ALDH7A1

The ALDH7A1 gene provides instructions for making the enzyme α-aminoadipic semialdehyde (α-AASA) dehydrogenase, also known as antiquitin. 

This enzyme plays a crucial role in lysine breakdown in the brain, catalyzing the conversion of α-aminoadipic semialdehyde to α-aminoadipate, and mutations in ALDH7A1 are associated with pyridoxine-dependent epilepsy, PDE-ALDH7A1, a condition characterized by seizures that respond to high doses of vitamin B6.

PDE-ALDH7A1 presents in two forms: classic, with seizures beginning in the first weeks to months of life, and atypical, with later-onset seizures. 

The diagnosis is confirmed through genetic testing and elevated α-AASA levels in biological fluids. Management includes lifelong high-dose pyridoxine supplementation and dietary modifications to reduce lysine intake, with some patients also benefiting from L-arginine supplementation. 

Early diagnosis and treatment are critical for improving clinical outcomes and quality of life.

What is ALDH7A1? 

The ALDH7A1 gene encodes an enzyme known as alpha-aminoadipic semialdehyde (α-AASA) dehydrogenase, also referred to as antiquitin. 

This enzyme is a member of the aldehyde dehydrogenase (ALDH) family, which plays a crucial role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. 

Antiquitin is involved in the catabolism of lysine, an essential amino acid, particularly in the brain. It facilitates the conversion of α-aminoadipic semialdehyde to α-aminoadipate, a necessary step for energy production and the synthesis of other important molecules in the central nervous system. [1.] 

Antiquitin is found in the cytosol and the nucleus of cells. It is also reported to localize in the mitochondria, with different forms of the enzyme arising from the use of alternative translation initiation sites.

Mutations in ALDH7A1 cause pyridoxine-dependent epilepsy (PDE), characterized by seizures in infants and young children, which can be prevented with high-dose pyridoxine (Vitamin B6) supplementation. 

This deficiency leads to the accumulation of alpha-aminoadipic semialdehyde (AASA) and its cyclic Schiff base, piperideine-6-carboxylate (P6C), which inactivate and deplete the coenzyme pyridoxal phosphate (PLP). 

PLP, the active form of vitamin B6, is essential in amino acid and neurotransmitter pathways, and its disruption due to ALDH7A1 deficiency leads to seizures. 

The enzyme is also involved in osmotic regulation, particularly in the cochlea of the ear. ALDH7A1 shares significant sequence identity with a plant osmoregulatory protein, suggesting a conserved function, although its role in humans remains to be fully understood. 

ALDH7A1 is involved in methylation via its metabolism of betaine, by oxidizing betaine aldehyde to betaine.  [3.] 

Mutations in ALDH7A1 that cause a depletion of PLP will also deplete gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, as GABA production is dependent on PLP as a cofactor.  

ALDH7A1 in Health and Disease

Pyridoxine-Dependent Epilepsy [2., 4.] 

ALDH7A1 mutations lead to pyridoxine-dependent epilepsy (PDE), a condition where the enzyme α-aminoadipic semialdehyde dehydrogenase is deficient. This enzyme is crucial in lysine metabolism, and its deficiency results in the accumulation of neurotoxic substances that deactivate pyridoxal phosphate (PLP), a cofactor essential for many enzymatic reactions.

The PLP deficiency reduces the function of the enzyme glutamic acid decarboxylase, which converts excitatory glutamic acid into the inhibitory neurotransmitter GABA. 

Decreased conversion results in a decreased synthesis of GABA, leading to an imbalance between excitatory and inhibitory neurotransmission, which contributes to the epileptic encephalopathy observed in PDE-ALDH7A1 patients. [2.] 

Elevated CSF glutamate levels in PDE-ALDH7A1 patients further suggest the involvement of the GABA synthetic pathway in this disorder. [2.] 

Pyridoxine-dependent epilepsy is characterized by seizures that are resistant to typical anti-seizure medications but respond to high doses of pyridoxine (vitamin B6). 

This disorder presents in two forms: classic and atypical. 

In classic PDE-ALDH7A1, seizures begin within the first weeks to months of life and can manifest as prolonged or recurrent episodes of status epilepticus, partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms. 

Intellectual disability is common, particularly when diagnosis and treatment are delayed. 

Atypical PDE-ALDH7A1 includes later onset seizures, initially responsive seizures that become intractable, seizures that respond to pyridoxine after a delay, and prolonged seizure-free intervals post-pyridoxine discontinuation.

The diagnosis of PDE-ALDH7A1 is suspected in individuals with pyridoxine-responsive seizures and confirmed through genetic testing revealing biallelic pathogenic variants in ALDH7A1 and elevated α-AASA levels in urine or plasma. 

Management involves lifelong high-dose pyridoxine supplementation (with recommended doses varying by age) and dietary modifications to reduce lysine intake. [4.] 

