Metabolic Disorders Overview

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Questions and Answers

What are metabolic disorders and how do they arise?

Metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to an accumulation or deficiency of specific metabolites.

Name three categories under small molecule disorders and provide one example from each.

The three categories are Amino Acid Disorders (e.g., PKU), Organic Acid Disorders (e.g., Propionic Acidemia), and Urea Cycle Disorders (e.g., OTC deficiency).

Describe the primary issue in Glycogen Storage Diseases and name two specific types.

Glycogen Storage Diseases primarily involve deficiencies in enzymes responsible for glycogen metabolism. Two specific types are von Gierke disease (GSD I) and Pompe disease (GSD II).

What defines carbohydrate intolerance disorders, and list one condition associated with this classification?

Carbohydrate intolerance disorders are characterized by the inability to properly metabolize certain carbohydrates. An example is galactosemia. Signup and view all the answers

Explain the impact of deficiencies in gluconeogenesis and name one related disorder.

Deficiencies in gluconeogenesis impact the body's ability to produce glucose from non-carbohydrate sources, which can lead to hypoglycemia. Pyruvate Carboxylase Deficiency is one related disorder. Signup and view all the answers

What are some common mitochondrial disorders?

Leigh syndrome, Kearns-Sayre syndrome, MELAS, and MERRF are common mitochondrial disorders. Signup and view all the answers

Describe the metabolic emergency indicated by a low pH and low bicarbonate levels.

This condition is metabolic acidosis, commonly seen with amino acid disorders and organic acid disorders. Signup and view all the answers

What metabolic disorder is characterized by severe hypotonia and developmental regression?

These symptoms are indicative of acute presentations in metabolic emergencies, such as those related to lysosomal storage disorders. Signup and view all the answers

Identify two types of fatty acid oxidation disorders.

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) and Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) are two types. Signup and view all the answers

What are the initial tests to conduct when handling a metabolic emergency?

Initial tests include CBC, glucose, urinalysis, ammonia, and arterial blood gases (ABG). Signup and view all the answers

Explain hyperammonemia and its significance in metabolic disorders.

Hyperammonemia is characterized by elevated ammonia levels, often seen in urea cycle defects and organic acidemia. Signup and view all the answers

What is the significance of treating hypoglycemia in metabolic emergencies?

Treating hypoglycemia is crucial because it helps restore energy levels and prevents further catabolism. Signup and view all the answers

What types of presentations are typically observed with amino acid metabolism disorders?

Amino acid metabolism disorders typically present with lethargy or vomiting in infancy. Signup and view all the answers

How do respiratory alkalosis and metabolic acidosis differ in their causes?

Respiratory alkalosis is caused by hyperventilation, while metabolic acidosis results from increased acid production or decreased bicarbonate. Signup and view all the answers

What is a characteristic feature of lysosomal storage disorders?

A characteristic feature is organomegaly, along with developmental delays or neurologic decline. Signup and view all the answers

What infusion rate of dextrose is suggested to suppress catabolism?

8-10 mg/kg/min Signup and view all the answers

Name two medications that can assist with the urea cycle.

L-carnitine and L-arginine Signup and view all the answers

Which type of glycogen storage disease is associated with acid maltase deficiency?

Pompe disease (GSD Type II) Signup and view all the answers

In GSD Type I, what characteristic physical feature is often described?

Doll face appearance Signup and view all the answers

What is the second-wind phenomenon observed in McArdle’s disease?

Improvement in exercise tolerance after slowing down. Signup and view all the answers

List the primary triggers for fatty acid oxidation defects.

Prolonged fasting and significant stress Signup and view all the answers

What does the elevated lactate level indicate in mitochondrial disorders?

A defect in high-energy systems metabolism. Signup and view all the answers

Which syndrome is characterized by regression after a viral infection, ataxia, and seizures?

Leigh Syndrome Signup and view all the answers

What genetic inheritance pattern is associated with MELAS?

Maternal inheritance due to mitochondrial DNA mutations. Signup and view all the answers

How is classic PKU primarily diagnosed biochemically?

By measuring elevated blood and urine levels of phenylalanine. Signup and view all the answers

Describe a potential outcome of untreated MCAD deficiency.

It may result in sudden infant death. Signup and view all the answers

What dietary intervention is typically recommended for patients with glycogen storage diseases?

High protein and low carbohydrate diet. Signup and view all the answers

What metabolic change can occur during catabolic insults such as fasting?

Metabolic decompensation with poor feeding and lethargy. Signup and view all the answers

In mitochondrial disorders, which organs are most commonly affected?

