Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare disease that affects the nervous system, particularly the
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
in the brain.
It is a treatable neurometabolic disorder with
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance.
First described in 1998 and then genetically distinguished in 2005,
the disease is characterized by progressive brain damage that, if left untreated, can lead to coma and/or death.
Commonly observed in individuals with BTBGD is recurring subacute
encephalopathy along with confusion, seizures, and disordered movement (
hypokinesia
Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...
).
BTBGD has several alternate names, including:
* BTRBGD
* Biotin-responsive basal ganglia disease (BBGD)
* Thiamine metabolism dysfunction syndrome 2 (biotin or thiamine-responsive type) (THMD2)
* Thiamine-responsive encephalopathy
* Thiamine transporter-2 deficiency
Signs and Symptoms
The onset of signs and symptoms can occur at any age but is most common in childhood between the ages of 3 and 10.
Less commonly, it may present in early infancy or adulthood. The neurological symptoms usually present as episodes of increasing severity. A less common exhibition of BTBGD involves persistent symptoms, rather than recurrent episodes.
In these cases, fewer symptoms are usually present, with their severity slowly increasing over time.
Classic Presentation (Childhood)
Recurrent subacute encephalopathy is the most commonly observed symptom, followed by
dystonia
Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
, both of which are nearly always present. Additional observed symptoms include
spasticity or cogwheel rigidity,
seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s, difficulty swallowing (
dysphagia
Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right.
It may be a sensation that suggests difficulty in the passag ...
),
ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
, slurred speech (
dysarthria
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...
),
ophthalmoplegia
Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease.
Internal o ...
,
opisthotonus
Opisthotonus or opisthotonos (from grc, ὄπισθεν, translit=opisthen, lit=behind and grc, τόνος, translit=tonos, lit=tension, label=none) is a state of severe hyperextension and spasticity in which an individual's head, neck and spinal ...
,
facial palsy
Facial nerve paralysis is a common problem that involves the paralysis of any structures innervated by the facial nerve. The pathway of the facial nerve is long and relatively convoluted, so there are a number of causes that may result in facial ...
,
confusion,
hyperreflexia, Babinski responses, and ankle
clonus.
Early Infancy Presentation
In early infancy, the presentation of BTBGD is considered as
Leigh-like syndrome or atypical infantile spasms.
It is characterized by acute encephalopathy, vomiting, metabolic acidosis (specifically lactic acidosis), and poor feeding during the first 3 months of life.
Late-Onset Presentation (Adulthood)
Presentation of late-onset BTBGD is considered a
Wernicke-like encephalopathy.
It is characterized by ataxia, ophthalmoplegia, double vision (
diplopia), rapid and uncontrollable eye movement (
nystagmus),
status seizures, and droopy eyelid
(ptosis). The onset of signs and symptoms for adulthood presentation occurs during or after the second decade of life.
Causes
Genetics
''SLC19A3'' gene mutations cause BTBGD.
''SLC19A3'' is a gene on chromosome 2q36.3 that encodes the protein
thiamine transporter 2
Thiamine transporter 2 (ThTr-2), also known as solute carrier family 19 member 3, is a protein that in humans is encoded by the ''SLC19A3'' gene. SLC19A3 is a thiamine transporter.
Function
ThTr-2 is a ubiquitously expressed transmembrane thiam ...
.
Thiamine transporter 2 moves
thiamine (vitamin B1) into cells, which is essential for nervous system functioning. Mutations of the gene encoding this protein (''SLC19A3'') are likely to impair the functioning of this protein and inhibit the transportation and absorption of thiamine.
The role of biotin in BTBGD is unclear.
Triggers
Episodes of symptoms can be triggered by several things:
* Febrile illness
* Stress
* Trauma
Diagnosis
BTBGD can be diagnosed based on brain imaging and confirmed with genetic testing. Additional diagnostic tools include laboratory testing of biological fluids and reviewing autosomal recessive inheritance in the family history.
Clinical Findings
Brain Magnetic Resonance Imaging (MRI)
The MRI of individuals with BTBGD may reveal lesions on the basal ganglia and central bilateral necrosis in the caudate nucleus and putamen.
Vasogenic edema is also characteristic of BTBGD.
Additional MRI findings include high T
2 signal intensity with possible swelling in basal ganglia, and abnormal diffuse involvement of the subcortical white matter, cortical, and infratentorial brain.
Involvement in the thalami, brain stem, and cerebellum may also be observed.
Molecular Genetic Testing
Molecular genetic tests that can be performed for BTBGD include:
* Sequence analysis of the entire coding region or select exons
* Duplication/deletion analysis
* Targeted variant analysis
Differential Diagnosis
Other disorders that present similar clinical findings include:
* Juvenile
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
*
Leigh syndrome
*
Organic acidemia
*
Sepiapterin reductase deficiency
Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. Symptoms are usually present within the ...
*
Sydenham's chorea
Sydenham's chorea, also known as rheumatic chorea, is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. Sydenham's chorea is an autoimmune disease that results from childhood infecti ...
*
Tyrosine hydroxylase deficiency Tyrosine hydroxylase deficiency (THD) is a disorder caused by disfunction of tyrosine hydroxylase, an enzyme involved in the biosynthesis of dopamine. This condition is one of the causes of dopa-responsive dystonia.
Symptoms
Patients present with ...
*
Wernicke encephalopathy
*
Wilson's disease
Treatment
Treatment of BTBGD is done to manage specific symptoms and concerns.
If left untreated, the disease can be fatal. Treatment may vary by symptom, though it is common to administer thiamine (up to 40 mg/kg/day) and sometimes biotin (5-10 mg/kg/day) orally. This treatment is specifically used to address neurological symptoms and can reverse these symptoms if taken early enough. Biotin and thiamine oral therapy must continue throughout the entirety of the individual's life.
Other symptomatic treatments include anti-seizure medication to treat seizures and
trihexyphenidyl
Trihexyphenidyl (THP, benzhexol, trihex, marketed as Artane and others) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Pa ...
or
L-dopa to treat dystonia. Rehab and therapy are used for developmental and social concerns.
Management
Management of BTBGD includes prevention of symptoms and routine surveillance.
Avoiding stressors is essential in managing BTBGD since stress and trauma can trigger episodes. Fevers are also triggers, so fever control is important. Other triggers that should be avoided include infections and excessive exercise. Routine surveillance should include evaluation of the individual's nervous system, education and development, and any other relevant areas.
Family Screening
Family members of individuals with BTBGD may be tested regardless of symptoms.
Family members may be affected by the disease, may be asymptomatic carriers of the mutation, or may be completely unaffected.
Genetic testing of family members allows for the identification of subtle symptoms, asymptomatic carriers, and increased-risk individuals, which allows for early treatment as needed.
Prevalence/Epidemiology
The prevalence of BTBGD is unknown.
Of the reported cases, it is predominately observed in individuals from Arab populations.
References
Basal ganglia
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