The food we eat is composed of carbohydrates, proteins, and fats. After consumption, these nutrients are digested and absorbed through the intestine. Once absorbed, the bloodstream transports them to the liver, where they are further broken down into simple sugars, amino acids, and fatty acids/cholesterol.
During this breakdown process, energy is released in the form of heat, which helps maintain body temperature. The liver then uses these basic building blocks to synthesize complex sugars, proteins, and fats required for the body’s growth, repair, and development.
These complex biochemical reactions—both the breakdown and synthesis of nutrients—depend on specific enzymes. When one or more of these enzymes are absent or defective due to genetic abnormalities, the metabolic processes become incomplete or inefficient. This leads to the accumulation or deficiency of certain substances in the body, resulting in a group of conditions known as metabolic disorders.
There are hundreds of different metabolic disorders identified to date. The human body contains thousands of enzymes responsible for breaking down and re-synthesizing the nutrients we consume—proteins, sugars, and fats. These biochemical processes occur in multiple steps, and each step depends on the proper function of a specific enzyme.
If even one of these enzymes is missing or defective, the metabolic pathway becomes blocked. This can lead to the accumulation of toxic by-products or a deficiency of essential substances, resulting in damage to vital organs such as the liver, kidneys, or brain.
Therefore, metabolic disorders represent a large and diverse group of conditions—some are relatively common and well understood, while many others are extremely rare. In simple terms, the term metabolic disorder serves as an umbrella covering hundreds of individual genetic conditions, each affecting a different aspect of the body’s chemical processes.
These disorders are genetic - meaning they're passed down from parents to children through genes. It's like inheriting your parent's eye color, but instead you inherit a "broken instruction manual" for making a particular enzyme.
Some of the examples are :
ERT is most established in lysosomal storage disorders (LSDs) where the missing enzyme can be infused to reduce substrate accumulation.
Enzyme: Imiglucerase / Velaglucerase / Taliglucerase
Benefits: Improves hepatosplenomegaly, anemia, bone disease.
Enzyme: Agalsidase alfa or beta
Benefits: Reduces pain crises, stabilizes renal & cardiac function.
Enzyme: Alglucosidase alfa
Benefits: Improves cardiac hypertrophy and muscle strength; lifesaving in infantile-onset disease.
Benefits: Improved endurance, respiratory function, reduced GAG storage.
Enzyme: Sebelipase alfa
Benefits:Improve Liver enzymes,reduces dyslipidemia,slows fibrosis.
Enzyme: Cerliponase alfa (intraventricular ERT)
Benefits: Slows neurologic deterioration.
BMT helps when the donor’s hematopoietic cells produce the missing enzyme, or when disease progression involves immune or inflammatory mechanisms.
BMT is the treatment of choice if diagnosed early (2 years)
Benefits: Improves survival, preserves cognition, slows somatic disease.
BMT is effective before neurologic symptoms progress too far.
Benefits: Halts cerebral demyelination.
Benefits: Slows neuroregression if performed early.
Benefits: Preserves neurologic function only if transplanted pre-symptomatically (e.g., NBS-identified).
HSCT has been attempted historically; now largely replaced by ERT but still considered in refractory cases.
HSCT can improve survival and neurologic outcome
Think of managing a metabolic disorder like managing diabetes - it requires daily attention and special care, but children can still live happy, healthy lives with the right support and treatment.
Remember: If you have concerns about your child's growth, development, or unusual symptoms, don't hesitate to talk to your pediatrician. Early intervention makes all the difference!