Brain, heart, muscles, and liver. Signup and view all the answers

What initial treatment should be administered for an acute episode of fatty acid oxidation defects?

IV dextrose. Signup and view all the answers

What is the main dietary treatment for phenylketonuria (PKU)?

A protein-formula without phenylalanine. Signup and view all the answers

What inheritance pattern is associated with Nonketotic Hyperglycinemia?

Autosomal recessive (AR). Signup and view all the answers

What clinical feature is associated with classic homocystinemia?

Tall, thin body stature and marfanoid features. Signup and view all the answers

During which period do persistent hiccups in utero indicate potential Nonketotic Hyperglycinemia?

In the fetal period. Signup and view all the answers

What does elevated glycine in CSF indicate in the context of Nonketotic Hyperglycinemia?

A glycine level that is 30 times normal. Signup and view all the answers

What is the recommended treatment for Methylmalonic Aciduria?

Dietary management and possibly B12 supplementation. Signup and view all the answers

What key finding distinguishes Glutaric Aciduria Type I from other disorders?

Macrocephaly and frontotemporal atrophy visible on MRI. Signup and view all the answers

In classic Maple Syrup Urine Disease (MSUD), what are the elevated branched-chain amino acids during an attack?

Leucine, isoleucine, and valine. Signup and view all the answers

What is the primary neurodevelopmental impact of Organic Aciduria in neonates?

Coma and lethargy following poor feeding and vomiting. Signup and view all the answers

What is the role of sodium benzoate in managing Nonketotic Hyperglycinemia?

It lowers plasma glycine levels. Signup and view all the answers

What is a key clinical feature of Tyrosinemia?

Coagulopathy leading to liver failure. Signup and view all the answers

What metabolic abnormality is observed in patients with Biotinidase deficiency?

Hearing loss, optic atrophy, and skin rash. Signup and view all the answers

What is the significance of the CSF:plasma glycine ratio in diagnosing Nonketotic Hyperglycinemia?

It should be greater than 0.08. Signup and view all the answers

What is the primary metabolic consequence of urea cycle defects?

The primary consequence is the accumulation of toxic ammonia in the body. Signup and view all the answers

Describe a common clinical feature of Ornithine Transcarbamylase (OTC) deficiency.

Symptoms include irritability, feeding dysfunction, and lethargy in affected neonates. Signup and view all the answers

What laboratory findings are typically seen in galactosemia?

Typically, there are mutations in GALK, GALT, or GALE genes with clinical symptoms like jaundice and vomiting. Signup and view all the answers

What is the treatment for acute hyperammonemia in urea cycle defects?

Treatment includes stopping protein intake and providing glucose and lipids to promote anabolism. Signup and view all the answers

Name one characteristic clinical sign of Fabry disease.

A characteristic sign is the presence of acroparesthesia, particularly during physical activity. Signup and view all the answers

How does Niemann-Pick disease primarily manifest?

Niemann-Pick disease manifests with hepatomegaly, developmental delays, and neurologic decline. Signup and view all the answers

What type of inheritance pattern do lysosomal storage diseases commonly exhibit?

Most lysosomal storage diseases are inherited in an autosomal recessive pattern. Signup and view all the answers

What is a key feature of Mucopolysaccharidosis I (Hurler syndrome)?

Key features include intellectual disability, corneal clouding, and cardiac disease. Signup and view all the answers

What neurodevelopmental issue is associated with Glut-1 deficiency syndrome?

Infants typically present with refractory seizures and developmental impairment. Signup and view all the answers

What type of metabolic derangement occurs in acute intermittent porphyria (AIP)?

AIP is characterized by neurovisceral symptoms triggered by various stressors. Signup and view all the answers

What are the typical presenting symptoms of Smith-Lemli-Opitz syndrome?

Symptoms include microcephaly, facial dysmorphisms, and self-injurious behavior. Signup and view all the answers

Identify a significant clinical manifestation of Menkes syndrome.

Clinical manifestations include developmental regression and seizures in early childhood. Signup and view all the answers

What is a hallmark of neuronal ceroid lipofuscinosis (NCL)?

NCL is characterized by progressive cognitive and motor deterioration. Signup and view all the answers

What should be included in the management plan for a patient with Hypohidrotic Ectodermal Dysplasia?

