Keywords
Biotinidase deficiency - developmental delay - neurometabolic disorder - seizures
Introduction
Congenital biotinidase deficiency is one of the rare congenital neurometabolic disorders
with autosomal recessive inheritance. Early diagnosis is key to prevention of clinical
manifestations including mental and physical developmental delay. These cases usually
present in infantile age group with signs and symptoms which are common to multiple
other inborn errors of metabolism. Therefore, magnetic resonance imaging (MRI) plays
an important role in establishing the diagnosis which is confirmed by biochemical
assay. Sporadic cases of congenital biotinidase deficiency have been reported in literature
with most of reports showing brain atrophy and delayed myelination as imaging findings.
Here, we are presenting MRI findings in two proven cases of biotinidase deficiency,
including findings other than brain atrophy and delayed myelination.
Case 1
A 5-month-old male child, first born baby of consanguineous marriage, presented with
failure to thrive, alopecia, and multiple episodes of generalized tonic–clonic seizures.
His milestones were delayed and neck holding was still absent. His routine blood investigations
were within normal limit. MRI brain (noncontrast) was done which revealed extensive
areas of restricted diffusion seen as hyperintensity on diffusion-weighted images
(with increasing brightness on higher b-value) and low signal intensity on apparent
diffusion coefficient, in bilateral cerebral white matter – in periventricular location
extending along pyramidal tracts in bilateral cerebral peduncles [[Figure 1]]A, [[Figure 1]]B, [[Figure 1]]C, [[Figure 2]], and [[Figure 3]]. There was involvement of central tegmental tracts, posterior limb of internal
capsule, splenium of corpus callosum, and pyramidal tracts in brain stem [[Figure 1]]A, [[Figure 1]]B, [[Figure 1]]C, [[Figure 2]], and [[Figure 3]]. Periventricular cerebellar white matter and middle cerebellar peduncles were also
involved [[Figure 2]]. Medial temporal lobe, optic radiation, and parahippocampal region were also involved.
Delayed myelination was noted with mild cerebral atrophy especially in bilateral frontal
lobes. The areas of restricted diffusion revealed T2 and FLAIR hyperintense signal
[[Figure 1]]. Based on these findings, possibility of inborn error of metabolism was raised
and differential diagnosis of maple syrup urine disease (MSUD) and biotinidase deficiency
was given, although age of presentation of patient was older for MSUD. His urine examination
was negative for MSUD. Biochemical assay of blood revealed congenital biotinidase
deficiency.
Figure 1 (A-C): (A) Case 1. DWI showing restricted diffusion in posterior limb of internal capsule
(thin arrow), optic radiation, and splenium of corpus callosum (thick arrow). T1 and
T2W/FLAIR image showing delayed myelination and cerebral atrophy with T2 hyperintense
signal in involved area. (B) Case 1. DWI with corresponding ADC map showing restricted
diffusion in posterior limb of internal capsule (red arrow), optic radiation (thin
black arrow), splenium of corpus callosum (blue arrow), and cerebral peduncle (thick
black arrow). (C) Case 1. Diffusion-weighted image with corresponding ADC map showing
restricted diffusion in posterior limb of internal capsule, optic radiation, splenium
of corpus callosum, and cerebral peduncle. T1- and T2-weighted image showing delayed
myelination and cerebral atrophy with T2 hyperintense signal in involved area
Figure 2: Case 1. Diffusion-weighted images showing restricted diffusion in posterior limb
of internal capsule (red arrow), splenium of corpus callosum (black arrow), and periventricular
white matter (blue arrow)
Figure 3: Case 1. Diffusion-weighted images showing restricted diffusion in brain stem (red
arrow), middle cerebellar peduncle (blue arrow), and cerebellar white matter (black
arrow)
Case 2
Another 7-month-old female child, first baby of nonconsanguineous marriage, presented
with seizure, hypotonia, and neurodevelopmental delay. Her milestones were delayed
and neck holding was still incomplete. Her routine blood investigations were within
normal limits. Noncontrast MRI brain revealed similar changes in T2 and FLAIR hyperintense
signal with restricted diffusion as seen in case 1, but involvement of periventricular
cerebral white matter and splenium of corpus callosum was less marked, with noninvolvement
of cerebellar white matter [[Figure 4]] and [[Figure 5]]. Delayed myelination was also noted with more prominent cerebral atrophy especially
involving frontal lobes. Biochemical assay of blood was positive for biotinidase deficiency.