| Category | Disorders |
|---|---|
| Amino Acid Metabolism Disorders |
Tyrosinemia Type 1 Maple Syrup Urine Disease (MSUD) Urea Cycle Disorders (UCDs) - OTC, CPS1, ASS1 Methylmalonic Acidemia (MMA) Propionic Acidemia (PA) |
| Carbohydrate Metabolism Disorders |
Galactosemia (GALT deficiency) Hereditary Fructose Intolerance Glycogen Storage Disease (GSD) Type I, III, IV |
| Fatty Acid Oxidation Disorders | LCHAD / VLCAD Deficiency |
| Transport / Excretion Disorders |
Wilson Disease Progressive Familial Intrahepatic Cholestasis (PFIC 1,2,3,4,5,6) Bile Acid Synthesis Defects Primary Hyperoxaluria |
| Mitochondrial / Energy Disorders |
Mitochondrial DNA Depletion Syndromes (MPV17, POLG, etc.) Pyruvate Dehydrogenase Complex Deficiency |
Methylmalonic Acidemia (MMA) is a rare inherited metabolic disorder in which the body cannot properly break down certain proteins and fats. This leads to the accumulation of methylmalonic acid, a toxic substance that can damage vital organs, especially the kidneys, brain, and liver.
MMA affects approximately 1 in 50,000–100,000 newborns.
MMA is caused by a problem with:
Normally:
In MMA:
1. Enzyme Defect Types
2. Vitamin B12–Related Types
3. B12-Responsive vs. Unresponsive MMA
Early symptoms often appear in the first days or weeks of life:
Symptoms in Childhood:
Even with treatment, some children may develop:
Early diagnosis and strict management greatly reduce the severity of complications.
1. Newborn Screening:
Most MMA cases are detected through routine heel-prick screening by identifying high C3 (propionylcarnitine).
2. Confirmatory Testing:
MMA requires lifelong, daily treatment and emergency planning.
1. Special Diet (Cornerstone of Treatment):
Diet is supervised by a metabolic dietitian.
2. Vitamin B12 Therapy:
Applies only to B12-responsive types (cblA, some cblB, some cblC):
3. Carnitine Supplementation:
4. Medications to Reduce Toxin Production:
5. Managing a Metabolic Crisis:
A crisis may occur during:
Emergency care includes:
Families should always carry a written emergency protocol.
Liver Transplant:
Helps in severe or unstable MMA by:
Important: Liver transplant does not cure MMA.
Kidney disease and neurologic issues may still progress.
Combined Liver–Kidney Transplant:
Considered in children with advanced kidney disease.
Children require follow-up every 3–6 months, including:
Most children with MMA can:
Families benefit from:
Propionic acidemia (PA) is a rare inherited metabolic disorder in which the body cannot properly break down some parts of proteins and fats. As a result, propionic acid and related toxins build up in the blood and tissues. This can make a child very sick, especially during illness or fasting.
PA occurs when there is a deficiency of the enzyme propionyl-CoA carboxylase (PCC).
This enzyme is needed to process:
PA is autosomal recessive, meaning both parents are usually healthy carriers.
Normal Process:
In Propionic Acidemia:
Newborn Period (Most Common):
Symptoms often appear in the first days or weeks of life, especially after starting feeds:
Some milder cases present later:
Even with treatment, children may develop:
Good early control and careful long-term management can reduce these risks.
In many regions, PA is detected on the heel-prick newborn screen by measuring elevated propionylcarnitine (C3).
If screening suggests PA:
Early diagnosis allows prompt treatment and helps prevent severe brain injury.
1. Special Diet (Foundation of Treatment):
Diet aims to limit precursors of propionic acid while allowing normal growth.
A metabolic dietitian is essential to plan and adjust the diet.
Carnitine
Antibiotics (e.g., Metronidazole)
Supplements / Buffers
A crisis can be triggered by:
Warning Signs:
Emergency Treatment (Hospital):
Families should have a written “sick-day” or emergency protocol to show local doctors.
In selected children with:
Liver transplantation may:
However:
Children with PA need ongoing care from a multidisciplinary metabolic team.
Typical monitoring includes:
Early detection of complications allows timely interventions.
With early diagnosis and careful management:
With the right care, many children and adults with propionic acidemia can lead active, meaningful lives.
Galactosemia is an inherited metabolic disorder in which the body cannot properly break down galactose, a sugar found in milk. It is caused most commonly by deficiency of the enzyme GALT (galactose-1-phosphate uridyltransferase).
Classic Galactosemia (GALT deficiency) – most severe
Galactokinase deficiency (GALK) – mainly causes cataracts
When galactose cannot be metabolized, galactose-1-phosphate and galactitol accumulate, causing toxicity to the liver, kidneys, brain, and lens of the eye.
