin B6 (5-100 mg/kg) result in dramatic alleviation of seizures but do not seem to alter the devastating neurologic outcome. Most children die in the 1st 2 yr of life.
  34. 34. HARTNUP DISORDER  In this autosomal recessive disorder, named after the first affected family, there is a defect in the transport of monoamino-monocarboxylic amino acids (neutral amino acids), including tryptophan, by the intestinal mucosa and renal tubules.  Most children with Hartnup defect remain asymptomatic. The major clinical manifestation in the rare symptomatic patient is cutaneous photosensitivity.  Some patients may have intermittent ataxia manifested as an unsteady, widebased gait. The ataxia may last a few days and usually recovers spontaneously.
  35. 35.  Mental development is usually normal  Two individuals in the original kindred were cognitively impaired. Episodic psychiatric manifestations such as irritability, emotional instability, depression, and suicidal tendencies, have been observed; these changes are usually associated with bouts of ataxia.  The main laboratory finding is aminoaciduria, which is restricted to neutral amino acids (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine).
  36. 36.  Urinary excretion of proline, hydroxyproline, and arginine remains normal. This finding differentiates Hartnup disorder from other causes of generalized aminoaciduria, such as Fanconi syndrome  Diagnosis is established by the striking intermittent nature of symptoms and the previously described urinary findings.  Treatment with nicotinic acid or nicotinamide (50- 300 mg/24 hr) and a high-protein diet results in a favorable response in symptomatic patients
  37. 37. ORGANIC ACIDURIA
  38. 38.  The term "organic acidemia" or "organic aciduria" (OA) applies to a group of disorders characterized by the excretion of nonamino organic acids in urine.  Most organic acidemias result from dysfunction of a specific step in amino acid catabolism, usually the result of deficient enzyme activity.  The pathophysiology results from accumulation of precursors and deficiency of products of the affected pathway.  The majority of the classic organic acid disorders are caused by abnormal amino acid catabolism of branched chain amino acids or lysine.  OA also includes disorders causing accumulation of other organic acids include those derived from those associated with lactic acid and dicarboxylic acidemias associated with defective fatty acid degradation
  39. 39. CLINICAL APPROCH TO INFANTS WITH OA
  40. 40. CLINICAL MANIFESTATIONS OF OA  The organic acidemias share many clinical similarities.  A neonate affected with an organic acidemia (OA) is usually well at birth and for the first few days of life.  The usual clinical presentation is that of toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma.  Several rare OAs present with neurologic signs without concomitant biochemical findings such as hyperammonemia and acidosis, e.g. D2hydroxyglutaric aciduria, 3methylglutaconic aciduria caused by 3methylglutaconic acid dehydratase deficiency, and malonic aciduria.
  41. 41.  Methylmalonic aciduria, cblC variant, may present with developmental delay, minor dysmorphology, and hypotonia without acidosis.  Lateonset 3methylcrotonyl carboxylase deficiency may present as developmental delay without Reyelike syndrome, in contrast to the earlyonset form.  In the older child or adolescent, variant forms of the OAs can present as loss of intellectual function, ataxia or other focal neurologic signs, Reye syndrome, recurrent ketoacidosis, or psychiatric symptoms.  A variety of MRI abnormalities have been described in the OAs, including distinctive basal ganglia lesions in glutaricacidemia type I (GA I), white matter changes in maple syrup urine disease (MSUD), and abnormalities of the globus pallidus in methylmalonic acidemia. Macrocephaly is common in GA I.
  42. 42. CLINICAL COURSE  Individuals with organic acidemias have a greater risk of infection and a higher incidence of pancreatitis, which can be fatal.  Methylmalonic acidemia is associated with an increased frequency of renal failure and the cblC variant of methylmalonic acidemia is associated with pigmentary retinopathy and poor developmental outcome in the earlyonset form.
  43. 43. DIAGNOSIS  Acidosis: Serum bicarbonate lower than:  22 mmol/L in individuals younger than age one month  17 mmol/L in neonates  In most organic acidemias, the acidosis is severe, with an anion gap higher than 20. Early in the course, however, the acidosis may be less severe and the anion gap smaller.
  44. 44.  Ketosis: A positive (not trace) urine dipstick for ketones OR A urine organic acid profile containing excess βhydroxybutyrate and acetoacetic acid as defined by the norms of the laboratory performing the test.  Neonates do not normally produce much acetoacetate, ketosis detected in neonates by dipstick should prompt serious consideration of an organic acidemia.  Hyperammonemia: Plasma ammonium concentration exceeding the reference range for the laboratory performing the test and the age of the affected individual, usually greater than:  150 μg/dL in neonates  70 μg/dL in infants to age one month  35-50 μg/dL in older children and adults
  45. 45.  Abnormal liver function tests:  Hypoglycemia: Serum glucose lower than:  40 mg/dL in term and preterm infants  60 mg/dL in children  76 mg/dL over age 16 years  Neutropenia: Absolute neutrophil count (ANC) less than 1500/mm . Total white cell counts vary with age and local laboratory reference ranges may need to be taken into account.
