Tegay - Organic Acidemias

Organic Acidemias Background

• All autosomal recessive

• Primarily disorders of amino acid catabolism

  • Branch chain amino acids or Lysine

• Major toxicity is from organic acid accumulation causing a metabolic “anion gap”

• Secondary toxic effects of acidosis on

  • Mitochondria → Lactic acidemia

  • Urea Cycle → Hyperammonemia

  • Bone Marrow → Bone marrow suppression

  • CNS Function → Encephalopathy / MR

• Major toxicity is from Organic Acid Accumulation

  • Causes metabolic acidosis with increased anion gap due to decrease in bicarbonates

• Major presentation is neonatal encephalopathic acidosis, late chronic / intermittent

Metabolic Acidosis / Anion Gap

• Blood pH low from excessive acid vs based

• AG = [Na⁺] - ([Cl^-] + [HCO₃^-]

• Multiple etiologies for Metabolic Acidosis

  • Lowered HCO₃^- from diarrhea, medications, RTA

  • Elevated H+ from DKA, starvation, lactic acidosis, acid ingestions, organic acidosis

• Causes

  • Neonate: lethargy, vomitting, tachypnea, hypotonia, seizures, coma, death

  • Adult: DD, ataxia, neurological deficits, lethargy, vomitting, tachypnea, seizures, coma, death

Organic Acidemias Treatment

• Restrict dietary protein

• Prevent catabolism via sufficient protein free calories

• Reverse acidosis ± hyperammonemia

  • Hemodialysis

  • Ammonia and lactic acid scavengers

• Cofactory therapy for specific disorders

Proprionic Acidemia (PA)

• Autosomal recessive

  • Proprionyl-CoA Carboxylase (PCC) alpha or beta subunit genes

    • Gene sequencing with deletion / duplication analysis

• Aka

  • Classic organic acidemia with neonatal toxic encephalopathy

• Proprionyl-CoA Carboxylase (PCC) alpha or beta subunit genes cofactor is biotin

  • Proprionic acid accumulation from MET/THR/VAL/ISO catabolism, gut bacteria, odd chain fatty acids

• Symptoms

  • Classic

    • Normal at birth

    • Within a few days, poor feeding, lethargy, vomiting, hypotonia → encephalopathy, seizures, coma, death

  • Late onset

    • Developmental delay / regression, cyclic vomiting, protein intolerance, growth impairment, hypotonia, metabolic basal ganglia strokes, cardiomyopathy

    • Acute episodes of toxic encephalopathy

  • Rare cardiac subtype

    • Isolate cardiomyopathy

  • Diagnosed via elevated C3 (Proprionyl) Acylcarnitine (and ratios)

    • Arterial blood gas, Complete metabolic profile, Ammonia, Complete blood count

    • Urine organic acid analysis

      • High 3-OH-proprionate, methylcitrate, tigyl / proprionylglycine but not MMA

    • Plasma amino acid profile

      • Elevated glycine and glutamine but not homocysteine

    • Acyl-Carnitine profile

    • PCC Enzyme Activitiy

      • Can measure PCC enzyme in leukocytes or fibroblasts

      • Useful prenatal when measuring enzyme activity from amniotic fluid, CVS, amnio

• Treatment

  • Improved outcomes with treatments but still some degree of MR, metabolic basal ganglia stroke, pancreatitis, growth impairment, AA deficiencies, renal failure, visual deficits

    • Acute

      • Hemodialysis

      • Protein restriction

      • IV glucose and lipids

      • IV Carnitine

      • IV Ammonia scavengers

      • Antibiotics

      • Biotin

    • Chronic

      • Protein restruction

      • Oral L-Carnitine, Biotin, Antibiotics

      • Avoid decompensation (Infex, surgery, fever, protein)

      • May consider liver transplant

Isovaleric Acidemia (IVA)

• Autosomal recessive

  • IsoValeryl-CoA Dehydrogenase (IVD) Gene Mutation

  • IVD Gene with deletion / duplication

• Symptoms

  • Disorder of leucine metabolism, increased isovaleric acid

  • Sweaty feet odor

  • Severe neonatal onset form

    • Normal birth

    • Within a few days, poor feeding, lethargy, vomiting, hypotonia, encephalopathy, seizures, coma, death

  • Mild / Late Onset Form

    • Unexplained failure to thrive and DD, at risk for catastrophic decompensation with fasting, protein loads, or illness

  • Benign form

    • Typically asymptomatic but may mildly decompensate

  • Diagnosed via elevated C5 (Isovaleryl) Acylcarnitine

    • Arterial blood gas, Complete metabolic profile, Ammonia, Complete blood count

    • Urine organic acid analysis

      • High IVA and Isovaleryl Glycine but no 2MBG

    • Plasma amino acid profile

      • Elevated glycine and glutamine

    • Acyl-Carnitine profile

    • Enzyme Activitiy

      • Can measure enzyme in fibroblasts

      • Useful prenatal when measuring enzyme activity from amniotic fluid, CVS, amnio

• Treatment

  • Outcome normal if detected and treated before severe symptoms

  • Acute

    • Hemodialysis

    • Protein restriction

    • IV glucose and lipids

    • IV Carnitine

    • IV Ammonia scavengers

    • Glycine supplementation

  • Chronic

    • Protein restruction

    • Oral L-Carnitine, L-Glycine

    • Avoid decompensation (Infex, surgery, fever, protein)

Biotinidase Deficiency (BTD)

