Misplaced Pages

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare disease that affects the nervous system, particularly the basal ganglia in the brain. It is a treatable neurometabolic disorder with autosomal recessive 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).

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, both of which are nearly always present. Additional observed symptoms include spasticity or cogwheel rigidity, seizures, difficulty swallowing (dysphagia), ataxia, slurred speech (dysarthria), ophthalmoplegia, opisthotonus, facial palsy, 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 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 T₂ 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
• Leigh syndrome
• Organic acidemia
• Sepiapterin reductase deficiency
• Sydenham's chorea
• Tyrosine hydroxylase deficiency
• Wernicke encephalopathy
• Wilson's disease

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.

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 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.

Epidemiology

The prevalence of BTBGD is unknown. Of the reported cases, it is predominately observed in individuals from Arab populations.

References

1. ^ Al-Anezi A, Sotirova-Koulli V, Shalaby O, Ibrahim A, Abdulmotagalli N, Youssef R, Hossam El-Din M (April 2022). "Biotin-thiamine responsive basal ganglia disease in the era of COVID-19 outbreak diagnosis not to be missed: A case report". Brain & Development. 44 (4): 303–307. doi:10.1016/j.braindev.2021.12.003. PMC 8696467. PMID 34953623.
2. ^ "Biotin-thiamine-responsive basal ganglia disease - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2022-11-27.
3. ^ "#607483 - THIAMINE METABOLISM DYSFUNCTION SYNDROME 2 (BIOTIN- OR THIAMINE-RESPONSIVE TYPE); THMD2". omim.org. Retrieved 2022-11-27.
4. ^ "Biotin-thiamine-responsive basal ganglia disease: MedlinePlus Genetics". medlineplus.gov. Retrieved 2022-11-27.
5. ^ Tabarki, Brahim; Al-Hashem, Amal; Alfadhel, Majid (1993), Adam, Margaret P.; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Biotin-Thiamine-Responsive Basal Ganglia Disease", GeneReviews, University of Washington, Seattle, PMID 24260777, retrieved 2022-11-27
6. Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, et al. (July 1998). "Biotin-responsive basal ganglia disease: a novel entity". Brain. 121 ( Pt 7) (7): 1267–1279. doi:10.1093/brain/121.7.1267. PMID 9679779.
7. ^ Zeng WQ, Al-Yamani E, Acierno JS, Slaugenhaupt S, Gillis T, MacDonald ME, et al. (July 2005). "Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3". American Journal of Human Genetics. 77 (1): 16–26. doi:10.1086/431216. PMC 1226189. PMID 15871139.
8. "Biotin thiamine responsive basal ganglia disease". Orphanet. Retrieved 2022-11-27.
9. Majumdar S, Salamon N (March 2022). "Biotin-thiamine-responsive basal ganglia disease: A case report". Radiology Case Reports. 17 (3): 753–758. doi:10.1016/j.radcr.2021.12.029. PMC 8717433. PMID 35003475.
10. Alfadhel M, Umair M, Almuzzaini B, Alsaif S, AlMohaimeed SA, Almashary MA, et al. (October 2019). "Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening". Annals of Clinical and Translational Neurology. 6 (10): 2097–2103. doi:10.1002/acn3.50898. PMC 6801173. PMID 31557427.
11. ^ Alfadhel M, Almuntashri M, Jadah RH, Bashiri FA, Al Rifai MT, Al Shalaan H, et al. (June 2013). "Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases". Orphanet Journal of Rare Diseases. 8 (1): 83. doi:10.1186/1750-1172-8-83. PMC 3691666. PMID 23742248.
12. Aljabri MF, Kamal NM, Arif M, AlQaedi AM, Santali EY (October 2016). "A case report of biotin-thiamine-responsive basal ganglia disease in a Saudi child: Is extended genetic family study recommended?". Medicine. 95 (40): e4819. doi:10.1097/MD.0000000000004819. PMC 5059037. PMID 27749535.

• Basal ganglia
• Rare diseases
• Genetic diseases and disorders
• Autosomal recessive disorders
• Neurogenetic disorders
• Inborn errors of metabolism