Symptoms usually appear within days of starting breast milk or formula.
With early treatment, acute symptoms resolve, but long-term neurodevelopmental and speech issues may persist.
Hereditary Fructose Intolerance (HFI) is an autosomal recessive disorder caused by deficiency of aldolase B, leading to inability to metabolize fructose, sucrose, and sorbitol .
Accumulation of fructose-1-phosphate in the liver and kidney leads to:
Inhibition of gluconeogenesis → severe hypoglycemia
Symptoms begin when the infant is exposed to fructose-containing foods (fruit juices, fruits, sweetened foods, sucrose-containing formulas).
Excellent when diagnosed early and diet strictly followed. Untreated disease leads to liver failure and renal damage.
(Includes Type Ia: G6PC deficiency and Type Ib: SLC37A4 deficiency)
Glycogen Storage Disease Type I is a genetic disorder where the liver cannot release glucose into the bloodstream. As a result, blood sugar drops dangerously low, and glycogen (stored sugar) builds up in the liver and kidneys.
GSD I is autosomal recessive, meaning both parents are usually carriers.
The enzymes responsible for converting stored glycogen into glucose are not working:
This leads to:
Diet is the main treatment:
(Also called Forbes–Cori Disease; due to AGL gene mutation)
Glycogen Storage Disease Type III (GSD III) is caused by a deficiency of the debranching enzyme, resulting in incomplete breakdown of glycogen. This condition affects the liver, muscles, and sometimes the heart. It is generally less severe than Type I.
Two major forms ecist:
The debranching enzyme deficiency Causes:
Childhood:
Later Childhood / Teens:
Diet:
Monitoring:
Children with GSD III often improve in puberty as liver Shrinks and blood sugars stabilize. Adults may develop muscle weakness or heart issues, so lifelong monitoring is important. Most individuals lead normal, productive lives with proper care.
(Also called Andersen Disease; due to GBE1 gene mutation)
Glycogen Storage Disease Type IV (GSD IV) is a rare and more serious glycogen storage disease caused by deficiency of the branching enzyme. This leads to accumulation of abnormal glycogen (“amylopectin-like”) in tissues—especially the liver, heart, and muscles This condition can present with jaundice and liver chirrhosis..
GSD IV has several subtypes ranging from severe infantile disease to milder childhood forms.
Without the branching enzyme:
Symptoms vary by subtype but may include:
Severe infantile liver form:
Other forms:
Diagnosis often occurs early due to liver symptoms.
Liver disease care:
Liver Transplantation:
This is the only effective treatment for the progressive liver form. It:
Ongoing Monitoring:
Wilson disease is a genetic disorder that affects about 1 in 30,000 people worldwide. It is a condition where the body cannot properly remove copper, causing it to build up in vital organs like the liver, brain, and eyes. Think of it like a plumbing system where the drain is blocked—copper keeps accumulating instead of being flushed out naturally.
Wilson disease is caused by mutations in the ATP7B gene, which normally produces a protein responsible for transporting copper out of the liver and into bile for elimination. When this gene doesn't work properly, copper accumulates in the liver first, then spills over into other organs, causing damage.
Copper is actually essential for our health — we need small amounts for:
However, too much copper becomes toxic. In Wilson disease, the body absorbs normal amounts of copper from food but cannot eliminate the excess, leading to dangerous buildup.
Wilson disease symptoms can vary greatly depending on which organs are affected and the person's age when symptoms begin.
Liver-Related Symptoms:
Brain and Nervous System Symptoms:
Eye Signs:
Other Symptoms:
Clinical Evaluation:
Doctors look for the combination of:
The good news is that Wilson disease is treatable! Early diagnosis and treatment can prevent organ damage and allow people to live normal lives.
These medications bind to copper and help remove it from the body through urine.
With Early Treatment:
Without Treatment:
Wilson disease may seem overwhelming at first, but with proper understanding and treatment, people with this condition can lead healthy, productive lives. The key is early diagnosis, consistent treatment, and regular medical follow-up. If you or a family member has been diagnosed with Wilson disease, work closely with your healthcare team to develop the best treatment plan for your specific situation.
