Department of Neurology, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research, Kolkata, India
Corresponding author: Adreesh Mukherjee, MD, DM Department of Neurology, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research, 52/1A, Sambhu Nath Pandit Street, Kolkata, West Bengal 700025, India / Tel: +91-9836146252 / E-mail: adreesh03@yahoo.co.in
• Received: September 27, 2023 • Revised: December 18, 2023 • Accepted: December 20, 2023
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Uner Tan syndrome (UTS) comprises a classical constellation of habitual quadrupedal locomotion, intellectual disability, and rudimentary language. The pathogenesis of UTS has been poorly elucidated, ranging from an expanding genetic spectrum to an expanding environmental contribution. The authors hereby report a 30-year-old male patient with intellectual disability and habitual quadrupedalism in the presence of a posterior fossa intracranial tumor with marked cerebellar atrophy and a novel genetic mutation. A 30-year-old Indian Bengalee male born to nonconsanguineous parents with global delay in developmental milestones and intellectual disability presented with a history of walking on all four limbs since childhood. On examination, his language was unaffected, and there was no macrocephaly, cranial nerve dysfunction, motor or sensory deficit, or sphincter abnormalities. He had normal deep tendon reflexes and bilateral flexor plantar response. However, there was bidirectional gaze-evoked coarse nystagmus with appendicular incoordination. The patient walked habitually on all four limbs, with his ipsilateral hand followed by his ipsilateral foot and his contralateral hand followed by his contralateral foot, suggesting a diagonal sequence (Supplementary Video 1 in the onlineonly Data Supplement). However, he can assume an erect posture with support and tends to fall backward in an attempt to stand without support. No similar/related phenotypes were reported in his family. No spinal deformity was noted on clinical examination. Routine laboratory investigations, including complete hemogram, liver, renal and thyroid function tests, were within normal limits. Brain imaging revealed an intracranial space-occupying lesion (3 cm × 3.3 cm × 3.3 cm) extending along the bilateral foramen of Luschka with heterogeneous texture and a lobulated surface with areas of intralesional calcification; postcontrast T1 sequence revealed avid heterogeneous contrast enhancement suggestive of choroid plexus papilloma (Figure 1). Diffuse cerebellar atrophy and mild dilatation of ventricles were noted. Whole-exome sequencing revealed a heterozygous mutation in exon 17 of the CPT1C gene (c.1922G>A), which was reported as a variant of uncertain significance (VUS). To our knowledge, the missense variant NM_001136052.3 (CPT1C):c.1922G>A (p.Arg641His) has not been reported previously as a pathogenic variant or as a benign variant. The p.Arg641His variant is novel in 1kG and is absent from individuals of South Asian background in gnomAD. The p.Arg641His missense variant is predicted to be damaging by both SIFT and PolyPhen2.
Gait initiation is a transient stage between erect posture and locomotion that encompasses anticipatory anteroposterior and lateral body motion; UTS has been reported as a probable disorder of asymmetric lateral balance. Individuals with UTS may walk upright with marked ataxia and hence prefer to walk on all four limbs without any evidence of imbalance. Cerebellar involvement on neuroimaging is commonly noted in UTS, and it ranges from mild to severe cerebello-vermian hypoplasia with gyral simplification of the cerebral cortex in rare instances. However, no intracranial space-occupying lesion, as observed in the present case, has been reported until now in UTS. Animal models have suggested that impairments in vestibular input may lead to striking retardation of postural control. UTS patients tend to have impaired intelligence and limited vocabulary with rudimentary language in some instances. The UTS phenotype has been extended to individuals who walk on all four limbs habitually, even without cerebellar atrophy or intellectual disability [1]. Compared with lateral sequence diagonal/lateral couplets (LSDC/LSLC), primates exhibit a diagonal sequence/diagonal couplet (DSDC) gait [2]. Habitual quadrupedalism in UTS can be attributed to an adaptation to marked postural instability due to cerebellar dysfunction. An important differential characteristic of UTS is disequilibrium syndrome (DES-H), characterized by cerebellar hypoplasia with predominant truncal ataxia, dysarthria with limited vocabulary, hypotonia and intellectual disability; this syndrome lacks habitual quadrupedal gait. Cayman syndrome is another closely related disorder attributable to a genetic mutation in the ATCAY gene mapped to chromosome 19p13 and comprises severe truncal ataxia, congenital hypotonia, and marked dysarthria with mild to severe intellectual disability [1]. UTS is associated with consanguinity, which suggests autosomal recessive transmission. A genetic defect has been mapped to a region on chromosome 9p24, which includes the very low-density lipoprotein receptor gene (VLDLR), which is involved in neuroblast migration. VLDLR deficiency at an early stage of neurodevelopment may disrupt normal neural migration during the formation of intricate cerebrocerebellar structures critical for gait, resulting in quadrupedal locomotion instead of normal bipedal locomotion. However, since the syndrome is genetically heterogeneous, quadrupedalism cannot be attributed to a single genetic defect in VLDLR [3]. Several mutations have been reported in UTS, such as in WDR81, CA8, ATP8A2, and TUBB2B. The genetic mutations linked to UTS reported to date with corresponding phenotypic expression data are tabulated in Supplementary Table 1 (in the online-only Data Supplement) [3-6]. The CPT1C gene encodes the neuronal isoform of carnitine palmitoyl-transferase, which has a minimal role in fatty acid oxidation. Heterozygous missense mutations in CPT1C have been linked to autosomal dominant spastic paraplegia-73 [7]. Prior cases of CPT1C mutation associated with autosomal dominant spastic paraplegia did not report any structural brain abnormalities. To date, CPT1C mutations have not been linked to UTS and hence are reported as VUS in the index patient. Although animal models have demonstrated impaired gait and coordination with underexpression of the CPT1C gene, the significance of this mutation in UTS is questionable. Thus, the present case describes a patient with UTS from India with atypical neuroimaging findings and a novel mutation of uncertain significance.
MRI brain sagittal T1WI postcontrast section showing a complex space-occupying lesion 3 cm × 3.3 cm × 3.3 cm in length in the fourth ventricle with avid heterogeneous contrast enhancement (yellow arrow) and diffuse cerebellar atrophy (white arrow) (A), axial section confirming the same (B) as moderate ventriculomegaly (C); MRI cervical spine T2WI sagittal section showing the normal cervical spine and craniovertebral junction anatomy (D). MRI, magnetic resonance imaging; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging.
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