What are the other Names for this Condition? (Also known as/Synonyms)

• 3-Alpha Methylglutaconic Aciduria Type I
• 3-Methylglutaconyl CoA Hydratase Deficiency Disorder
• 3-MGA Type I

What is 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder? (Definition/Background Information)

3-Methylglutaconyl-CoA Hydratase Deficiency Disorder (also known as AUH Defect Disorder) or 3-Methylglutaconic Aciduria (3-MGA) Type 1 is an inborn error of leucine metabolism with a variable clinical phenotype. Clinical manifestations can range from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis, and dystonia.

This disorder usually becomes apparent in the neonatal period or during infancy, but diagnosis may not be made until childhood. Some of the reported patients also displayed hypoglycemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia, and hepatomegaly.

Patients with 3-MGA Type 1 can be distinguished from those with other forms of 3-MGA (types II, III, and IV) by the distinctive pattern of metabolite excretion. In patients with Type 1, 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA), whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).

Prenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes. This could allow for early intervention and treatment.

The disorder is inherited as an autosomal recessive trait, which means that both parents must carry a copy of the mutated gene for their child to be affected. Genetic counseling can be helpful in determining the risk of recurrence in future pregnancies.

In summary, 3-Methylglutaconyl-CoA Hydratase Deficiency Disorder (AUH Defect Disorder) or 3-Methylglutaconic Aciduria (3-MGA) Type 1 is a rare genetic disorder that affects leucine metabolism. It has a variable clinical phenotype and can range from mildly delayed speech to severe symptoms like coma and dystonia. Early diagnosis through prenatal testing or newborn screening can be helpful in managing the condition. The disorder is inherited as an autosomal recessive trait, and genetic counseling can provide information on recurrence risk.

Summary::

• 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder, or 3-Methylglutaconic Aciduria (3-MGA) Type 1, is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia
• Clinical manifestations usually become apparent in the neonatal period or during infancy, but the diagnosis may not be made until childhood
• Some of the reported patients also displayed hypoglycemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia and hepatomegaly
• Patients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA), whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA)
• Prenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes
• The syndrome is inherited as an autosomal recessive trait

Who gets 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder? (Age and Sex Distribution)

• 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder is a rare congenital disorder, with less than 20 cases reported in the medical literature
• The presentation of symptoms may occur soon after birth or infancy
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder? (Predisposing Factors)

• A positive family history may be an important risk factor, since 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder can be inherited
• Currently, no other risk factors have been clearly identified for this deficiency disorder

Summary: The risk of inheriting AUH Defect is dependent on the genetic makeup of the parents. Individuals who have a family history of the disorder are at an increased risk of passing it on to their children.

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder? (Etiology)

• 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder is caused by mutations in the AUH gene (chromosome 9) encoding 3-methylglutaconyl-CoA hydratase, an enzyme involved in leucine degradation
• The disorder is inherited in an autosomal recessive manner

Summary: AUH Defect is caused by mutations in the AUH gene. This gene provides instructions for making the enzyme 3-Methylglutaconyl-CoA Hydratase, which is required for the breakdown of leucine and fatty acids. When this enzyme is deficient or not functioning correctly, the leucine and fatty acids and their byproducts accumulate in the body, leading to the symptoms of the disorder. 

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder?

The signs and symptoms of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder may include:

Very frequently present symptoms in 80-99% of the cases:

• 3-methylglutaconic aciduria: A rare metabolic disorder characterized by high levels of 3-methylglutaconic acid in the urine and blood. This condition can be caused by various genetic mutations and may present with a variety of symptoms, including developmental delays, muscle weakness, and seizures.

• Failure to thrive: A condition in which an infant or child fails to gain weight or grow at the expected rate for their age and sex. Failure to thrive can be caused by various factors, such as malnutrition, feeding difficulties, or underlying medical conditions. It may also be a sign of neglect or abuse.

Frequently present symptoms in 30-79% of the cases:

• Delayed speech and language development: A condition in which a child's ability to speak or understand language is slower to develop than expected for their age. Delayed speech and language development can be caused by a variety of factors, such as hearing loss, neurological conditions, or developmental disorders like autism.

• Global developmental delay: A condition in which a child's development in multiple areas, such as motor skills, language, and social interactions, is delayed compared to their peers. Global developmental delay can be caused by genetic or environmental factors, and may be a sign of an underlying developmental disorder such as cerebral palsy or Down syndrome.