Management should include addressing hydration needs and symptom control for related skin issues. Signup and view all the answers

Study Notes

Metabolic Disorders Classification

Small Molecule Disorders: These are typically associated with acute or progressive intoxication or encephalopathy.
- Amino Acid Disorders: Examples include phenylketonuria (PKU), tyrosinemia, and maple syrup urine disease (MSUD).
- Organic Acid Disorders: Examples include MSUD, methylmalonic aciduria, propionic acidemia, and isovaleric acidemia.
- Urea Cycle Disorders: Examples include ornithine transcarbamylase (OTC) deficiency, carbamoyl phosphate synthetase (CPS) deficiency, and N-acetylglutamate synthetase deficiency.
- Carbohydrate Intolerance Disorders: Examples include galactosemia, hereditary fructose intolerance, and galactokinase deficiency.
Disorders of Energy Generation: These involve defects in processes like glycogenesis, gluconeogenesis, fatty acid oxidation, and ketogenesis.
- Glycogen Storage Disease (GSD): These disorders affect the storage or breakdown of glycogen, leading to energy deficiencies.
  - GSD Type II (Pompe Disease): A lysosomal storage disorder caused by acid maltase deficiency, leading to accumulation of glycogen in lysosomes.
  - GSD Type I (von Gierke Disease): Caused by glucose-6-phosphatase deficiency, resulting in hypoglycemia, hepatomegaly, and "doll face" appearance.
  - GSD Type V (McArdle Disease): Caused by phosphorylase deficiency, leading to muscle cramps and fatigue during exercise.
- Gluconeogenesis: Defects in this process affect the production of glucose from non-carbohydrate sources, leading to hypoglycemia.
- Mitochondrial Disorders: These affect the function of mitochondria, the powerhouses of the cell.
  - Leighs Syndrome: A progressive neurological disorder with characteristic MRI findings.
  - Kearns-Sayre syndrome, MELAS, MERRF, and Freidrich’s ataxia: These are examples of mitochondrial disorders with varying clinical presentations.
- Fatty Acid Oxidation Disorders (FAOD): These affect the breakdown of fatty acids for energy.
  - MCAD, LCHAD, and VLCAD: These are examples of FAODs.
- Ketogenesis: Defects in this process affect the production of ketones, which are an alternative energy source.
Disorders of Complex/Large Molecules: These disorders affect the metabolism of complex macromolecules like carbohydrates, lipids, and proteins.
- Lysosomal Storage Disorders: These involve the buildup of undigested substances in lysosomes.
  - Mucopolysaccharidoses (MPS): A group of disorders affecting the breakdown of mucopolysaccharides.
  - Sphingolipidoses: A group of disorders affecting the breakdown of sphingolipids.
  - Oligosaccharidoses: A group of disorders affecting the breakdown of oligosaccharides.
  - Mucolipidosis: A group of disorders affecting the transport of lysosomal enzymes.
- Peroxisomal Disorders: These affect the function of peroxisomes, organelles responsible for various metabolic processes.
  - Zellwegers, neonatal adrenoleukodystrophy, and infantile Refsum: These are examples of peroxisomal disorders.
- Single Peroxisomal Enzyme Disorders: These involve defects in specific enzymes within peroxisomes.
  - X-linked adrenoleukodystrophy (ALD) and Refsum disease (phytanoyl CoA hydroxylase deficiency): Examples of single peroxisomal enzyme disorders.
- Congenital Disorder of Glycosylation (CDG): These disorders affect the glycosylation process in the cell.
  - CDG type 1a:: An example of a CDG disorder.
- Inborn Errors of Cholesterol Synthesis: These disorders disrupt the production of cholesterol.
  - Smith-Lemli-Opitz syndrome: An example of an inborn error of cholesterol synthesis.
- Purine and Pyrimidine Metabolism: These disorders involve defects in the metabolism of purine and pyrimidine bases, which are essential for DNA and RNA synthesis.
Neurotransmitter Metabolism and Vitamins/Other Disorders: These disorders involve defects in the metabolism of neurotransmitters, vitamins, or other essential substances.
- Glycine and serine metabolism: These disorders affect the metabolism of these amino acids.
- Pterin and biogenic amine metabolism: These disorders affect the metabolism of pterins and biogenic amines, which are involved in various metabolic processes.
- Gamma-aminobutyrate (GABA) metabolism: This involves defects in the metabolism of GABA, an inhibitory neurotransmitter.
- Other: Examples include pyridoxine-dependent seizures, folinic acid-dependent seizures, and sulfite oxidase deficiency.

Categories of Inherited Metabolic Errors (IEM)

Disorders caused by energy failure: These include glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial disorders.
Disorders of amino acid metabolism: These often present in infancy with lethargy, vomiting, or failure to thrive.
Disorders of carbohydrate metabolism: These involve defects in the metabolism of carbohydrates like glucose, galactose, and fructose.
Lysosomal storage disorders: These disorders affect the breakdown of complex molecules within lysosomes.
Peroxisomal biogenesis disorders: These disrupt the formation and function of peroxisomes.
White matter disorders: These involve damage to the white matter of the brain.
Grey matter disorders: These involve damage to the grey matter of the brain.