Figure 4: Case 2. Diffusion-weighted images showing restricted diffusion in dorsal mid brain
(red arrow), posterior limb of internal capsule (green arrow), and medial temporal
gyri and periventricular white matter/optic radiation (blue arrow)
Figure 5: Case 2. Diffusion-weighted images showing restricted diffusion in posterior limb
of internal capsule (red arrow) and medial occipital gyri and periventricular white
matter/optic radiation (black arrow)
Discussion
Biotin is an important vitamin found in some foods. It plays an important role as
cofactor for pyruvate, propionyl-CoA, beta-methylcrotonyl-CoA, and two isoenzymes
of acetyl-CoA carboxylase in gluconeogenesis, amino acidcatabolism, and fatty acid
synthesis.[[1]]
Biotinidase deficiency is a rare and treatable inherited neurometabolic disorder [[2]] with an estimated incidence of 1:61,067 population. This disorder in its severe
form is much rarer with incidence of 1:1,37,401.[[3]] Clinical findings of this disorder include neurological (seizure, ataxia, hypotonia,
neurodevelopmental delay), dermatological (eczematous skin rash, seborrheic dermatitis),
immunological, ophthalmological, respiratory problems (hyperventilation, apnea and
laryngeal stridor), and alopecia.[[1]],[[4]] Laboratory findings include abnormal organic acids in the urine, metabolic acidosis,
and elevated lactate and pyruvate levels in blood. Diagnosis can be confirmed by measuring
blood biotinidase activity.[[5]],[[6]]
Most of the literature have reported MRI findings in biotinidase deficiency as cerebral
atrophy, cerebral edema, and bilateral compensatory ventriculomegaly.[[4]] Apart from it, delayed myelination has also been reported. But these changes are
seen late in the course of disease, and there are few reports of imaging studies in
biotinidase deficiency in early stage. In late course of disease, MRI shows loss of
brain volume, with increased ventricular size and increased subarachnoid spaces. Subdural
hygromas or hematomas may also develop.[[7]] T1- and T2-weighted images show delayed myelination, with reduced diffusion and
increased fractional anisotropy in the deep white matter of the cerebral hemispheres.[[6]] One report suggests that uncommonly, cortical injury may occur.[[7]] Proton magnetic resonance spectroscopy (MRS) at long and intermediate (135 ms)
echoes shows marked elevation of lactate with decreased N-acetylaspartate (NAA) and
choline. All these abnormalities reverse rapidly if therapy is started early.[[7]],[[8]]
Karimzadeh et al.[[8]] in their study of 16 patients of biotinidase deficiency reported that 12 patients
had abnormal neuroimaging. Of these, nine patients had generalized brain atrophy and
myelination delay on brain imaging. Computed tomography (CT) scan showed multiple
calcifications in one case. One patient had left hemiatrophy, two showed dismyelination
in white matter, and one had abnormal signal changes in basal ganglia.
Two infants with early presentation of biotinidase deficiency (age 3 weeks and 2 weeks)
were described by Haagerup et al.[[9]] On admission, both children had severe neurological symptoms. In the first patient,
MRI of the brain showed frontal and temporal atrophy, and in the second patient, CT
of the brain showed diffuse periventricular hypodensities, particularly in the frontal
region.
Few studies have described findings on diffusion-weighted MRI in early stage of biotinidase
deficiency. Bhat et al.[[10]] have described unique MRI features in patients with biotinidase deficiency with
brain MRI demonstrating symmetrical diffusion restriction in bilateral hippocampi,
parahippocampalgyri, central tegmental tracts, and cerebellar white matter. Similar
findings were also seen in our cases, especially in case 1.
A description of diffusion-weighted MRI findings in a case of biotinidase deficiency
by Desai et al.[[6]] demonstrated markedly reduced diffusion in the brain stem, middle cerebellar peduncles,
splenium of the corpus callosum, posterior limbs of the internal capsules, corona
radiata, and parieto-occipital white matter. Similar findings were also seen in our
first case.
Diffusion-weighted imaging (b = 1000 s/mm2) and diffusion tensor imaging findings in cases of biotinidase deficiency have also
been described by Soares-Fernandes et al.[[11]] Their study revealed symmetric moderately reduced diffusion with abnormally increased
fractional anisotropy in the centrum semiovale and perirolandic white matter. However,
corpus callosum was not involved, although there was involvement of posterior limb
of internal capsule. Similar findings were observed in case 2; however, diffusion
tensor imaging was not performed in our case.
Therefore, overall the MRI findings that have been described in literature in cases
of congenital biotinidase deficiency and seen in our cases include the following:
(1) early presentation – symmetrical diffusion restriction in bilateral hippocampi,
parahippocampalgyri, corona radiata, posterior limb of internal capsule, splenium
of corpus callosum, central tegmental tracts, cerebellar white matter, brain stem,
and middle cerebellar peduncles with features of delayed myelination. (2) Late presentation
– brain atrophy especially in temporal and frontal lobes. (3) Rare features – subdural
hygromas and abnormal signal intensity changes in basal ganglia. (4) MR spectroscopy
findings – on long and intermediate (135 ms) echoes, marked elevation of lactate with
decreased NAA and choline. (5) Diffusion tensor imaging findings of abnormally increased
fractional anisotropy in the centrum semiovale and perirolandic white matter.
Imaging differentials of congenital biotinidase deficiency include MSUD and Leigh’s
syndrome. Most close differential diagnosis is MSUD which shows marked diffusion restriction
in white matter tracts, however, with involvement of thalami and basal ganglia as
well. In addition, MSUD presents at an earlier age in neonatal period with symptoms
of poor feeding, vomiting, poor weight gain, increasing lethargy, and maple-syrup-like
urine odor.[[12]] In Leigh’s syndrome, involvement of grey matter nuclei is more marked when compared
with white matter tract involvement. Also, diffusion restriction is less marked in
Leigh’s syndrome when compared with biotinidase deficiency and seen predominantly
during acute phase.[[13]],[[14]]
Conclusion
Biotinidase deficiency is a rare neurometabolic disorder that has clinical features
common to other inborn errors of metabolism. In addition to findings of delayed myelination
and brain atrophy, diffusion-weighted MRI findings as seen in our cases and few other
previous case series would be helpful in early diagnosis of disease and thus early
institution of treatment leading to prevention of devastating clinical manifestations.
Acknowledgement
The authors are thankful to Mr. Mohan Chandra, Medical Transcriptionist, Rama Medical
College, in helping to prepare the article.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
