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

Consanguinity was confirmed in 17 of the 18 (95%) patients. Eight patients were from three families (see Table 1), and 9 of the 18 (50%) patients had a positive family history of a similarly affected sibling. Thirteen of the 18 (72%) patients came from the same tribe.

The age of onset is variable, but onset commonly occurs between 3 and 4 years (45%). All patients presented with the classical clinical features of subacute encephalopathy (confusion, drowsy, altered level of consciousness) and ataxia triggered by febrile illness. Seizures occurred in 13 of the 18 (72%) patients, and the seizures were mainly partial or generalized tonic-clonic seizures. Neurological examination showed: extrapyramidal sign dystonia and/or dysarthria were found in 12 of the 18 (67%) patients. quadriparesis and hyperreflexia in 9 of 18 (50%). Fundus examination were normal in all patients.

All of the following were unremarkable which includes: lactate level in blood and CSF, ammonia, biotinidase, creatine phosphokinase, acylcarnitine profile, copper, ceruloplasmin, blood for biotin and thiamine level, plasma aminoa acids, urine for amino acids, urine for organic acids, liver enzymes, coagulation profile, lipid profile and cerebrospinal fluid for cell counts, protein, glucose and culture. Magnetic resonance imaging findings (see Figure 1) consisted of abnormal signal intensity at the caudate and putamen with diffuse involvement of the brain including the cortical and subcortical white matter and the infratentorial region, while atrophy and necrosis of the basal ganglia was demonstrated in all patients who had MRIs during chronic follow-up. Cerebellar, thalami and brain stem involvement were confirmed in 4 of the 13 (31%) patients, while one patient had a spinal lesion with increased T2 signal intensity, particularly in the cervical region. Fifteen of the 18 (83%) patients were diagnosed based on DNA molecular testing, and all were found to have the same homozygous missense mutation in exon 5 of the SLC19A3 gene (Table 2); their parents were heterozygous for this mutation. The remaining three patients were diagnosed retrospectively after the diagnosis of their younger siblings.

In 8 of the 18 (45%) patients, the diagnosis was delayed, while immediate diagnosis was achieved in 7 individuals.

Four of the 18 (22%) patients died. Three patients died because treatment was not initiated due to lack of diagnosis. One patient who was diagnosed died at 26 years of age following an acute crisis; he had been receiving biotin therapy for 18 years. One-third of the patients showed mild to moderate neurological deficit, mainly in speech and motor function; one-third of the patients were normal; and two patients had severe global neurological deficits and spastic quadriplegia. In general, the cognitive outcome is better than speech and motor outcomes. All diagnosed patients improved with biotin (5–10 mg/kg/day) therapy while alive. The maximum dose of biotin was used 12 mg/kg/day, the dose schedule range from 1–3 times daily with no consistent regimen and the tablet strength was 10mg tablet. Six of the 18 (33%) patients had a recurrence of acute crises while on biotin alone, but after the addition of thiamine, there were no recurrences of those crises.

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.

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.

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.

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.

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].