Presentation

Chronic Presentation: This may include developmental delay, failure to thrive, organomegaly, and neuropathy.
Acute Presentation: (Emergency) This may include developmental regression, recurrent vomiting, acute liver or heart failure, severe hypotonia, or rhabdomyolysis.

Metabolic Emergencies: Key Indicators

Metabolic Acidosis: Low pH and bicarbonate levels, often seen in amino acid and organic acid disorders.
Respiratory Alkalosis: High pH and low carbon dioxide levels, often seen in urea cycle defects and some organic acid disorders.
Hyperammonemia: Elevated ammonia levels, often seen in urea cycle defects and organic acidemias.
Hypoglycemia: Low blood sugar levels seen in disorders of ketogenesis, FAOD (MCAD), GSDs, disorders of gluconeogenesis, and hereditary fructose intolerance.

Metabolic Emergencies Work Up

Initial Investigations: Include complete blood count (CBC) differential, blood glucose, urinalysis, creatinine, arterial blood gas (ABG), ammonia levels, AST, ALT, bilirubin, and coagulation studies.
Specialized Tests: These may include urine organic acids (organic acid disorders and FAODs), urine reducing substances, serum amino acids (amino acid and urea cycle disorders), acylcarnitine profile, free and total carnitine (FAOD and organic acid disorders), lactate and pyruvate levels, and a cerebrospinal fluid (CSF) analysis.

Metabolic Emergencies: Management

ABCs: Secure airway, breathing, and circulation.
Fluid Resuscitation: Administer normal saline to restore fluid balance.
Treat Hypoglycemia: Provide IV dextrose to raise blood sugar levels and prevent catabolism.
Treat Acidosis: If acidosis is present, consider administering bicarbonate.
Hyperammonemia Management: Significant hyperammonemia may require hemodialysis, medications such as L-carnitine and L-arginine (to support the urea cycle), sodium benzoate or phenylbutryate (to act as ammonia scavengers).
Cerebral Edema: Treat cerebral edema as indicated. Consider hemofiltration to remove offending metabolites.

Disorders Caused by Energy Failure

Glycogen Storage Disorders (GSD): These affect the storage or breakdown of glycogen, leading to energy deficiencies during fasting or exercise.
Fatty Acid Oxidation Defects (FAOD): These affect the breakdown of fatty acids for energy.
Mitochondrial Disorders These affect the function of mitochondria, the powerhouses of the cell, and result in various clinical manifestations depending on the specific defect.

Glycogen Storage Disease

GSD Type II (Pompe Disease): A lysosomal storage disorder affecting the breakdown of glycogen.
- Clinical presentation varies based on age of onset.
- Treatment involves enzyme replacement therapy and dietary management.
GSD Type I (von Gierke Disease): A deficiency in glucose-6-phosphatase, leading to hypoglycemia, hepatomegaly, and distinctive features like "doll face" appearance.
GSD Type V (McArdle Disease): A deficiency in muscle phosphorylase, leading to muscle cramps and fatigue during exercise.

Fatty Acid Oxidation Defects (FAOD)

These disorders affect the breakdown of fatty acids for energy, often presenting with hypoglycemia, hyperammonemia, and elevated acylcarnitine levels.
Triggered by prolonged fasting, illness or stress, or exercise.
Carnitine Transporter Deficiencies (CPT): Defects in the transport of fatty acids into mitochondria.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD): Affects the breakdown of medium-chain fatty acids.
Glutaric Acidemia Type II: Affects both FAO and amino acid metabolism.

Mitochondrial Disorders

A heterogeneous group of disorders with varying clinical presentations, affecting multiple organ systems.
Leigh Syndrome: A progressive neurological disorder with characteristic MRI findings.
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes): A disorder causing stroke-like episodes, encephalopathy, and lactic acidosis.
MERRF (Myoclonic Epilepsy with Ragged Red Fibers): A disorder presenting with myoclonic epilepsy, ataxia, and ragged red fibers in muscle biopsies.
Friedreich's Ataxia: A disorder affecting the nervous system, leading to progressive ataxia and other neurological symptoms.

Disorders of Amino Acid Metabolism

These disorders involve defects in the metabolism of amino acids, often presenting in infancy with feeding difficulties, lethargy, or vomiting.
Aminoacidopathies: These involve the accumulation of specific amino acids due to enzyme deficiencies.
Organic Acidurias: These result from the buildup of toxic organic acids.
Urea Cycle Disorders: These involve defects in the urea cycle, leading to hyperammonemia.

