Diagnosis of PIGG-related neurodevelopmental disorder in a patient with distal hereditary motor neuropathy



Poster Number: T404


Jordan Bontrager, MS, CGC, U of R School of Medicine and Dentistry Neurology, Phillip Mongiovi, MD, U of R School of Medicine and Dentistry Neurology

Background: Pathogenic variants in the PIGG gene have been associated with a recessive neurodevelopmental disorder (NDD) characterized by developmental delay, hypotonia, and variable accompanying features such as intellectual disability, seizures, ataxia, cerebellar atrophy, nystagmus, tremor, absent deep tendon reflexes and dysmorphisms.

Methods: We present a 40-year old female patient with distal hereditary motor neuropathy (dHMN) and significant small fiber sensory symptoms, subsequently diagnosed with a PIGG-related NDD.

Results: The patient endorsed a history of foot deformities and frequent ankle sprains since childhood. She reported diffuse pain and autonomic symptoms. Her exam was notable for absent deep tendon reflexes, decreased tone and muscle bulk, and distal weakness.

Previous medical history included diagnosis of ataxic cerebral palsy, as well as motor and speech delays. Patient received special education support throughout school years, and obtained her GED. She has history of seizures, which were frequent from infancy until age 16. Previous electroencephalogram (EEG) studies were abnormal, showing diffuse slowing.

Electromyography and nerve conduction studies (EMG/NCS) were performed, which demonstrated evidence of a diffuse motor neuropathy with low CMAP amplitudes and evidence of denervation and reinnervation in nearly all muscles tested. Sensory nerve responses were normal.

Whole exome sequencing (WES) identified a pathogenic variant in the SCN9A gene (c.5318del) which was felt to be contributory to her painful small fiber symptoms. Two likely pathogenic variants in the PIGG gene (c.1106_1107del, p.Y369*; c.1231CT, p.Q411*) were also reported. Phasing of the two variants was not confirmed, but population frequency data suggests they are in trans.

Conclusion: To our knowledge, dHMN has not been reported in patients with confirmed PIGG-related NDDs. This report suggests that dHMN may be an additional feature of PIGG-related disorders. EMG/NCS in patients with this diagnosis would be helpful to further explore the effect of this gene on motor nerve function.