A Novel Synergistic Association of Variants in PTRH2 and KIF1A Relates to a Syndrome of Hereditary Axonopathy, Outer Hair Cell Dysfunction, Intellectual Disability, Pancreatic Lipomatosis, Diabetes, Cerebellar Atrophy, and Vertebral Artery Hypoplasia.

Abstract

The gene PTRH2 encodes a protein with peptidyl-tRNA hydrolase activity and is involved in the translation process in protein synthesis. The kinesin family member 1-A (KIF1A) gene encodes a molecular motor involved in axonal transport along microtubules. Mutations in these genes lead to respective phenotypical conditions that have been reported in the literature. In this paper, we present a novel syndrome of concurrent occurrence of mutations in the PTRH2 and KIF1A genes in a 19-year-old girl of Dravidian-Tamil descent from the Southern part of India. The girl presented with global developmental delay, intellectual disability, weakness of upper and lower limbs, and diabetes. On workup, she was found to have severe peripheral axonopathy, outer hair cell (OHC) dysfunction, severe bilateral sensorineural hearing loss (SNHL), total pancreatic lipomatosis, exocrine pancreatic insufficiency, cerebellar atrophy, vertebral artery hypoplasia, and scoliosis. The patient had a deceased elder sibling who also had had a similar phenotype. Whole exome sequencing (WES) revealed a novel variant in the PTRH2 gene and a rare variant in the KIF1A gene. The predominant axonal involvement seen in our patient, which was attributable to KIF1A involvement, distinguishes this syndrome from the infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) caused by PTRH2 involvement alone. To the best of our knowledge, this is the first report in the medical literature of a syndrome caused by the synergistic occurrence of mutations in the PTRH2 and KIF1A genes. In order to provide more clarity on the genetic and clinical features of such syndromes and to aid the treating clinician to recognize the existence of such syndromes, we propose the broader umbrella term “neuro-pancreatic syndromes” (NPS). Presently, under NPS, we include two entities: the syndrome described by us in this paper and the IMNEPD. Prompt and effective recognition and management of such NPS would immensely benefit the patient in terms of treatment and prognosis. Furthermore, we hope that this paper will promote further understanding of NPS and foster more research, both clinical and genetic, which would widen the spectrum of NPS. Eventually, this would throw more light on treatment options and ultimately benefit patients with NPS.