Inborn Errors of Metabolism & Amino Acid Metabolism

Inborn Errors of Metabolism (IEM)

• IEMs originate from Garrod's idea of chemical individuality.
• Beadle and Tatum expanded this with the "one gene-one enzyme" hypothesis.
• There are over 200 different types of IEMs, affecting food-to-energy conversion.
• Most are inherited in an autosomal recessive or X-linked recessive pattern and are caused by enzyme deficiencies.

Amino Acid Metabolism

• Phenylalanine converts to tyrosine, melanin, and neurotransmitters via phenylalanine hydroxylase and BH4.
• Tyrosine is metabolized to homogentisic acid, which then becomes CO2 and H2O via homogentisic acid oxidase.
• Tyrosine transforms into melanin through tyrosinase, DOPA, dopaquinone, and several steps.

Amino Acid Metabolism Disorders

• Phenylketonuria (PKU) results from deficiency in phenylalanine hydroxylase (PAH), preventing conversion of phenylalanine to tyrosine.
• PKU leads to the accumulation of phenylalanine and phenylpyruvic acid, resulting in intellectual impairment and seizures.
• Tyrosine deficiency reduces melanin formation in PKU, leading to blond hair, blue eyes, and hypopigmentation of the brain.
• PKU treatment involves a phenylalanine-restricted diet to prevent mental impairment if started early, and is diagnosed through newborn screening via the Guthrie test or biochemical assays.
• Alkaptonuria is caused by homogentisic acid oxidase deficiency, leading to homogentisic acid accumulation.
• Alkaptonuria signs include dark urine, dark ear wax, and joint problems.
• Albinism results from a missing tyrosinase enzyme, which can't make melanin, and affects the skin, hair, and eyes.
• Albinism signs include no pigment in the skin, hair, or eyes, and vision problems, and treatment includes sun protection and vision aids.
• Homocystinuria is due to cystathionine B-synthase deficiency that causes homocystine accumulation.
• Homocystinuria symptoms include learning disability, seizures, Marfan-like features, osteoporosis, scoliosis, and thrombophilia
• Homocystinuria is diagnosed with a positive cyanide nitroprusside test and elevated plasma homocystine.
• Treatment involves a low-methionine diet with cystine supplementation and sometimes pyridoxine (B6).
• Maple Syrup Urine Disease (MSUD) results from deficiency of branched-chain ketoacid decarboxylase, leading to accumulation of leucine, isoleucine, and valine.
• Branched-chain amino acids accumulate resulting in neurotoxicity
• MSUD symptoms include sweet-smelling urine (maple syrup odor), vomiting, and seizures.
• Detection of branched-chain amino acids in blood and urine is used in diagnosis, and strict dietary restriction of branched-chain amino acids is used in treatment.

Urea Cycle Disorders

• The urea cycle is a five-step metabolic pathway in liver cells that removes waste nitrogen from amino acids.
• The urea cycle converts ammonia (NH3) and bicarbonate (HCO3¯) into urea for excretion.
• Enzyme deficiencies disrupt this cycle, causing hyperammonemia (toxic ammonia buildup).
• Neurological toxicity, potentially leading to coma and death if untreated is a key symptom
• Urea Cycle Disorders are mostly autosomal recessive, except for X-linked ornithine transcarbamylase deficiency, and are rare but life-threatening if not managed.

Carbohydrate Metabolism Disorders

Galactosemia

• Galactosemia is an autosomal recessive disorder due to galactose 1-phosphate uridyl transferase deficiency, preventing metabolism of galactose from lactose (milk sugar), and causing a toxic buildup.
• Symptoms include liver problems, brain damage, and cataracts, and it's diagnosed with a test for reducing substances in urine (specific galactose test)
• Treatment involves galactose/lactose-free milk substitutes.

Glycogen Storage Diseases (GSDs)

• GSDs are due to deficiencies in enzymes for glycogen metabolism, leading to glycogen accumulation
• GSDs cause hypoglycemia, liver dysfunction, muscle weakness, and neurological issues, and are typically autosomal recessive, aside from some X-linked variants.

Glycogen Storage Diseases Primarily Affecting the Liver

• In von Gierke Disease (GSD-I), a Glucose-6-phosphatase deficiency prevents glycogen breakdown to glucose, leading to the inability to release glucose from the liver, low blood sugar, and an enlarged liver. Frequent feeding and avoiding fasting is the course of treatment.
• In Cori Disease (GSD-III), an Amylo-1,6-glucosidase (debrancher enzyme) deficiency allows complex glycogen structures to accumulate, affecting both the liver and muscles. Frequent feeding and avoiding fasting is the course of treatment.
• Anderson Disease (GSD-IV) results from Glycogen brancher enzyme deficiency (which forms long, abnormal glycogen chains), causing hypotonia and liver dysfunction, progressing to liver failure. There is no effective treatment, but a liver transplant is potentially an option.
• Hepatic Phosphorylase Deficiency (GSD-VI) results from deficiency of hepatic phosphorylase (multimeric enzyme, some X-linked cases), causing hepatomegaly, hypoglycemia, and failure to thrive in early childhood. Treatment uses carbohydrate supplementation.