Aminoacidopathies

Phenylketonuria (PKU): A deficiency in phenylalanine hydroxylase, leading to excessive accumulation of phenylalanine.
- Treated with a phenylalanine-restricted diet.
Nonketotic Hyperglycinemia (NHK): Aka glycine encephalopathy, a disorder characterized by high glycine levels in the brain.
- Treated with sodium benzoate, dextromethorphan, and sometimes a ketogenic diet.
Classic Homocystinemia: A disorder affecting the metabolism of homocysteine.
- Treated with pyridoxine, folate, and cobalamin.
Maple Syrup Urine Disease (MSUD): A disorder affecting the breakdown of branched-chain amino acids (leucine, isoleucine, and valine).
- Treated with dietary restrictions, protein restriction, and amino acid supplementation.
Hartnup Disease: A disorder affecting the absorption of certain amino acids in the gut and kidneys.
- Treated with a high-protein diet and supplemental niacin.
Tyrosinemia: A disorder affecting the metabolism of tyrosine, leading to liver failure and neurological problems.
- Treated with dietary restrictions, medications, and in some cases, liver transplantation.

Organic Acid Disorders

Organic Acidurias: These result from the buildup of toxic organic acids due to enzyme deficiencies.
Propionic Aciduria: A disorder affecting the metabolism of propionic acid.
Methylmalonic Aciduria: A disorder affecting the metabolism of methylmalonic acid.
Biotinidase Deficiency: A disorder affecting the breakdown of biotin.
Glutaric Acidemia Type I: A disorder affecting the metabolism of glutaric acid.
Glutaric Acidemia Type II: A disorder affecting both fatty acid oxidation and amino acid metabolism.

Urea Cycle Disorders

Urea Cycle Disorders: These involve defects in the metabolic pathway that eliminates ammonia from the body.
Ornithine Transcarbamylase (OTC) Deficiency: One of the most common urea cycle disorders.
Carbamoyl Phosphate Synthetase (CPS) Deficiency: An enzyme deficiency in the first step of the urea cycle.
N-Acetylglutamate Synthase (NAGS) Deficiency: An enzyme deficiency affecting urea cycle regulation.
Citrullinemia: A disorder affecting the conversion of citrulline to arginine.
Argininosuccinate Synthetase (ASS) Deficiency: A disorder affecting the conversion of citrulline to argininosuccinate.
Argininosuccinate Lyase (ASL) Deficiency: A disorder affecting the conversion of argininosuccinate to arginine.
Ornithine Translocase (ORNT1) Deficiency: A disorder affecting the transport of ornithine.
Arginase Deficiency: A disorder affecting the breakdown of arginine.
Note:* This information is intended for educational purposes only and should not be considered medical advice. If you have concerns about your health or the health of a child, please consult a healthcare professional.

Urea Cycle Defects

Inability to convert toxic ammonia into urea
Mostly autosomal recessive (AR) inheritance pattern, except ornithine transcarbamylase (OTC) deficiency which is X-linked
Acute crisis of encephalopathy leads to seizures, coma, and death
May see strokes and cerebral edema
Symptoms include vomiting, protein aversion, temperature changes, and psychiatric issues in adults
Diagnosis: Hyperammonemia without acidosis, provoked by catabolic states (e.g., neonates after initiating protein feeds)
Permanent neurological deficits can occur after a single crisis
Treatment: Stop protein intake, increase glucose and lipids (promote anabolism), sodium benzoate (ammonia scavenger), and consider dialysis
Liver transplant is curative but will not reverse neurological damage

OTC Deficiency

X-linked recessive (females are symptomatic carriers in 10% of cases)
Most common urea cycle disorder
Clinical features:
- Male neonates with irritability, feeding dysfunction, and lethargy
- May have seizures leading to coma if untreated
- Late presentation: headaches, vomiting, bizarre behavior, and seizures
- May be milder in females due to X inactivation
Symptoms are often triggered by protein loads or catabolic postpartum states
Diagnosis: High ammonia levels and urine orotic acid, low serum citrulline, and arginine
Treatment: Sodium benzoate (ammonia scavenger), arginine, dialysis, protein restriction, and liver transplant

Other Urea Cycle Defects

CPS1 deficiency: Normal urine orotic acid
Argininemia: Mild elevation in ammonia, progressive spasticity, weakness, tremor, regression, seizures, and possible spastic cerebral palsy (CP)
Hyperornithemia-Hyperammonemia-Homocitrullinemia (HHH) syndrome:
- Develops in older children
- Spasticity and coagulation defects

