PNPT1 Spectrum Disorders: An Underrecognized and Complex Group of Neurometabolic Disorders

Abstract

An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise.

Keywords: PNPT1; inherited metabolic disorders; mitochondrial disease; optic atrophy; spastic ataxia; spinocerebellar ataxia.

Figure 1

Brain MRI study of the proband at age 18 years old. (A) Sagittal brain MRI showing cerebellar atrophy (white asterisk) and normal corpus callosum in T1-weighted sequence. Axial brain MRI disclosing atrophy of the vermis and cerebellar hemispheres (black asterisks) in T1 (B), T2 (C), and FLAIR sequences (D). (E) Axial brain MRI showing mild atrophy of the optic nerves (white arrows) in T2-weighted imaging. No basal ganglia signal changes were observed in T2 (F) and FLAIR sequences (G). (H) Axial brain MRI showing hypointense sign in medial globus pallidus (black arrow) in SWI sequence.

Figure 2

Deltoid muscle biopsy study. (A) Hematoxylin and Eosin-stained tissue section disclosed mild variation in muscle fiber caliber and no detectable abnormalities in the conjunctive tissue. (B) Modified Gömöri trichrome stain disclosed mild subsarcolemmal mitochondrial proliferation (white arrows; 1, 2, 3). (C) Succinate dehydrogenase (SDH) stain showed several foci of subsarcolemmal mitochondrial proliferation (black arrowheads; 1, 2, 3). (D) Nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) staining disclosed areas of scattered moth-eaten appearance in muscle fibers (black asterisks; 1, 2). Size scale bars (A–D): 50 μm.