Myasthenic syndrome, congenital, 22\; CMS22

Alternative name(s) : Myasthenic syndrome, congenitzl, 22\; CMS22, PREPL deficiency

Gene_locus : human-PREPL

Mutation : 11 mutations M270X_human-PREPL Del_exon10-15_human-PREPL V121IfsX121_human-PREPL L535X_human-PREPL R295X_human-PREPL R510X_human-PREPL R647Q_human-PREPL K698N_human-PREPL E206GfsX22 F428RfsX18_human-PREPL V115LfsX39_human-PREPL

OMIM : 616224 , 609557

Comment
(from OMIM) Congenital myasthenic syndrome-22 (CMS22) is caused by homozygous or compound heterozygous mutation in the PREPL gene on chromosome 2p21. Homozygous deletion of both PREPL and the neighboring gene SLC3A1 causes hypotonia-cystinuria syndrome. Regal et al. (2014) reported a female infant who presented with marked neonatal hypotonia, eyelid ptosis, tented upper lip, and feeding difficulties. She was treated with a feeding tube and showed a favorable response to the acetylcholinesterase (AChE) inhibitor pyridostigmine, from which she was weaned at age 12 months without deterioration, suggesting spontaneous improvement with age. She walked at 17 months, but had a waddling gait and used a walker. She also had growth hormone deficiency but did not have cystinuria. Language development and brain imaging were normal. Regal et al. (2018) reported 5 new patients with CMS22. All manifested severe neonatal hypotonia, neonatal feeding problems, and nasal dysarthria. All had high-arched palates and narrow bitemporal diameter. Patients with CMS22 walked at a median age of 23 months and had residual signs of neuromuscular involvement in adulthood, including facial weakness, nasal dysarthria, and paretic neck flexion. Most subjects had ptosis and facial weakness as well as fluctuating weakness. Most also had hypergonadotropic hypogonadism. The cognitive profile of patients with either CMS22 or the hypotonia-cystinuria syndrome ranged from mild intellectual disability to normal intelligence. The median IQ was 70. Growth hormone deficiency was detected in 4 of 5 subjects, with an age of onset ranging from 20 months to 11 years. Regal et al. (2018) remarked that in all of the 5 patients they described with CMS22. They noted that patients with CMS22 have ptosis, which is absent in patients with Prader-Willi syndrome. In a girl with CMS22, Regal et al. (2014) identified a heterozygous 33.6-kb deletion of chromosome 2p21 including exons 5 to 10 of the SLC3A1 gene (104614) and exons 9 to 14 of the PREPL gene inherited from the unaffected mother, and a heterozygous frameshift mutation in the PREPL gene inherited from the unaffected father. These findings indicated that the patient retained a functional SLC3A1 allele, and that the phenotype was determined by homozygous mutation in PREPL. Immunoblot analysis of patient muscle showed absence of PREPL in muscle fibers and at the endplates in the neuromuscular junction. Patient endplates showed normal AChR and AChE expression, as well as abundant synaptic vesicles. However, one endplate showed a degenerating nerve terminal, and another had autophagic vacuoles in the junctional sarcoplasm and an abandoned postsynaptic region. Microelectrode studies showed reduced MEPP and MEPC amplitudes and decreased quantal content with decreased levels of ACh in the synaptic vesicles. Additional changes noted at the endplate pointed to a defect in the late stages of exocytosis. Regal et al. (2014) hypothesized that PREPL deficiency may affect function of the clathrin-associated adaptor protein-1 (see AP1M1, 603535) and filling of synaptic vesicles. Regal et al. (2018) described 5 previously unreported patients with isolated PREPL deficiency (CMS22) and detected novel PREPL mutations in each (e.g., 609557.0002-609557.0005)