Cerebral Creatine Deficiency Syndromes

Inborn errors of creatine metabolism
- GAMT deficiency (AR)
- AGAT deficiency (AR) - Disorders of creatine biosynthesis
- CRTR deficiency (X-linked) - Disorders of creatine transporter
Clinical features:
- Seizures, intellectual disability (ID), behavioral issues (autism, self-mutilation), and movement disorders (chorea/dystonia)
Diagnosis: Urine creatine/creatinine levels, magnetic resonance spectroscopy (MRS) (absence of creatine peak), and genetic testing
Treatment: Oral creatine in biosynthesis disorders

Galactosemia

Mutations in GALK, GALT, or GALE genes
Neonates present with vomiting and poor feeding
Jaundice, hepatomegaly, and cataracts can develop if untreated
Often develop E. coli sepsis
Treatment: Avoid galactose and fructose

Congenital Disorders of Glycosylation

Infants or children with a combination of liver, gastrointestinal, and coagulation disturbances
FTT, hypotonia, stroke-like episodes, bleeding, cerebellar hypoplasia, peripheral neuropathy, inverted nipples, and hypogonadism
Diagnosis: Transferrin electrophoresis

Lafora Body Disease

Autosomal recessive (AR) inheritance
Mid-teens: Myoclonic epilepsy and rapid neurologic decline
Lafora bodies: Dark with acid Schiff stain, lighter outer halo

Lysosomal Storage Diseases

Lysosomes break down and recycle complex substrates, including glycosaminoglycans, sphingolipids, glycogen, and proteins
Accumulation of large carbohydrate-lipid complexes
Classification based on the primary stored substance (examples include sphingolipids, mucopolysaccharides, lipids, mucolipids, glycogen, and cholesterol)
Clinical features:
- Progressive dysmorphisms
- Organomegaly
- Psychiatric symptoms
- White matter (WM) disease

Mucopolysaccharidosis

Mostly AR
Coarse facial features, short stature, dysostosis multiplex (progressive skeletal dysplasia, bullet-shaped phalanges, flattening of vertebral bodies), and hepatosplenomegaly
Subtypes:
- MPS I (Hurler): ID, corneal clouding, and cardiac disease
- MPS II (Hunter): No corneal clouding, aggressive behavior, papules on thighs (X-linked recessive)
- MPS III (Sanfilippo): ID, behavioral/speech problems, and progressive CNS degeneration
- MPS IV (Morquio): Odontoid hypoplasia
Diagnosis: Urine MPS and enzyme assays (leukocytes or fibroblasts)
MRI findings: Dilated perivascular spaces (Virchow-Robbins) in periventricular WM, corpus callosum, basal ganglia, subcortical white matter, thalami, or brainstem
Treatment: Enzyme replacement therapy

Sphingolipidoses

GM2 gangliosidosis (aka Tay-Sachs, type alpha)
- HEXA gene, AR (Ashkenazi Jewish population)
- Infants with excessive startle, cherry red spot, regression, encephalopathy, spasticity, seizures, blindness, and megalencephaly
- Late-onset GM2 gangliosidosis: Childhood and adults with cognitive/behavioral decline, spasticity, seizures (No cherry red spot)
- Caused by hexosaminidase A deficiency
- Diagnosis: Absent hexosaminidase A with normal/elevated hexosaminidase B levels
GM2 gangliosidosis (aka Sandhoff’s disease, type beta)
- Like Tay-Sachs, plus hepatosplenomegaly and bony deformities
- Caused by deficiency of both hexosaminidase A and B
- Diagnosis: Low hexosaminidase A and B levels

Fabry Disease

GLA gene, X-linked recessive
Alpha-galactosidase A deficiency, sphingolipid
Clinical features:
- Young adult males
- Brain: Stroke
- Ganglion cells in the dorsal root ganglia: Neuropathic pain (acroparasthesias - associated with physical activity, fever, cold)
- Heart: Arrhythmias, hypertrophic cardiomyopathy (HCM)
- Kidneys: End-stage renal disease (ESRD)
- Skin: Angiokeratomas around the lips, abdomen, or genitalia
- Hearing loss, corneal opacities
Diagnosis: Blood spot screening test for enzyme analysis, confirmed by leukocyte/plasma enzyme measurement
Treatment: Enzyme replacement therapy