  46. 46. Clinical Findings in Organic Acidemias
  47. 47. DIAGNOSIS CONT…  Gas chromatography/mass spectrometry (GC/MS):  Firstline diagnosis in the organic acidemias is urine organic acid analysis by GC/MS, utilizing a capillary column.  Organic acids can be measured in any physiologic fluid. However, it is most effective to use urine to identify the organic acids that signal these disorders, as semiquantitative methods may not identify the important compounds in plasma  The organic acids found in the urine provide a high degree of suspicion for the specific pathway involved.
  48. 48.  The urinary organic acid profile is nearly always abnormal in the face of acute illness with decompensation.  However, in some disorders the diagnostic analytes may be present only in small or barely detectable amounts when the affected individual is not acutely ill.  Thus, it is critical to obtain a urine sample during the acute phase of the illness, even if the sample needs to be frozen and saved until the testing can be performed.
  49. 49. Metabolic Findings in Organic Acidemias Caused by Abnormal Amino Acid Catabolism
  50. 50. MANAGEMENT  Many of the organic acidemias respond to treatment, and in the neonate especially, early diagnosis and prompt management are essential to a good outcome.  The aim of therapy is to restore biochemical and physiologic homeostasis.  The treatments, while similar in principle, depend on the specific biochemical lesion and are based on the position of the metabolic block and the effects of the toxic compounds
  51. 51.  Treatment strategies are:  Dietary restriction of the precursor amino acids  Use of adjunctive compounds to:  Dispose of toxic metabolites  Increase activity of deficient enzymes o Longterm care: Frequent monitoring of growth, development, and biochemical parameters is essential. Longterm outcome can be excellent in the organic acidemias. However, appropriate management does not guarantee a good outcome, as individuals affected with an OA are medically fragile.
  52. 52. MANAGEMENT OF ACUTE DECOMPENSATION  Frequent episodes of decompensation can be devastating to the central nervous system.  Any source of catabolic stress,such as vomiting, diarrhea, febrile illness, and decreased oral intake can lead to decompensation, which requires prompt and aggressive intervention.  During acute decompensation, treatment strategies are directed toward elimination of the toxic amino acid precursors by restriction of their intake and the use of adjunctive measures such as hemodialysis.  During acute decompensation, critical care support is often required, acidosis may need to be corrected, and careful and frequent biochemical monitoring is crucial.
  53. 53. INDIVIDUAL ORGANIC ACIDURIAS
  54. 54. CLASSIC MAPLE SYRUP URINE DISEASE  Decarboxylation of leucine, isoleucine, and valine is accomplished by a complex enzyme system (branched-chain α-ketoacid dehydrogenase [BCKDH]) using thiamine (vitamin B1) pyrophosphate as a coenzyme.  This mitochondrial enzyme consists of 4 subunits: E1α, E1β, E2, and E3. The E3 subunit is shared with 2 other dehydrogenases in the body, namely pyruvate dehydrogenase and α-ketoglutarate dehydrogenase.  Deficiency of any of these subunits causes maple syrup urine disease (MSUD)named after the sweet odor of maple syrup found in body fluids, especially urine.
  55. 55.  This form has the most severe clinical manifestations.  Affected infants who are normal at birth develop poor feeding and vomiting in the 1st wk of life; lethargy and coma may ensue within a few days.  Physical examination reveals hypertonicity and muscular rigidity with severe opisthotonos. Periods of hypertonicity may alternate with bouts of flaccidity manifested as repetitive movements of the extremities (boxing and bicycling).  Neurologic findings are often mistakenly thought to be caused by generalized sepsis and meningitis.
  56. 56.  Cerebral edema may be present; convulsions occur in most infants, and hypoglycemia is common.  In contrast to most hypoglycemic states, correction of the blood glucose concentration does not improve the clinical condition.  Aside from the serum glucose, routine laboratory findings are usually unremarkable, except for varying degrees of metabolic acidosis.  Death usually occurs in untreated patients in the first few weeks or months of life.