Glycogen Storage Diseases Primarily Affecting the Muscle

• Pompe Disease (Type II) results from a missing Alpha-1,4-glucosidase enzyme, causing glycogen to accumulate in muscles, severe muscle weakness, and heart problems, and often leads to fatality in infancy without treatment.
• McArdle Disease (Type V) is due to missing muscle phosphorylase enzyme, making it impossible to use stored muscle glycogen, causing exercise intolerance. Exercise-induced cramps are a sign.

Steroid Metabolism Disorders

Congenital Adrenal Hyperplasia (CAH)

• CAH is often caused by a missing 21-Hydroxylase enzyme, disrupting cortisol production and causing excess male hormone production.
• In CAH, girls may develop masculine features, and salt loss is possible.
• Treatment involves hormone replacement.

Androgen Insensitivity Syndrome

• Androgen Insensitivity Syndrome results from a defective androgen receptor.
• The body can't respond to male hormones, and XY individuals can develop female features.
• Female external features, no uterus/ovaries, and presence with hernias or amenorrhea are all signs.
• Treatment involves removing the testes (cancer risk) and estrogen replacement.

Important Points to Remember

• Most disorders involve missing/defective enzymes.
• Problems arise both from harmful substance buildup and essential product deficiency.
• Many disorders are treatable but not curable.
• Early diagnosis improves outcomes.
• Lifelong management is required for most.

Lipid Metabolism Disorders

Familial Hypercholesterolemia (FH)

• High cholesterol levels increase the risk of premature coronary artery disease.
• FH can present with xanthomata (lipid deposits under the skin) in childhood or adolescence.
• Defective or deficient LDL receptors lead to increased cholesterol synthesis.
• Four main LDL receptor mutations include: defective biosynthesis, defective transport to the Golgi, abnormal LDL binding, and abnormal LDL internalization.
• Treatment involves dietary restriction and statins (inhibit HMG-CoA reductase).

Lysosomal Storage Disorders (LSDs)

• Deficiency of lysosomal enzymes leads to accumulation of macromolecules.
• Symptoms only become apparent after birth
• Defective degradation of glycosaminoglycans (GAGs) causes progressive skeletal, vascular, and CNS issues, also known as Mucopolysaccharidoses (MPSs).
• MPSS is diagnosed via urinary GAG excretion and enzyme assays.
• All disorders are autosomal recessive except Hunter syndrome (X-linked).

Specific Lysosomal Storage Disorders

• Hurler Syndrome (MPS-I) is the most severe MPS, presenting in the first year with corneal clouding, coarse facial features, hepatosplenomegaly, and joint stiffness, progressing to mental deterioration and death by adolescence. Alpha-L-iduronidase deficiency is involved.
• Hunter Syndrome (MPS-II), an X-linked disorder, presents between 2-5 years with hearing loss, facial coarsening, hepatosplenomegaly, and skeletal abnormalities, leading to progressive deterioration and death in adolescence. Iduronate sulfate sulfatase deficiency is involved.
• Sanfilippo Syndrome (MPS-III) is the most common MPS, causing progressive intellectual decline, behavioral issues, seizures, and death in early adulthood. Four different enzymes involved in heparan sulfate degradation.
• Morquio Syndrome (MPS-IV) presents around age 2-3 with short stature, kyphoscoliosis, normal intelligence, and the risk of spinal cord compression. Deficiencies in Galactosamine-6-sulfatase (MPS-IV A) and ẞ-galactosidase (MPS-IV B) is involved.
• Sly Syndrome (MPS-VII) has a variable presentation with skeletal abnormalities, hepatosplenomegaly, corneal clouding, and cardiac issues, leading to death in childhood or adolescence. B-glucuronidase deficiency is involved.
• Enzyme replacement therapy has limitations and Bone marrow transplantation provides only partial improvement.

Lipid Storage Disorders

• Deficient degradation of sphingolipids leads to accumulation in the brain, liver, and spleen, and also to progressive mental decline and seizures

Tay-Sachs Disease

• Tay-Sachs results from hexosaminidase A deficiency, with GM2 ganglioside accumulating and causing neuronal damage.
• Signs/symptoms include cherry-red spot in retina, developmental regression, and supportive care is the treatment.

Gaucher Disease

• Gaucher Disease is the most common sphingolipidosis
  • Type I (adult onset) involves Hepatosplenomegaly, bone pain, anemia, pathological fractures, and No CNS involvement. ERT treatment is used (β-glucosidase with mannose 6-phosphate).
  • Type II (infantile onset) presents at 3-6 months with failure to thrive, neurological decline, and seizures
• Deficiency: Glucosylceramide B-glucosidase affects both Type I & II

Niemann-Pick Disease

• Niemann-Pick involves P failure to thrive, hepatomegaly, and a cherry-red macula during infancy, progressive neurodegeneration resulting in death by age 4 occurs.
• Foam cells present in bone marrow due to Sphingomyelinase deficiency.

