Around 40 years ago, research on biotin's use in curing carboxylase deficits began. Clinical responses to biotin supplementation were seen in patients with beta-methylcrotonylglycinuria, a carboxylase deficiency, in 1971 [3]. A decade later, Wolf et al. discovered biotin insufficiency-related multiple carboxylase deficiency [4]. Biotinidase (BTD) gene mutations (located at chromosome 3p25.1) cause biotinidase deficiency. The most common pattern of inheritance is autosomal recessive [1].

CBD is an uncommon form of metabolic encephalopathy where the lack of biotinidase enzyme prevents the cleavage of biotin from biocytin. It functions as a coenzyme for four carboxylases, which play an important role in amino acid metabolism, gluconeogenesis, and fatty acid synthesis [5].

CBD can be profound (<10% of mean normal enzyme activity) or partial (10 to 30%). The age of presentation greatly depends on the level of enzyme activity, with profound cases typically manifesting between six months of life and 10 years. Globally, the incidence of biotinidase deficiency ranges from 1 in 40,000 to 1 in 60,000 births, making it an uncommon disorder. In the US, partial cases ranged from 1 per 31,000 to 1 per 40,000 in 2006, while profound cases were 1:80,000 [6].

Developmental delay, seizures, ataxia, hypotonia, visual impairment, sensorineural hearing loss, skin pigmentation, alopecia, and dermatitis are a few of the clinical characteristics of CBD. Neurological symptoms like seizures, hypotonia, ataxia, and developmental delay occur in early infancy. Dermatological and metabolic manifestations are reported to occur in later stages of life, depending on the severity of deficiency. Our patient was a six-year-old child with breathlessness and a history of seizures. The patient also developed respiratory alkalosis with metabolic acidosis. These manifestations can be attributed to a lack of biotin, leading to energy loss and anaerobic metabolism, thereby increasing lactate levels. Early diagnosis with a biotin supplement in infancy can potentially reverse the underlying acid-base balance abnormalities completely.

Only a few earlier case studies have described the neuroimaging findings in CBD, which are highly dependent on the age of presentation. MRI is the imaging modality of choice. Cerebral atrophy is the most common imaging abnormality described in previous studies, which can occasionally be linked to subdural hygromas or hemorrhages. Other frequent MRI abnormalities include white matter swelling and delayed myelination [7]. The corona radiata, perirolandic white matter, posterior limb of internal capsule (PLIC), parieto-occipital grey matter, brainstem, middle cerebellar peduncle (MCP), and splenium of corpus callosum showed bilateral symmetrical diffusion restriction in diffusion imaging in four patients [7-9].

In our case, cerebral atrophy was not present. However, restricted diffusion was seen in the genu, posterior limb of the internal capsule, and periventricular white matter. A post-biotin supplement scan showed complete resolution of restricted diffusion in these areas. Magnetic resonance spectroscopy (MRS) typically exhibits a low N-acetyl aspartate (NAA), lactate peak, and reversal of the choline-to-creatine ratio [8]. NAA is considered a marker of neuronal integrity. Reduced NAA levels in biotinidase deficiency suggest potential neuronal damage or dysfunction.

Several theories have been put forth for diffuse white matter signal abnormality in infants with biotinidase deficiency, including leukodystrophy, interstitial edema, delayed myelination, dysmyelination, and ischemia. We agree with Biswas et al. that interstitial edema, neither leukodystrophy nor dysmyelination, is the primary process causing these alterations [10]. Our patient and the majority of patients in their series had a diffuse pattern of involvement, and these changes were reversible, which supports this hypothesis.

The major differential diagnosis in our case was holocarboxylase deficiency. Neurological and dermatological manifestations in both biotinidase deficiency and holocarboxylase deficiency are quite similar. This similarity can be explained by the fact that holocarboxylase synthetase deficiency results from a defect in the enzyme responsible for attaching biotin to carboxylases. Hence, differentiating the two based solely on clinical features is difficult. MRI findings in holocarboxylase synthetase deficiency may include subependymal cysts, ventriculomegaly, and intraventricular hemorrhage. Other major findings are diffuse cerebral edema, cerebral atrophy, and diffusion restriction in the cerebellum and bilateral basal ganglia [11]. Seizures with encephalopathy and acidosis can also be features of other organic acidemias. In infants, seizures and altered sensorium are often initially attributed to sepsis, which is far more commonly encountered in day-to-day clinical practice. Although neurological manifestations in biotinidase deficiency can mimic those of Maple Syrup Urine Disease (MSUD), the characteristic burnt sugar or maple syrup odor of urine, feeding difficulties, and the MRI findings in our case helped in ruling out MSUD as a differential diagnosis [12].

The degree of biotinidase deficiency (less than 10% vs. 10-30% of mean normal enzyme activity) and its impact on the treatment strategy are important considerations. In other circumstances, there may be no or few symptoms. Treatment with biotin usually reverses most of the symptoms, except in cases of moderate-severe developmental delay, optic atrophy, and established hearing loss. Similarly, early biotin supplementation can prevent the development of clinical manifestations of biotinidase deficiency. Hence, many countries are now doing routine neonatal screening as a protocol for biotinidase deficiency [13].

The recommended treatment of biotin replacement is 5 to 20 mg daily, which can be increased up to 40 mg per day if the symptoms persist. Apart from replacement therapy, it is important to counsel the family members regarding the lifelong need for supplementation. As the disorder is autosomal recessive, parents must explain that there is a 25% probability with each pregnancy of having another child with this condition [13].