Congenital myasthenic syndrome type 19 due to a novel mutation in the COL13A1 GENE

CASE PRESENTATION

A 45 year-old man presented for an evaluation of longstanding ptosis and subjective limb weakness. Ever since birth he had had bilateral droopy eyelids that did not respond to eyelid lift surgery in his thirties. There was no double vision. He noted weakness in his legs for the past 8–9 years and reported occasionally dropping objects from his hands for several months prior to his evaluation at our institution. Other symptoms included a feeling of food getting stuck in his throat when swallowing solids, frequent coughing due to saliva accumulation, and difficulty speaking for more than 10 min secondary to shortness of breath. There was no numbness or pain. Four months prior to his presentation, he developed shortness of breath and oxygen desaturation after a cholecystectomy. He subsequently developed oxygen dependence and required intermittent usage of positive airway pressure ventilation. Evaluation revealed no evidence of pulmonary embolism. There was no known family history of neurological disease on the maternal side, and paternal family history was unknown. Pulmonary function testing showed a restrictive disease pattern without a bronchodilator response and a forced vital capacity of 1.63 L (35% of predicted). Reduced excursion of the left hemidiaphragm was revealed by imaging.

At examination, he had a high arched palate and periorbital muscle atrophy. There was no micrognathia, low-set ears, or limb contracture. A mild flaccid dysarthria was present. He demonstrated prominent, nonfatigable bilateral ptosis and mild weakness of the orbicularis oculi muscles. Cranial nerve examination results were otherwise normal. Limb strength, reflexes, sensation, and gait were all normal. Creatine kinase, aldolase, pyruvate, lactate, carnitine, ammonia, and acid α-glucosidase levels were normal. Test results for antibodies for acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase, and voltage-gated calcium channel were negative.

Results of sensory conduction studies of the median and sural nerves and motor nerve conduction studies of the median, peroneal, and tibial nerves were normal. Phrenic motor responses were absent bilaterally. Ultrasound study of the diaphragm revealed no thickening or descent of the diaphragm muscle with inspiration. Repetitive nerve stimulation (RNS) of 3 trains at 2 Hz revealed decrements of the compound muscle action potential amplitude at baseline of 15% for the spinal accessory nerve recording at trapezius, 9% for the median nerve recording at abductor pollicis brevis, and 50% for the facial nerve recording at nasalis. After exercises of 30-s duration, immediate improvement of the decrement was observed in each nerve, followed by postexercise exhaustion, with maximum decrements of 10%, 16%, and 44% noted 120, 150, and 180 s, respectively, postexercise. This pattern of RNS was consistent with a postsynaptic neuromuscular junctional defect. Needle examination revealed unstable short-duration, low-amplitude motor unit potentials in the deltoid, triceps, and cervical paraspinal muscles, without the presence of abnormal spontaneous activity or clear early recruitment. Clinical suspicion for a congenital myasthenic syndrome (CMS) diagnosis was raised and further supported by the patient's positive response to pyridostigmine 60 mg 3 times daily. Next-generation high-throughput sequencing with a focus on genes responsible for CMS revealed a previously unreported homozygous c.739C>T; p.Arg247* mutation (NM_001130101.1) in the collagen type XIII α1 chain (COL13A1) gene, which results in an early stop codon and loss of COL13A1 protein function, confirming a diagnosis of CMS type 19.

DISCUSSION

Congenital myasthenic syndrome comprises a group of inherited disorders characterized by genetic defects affecting the neuromuscular junction (NMJ). Currently, more than 30 distinct CMS types have been described.1 They are classified according to the anatomic site of the disease protein (e.g., presynaptic, synaptic space, and postsynaptic) for those with defined function at the NMJ or as proteins that are ubiquitously expressed but have the most apparent defective function at the NMJ.1, 2 Defects in the postsynaptic region are the most common, and, in 1 study of 359 patients with CMS, mutations in AChR, Rapsyn, Dok-7, or acetylcholinesterase (AChE) proteins were present in 87% of patients.1

Our patient has a novel homozygous c.739C>T; p.Arg 247* mutation (NM_001130103.1) of COL13A1, a large gene encoding nonfibrillar transmembrane collagen, which is concentrated on the postsynaptic junctional folds from where its ectodomain can be cleaved and shed into the synaptic cleft. Collagen type XIII α1 chain binds directly to the collagen-like tail subunit of AChE.3 Its function is essential for the correct assembly of the presynaptic, synaptic, and postsynaptic regions. Collagen type XIII α1 chain promotes synaptic development and maturation as well as regeneration after peripheral nerve injury.4 COL13A1^−/− mice have small nerve terminals, decreased neurotransmitter release, and decreased postsynaptic AChR clustering.3, 5

Congenital myasthenic syndrome associated with mutation in the COL13A1 gene (CMS type 19) has been described in 3 patients from 2 kindreds.6 These 3 patients shared the following similar features: onset at birth, slight dysmorphic facial features (high-arched palate, low-set ears, and micrognathia), marked ptosis with limited fatigability, normal eye movements, and respiratory involvement in the form of apnea and dyspnea. Two patients did not respond to pyridostigmine, but 1 patient benefited from 3,4-diaminopyridine and salbutamol. One patient had a homozygous c.1171delG frameshift mutation, and the other 2 patients had a homozygous splice site c.523-1delG that is predicted to cause a frameshift.

Our patient's presentation was similar, with marked but nonfatigable ptosis, breathing difficulty, and facial dysmorphism. His ptosis was reportedly present at birth, but his other symptoms developed in his late 30s, and he did not seek neurological evaluation until his mid-40s. The previously reported patients all were symptomatic from birth, and 1 patient died at 8 years of age as a result of respiratory failure. Notable differences in phenotypic severity were noted in both patients from the same kindred.6 This implies that there are other contributing genetic and/or environmental factors influencing phenotypic expression that have yet to be elucidated.

In summary, we report a rare patient with CMS type 19 who has a previously unidentified mutation in the COL13A1 gene and shares several features similar to previously identified patients.

Ethical Publication Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.