Introduction
Causes and Symptoms
The human BCS1L gene
Case reports
Epidemiology
Diagnosis and Treatment
References
A rare condition, Bjornstad syndrome is associated with mutations in the BCS1L gene. The two hallmark features of the syndrome include pili torti and sensorineural hearing loss. Professor Bjornstad first described it in 1965. The syndrome follows the autosomal recessive pattern of inheritance.
Causes and Symptoms
Mutations in the BCS1L gene cause Bjornstad syndrome. This gene has also been associated with GRACILE syndrome and the more severe complex III deficiency.
Most patients (80-90%) experience alopecia (hair loss), brittle hair, and sensorineural hearing impairment. Around 5-29% of the patients suffer from hypogonadism (decreased activity of gonads) and intellectual or mental disability. Other symptoms may include anhidrosis (lack of sweating), coarse or dry hair, and pili torti of variable intensity.
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The human BCS1L gene
BCS1L is a 419-amino-acid protein present in the inner mitochondrial membrane. It works as a translocase for the Rieske Fe-S protein from the matrix to the inner mitochondrial membrane. A sorting sequence, a Bcs1-specific sequence, and the AAA-domain are all functional domains of the BCS1L protein.
The extreme clinical variability is likely due to the nature of the amino acids involved, the different expression in tissues, and increased reactive oxygen species production caused by BCS1L functional inhibition. Pathogenetic variants are present in different regions of BCS1L, and there is no correlation between genotype and phenotype.
BCS1L is an ATPase from the "ATPases Associated with Diverse Cellular Activities" (AAA) family required for complex III assembly in the mitochondria. In the past, its variants have been linked to two conditions, complex III deficiency and GRACILE syndrome. The GRACILE syndrome is a more severe condition. It is marked by aminoaciduria, intrauterine growth retardation, lactic acidosis, cholestasis, iron overload, and early death. It was first recognized in the Finnish population.
There are currently only 12 mutations in BCS1L that cause Bjornstad syndrome. Mutations in the BCS1L gene (e.g., 603647.0008) among affected members of families segregating for the disorder were discovered using DNA sequencing of 44 genes inside the key region for Bjornstad syndrome on chromosome 2q. A homozygous missense mutation in the BCS1L gene was discovered in 5 affected members of a consanguineous Pakistani family with Bjornstad syndrome.
In the mitochondrial electron transport chain, BCS1L is involved in the assembly of complex III. The electron transport chain is in charge of generating the energy required by cells. Complex III also produces reactive oxygen species. These reactive chemicals will induce tissue damage if they are present in large quantities. Even though this aberrant protein reduces complex III's activity, the complex nevertheless produces more reactive oxygen species. The inner ear's hair follicles and cells are particularly vulnerable to reactive oxygen species. It is assumed to cause hair loss and hearing loss in people who have developed Bjornstad syndrome.
Case reports
Bjornstad first recognized the disease in 1965. He observed that out of eight patients of pili torti, five had nerve deafness. Deafness was noticeable as early as the first year of life. In the cases of Bjornstad (1965) and Reed (1966), the condition was seen in siblings. Crandall et al. (1973) characterized three male siblings with neurosensory deafness, pili torti-induced baldness, and secondary hypogonadism. Severe mental retardation has also been linked to Bjornstad syndrome in the past.
Bjornstad syndrome was found in five members of a large consanguineous Pakistani family, according to Siddiqi et al. (2013). At birth, the patients' scalp hair began to fall out at 2 to 3 months. Eyelashes were also lost. The hair threads were devoid of color and coiled about their axes. All of the patients had anhidrosis and light eye color, but their teeth, nails, palms, and soles were normal. Males that were affected were petite in stature. Audiometric tests detected variable degrees of progressive sensorineural hearing loss.
Epidemiology
To date, less than 50 cases of Bjornstad syndrome have been reported worldwide. The syndrome affects both genders equally.
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Diagnosis and Treatment
Individuals with twisted hair, which may be visible at birth or in the first months of life, may be suspected of having the syndrome. The diagnosis is confirmed by an electron microscope analysis of hair shafts from affected patients, which shows typical twisting of the hair shafts at regular intervals. All newborns with this hair anomaly should be investigated for probable sensorineural deafness, which can be confirmed using several specialized hearing (auditory) tests. Molecular genetic testing for mutations in the BCS1L gene confirms the diagnosis.
Patients with Bjornstad syndrome do not have a specific treatment. Treatment is symptomatic and supportive, focusing on the specific symptoms that each kid is experiencing. Pediatricians, audiologists, and dermatologists could be among the first to respond. Wigs and other hair replacement techniques may be used to treat alopecia. Sensorineural deafness should be detected and treated early to avoid potential speech issues. Administration of hearing aids may treat hearing loss.
Early intervention is critical for children with BS to achieve their full potential. Specific remedial schooling, special assistance for children with congenital sensorineural deafness, and additional medical, social, and/or occupational services may be advantageous. Affected individuals and their families may seek genetic counseling to understand the syndrome better.
A recent study explored the potential of ketogenic diets in treating Bjornstad syndrome-related alopecia. In some individuals with mitochondrial illness and epilepsy, ketogenic diets have been used to boost mitochondrial biogenesis, improve mitochondrial function, and reduce oxidative stress. A 7-year-old female was put on a mildly ketogenic diet, and improvement in hair growth was observed during treatment. Future research projects are required to provide more insights.
References:
- Della Marina, A., Leiendecker, B., Roesch, S., & Wortmann, S. B. (2020). Ketogenic diet for treating alopecia in BCS1l-related mitochondrial disease (Bjornstad syndrome). JIMD reports, 53(1), 10–11. https://doi.org/10.1002/jmd2.12109
- Falco, M., Franzè, A., Iossa, S., De Falco, L., Gambale, A., Marciano, E., & Iolascon, A. (2017). Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings. American journal of medical genetics. Part A, 173(5), 1348–1352. https://doi.org/10.1002/ajmg.a.38146
- Cassandra L. Kniffin. (2016). BJORNSTAD SYNDROME; BJS (# 262000). [Online] OMIM. Available at: https://www.omim.org/entry/262000#clinicalFeatures
- Siddiqi, S., Siddiq, S., Mansoor, A., Oostrik, J., Ahmad, N., Kazmi, S. A., Kremer, H., Qamar, R., & Schraders, M. (2013). Novel mutation in AAA domain of BCS1L causing Bjornstad syndrome. Journal of human genetics, 58(12), 819–821. https://doi.org/10.1038/jhg.2013.101
- (2007). Bjornstad Syndrome. [Online] (GARD) National Center for Advancing Translational Sciences. Available at: https://rarediseases.info.nih.gov/diseases/22/bjornstad-syndrome
- Björnstad Syndrome. [Online] National Organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/bjornstad-syndrome/
Further Reading