Myasthenic Syndrome, Congenital, 22

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-22 (CMS22) is caused by homozygous or compound heterozygous mutation in the PREPL gene (609557) on chromosome 2p21.

Homozygous deletion of both PREPL and the neighboring gene SLC3A1 (104614) causes hypotonia-cystinuria syndrome (606407).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Clinical Features

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, Prader Willi syndrome (PWS; 176270) was considered and ruled out in the newborn period. They noted that patients with CMS22 have ptosis, which is absent in patients with Prader-Willi syndrome.

Inheritance

The transmission pattern of CMS22 in the family reported by Regal et al. (2014) was consistent with autosomal recessive inheritance.

Diagnosis

Regal et al. (2018) developed a functional blood assay to detect PREPL protein and its reactivity with the activity-based probe biotinylated fluorophosphonate (FP-biotin). The assay reliably distinguished between PREPL deficiency and control values, and Regal et al. (2018) used the assay to diagnose several new patients and delineate the phenotype.

Molecular Genetics

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 (609557.0001) 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).

Cytogenetics

Bartholdi et al. (2013) reported 2 sibs, born of unrelated Swiss parents, with severe hypotonia, growth failure, and mild to moderate delay in psychomotor development. Both had decreased fetal movements in utero. Additional features included dolichocephaly, hypotonic face with open mouth, cleft palate, mild ptosis, almond-shaped eyes, frontal bossing, hypoplastic midface, and small hands and feet. The girl had hypoplastic labia majora and the boy had hypospadias. Assessment of growth hormone deficiency in the boy showed normal results. SNP array molecular karyotyping identified a homozygous 83-kb deletion of chromosome 2p21 including the entire PREPL gene and exons 1 to 3 of the CAMKMT (609559) gene, but not the SLC3A1 gene. The unaffected parents were heterozygous for the deletion. Bartholdi et al. (2013) suggested that the intellectual disabilities in these sibs resulted from deletion in the CAMKMT gene, and that the severe hypotonia and growth failure resulted from deletion of the PREPL gene.

Animal Model

Lone et al. (2014) found that Prepl-null mice were significantly smaller than wildtype littermates and showed neonatal hypotonia. The findings suggested a role for Prepl in the developing musculoskeletal system.