In this study, we report the largest cohort to date of patients with BBGD. Our results support the findings of previous reports regarding the classical clinical presentation, the high prevalence of this disease in Saudi Arabia compared to other countries, the deterioration and death of patients who do not receive biotin treatment, autosomal recessive inheritance, the importance of biotin in treatment regimens and the cause of the disease in a mutation of the SLC19A3 gene, which was found in all patients [1, 3–6]. Our study demonstrated the following important points:
The natural history and the dosage regimens for biotin and/or thiamine in BBGD patients are incompletely understood
Previous reports showed highly variable neurological outcomes even among siblings from the same family [1, 3–6]. Ozand et al. reported that 5 of 10 (50%) patients with BBGD were normal with 5–10 mg/kg/day of biotin over a variable period of follow-up ranging from 5 to 10 years [1], while 5 mg/kg/day of biotin was ineffective in another report, and the patient was bedridden [6]. Interestingly, one BBGD child responded well to lower dosages of biotin (5–30 mg/day) [3]. Furthermore, Debs et al. reported on two siblings with BBGD, a 33 year old and a 29 year old, both had the same mutation. The man responded well to biotin alone, while the woman did not improve until thiamine was added to the treatment regimen. This significant heterogeneity demonstrates the complexity and ambiguity of the natural history and treatment of BBGD. Furthermore, this cohort demonstrated intrafamilial heterogeneity as we observe different outcomes within siblings of the same family, same environments and same molecular findings (see Table 1). However, the favorable outcome could be related to early initiation of treatment in several of them.
Thiamine and biotin are essential in the treatment regimens of BBGD
In original reports, thiamine was not effective [1]. However, one-third of the patients reported in this cohort showed recurrence of acute crises while on biotin alone, but with the addition of thiamine, the recurrence of these crises was prevented. This result supports the hypothesis that the impairment of thiamine transport in the brain has a critical role in this disorder. Furthermore, the SLC19A3 gene encodes hTHTR2, a second thiamine-transporter and not a biotin transporter [2]. In fact, hTHTR2 demonstrates 48% structural identity to hTHTR1, which is also a thiamine transporter, while demonstrating only 17% identity with hSMVT, which is a known biotin transporter [7]. Additionally, Subramanian et al. proved that biotin is not a substrate for hTHTR2 [7]. This evidence supports the importance of thiamine in the treatment of this disease but leaves the mechanism by which BBGD patients improved dramatically on biotin, as we observed in 100% of our cohort, unclear. However, it could be hypothesized that the biotin and thiamine transporters in the basal ganglia are closely associated and thus act synergistically [7]. Therefore, we recommend that the treatment regimen for patients with BBGD contain both thiamine and biotin.
Factors contributing to clinical outcome
The gap between the age of disease onset and the date of diagnosis correlates directly with the neurological outcome. Eight of the 18 patients who had a delayed diagnosis displayed mild to moderate neurological deficits, while seven patients who were diagnosed immediately achieved normal development. Another important factor is the number of attacks of acute crises, as a poor outcome is directly associated with more acute crises in the present patients. All those children with normal outcome had only one event. Additionally, the immediate treatment with biotin and thiamine is an important aspect that contributes to normal outcomes, as reported cohort showed no recurrence of crises on this regimen for a period of up to 5 years of follow-up. However, it is very difficult to extrapolate firm conclusion with regards to aforementioned factors as the median follow up of normal children were 16 months (1 month-3 year) which is too short compare to poorer outcome individuals.
Magnetic resonance imaging commonly shows an effect in the basal ganglia and could involve other parts of the brain and spinal cord
In the original report by Ozand et al., the MRI findings consist of bilateral necrosis in the basal ganglia, particularly at the central part of the caudate heads and part or all of the putamen with severe edema during the acute crisis in addition to white matter involvement at the grey–white matter junction [1]. Subsequent reports confirmed these findings and added the involvement of the globi pallidi, thalami, cerebellum and brain stem [3, 6]. Our largest cohort demonstrated these findings and showed abnormal signal intensity and swelling at the caudate and pautamen with diffuse involvement of the brain including the cortical, subcortical white matter and infratentorial region, while atrophy and necrosis of the basal ganglia appeared during chronic follow-up. Cerebellar, thalami and brain stem involvement are found in one-third of patients (see Figure 1). Interestingly, one patient demonstrated spinal cord involvement with increased T2 signal intensity particularly at the cervical region, which was not reported previously. This could be easily explained by the fact that previous patients did not undergo MRI of the spine, and neither did the patients in this report. It would be valuable to perform spinal MRI for all patients affected with this disease to see the extent of this finding.
The genotype-phenotype correlation is poor
All current patients have a homozygous missense mutation in exon 5 of the SLC19A3 gene [c.1264 A>G (p.T422A)]. This mutation is a founder mutation in Saudi families, because all of the patients of Saudi origin reported as having BBGD also carry this mutation. Other reported mutations in the SLC19A3 gene include a homozygous missense mutation in exon 5 of the gene [c.68 G>T (p.G23 V)] in a Yemeni family; a homozygous missense mutation in exon 3 of the gene [c.958 G>C (p.E320Q0] reported in four Japanese patients who are biotin unresponsive; a frame shift mutation in exon 2 [c.74dupT(p.Ser26 LeufsX19)]; and an intron mutation (c.980-14 A>G), which was discovered in 2 siblings in a heterozygous state of European ancestry. Despite having the same mutation, children from the same family have extremely variable outcomes, ranging from normal to severely handicapped [1–3, 5, 6].
Future directions
Despite its discovery 14 years ago, several questions regarding BBGD remain unanswered. Animal models are vital to understanding the pathophysiology of thiamine and biotin transport in the brain, particularly the levels of biotin and thiamine in the brain at the basal ganglia. This information is critical to understanding the clinical picture, complications and management of this disease. Moreover, investigators should make an effort to find a biomarker for this disease, which will help to accurately determine the appropriate dosages of biotin and thiamine to consequently improve the outcome of the disease. Finally, diagnosing more asymptomatic cases through the screening of high risk tribes and international registries to accommodate more cases of the SLC19A3 gene defect will lead to a better understanding of the natural history of the disease and will facilitate well designed treatment and outcome studies.