  57. 57.  Diagnosis is often suspected because of the peculiar odor of maple syrup found in urine, sweat, and cerumen.  It is usually confirmed by amino acid analysis showing marked elevations in plasma levels of leucine, isoleucine, valine, and alloisoleucine (a stereoisomer of isoleucine not normally found in blood) and depression of alanine.  Leucine levels are usually higher than those of the other 3 amino acids.  Urine contains high levels of leucine, isoleucine, and valine and their respective ketoacids.  These ketoacids may be detected qualitatively by adding a few drops of 2,4-dinitrophenylhydrazine reagent (0.1% in 0.1N HCl) to the urine; a yellow precipitate of 2,4-dinitrophenylhydrazone, is formed in a positive test.
  58. 58.  Neuroimaging during the acute state may show cerebral edema, which is most prominent in the cerebellum, dorsal brainstem, cerebral peduncle, and internal capsule.  After recovery from the acute state and with advancing age, hypomyelination and cerebral atrophy may be seen in neuroimaging of the brain.  The enzyme activity can be measured in leukocytes and cultured fibroblasts.
  59. 59. T2-weighted MRI demonstrates elevated signal intensity of white matter in the thalamus, globus pallidus, and posterior limb of the internal capsule (A); midbrain (B); and pons and cerebellar white matter (C)
  60. 60.  Treatment of the acute state is aimed at hydration and rapid removal of the branched-chain amino acids and their metabolites from the tissues and body fluids by hemodialysis or peritoneal dialysis.  Cerebral oedema should be treated with mannitol, diuretics or hypertonic saline.  Treatment after recovery from the acute state requires a diet low in branched-chain amino acids.  These amino acids cannot be synthesized endogenously, small amounts of them should be added to the diet; the amount should be titrated carefully by performing frequent analyses of the plasma amino acids.
  61. 61.  Liver transplantation has been performed in a number of patients with classic MSUD with promising results. These children have been able to tolerate a normal diet.  The long-term prognosis of affected children remains guarded.  Severe ketoacidosis, cerebral edema, and death may occur during any stressful situation such as infection or surgery, especially in midchildhood.  Cognitive and other neurologic deficits are common sequelae.
  62. 62. ISOVALERIC ACIDEMIA  This condition is caused by the deficiency of the enzyme isovaleryl CoA dehydrogenase.  Lethargy, convulsions, and coma may ensue in acute form.  The characteristic odor of “sweaty feet” may be present (in body sweat and cerumen, but not in the urine).  Diagnosis is established by demonstrating marked elevations of isovaleric acid and its metabolites (isovalerylglycine, 3-hydroxyisovaleric acid) in body fluids, especially urine. The main compound in plasma is isovalerylcarnitine, which can be measured even in a few drops of dried blood on a filter paper.
  63. 63.  Along with other supportive measures,as isovalerylglycine has a high urinary clearance, administration of glycine (250 mg/kg/24 hr) is recommended to enhance formation of isovalerylglycine. l-Carnitine (100 mg/kg/24 hr orally) also increases removal of isovaleric acid by forming isovalerylcarnitine, which is excreted in the urine.  After recovery from the acute attack, the patient should receive a low-protein diet (1.0-1.5 g/kg/24 hr) and should be given glycine and carnitine supplements. Pancreatitis (acute or recurrent forms) has been reported in survivors.  Normal development can be achieved with early and proper treatment.
  64. 64. HOLOCARBOXYLASE SYNTHETASE DEFICIENCY (MULTIPLE CARBOXYLASE DEFICIENCY NEONATAL OR EARLY FORM)  Infants with this rare autosomal recessive disorder become symptomatic in the first few weeks of life.  Symptoms may appear as early as a few hours after birth to 21 mo of age.  Clinically, the affected infants who seem normal at birth develop breathing difficulties (tachypnea and apnea) shortly after birth.  Feeding problems, vomiting, and hypotonia are also commonly present.
  65. 65.  If the condition remains untreated, generalized erythematous rash with exfoliation and alopecia (partial or total), failure to thrive, irritability, seizures, lethargy, and even coma may occur.  Developmental delay is common.  Immune deficiency manifests with susceptibility to infection.  The urine may have a peculiar odor, which has been described as similar to tomcat urine.  Laboratory findings include metabolic acidosis, ketosis, hyperammonemia, and the presence of a variety of organic acids (lactic acid, propionic acid, 3- methylcrotonic acid, 3-methylcrotonylglycine, tiglylglycine, methylcitrate, and 3-hydroxyisovaleric acid) in body fluids.  Diagnosis is confirmed by the enzyme assay in lymphocytes or cultured fibroblasts or by identification of the mutant gene
  66. 66.  Treatment with biotin (10 mg/day orally) usually results in an improvement in clinical manifestations and may normalize the biochemical abnormalities.  Early diagnosis and treatment are critical to prevent irreversible neurologic damage.  In some patients, however, complete resolution may not be achieved even with large doses (up to 80 mg/day) of biotin.