Some individuals also benefit from L-arginine supplementation, which helps lower lysine levels. [4.] 

Supportive care includes developmental and educational interventions for intellectual disability and regular neurological evaluations to monitor seizure control and sensory neuropathy. 

Prenatal testing and genetic counseling are recommended for at-risk families to ensure early diagnosis and treatment. Maternal pyridoxine supplementation during pregnancy is advised if the fetus is at risk.

Genetic Alterations in the ALDH7A1 Gene

The gene for the ALDH7A1 protein may contain alterations or mutations that cause increase or decrease of function of the ALDHA1 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in ALDH7A1 Function 

Glu399Gln (E399Q) [1.] 

This mutation, which replaces the amino acid glutamine with glycine at position 399 in the antiquitin protein, has been found in multiple people with pyridoxine-dependent epilepsy. 

It produces a nonfunctional antiquitin protein, leading to a deficiency that disrupts pyridoxine (vitamin B6) activity. 

Laboratory Testing for ALDH7A1

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

FAQ: ALDH7A1 (Aldehyde Dehydrogenase 7 Family Member A1)

What is ALDH7A1?

ALDH7A1 (Aldehyde Dehydrogenase 7 Family Member A1) is an enzyme that belongs to the aldehyde dehydrogenase family. It plays a crucial role in the breakdown of aldehydes, which are toxic byproducts of various metabolic processes. 

ALDH7A1 is also involved in the metabolism of certain amino acids and the processing of betaine, important in the methylation pathway.

What is the Function of ALDH7A1 in the Body?

ALDH7A1 is involved in:

• Detoxification: Converting toxic aldehydes into less harmful acids, thus protecting cells from oxidative stress and damage.

• Amino acid metabolism: Playing a key role in the breakdown of lysine, an essential amino acid, by converting its toxic intermediate, α-aminoadipic semialdehyde, into α-aminoadipic acid.

What is ALDH7A1 Deficiency?

ALDH7A1 deficiency is a genetic disorder caused by mutations in the ALDH7A1 gene, leading to reduced or absent enzyme activity. 

This deficiency is also known as pyridoxine-dependent epilepsy (PDE) because it commonly manifests as seizures that respond to vitamin B6 (pyridoxine) treatment.

What are the Symptoms of ALDH7A1 Deficiency?

Symptoms of ALDH7A1 deficiency can include:

• Seizures: Often beginning in infancy and responding to vitamin B6 (pyridoxine) treatment.

• Developmental delays: Delays in reaching developmental milestones.

• Intellectual disability: Varying degrees of cognitive impairment.

• Behavioral issues: Such as hyperactivity or attention deficits.

How is ALDH7A1 Deficiency Diagnosed?

ALDH7A1 deficiency is diagnosed through:

• Genetic testing: To identify mutations in the ALDH7A1 gene.

• Biochemical tests: Measuring levels of specific metabolites, such as α-aminoadipic semialdehyde, in blood or urine.

• Response to treatment: Improvement of seizures with pyridoxine treatment can also support the diagnosis.

What are the Health Implications of ALDH7A1 Deficiency?

ALDH7A1 deficiency can lead to several health issues, including:

• Neurological disorders: Seizures, developmental delays, and intellectual disabilities.

• Metabolic disturbances: Accumulation of toxic metabolites that can affect overall health and development.

How is ALDH7A1 Deficiency Managed?

Management of ALDH7A1 deficiency involves:

• Pyridoxine supplementation: lifelong supplementation with vitamin B6 (pyridoxine) to control seizures and manage metabolic disturbances.

• Dietary adjustments and/or supplementation: a low-lysine diet is often recommended, and additionally arginine supplementation may also be recommended. [GOSPE>>>>>>>

• Regular monitoring: regular check-ups with healthcare providers to monitor neurological development and metabolic health.

• Supportive therapies: including physical, occupational, and speech therapy to support developmental needs.

Can Lifestyle Changes Affect ALDH7A1 Deficiency?

While lifestyle changes cannot directly affect the genetic basis of ALDH7A1 deficiency, certain measures can help manage symptoms and improve quality of life:

• Adherence to treatment: ensuring regular intake of prescribed pyridoxine supplements.

• Balanced diet: Supporting overall health with a nutritious diet, and avoiding foods high in lysine.

• Regular therapy sessions: Engaging in recommended therapies to aid in development.

Where Can I Find More Information About ALDH7A1 and Related Conditions?

For more information about ALDH7A1 and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis.

• Scientific literature: Research articles and reviews on ALDH7A1 and its role in metabolism and health.

• Reputable health organizations: Websites of organizations such as the National Institutes of Health (NIH), Genetic and Rare Diseases Information Center (GARD), and American Epilepsy Society (AES).

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