Gaucher’s Disease

AR, deficiency of lysosomal enzyme glucocerebrosidase
Clinical features:
- Osteopenia, osteosclerosis, bone pain/crises
- Hepatosplenomegaly, interstitial lung disease, pulmonary hypertension (PH), hematologic malignancies, delayed growth/puberty
Subtypes:
- GDS 1: Non-neuropathic
- GDS 2: Congenital ichthyosis, oculomotor dysfunction, hypertonia, opisthotonos, seizures
- GSD 3: Progressive dementia, ataxia, myoclonus, seizures
Diagnosis: Enzyme analysis
Gaucher cells (macrophages filled with lipid material are seen on bone marrow examination)
Treatment: Enzyme replacement therapy

Neimann-Pick Disorders

Disorder of impaired cholesterol esterification
NPA: Cherry red spot, opisthotonos, hyperreflexia, hepatomegaly, and infants with FTT and lung disease
NPC: NPC1 & NPC2 genes, AR
- Severe liver/lung disease, upgaze palsy, ataxia, apraxia, seizures, dystonia, and dementia
- Childhood onset: Cerebellar ataxia, vertical supranuclear gaze palsy, dystonia, seizures, spasticity, and gelastic cataplexy
- Adolescent onset: Progressive learning difficulties and/or behavioral dysfunction
- Adult onset: Psychosis, mood disorders
Treatment: Cholesterol-lowering agents (statins), miglustat (decreases lipid storage)

Neuronal Ceroid Lipofuscinosis (NCL)

Group of disorders characterized by progressive cognitive and motor deterioration, seizures, vision loss, and early death
Most common cause of inherited childhood neurodegenerative disease
Classification: Initially classified by age of onset, now by genetic etiology (multiple chromosomes)
Subtypes:
- Infantile NCL (onset 6-24mo): Delay, myoclonic jerks, and progressive impairment
- Late infantile NCL (2-4 yr): Seizures followed by cognitive decline, ataxia, spasticity, movement disorders, visual impairment to blindness (CLN2 gene)
- Juvenile NCL (Batten disease, 5-12 yr): Visual failure, academic decline, hallucinations, myoclonic and tonic-clonic seizures, ataxia, and rigidity (death within 10-15 yr) (CLN3 gene: Most common)
Skin biopsy: Curvilinear or granular osmiophilic deposits (fingerprint profiles)
EEG: Encephalopathy with myoclonic seizures, large spike and slow-wave activity with photic stimulation
MRI: Progressive atrophy, decreased T2 signal intensity in the thalami, thinning of the corpus callosum, and possible diffuse WM changes
MRS: Reduced N-acetylaspartate (NAA)
Loss of somatosensory evoked potentials (SSEPs)
Treatment: Avoid Dilantin and Tegretol, benzodiazepines for seizures/spasticity, trihexyphenidate for dystonia, cerliponase alfa (ERT; intrathecal)

Other Lysosomal Disorders

Farber: Granulomatous tissue infiltration by foamy macrophages, swollen and deformed joints, hoarse cry, and nodules on fingers
Krabbe: AR, GALC gene, deficiency in galactosylceramidase activity. Irritability, psychomotor regression, visual impairment, and spasticity
Metachromatic Leukodystrophy: AR, ARSA gene, deficiency in arylsulfatase A. Spasticity, spasms, peripheral neuropathy
MRI: "Butterfly pattern" and "tigroid" appearance

Peroxisomal Disorders

Two major categories:
- Disorders of peroxisomal biogenesis (defect of assembly)
  - Zellweger (cerebrohepatorenal syndrome), Refsum, and neonatal adrenoleukodystrophy
- Single-enzyme disorder
  - X-linked adrenoleukodystrophy

Zellweger Syndrome

Aka cerebrohepatorenal syndrome or infantile Refsum
PEX1 gene, AR inheritance
Clinical features:
- Neonatal hypotonia, high forehead, wide fontanelle
- Hepatomegaly, hyporeflexia, renal cysts, patellar stippling
- Intractable seizures, liver dysfunction, sensorineural hearing loss (SNHL), pigmentary retinal abnormalities
MRI brain: Hypomyelination and neuronal migrational defects (centrosylvian pachygyria with lateral polymicrogyria)
Diagnosis: Elevated very-long-chain fatty acids (VLCFAs) and phytanic acid (peroxisomes degrade VLCFAs)

Refsum Disease

AR, PHYH gene (90%) or PEX7 gene
Clinical features:
- Infancy: Similar to Zellweger syndrome (hypotonia and GDD)
- Retinitis pigmentosa: Vision loss
- SNHL, ataxia, peripheral neuropathy, ichthyosis, cardiac conduction defects, and vitamin K-responsive bleeding
Diagnosis: Nerve conduction studies (NCS) (demyelinating), high serum phytanic acid levels
Treatment: Low phytanic acid diet