Purine/Pyrimidine Disorders

• Classic disorder of purine metabolism, caused by deposits of uric acid crystals in joints, potentially due to genetic and environmental factors, also increased purine turnover or reduced excretion

Lesch-Nyhan Syndrome

• X-linked disorder is caused by hypoxanthine guanine phosphoribosyltransferase deficiency.
• Leads to increased purine synthesis and uric acid accumulation
• Symptoms: neurological issues (uncontrolled movements, spasticity, mental retardation), compulsive self-mutilation
• Allopurinol treatment lowers uric acid, but isn't fully effective

Adenosine Deaminase Deficiency

• A severe combined immunodeficiency (SCID) that is autosomal recessive
• Affects B- and T-cell function, causing recurrent infections, fatal if untreated
• Diagnosis involves testing for low adenosine deaminase activity in red blood cells
• Treatment is bone marrow transplantation

Purine Nucleoside Phosphorylase Deficiency

• Causes isolated T-cell dysfunction, leading to recurrent, severe viral infections
• Temporary improvement with irradiated red blood cells is possible.

Porphyrin Metabolism Disorders

• These are due to deficiency of enzymes in the biosynthesis of heme (iron-containing component of hemoglobin)
• Mostly autosomal dominant, but congenital erythropoietic porphyria is autosomal recessive
• Can be classified as hepatic or erythropoietic
• Symptoms: neurological, visceral, or skin involvement due to porphyrin precursor accumulation.

Hepatic Porphyrias

Acute Intermittent Porphyria (AIP)

• Symptoms: recurrent attacks of abdominal pain, weakness, vomiting, confusion, emotional distress, hallucinations
• Women are more affected & symptoms are linked to their menstrual cycle
• It can be triggered by certain drugs (steroids, anticonvulsants, barbiturates)
• Caused by: partial deficiency of uroporphyrinogen I synthase which leads to increased urinary porphobilinogen and ō-aminolevulinic acid

Hereditary Coproporphyria (HCP)

• Autosomal dominant
• Clinically similar to AIP but ~1/3 of cases also have photosensitivity

Porphyria Variegata (PV)

• Particularly common in South African Afrikaans populations
• Symptoms: variable skin photosensitivity, neurological and visceral issues, drug-triggered attacks
• Diagnosis: increased fecal porphyrins (protoporphyrin, coproporphyrin)
• Cause: protoporphyrinogen oxidase deficiency

Erythropoietic Prophyrias

Congenital Erythropoietic Porphyria (CEP)

• Symptom: extreme photosensitivity with blistering and scarring
• Red-brown discoloration of teeth
• Often requires blood transfusions and splenectomy due to hemolytic anemia
• Cause: deficiency of uroporphyrinogen III synthase

Erythropoietic Protoporphyria (EPP)

• Cause: ferrochelatase deficiency, preventing proper heme formation
• Symptom: photosensitivity, sometimes chronic liver disease
• Treatment: B-carotene reported to help with photosensitivity

Other Metabolism Disorders

Organic Acid Disorders

• Common Symptoms: Poor feeding, vomiting, lethargy, metabolic acidosis, neutropenia, thrombocytopenia, hypoglycemia, hyperammonemia, hyperglycinemia
• Common Triggers: Intercurrent illness, increased protein intake
• Methylmalonic acidemia results from Deficiency of methylmalonyl-CoA mutase
• Propionic acidemia results from Deficiency of propionyl-CoA carboxylase
• Treatment: Infection management, fluid replacement, protein restriction
  • Some cases respond to biotin (propionic acidemia) or vitamin B12 (methylmalonic acidemia)

Disorders of Copper Metabolism

Menkes Disease

• X-linked recessive disorder
• Common Symptoms: Feeding difficulties, hypotonia, seizures, brittle/kinky hair, neurological decline, death by 3 years
• Cause: Defect in ATPase copper transport protein, resulting in limited success with copper supplementation

Wilson Disease

• Autosomal recessive disorder
• Common Symptoms: Neurological issues (tremors, dystonia, psychiatric symptoms), liver dysfunction, Kayser-Fleischer rings (corneal copper deposits)
• Cause: Defect in copper-transporting ATPase, leading to copper accumulation
• Treatment: Copper chelators (D-penicillamine, trientine)

Peroxisomal Disorders

Zellweger Syndrome

• Common Symptoms: Hypotonia, facial dysmorphisms, seizures, developmental regression, early death
• Cause: Defect in peroxisome biogenesis
• Diagnosis: Elevated plasma long-chain fatty acids

Adrenoleukodystrophy (ALD)

• X-linked
• Symptom: School difficulties, neurological decline, adrenal insufficiency
• Cause: ABCD1 gene mutation affecting peroxisomal membrane protein
• Treatment: The use of Lorenzo's oil

Mitochondrial Disorders

• Fatty acids undergo activation to acyl-CoA, transport into mitochondria (via carnitine shuttle), B-oxidation, Acetyl-CoA, TCA cycle, and then Energy (ATP)
• Common manifestations include: Neurological problems, Muscle weakness, Developmental issues, and Organ dysfunction