Biotin-Thiamine Responsive Basal Ganglia Disease - An Overview

Introduction

Biotin thiamine-responsive basal ganglia disease is a genetic disorder that shows symptoms related to the alteration of brain functions. The disease is diagnosed by clinical findings, radiological findings, and also by genetic testing. Treatment can be as simple as providing supplementation of biotin and thiamine as soon as possible, which can help in managing the disease, but in some cases, supplementation cannot help. Childhood and adult patients have a good prognosis, but the infantile presentation of the disease shows a poor prognosis even after the supplementation. Symptomatic treatment is also essential. The risk of occurrence of the genetic disorder in relatives can be estimated. Genetic counseling is necessary for the family members and the patient to be aware of the disease's occurrence and in case of family planning.

What Is Biotin Thiamine-Responsive Basal Ganglia Disease?

Biotin-thiamine-responsive basal ganglia disease is an autosomal recessive disorder resulting in the alteration of thiamine to cross the blood-brain barrier. The condition can be treated if vitamin supplementation is started early. The conditions present in three forms

• Infantile form: It is the most severe form and has the worst prognosis despite initiating vitamin supplementation at the earliest.

• Classic childhood form.

• Adult Wernicke-like encephalopathy.

What Are the Alternative Names for This Condition?

The other names are as follows:

• Thiamine metabolism dysfunction syndrome 2

• Thiamine transporter-2 deficiency

• Thiamine-responsive encephalopathy

• THMD2

• BBGD

• Biotin-responsive basal ganglia disease

• BTBGD

What Are the Causes of Biotin Thiamine-Responsive Basal Ganglia Disease?

This disease is caused due to mutations in the SLC19A3 gene. The gene is responsible for providing instructions in making thiamine transporter, which helps in the movement of thiamine into the cells. Thiamine is also known as vitamin B1, which can be sourced from the food humans consume and is also needed for better nervous system functioning.

Any mutations in the respective gene can result in impaired transportation of the thiamine, which results in decreased absorption of the vitamin, leading to a compromised neurological state. Generalized swelling can be seen in areas of the brain.

What Is the Inheritance Pattern of Biotin Thiamine-Responsive Basal Ganglia Disease?

It is an autosomal recessive pattern of inheritance in which each cell in two copies of the gene has mutations. Parents of an individual with this condition carry a copy of the gene mutation but do not show any symptoms of the disease.

What Are the Clinical Features of Biotin Thiamine-Responsive Basal Ganglia Disease?

• Abnormal eye movements such as downward gaze and increased frequency in the opening of the eyelid.

• Projectile vomiting.

• Loss of head control and social smile in infants.

• Subacute encephalopathy (alteration of mental status).

• Cognitive defects.

• Seizures.

• Deficits in facial expression and mastication.

• Chronic dystonia (involuntary muscle contractions leading to abnormal positions).

• Developmental delay.

What Is the Incidence of Biotin Thiamine-Responsive Basal Ganglia Disease?

The incidence of biotin-thiamine-responsive basal ganglia illness is unclear; it is a rare disorder. The medical literature has documented about 48 cases, the majority of which are from Arab communities.

What Is the Diagnosis of Biotin Thiamine-Responsive Basal Ganglia Disease?

This disease is suspected in individuals showing the following features:

Encephalopathy, along with seizures, dystonia (uncontrolled muscle contractions), dysarthria (difficulty in speaking), dysphagia (difficulty in swallowing), and hyperreflexia (increased muscle reflex response).

1. Radiographic Examination:

• Magnetic resonance imaging (MRI), which visualizes edema, necrosis, and atrophy, is carried out.

• Abnormal signal intensity also can be seen, which signifies loss of nervous tissue.

• Swelling and increased signal intensity can be identified. One can also detect the involvement of the spinal cord.

2. Laboratory Investigations:

• Blood investigations.

• Urine gas chromatography-mass spectrometry.

• Lactic acid concentrations.

• Activities of serum biotinidase.

• Coagulation profile.

• Levels of urine amino acids and plasma amino acids.

• Cerebrospinal fluid evaluation.

3. Confirmation of the Diagnosis: Diagnosis of this disease can be established in a proband, which is identified by molecular genetic testing. Molecular genetic testing includes the following:

• Gene target testing.

• Comprehensive genomic testing: The first part of testing requires the clinician to determine the involvement of the gene, whereas the latter does not require it. This condition is usually diagnosed using targeted testing, as individuals with this condition can show broad features.

• When the clinical features and lab investigations suggest the diagnosis of biotin thiamine-responsive basal ganglia disease, molecular genetic testing comes into the picture. Single-gene testing or multi-gene panel testing approaches can be included.

What Is the Management of Biotin Thiamine-Responsive Basal Ganglia Disease?

The following are the treatment options:

• Administration of biotin of 5 to 10 milligrams and thiamine up to 40 mg per day can be given orally as early as possible and can be continued for the lifetime.

• Within a few days, symptoms usually resolve.

• Care in the ICU (intensive care unit) to manage seizures is required for encephalopathic episodes.

• In certain conditions of acute decompensations, the dose of thiamine can be doubled to that of the regular dose and is administered intravenously. Seizures can be controlled using anti-seizure medication.

• Symptomatic management is done in case of dystonia, and treatment includes L-dopa administration.

• Physiotherapy, rehabilitation, speech therapy, and occupational therapy are all needed to meet the necessity of the individuals.

• The importance of lifelong medical therapy is explained to the family.

Prevention of Primary Manifestations:

Biotin and thiamine are administered early during the disease treatment.

Surveillance:

Follow-ups every six months for assessing neurological status and every 12 months for development progress, social support, and educational needs are carried out.

The following are to be avoided during the treatment:

• Stress, intense exercise, infections, and trauma.

• Drug treatment of epilepsy is avoided as there is a risk of acute attacks.

• It is advised for the affected women to continue thiamine and biotin even during pregnancy.

What Is Genetic Counseling?

It is the process of providing families of individuals suffering from genetic disorders with information about the hereditary nature and clinical symptoms of the condition to assist them in making appropriate treatment decisions. Genetic risk assessment and genetic testing can be done to obtain the genetic status of the family members, which helps rule out any risk of the disease. Parents of individuals suffering from the disorder are carriers mostly. They are usually asymptomatic and do not develop the disorder.

Conclusion

The disease needs an approach of a pediatric neurologist, physiotherapist, speech therapist, occupational therapist, psychologist, and consultation with a genetic counselor to achieve a proper treatment plan and outcome. Proper supplementation of biotin and thiamine and symptomatic treatment can help achieve recovery. It is to be noted that the supplementary is prescribed for a lifetime. Regular follow-ups and monitoring of the patient are necessary to eradicate the occurrence of complications.