  67. 67. 3-METHYLGLUTACONIC ACIDURIA TYPE III (COSTEFF OPTIC ATROPHY SYNDROME)  Clinical manifestations in these patients include early onset optic atrophy and later development of choreoathetoid movements, spasticity, ataxia, dysarthria, and mild developmental delay.  These patients excrete moderate amounts of 3- methylglutaconic and 3-methylglutaric acids.  Activity of the enzyme 3-methylglutaconyl CoA hydratase is normal.  The reason for the increased excretion of these organic acids remains unclear.  No effective treatment is available.
  68. 68. 3-HYDROXY-3-METHYLGLUTARIC ACIDURIA  This condition is a result of a deficiency of HMG- CoA lyase.This enzyme catalyzes the conversion of HMG-CoA to acetoacetate and is a rate-limiting enzyme for ketogenesis.  Episodes of vomiting, severe hypoglycemia, hypotonia, acidosis with mild or no ketosis, and dehydration may rapidly lead to lethargy, ataxia, and coma.  Urinary excretion of 3-hydroxy-3-methylglutaric acid and other proximal intermediate metabolites of leucine catabolism (3-methylglutaconic acid and 3- hydroxyisovaleric acid) is markedly increased causing the urine to smell like cat urine
  69. 69. MEVALONIC ACIDURIA  Mevalonic acid, an intermediate metabolite of cholesterol synthesis, is converted to 5- phosphomevalonic acid by the action of the enzyme mevalonate kinase (MVK).  Clinical manifestations in severe form include intellectual disability, failure to thrive,growth retardation, hypotonia, ataxia, hepatosplenomegaly, cataracts, and facial dysmorphism (dolichocephaly, frontal bossing, low-set ears, downward slanting of the eyes, and long eyelashes).  Along with high mevalonic acid in urine, Serum concentration of creatine kinase is markedly increased.
  70. 70. PROPIONIC ACIDEMIA (PROPIONYL COENZYME A CARBOXYLASE DEFICIENCY)  In the severe form of the condition, patients develop symptoms in the first few days or weeks of life.  Poor feeding, vomiting, hypotonia, lethargy, dehydration, and clinical signs of severe ketoacidosis progress rapidly to coma and death.  Seizures occur in approximately 30% of affected infants.  Moderate to severe intellectual disability and neurologic manifestations reflective of extrapyramidal (dystonia, choreoathetosis, tremor), and pyramidal (paraplegia) dysfunction are common sequelae in the older survivors.
  71. 71.  Neuroimaging shows these abnormalities, which usually occur after an episode of metabolic decompensation, to be a result of damage to the basal ganglia, especially to the globus pallidus.  This phenomenon has been referred to in the literature as metabolic stroke. This is the main cause of neurologic sequelae seen in the surviving affected children.  In acute form, besides supportive measures, gut sterilization by neomycin or metronedazole should be done to curtail the production of propionic acid by intestinal flora.  Long-term treatment consists of a low-protein diet (1.0-1.5 g/kg/24 hr) and administration of l-carnitine (50-100 mg/kg/24 hr orally).
  72. 72. METHYLMALONIC ACIDEMIA  Mental development and IQ of patients with methylmalonic acidemia may remain within the normal range despite repeated acute attacks and regardless of the nature of the enzyme deficiency.  Vitamin B12 should be added in treatment of the patients having defects in B12 metabolism.  Metabolic strokes have been reported in a few patients during an acute episode of metabolic decompensation.  These patients have survived with major extrapyramidal (tremor, dystonia) and pyramidal (paraplegia) sequelae.
  73. 73. GLUTARIC ACIDURIA TYPE 1  Glutaric aciduria type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-CoA dehydrogenase.  It results in the accumulation of 3-hydroxyglutaric and glutaric acid.  Glutaric acid has a cytotoxic effect and causes cerebral atrophy and brain damage.  It is characterized by macrocephaly at birth or shortly after, dystonia, and many times resembling seizures at the first episode, with degeneration of the caudate and the putamen.
  74. 74.  MRI brain reveals frontotemporal atrophy, dilated sylvian fissures with open opercula (arrow), diffuse hyperintense lesions in bilateral basal ganglia, and both frontal whitematter and bilateral periventricular area.Widening of the sylvian fissure gives the characteristic “bat-wing” appearance.
  75. 75.  Therapy consists in carnitine supplementation to remove glutaric acid, a diet restricted in amino acids capable of producing glutaric acid, and prompt treatment of intercurrent illnesses.  Early diagnosis and therapy reduce the risk of acute dystonia in patients with GA-1
  76. 76. THANK YOU………..

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