Occasionally present symptoms in 5-29% of the cases:

• Abnormality of the basal ganglia: The basal ganglia are a group of structures in the brain that are responsible for regulating movement and cognitive functions. An abnormality of the basal ganglia refers to any condition or disease that affects the structure or function of these brain regions, leading to problems with movement, muscle tone, or cognitive processing.

• Coma: A state of unconsciousness in which an individual is unable to respond to external stimuli or communicate. Coma can be caused by various factors, such as head injury, stroke, drug overdose, or metabolic disorders. It is a serious medical emergency that requires immediate attention.

• Dystonia: A movement disorder characterized by involuntary muscle contractions that cause twisting or repetitive movements and abnormal postures. Dystonia can affect any part of the body and can range from mild to severe. It can be caused by genetic or environmental factors, or as a side effect of medication.

• Hepatomegaly: A condition in which the liver becomes enlarged, usually due to an underlying disease or disorder. Hepatomegaly can be caused by viral hepatitis, liver cirrhosis, or fatty liver disease, among others. Symptoms may include abdominal pain, nausea, and jaundice.

• Hypoglycemia: A condition characterized by low blood sugar levels, which can cause symptoms such as dizziness, confusion, weakness, and seizures. Hypoglycemia can be caused by various factors, including diabetes medication, alcohol consumption, or an underlying medical condition.

• Microcephaly: A condition in which the head size is smaller than normal, often due to abnormal brain development. Microcephaly can be caused by genetic factors, infections during pregnancy, or exposure to certain toxins. It can lead to developmental delays, intellectual disabilities, and neurological problems.

• Progressive cerebellar ataxia: A neurological disorder characterized by progressive damage to the cerebellum, which can cause problems with movement, balance, and coordination. Progressive cerebellar ataxia can be caused by genetic factors or as a result of an underlying medical condition.

• Seizures: A sudden and uncontrolled electrical disturbance in the brain, which can cause a variety of symptoms, such as convulsions, loss of consciousness, and muscle stiffness. Seizures can be caused by various factors, such as epilepsy, head injury, or infections.

• Spastic tetraparesis: A type of cerebral palsy characterized by spasticity (stiffness) and weakness in all four limbs, usually caused by damage to the brain before or during birth. Symptoms may include difficulty with movement, coordination, and speech.

The following additional signs and symptoms may be present in some affected individuals:

• Ataxia: A neurological disorder that affects coordination and balance. Ataxia can be caused by damage to the cerebellum, spinal cord, or peripheral nerves. Symptoms may include gait disturbances, tremors, and difficulty with fine motor skills.

• Athetosis: A type of movement disorder characterized by slow, writhing movements, especially in the hands and feet. Athetosis is often associated with cerebral palsy and other neurological conditions.

• Cerebral atrophy: A condition in which the brain shrinks or loses mass due to various causes, such as aging, injury, or disease. Cerebral atrophy can lead to cognitive decline, motor deficits, and other neurological symptoms.

• Cognitive impairment: A broad term that refers to any condition that affects cognitive function, such as memory, attention, language, or perception. Cognitive impairment can be caused by various factors, such as brain injury, disease, or medication side effects.

• Dysarthria: A speech disorder characterized by difficulty with articulation and pronunciation due to weakness or coordination problems in the muscles involved in speech. Dysarthria can be caused by neurological conditions, such as stroke, cerebral palsy, or Parkinson's disease.

• Febrile seizures: Seizures that occur in young children during a fever, usually due to a sudden increase in body temperature. Febrile seizures are relatively common and usually do not cause long-term neurological damage.

• Hyperreflexia: A condition in which reflexes are exaggerated, often due to damage to the central nervous system or other neurological conditions. Hyperreflexia can lead to spasticity, muscle stiffness, and other motor deficits.

• Leukoencephalopathy: A disease that affects the white matter of the brain, causing damage to the myelin sheath that insulates nerve fibers. Leukoencephalopathy can be caused by genetic factors or as a side effect of certain medications or toxins.

• Metabolic acidosis: A condition in which the blood pH becomes too acidic due to an imbalance of acids and bases in the body. Metabolic acidosis can be caused by various factors, such as kidney failure, diabetes, or medication side effects.

• Motor delay: A developmental delay in motor skills, such as crawling, walking, or running. Motor delay can be caused by various factors, such as prematurity, neurological disorders, or muscle weakness.

