Acute respiratory failure in pregnancy: the presenting symptom of a disorder of gliomedin, an essential component of the nodes of Ranvier

Topic:

Clinical Management

Poster Number: P378

Author(s):

Ruchee Patel, MD, National Institutes of Health, Sandra Donkervoort, MS, CGC, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Colin Quinn, MD, Department of Neurology, University of Pennsylvania, Michael Baer, MD, University of Pennsylvania, Michael Rey, MD, MSHP, University of Pennsylvania, Jorge Mora, MD, University of Pennsylvania, A. Reghan Foley, MD, MD(Res), National Institute of Neurological Disease and Stroke, Carsten G Bönnemann, National Institute of Neurological Disorders and Stroke

GLDN encodes gliomedin, an integral protein in the formation of peripheral nodes of Ranvier. Biallelic pathogenic variants in GLDN are known to cause lethal congenital contracture syndrome 11, with only a few patients reported surviving beyond the neonatal period.

We report a 32-year-old female who presented acutely with respiratory failure at age 28 years while in the 3rd trimester of her first pregnancy. She required continuous non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) which was slowly weaned to nocturnal NIV following labor and delivery; however, progressive proximal limb-girdle weakness was noted at that time. In retrospect, the patient had early feeding difficulties, idiopathic infantile scoliosis requiring surgical repair (age 12 years), Adie syndrome, atypical refractory migraines, as well as mild clumsiness throughout her life. Exome sequencing identified compound heterozygous variants in GLDN: a maternally inherited deletion (chr15:51633881_51634245) involving the initiation codon in exon 1 and a paternally inherited canonical splice site variant (c.1179-2A>G). Examination at age 32 years was notable for an Adie’s pupil, mild symmetric proximal weakness (MRC 4/5), distal joint contractures, pes cavus, areflexia, large-fiber sensory deficits, and a hyperlordotic gait. On muscle ultrasound there was diffusely increased echogenicity in a streak-like pattern and fasciculations. Nerve conduction studies and EMG confirmed a predominantly motor neuropathy/neuronopathy with myokymic-like irritability in the biceps brachii. Somatosensory evoked potentials showed abnormal responses in the peripheral segments in both the upper and lower extremities. This case expands the phenotypic spectrum of biallelic GLDN-related disorder and belongs to a less severe presentation, with the unique manifestation of respiratory failure in pregnancy as the first sign of disease. Deep phenotyping of more patients with pathogenic GLDN variants may reveal an even wider spectrum of clinical presentations and provide more insights into the pathomechanisms of GLDN-related disorders.