Novel SLC16A2 Gene Mutation

Sir, Allan–Herndon–Dudley syndrome (AHDS) or MCT8-specific thyroid hormone cell membrane transporter deficiency is an X-linked disorder that presents with developmental delay, feeding difficulties during infancy, seizures, hypotonia, extrapyramidal signs, and later-onset pyramidal signs due to a state of dysthyroidism brought on by MCT8 transporter defect leading to a state of central hypothyroidism and peripheral hyperthyroidism that causes poor weight gain and reduced muscle mass.[1] A 5½-year-old boy presented with complaints of intellectual disability and stiffness of limbs with frequent episodes of sudden abnormal twisting movements of the limbs. He was born through a nonconsanguineous marriage and had a smooth perinatal period. After 6 months of age, there was a gradual decline in the pace of gaining milestones with persistent dystonia and stiffness. Examination revealed drooping neck and dysmorphic facies (tented upper lip, large-cupped ears, decreased facial creases, and long facies) [Figure 1]. The child had a weight of 15 kg, length of 105 cm, and head circumference of 48.5 cm (>−2 Standard Deviation (SD)). Electroencephalogram (EEG) was normal. Magnetic resonance imaging (MRIs) done at different time points revealed an abnormal myelination pattern, which gradually improved with age [Figure 2]. He had severe to profound intellectual disability. Brainstem Evoked Response Audiometry (BERA) showed bilateral sensory neural hearing loss. Thyroid function tests revealed normal thyroid stimulating hormone (TSH) with elevated T3 levels and low T4 levels (T3 2.73 [0.58–1.59] ng/ml, T4 2.99 [4.87–11.72] ng/ml, and TSH 2.8437 [0.35–4.93] uIU/ml). Free T3 was 5.91 (1.71–3.71) pg/ml and free T4 was 0.57 (0.7–1.48) ng/dl, with free T3/free T4 ratio of 10.36. Maternal thyroid function tests revealed normal T3, T4, and TSH levels, but elevated free T3/free T4 ratio (T3 0.94 ng/ml, T4 6.17 µg/dl, TSH 1.6997 µIU/ml, free T3 2.59 pg/ml, free T4 0.85 ng/dl, with a ratio of 3.05). Next-generation sequencing revealed a novel mutation c. 1193G>T (p.Gly398Val) in exon 5 of SLC16A2 gene, which can be associated with an X-linked disorder AHDS.Figure 1: Shows dysmorphism in the form of large cupped ears, long facies, tented upper lip, decreased facial creases, and dystoniaFigure 2: (a–d) MRI brain done at 10 months, 2 years 4 months, 3 years 4 months, and 5 years of age, respectively. Both T1 and T2 showing improving myelination with thin CC with some cortical atrophy. MRI = magnetic resonance imaging, CC = corpus callosumThe differentials are dyskinetic cerebral palsy, Pelizaeus–Merzbacher Disease (PMD), and Pelizaeus–Merzbacher-like disease (PMLD). Mothers show mild, clinically silent abnormal thyroid tests. Central nervous system is dependent on MCT8 transporter, which is encoded by SLC16A2, for availability of T3 inside the cells, while the peripheral organ systems which have alternate transporter pathways show features of thyrotoxicosis. Integrity of hypothalamo-pituitary-thyroid axis is compromised.[2] Results show low T4 and rT3, high T3, normal to high TSH, and free T3/T4 ratio >0.75. This gets misdiagnosed as congenital hypothyroidism. Treatment with l-thyroxine alone would do harm. T3 analogs like 3,5,3' triiodothyroacetic acid (TRIAC), best started before 4 years of age, significantly normalize dysthyroidism.[3] Other modalities under trial include 3,5 diiodo-thyropropionic acid (DITPA), sobetirome, gene replacement therapy, and pharmacological chaperones.[4] The mainstay of therapy is supportive care with good nutrition, physical and occupational therapy, rehabilitation, and family support. Authors' contribution AM and GK prepared the manuscript. AM, GK, PC, SG, BC, and PJ managed the case. AK provided radiological inputs. SG has critically reviewed the manuscript. The final manuscript has been agreed upon and approved by all the authors. SG will act as a guarantor. 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. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.