X-Linked Adrenoleukodystrophy

ABCD1 gene, Xp28
A peroxisomal disorder involving VLCFA, see the leukodystrophy lecture

Smith-Lemli-Opitz Syndrome

DHCR7 gene mutation (7-dehydrocholesterol reductase), AR
Impaired cholesterol synthesis
Clinical features:
- Microcephaly, ptosis, short upturned nose, self-injurious behavior
- Cleft lip/palate, syndactyly of toes, polydactyly of hands
- Hirschsprung disease, abnormal genitalia, cardiac malformations
Diagnosis: High 7-dehydrocholesterol, low cholesterol
MRI: Holoprosencephaly, agenesis of the corpus callosum (ACC), frontal hypoplasia, cerebellar hypoplasia, and Dandy-Walker malformation

Lesch-Nyhan Syndrome

X-linked recessive, HGPRT1 gene
Purine metabolism defect leading to hyperuricemia
Clinical features:
- Hypotonia and GDD, choreoathetosis, dystonia, self-mutilating behavior, renal failure, and gouty arthritis

Menkes Syndrome

X-linked recessive, ATP7A gene
Disorder of copper transport, resulting in low serum copper and ceruloplasmin (deficient absorption in the GI tract)
Presents after normal development for 2-3 months, followed by developmental delay, regression, myoclonic seizures in response to stimulation, dysautonomia, and hypotonia
Other clinical features: Kinky hair, skin laxity, sagging jowls (skin beneath the neck), light pigmentation, tortuous cerebral vessels (ischemic strokes, subdural hematoma)
Death before age 3
MRI: Defective myelination, atrophy, "corkscrew" appearance of vessels
Diagnosis: Low copper and ceruloplasmin levels
Treatment: Subcutaneous copper histidine or copper chloride

Wilson’s Disease

AR inheritance, ATP7B gene
Disorder of copper transporting ATPase, resulting in impaired binding to ceruloplasmin (low serum copper & ceruloplasmin, high urinary copper)
Accumulation of copper in the liver (liver disease, hepatomegaly, bronze skin), brain (tremor, chorea, dystonia, dysarthria, psychiatric symptoms, cognitive dysfunction), and eyes (Kayser-Fleischer rings)
MRI: Symmetric basal ganglia, thalamus, and brainstem lesions (T2 bright)
Treatment: Copper chelator (penicillamine)

Porphyria

Altered activities in the heme biosynthetic pathway
Most autosomal dominant (AD) with low penetrance, some autosomal recessive (AR) or X-linked
Acute intermittent porphyria (AIP) - HMBS gene pathogenic variant
- Neurovisceral symptoms triggered by drugs (cytochrome P450 inducers), progesterone, fasting, and stress
- Attacks of abdominal pain, red/brown urine, muscle weakness, convulsions, and hyponatremia
- Paresis, extreme pain, psychiatric symptoms, altered level of consciousness (LOC)
- Triad: Abdominal pain, CNS dysfunction, and peripheral neuropathy in young adult females
- Diagnosis: Urinary porphobilinogen
- MRI: May show posterior reversible encephalopathy syndrome (PRES) picture
- Treatment: Hemin, glucose

Cerebrotendinous Xanthomatosis (CTX)

Lipid storage disorder, deficiency of sterol 27-hydroxylase resulting in cholestanol and cholesterol accumulation
CYP27A1 gene, AR
Clinical features:
- Neuro: Pyramidal and cerebellar findings, dystonia, atypical Parkinsonism, peripheral neuropathy, seizures (onset 20-30s)
- Intellectual disability (ID), behavioral changes, aggression, depression
MRI: Hyperintensities in deep gray/supratentorial white matter (WM), microcalcifications in the dentate nuclei, and enlarged Virchow-Robbins spaces
High cholestanol, normal to low cholesterol
Treatment: Chenodeoxycholic acid (CDCA), CoQ10 for weakness

Glut-1 Deficiency Syndrome

AR, SLCA1 gene
Clinical features:
- Infantile epileptic encephalopathy associated with low cerebrospinal fluid (CSF) glucose concentration
- Refractory seizures of all clinical types (focal, generalized, myoclonic)
- Neurodevelopmental impairment of variable severity and acquired microcephaly
Diagnosis: Low CSF glucose (unable to transport across the blood-brain barrier), glucose ratio (blood glucose/CSF glucose)

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Description

This quiz explores the complexities of metabolic disorders, detailing their classifications and examples. It covers topics such as small molecule disorders, glycogen storage diseases, carbohydrate intolerance, and more. Test your knowledge on the causes, symptoms, and treatments associated with various metabolic conditions.