• Autosomal recessive

  • Biotinidase (BTD) Gene Mutation

    • Results in deficient biotin recycling and biotin deficiency

    • Biotin is a cofactor of multiple carboxylases

  • BTD Deletion / Duplication Analysie

• Symptoms

  • Profound Deficiency (<10% enzyme)

    • Normal at birth

    • Symptoms develop after a few months

    • Developmental delay, seizures, hypotonia, ataxia, hearing loss, visual problems (optic atrophy), alopecia & eczemetous skin rash​

    • With age develop visual loss, limb weakness & spastic paresis

  • Partial Delay (10-30% enzyme)

    • Intermittent symptoms with stress​

    • Hypotonia, skin rash, hair loss or any of the above symptoms

  • Symptoms irreversible once present

• Diagnosed via elevated C5-OH Acylcarnitine but many other conditions cause that

  • ABG, CMP, Ammonia, CBC​

    • +/- High AG metabolic acidosis, elevated ammonia, low glucose​

  • Urine Organic Acid Analysis​

    • 3-B-OH-isovaleric,3-methylcrotonic, 3-OH-propionic, Methylcitric, 3-OH-butyric acids, Acetoacetate, Propionyl glycine, Tiglylglycine​

  • Acyl-Carnitine Profile​

    • Elevated C5-OH acylcarnitine​

  • Enzyme Activity​

    • Can assay in blood (serum/plasma), if normal then it’s Holocarboxylase deficiency, useful for prenatal / preimplanation as can be measured in amniocytes

• Treatment

  • Normal outcomes if detected and treated before symptoms, the best out of all organic acidemias

    • If after, some symptoms irreversible

  • Rarely Severely Acidotic or Hyperammonemic

    • May occasionally need sodium bicarbonate ​

    • May occasionally need ammonia scavengers ​

    • Institute Biotin therapy immediately​

  • Chronic Treatment

    • Biotin therapy​

    • No protein restriction or other treatment necessary​

    • Avoid raw egg whites (avidin protein binds Biotin)​

3-MethylCrotonyl-CoA (3-MCC)

• Autosomal Recessive​

  • 3-Methylcrotonyl-CoA Carboxylase (3-MCCC) Subunit 1 or 2 Genes (Biotin is cofactor)​

    • A Leucine metabolism pathway defect​

• Symptoms​

  • May be asymptomatic ​

  • Some have episodic liver dysfunction, hypotonia, hypoglycemia​

  • May cause developmental delay and seizures ​

• Diagnosis​

  • Newborn Screen & acyl-carnitine profile = High C5-OH (if only NBS may be maternal)​

  • High Organic Acids: High 3-Methylcrotonylglycine and 3-hydroxyisovaleric acids

• Treatment​

  • Restrict Leucine, supplement with LEU free metabolic formula​

  • Carnitine Supplementation and Biotin supplementation (often responsive)​

• Prognosis​

  • May have no symptoms or if symptomatic may respond to Biotin​

  • If symptomatic but not Biotin responsive prognosis may be poor​

3-Hydroxy-3-methlglutaryl (3-HMG) CoA Lyase Deficiency

• Autosomal Recessive

  • 3-HMG-CoA Lyase (HMGCL) Gene Mutation

• Symptoms

  • Unknown prognosis

  • Another Leucine metabolism pathway defect

    • May be asymptomatic until decompensation, minimal acidosis in decompensations

      • Liver Dysfunction “Reye Syndrome” with hyperammonemia and hypoglycemia

• Diagnosed via acyl-carnitine profile

  • High C5-Hydroxyacylcarnitine (C5-OH)

  • High Organic Acids:  3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids

• Treatment

  • Restrict Leucine, LEU free metabolic formula

  • Carnitine Supplementation

Glutaric Acidemia Type 1 (GA1)

• Autosomal recessive

  • “Cerebral” Organic Acidemia

  • Glutaryl-CoA Dehydrogenase (GCDH) Gene Mutation

    • Deletion / Duplication analysis

• Symptoms

  • High AG metabolic acidosis, elevated ammonia, low glucose​, elevated glutaric acid and 3-hydroxyglutaric acid

  • Often normal at birth or only macrocephalic

  • Symptoms begin a 2 years

    • May start with neurologic decompensation

      • Often precipitated by fever, illness, surgery, metabolic stress

    • Stress-induced encephalopathy

    • Ataxia

    • Epilepsy

    • Myoclonus

    • Extrapyramidal symptoms

    • Stroke like symptoms

    • Hypotonia, irritability, motor delay, dyskinesias

• Diagnosed via

  • ABG, CMP, Ammonia, CBC,​

    • +/- High AG metabolic acidosis, elevated ammonia, low glucose​

  • Plasma and Urine Acyl-Carnitine Profile​

    • +/- Elevated C5-DC (glutaryl) acylcarnitine​

  • Urine and Plasma (and CSF if available) Organic Acid Analysis​

    • +/- 3-OH-glutaric acid and glutaric acid​

  • Enzyme Activity​

    • Fibroblast enzyme assay​

  • CT/MRI: ​

    • Cerebellar & cerebral atrophy, basal ganglia infarct & hemorrhage​

• Treatment

  • Reverse/Prevent catabolism when sick

    • Portein free calories (IV dextrose and intralipids)

  • Dietary modification

    • Low lysine and tryptophan diet

  • Medications

    • Riboflavin B2 cofactor

    • Carnitine helps bind excess glutaric acid

  • Avoid valproate (binds carnitine)