Remember: Wilson disease is not a death sentence — it's a manageable condition with excellent treatments available. With proper care, the future is bright for people living with Wilson disease.
Methylmalonic Acidemia (MMA) is a rare inherited metabolic disorder in which the body cannot properly break down certain proteins and fats. This leads to the accumulation of methylmalonic acid, a toxic substance that can damage vital organs, especially the kidneys, brain, and liver.
MMA affects approximately 1 in 50,000–100,000 newborns.
MMA is caused by a problem with:
Normally:
In MMA:
1. Enzyme Defect Types
2. Vitamin B12–Related Types
3. B12-Responsive vs. Unresponsive MMA
Early symptoms often appear in the first days or weeks of life:
Symptoms in Childhood:
Even with treatment, some children may develop:
Early diagnosis and strict management greatly reduce the severity of complications.
1. Newborn Screening:
Most MMA cases are detected through routine heel-prick screening by identifying high C3 (propionylcarnitine).
2. Confirmatory Testing:
MMA requires lifelong, daily treatment and emergency planning.
1. Special Diet (Cornerstone of Treatment):
Diet is supervised by a metabolic dietitian.
2. Vitamin B12 Therapy:
Applies only to B12-responsive types (cblA, some cblB, some cblC):
3. Carnitine Supplementation:
4. Medications to Reduce Toxin Production:
5. Managing a Metabolic Crisis:
A crisis may occur during:
Emergency care includes:
Families should always carry a written emergency protocol.
Liver Transplant:
Helps in severe or unstable MMA by:
Important: Liver transplant does not cure MMA.
Kidney disease and neurologic issues may still progress.
Combined Liver–Kidney Transplant:
Considered in children with advanced kidney disease.
Children require follow-up every 3–6 months, including:
Most children with MMA can:
Families benefit from:
Propionic acidemia (PA) is a rare inherited metabolic disorder in which the body cannot properly break down some parts of proteins and fats. As a result, propionic acid and related toxins build up in the blood and tissues. This can make a child very sick, especially during illness or fasting.
PA occurs when there is a deficiency of the enzyme propionyl-CoA carboxylase (PCC).
This enzyme is needed to process:
PA is autosomal recessive, meaning both parents are usually healthy carriers.
Normal Process:
In Propionic Acidemia:
Newborn Period (Most Common):
Symptoms often appear in the first days or weeks of life, especially after starting feeds:
Some milder cases present later:
Even with treatment, children may develop:
Good early control and careful long-term management can reduce these risks.
In many regions, PA is detected on the heel-prick newborn screen by measuring elevated propionylcarnitine (C3).
If screening suggests PA:
Early diagnosis allows prompt treatment and helps prevent severe brain injury.
1. Special Diet (Foundation of Treatment):
Diet aims to limit precursors of propionic acid while allowing normal growth.
A metabolic dietitian is essential to plan and adjust the diet.
Carnitine
Antibiotics (e.g., Metronidazole)
Supplements / Buffers
A crisis can be triggered by:
Warning Signs:
Emergency Treatment (Hospital):
Families should have a written “sick-day” or emergency protocol to show local doctors.
In selected children with:
Liver transplantation may:
However:
Children with PA need ongoing care from a multidisciplinary metabolic team.
Typical monitoring includes:
Early detection of complications allows timely interventions.
With early diagnosis and careful management:
With the right care, many children and adults with propionic acidemia can lead active, meaningful lives.
Galactosemia is an inherited metabolic disorder in which the body cannot properly break down galactose, a sugar found in milk. It is caused most commonly by deficiency of the enzyme GALT (galactose-1-phosphate uridyltransferase).
Classic Galactosemia (GALT deficiency) – most severe
Galactokinase deficiency (GALK) – mainly causes cataracts
When galactose cannot be metabolized, galactose-1-phosphate and galactitol accumulate, causing toxicity to the liver, kidneys, brain, and lens of the eye.
Symptoms usually appear within days of starting breast milk or formula.
With early treatment, acute symptoms resolve, but long-term neurodevelopmental and speech issues may persist.