• Optic atrophy: A condition in which the optic nerve, which transmits visual information from the eye to the brain, becomes damaged and begins to atrophy. Optic atrophy can cause vision loss or impairment.

• Short attention span: A condition in which an individual has difficulty sustaining attention or focusing on tasks for extended periods of time. Short attention span can be caused by various factors, such as ADHD or anxiety.

• Spastic tetraplegia: A type of cerebral palsy characterized by spasticity and weakness in all four limbs. Spastic tetraplegia is caused by damage to the brain before or during birth and can cause significant motor deficits.

• Urinary incontinence: A condition in which an individual loses control of their bladder, resulting in involuntary urine leakage. Urinary incontinence can be caused by various factors, such as neurological disorders, pelvic floor weakness, or medication side effects.

Summary: The symptoms of AUH Defect can vary widely, but typically include developmental delays, hypotonia, seizures, feeding difficulties, and muscle weakness. Some individuals may also experience liver or kidney problems. 

How is 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder Diagnosed?

The diagnosis of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder can be made by 

• Assay of 3-methylglutaconyl-CoA hydratase activity in fibroblasts or leukocytes: A laboratory test used to diagnose a rare genetic disorder called 3-methylglutaconic aciduria. This test measures the activity of the enzyme 3-methylglutaconyl-CoA hydratase in cells taken from the patient's skin (fibroblasts) or blood (leukocytes).

• Quantitative analysis of urinary organic acid excretion: A laboratory test used to diagnose various metabolic disorders by measuring the levels of organic acids in a patient's urine. This test can help identify conditions such as maple syrup urine disease, propionic acidemia, and methylmalonic acidemia.

• Analysis of bodily fluids by NMR spectroscopy: A non-invasive laboratory technique that uses nuclear magnetic resonance (NMR) to identify and quantify different molecules in bodily fluids, such as blood or urine. This technique can be used to diagnose a wide range of disorders, including metabolic disorders, neurological conditions, and cancer.

Diagnosis of 3-MCCD is typically made through a combination of clinical examination, blood and urine tests to detect elevated levels of leucine and its byproducts, and genetic testing to confirm the presence of mutations in the MCCC1 or MCCC2 genes.

The above assays are taken together with findings from:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Additional laboratory tests
• Imaging studies
• Biopsy studies, if necessary

Summary: Diagnosis of AUH Defect is typically made through a combination of clinical examination, blood and urine tests to detect elevated levels of leucine and fatty acids and their byproducts, and genetic testing to confirm the presence of mutations in the AUH gene. 

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder?

The potential complications of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder may include:

• Restricted movements due to low muscle tone, ataxia, and dystonia
• Delay in onset of speech
• Delay in achieving developmental milestones
• Risk of falls and injuries due to seizures
• Intellectual deficiency
• Coma

Summary: 

Complications of AUH Defect may include developmental delays, cognitive impairment, seizures, liver or kidney problems, and more severe symptoms. Complications may occur with or without treatment, and in some cases, due to treatment also.

How is 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder Treated?

• The treatment for 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder is largely symptomatic
• Dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases

Summary: There is currently no cure for AUH Defect, and treatment is aimed at managing symptoms and preventing complications. This may include a low protein and low fat diet, medication to control seizures, and physical therapy to improve muscle strength and coordination.

How can 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder be Prevented?

3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis through testing of the amniotic fluid (for high levels of 3-hydroxyisovaleric acid) or molecular testing of the fetus during pregnancy (to check for AUH gene mutation/s) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

Summary: As AUH Defect is a genetic disorder, it cannot be prevented. However, genetic counseling can help individuals with a family history of the condition to understand their risk of passing it on to their children. 

What is the Prognosis of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder? (Outcomes/Resolutions)

• The prognosis of 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Dietary restriction of leucine and L-carnitine supplementation may be beneficial 
• Typically, the prognosis may be assessed on a case-by-case basis

Summary: The prognosis for individuals with AUH Defect varies widely depending on the severity of the symptoms and the age of onset. With appropriate management, many individuals can lead relatively normal lives, while others may experience more severe symptoms and complications. 

Additional and Relevant Useful Information for 3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder:

3-Methylglutaconyl-CoA Hydratase Deficiency (AUH Defect) Disorder is also known by the following names:

• 3 Methylglutaconic Aciduria Type 1
• 3MG CoA Hydratase Deficiency
• 3-MGCA type I (3-MGCA-1)

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/

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