Hereditary Fructose Intolerance (HFI) is an autosomal recessive disorder caused by deficiency of aldolase B, leading to inability to metabolize fructose, sucrose, and sorbitol .
Accumulation of fructose-1-phosphate in the liver and kidney leads to:
Inhibition of gluconeogenesis → severe hypoglycemia
Symptoms begin when the infant is exposed to fructose-containing foods (fruit juices, fruits, sweetened foods, sucrose-containing formulas).
Excellent when diagnosed early and diet strictly followed. Untreated disease leads to liver failure and renal damage.
(Includes Type Ia: G6PC deficiency and Type Ib: SLC37A4 deficiency)
Glycogen Storage Disease Type I is a genetic disorder where the liver cannot release glucose into the bloodstream. As a result, blood sugar drops dangerously low, and glycogen (stored sugar) builds up in the liver and kidneys.
GSD I is autosomal recessive, meaning both parents are usually carriers.
The enzymes responsible for converting stored glycogen into glucose are not working:
This leads to:
Diet is the main treatment:
(Also called Forbes–Cori Disease; due to AGL gene mutation)
Glycogen Storage Disease Type III (GSD III) is caused by a deficiency of the debranching enzyme, resulting in incomplete breakdown of glycogen. This condition affects the liver, muscles, and sometimes the heart. It is generally less severe than Type I.
Two major forms ecist:
The debranching enzyme deficiency Causes:
Childhood:
Later Childhood / Teens:
Diet:
Monitoring:
Children with GSD III often improve in puberty as liver Shrinks and blood sugars stabilize. Adults may develop muscle weakness or heart issues, so lifelong monitoring is important. Most individuals lead normal, productive lives with proper care.
(Also called Andersen Disease; due to GBE1 gene mutation)
Glycogen Storage Disease Type IV (GSD IV) is a rare and more serious glycogen storage disease caused by deficiency of the branching enzyme. This leads to accumulation of abnormal glycogen (“amylopectin-like”) in tissues—especially the liver, heart, and muscles This condition can present with jaundice and liver chirrhosis..
GSD IV has several subtypes ranging from severe infantile disease to milder childhood forms.
Without the branching enzyme:
Symptoms vary by subtype but may include:
Severe infantile liver form:
Other forms:
Diagnosis often occurs early due to liver symptoms.
Liver disease care:
Liver Transplantation:
This is the only effective treatment for the progressive liver form. It:
Ongoing Monitoring:
Wilson disease is a genetic disorder that affects about 1 in 30,000 people worldwide. It is a condition where the body cannot properly remove copper, causing it to build up in vital organs like the liver, brain, and eyes. Think of it like a plumbing system where the drain is blocked—copper keeps accumulating instead of being flushed out naturally.
Wilson disease is caused by mutations in the ATP7B gene, which normally produces a protein responsible for transporting copper out of the liver and into bile for elimination. When this gene doesn't work properly, copper accumulates in the liver first, then spills over into other organs, causing damage.
Copper is actually essential for our health — we need small amounts for:
However, too much copper becomes toxic. In Wilson disease, the body absorbs normal amounts of copper from food but cannot eliminate the excess, leading to dangerous buildup.
Wilson disease symptoms can vary greatly depending on which organs are affected and the person's age when symptoms begin.
Liver-Related Symptoms:
Brain and Nervous System Symptoms:
Eye Signs:
Other Symptoms:
Clinical Evaluation:
Doctors look for the combination of:
The good news is that Wilson disease is treatable! Early diagnosis and treatment can prevent organ damage and allow people to live normal lives.
These medications bind to copper and help remove it from the body through urine.
With Early Treatment:
Without Treatment:
Wilson disease may seem overwhelming at first, but with proper understanding and treatment, people with this condition can lead healthy, productive lives. The key is early diagnosis, consistent treatment, and regular medical follow-up. If you or a family member has been diagnosed with Wilson disease, work closely with your healthcare team to develop the best treatment plan for your specific situation.
Remember: Wilson disease is not a death sentence — it's a manageable condition with excellent treatments available. With proper care, the future is bright for people living with Wilson disease.
