Biochemical characterization of two novel mutations in the human high-affinity choline transporter 1 identified in a patient with congenital myasthenic syndrome.

Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high-affinity choline transporter 1 (CHT1). CHT1 is expressed in presynaptic neurons of the neuromuscular junction where it uses the inward sodium gradient to reuptake choline. Biallelic CHT1 mutations often lead to neonatal lethality, and less commonly to non-lethal motor weakness and developmental delays. Here, we report detailed biochemical characterization of two novel mutations in CHT1, p.I294T and p.D349N, which we identified in an 11-year-old patient with a history of neonatal respiratory distress, and subsequent hypotonia and global developmental delay. Heterologous expression of each CHT1 mutant in human embryonic kidney cells showed two different mechanisms of reduced protein function. The p.I294T CHT1 mutant transporter function was detectable, but its abundance and half-life were significantly reduced. In contrast, the p.D349N CHT1 mutant was abundantly expressed at the cell membrane, but transporter function was absent. The residual function of the p.I294T CHT1 mutant may explain the non-lethal form of CMS in this patient, and the divergent mechanisms of reduced CHT1 function that we identified may guide future functional studies of the CHT1 myasthenic syndrome. Based on these in vitro studies that provided a diagnosis, treatment with cholinesterase inhibitor together with physical and occupational therapy significantly improved the patient's strength and quality of life.

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.

Effect of growth hormone therapy on severe short stature and skeletal deformities in a patient with combined Turner syndrome and Langer mesomelic dysplasia.

BACKGROUND: Homozygous mutation of the short stature homeobox-containing gene, SHOX, results in Langer mesomelic dysplasia (LMD). Our case presented with severe short stature and skeletal deformities with Turner syndrome (TS) and a SHOX gene abnormality due to a downstream allele deletion in her normal X chromosome. Medical literature review did not reveal similar cases that were treated with GH therapy. METHOD: We present an 11-yr-old with combined TS and LMD with severe short stature and skeletal deformities. She was studied for the effect of GH therapy on stature and skeletal deformities. Karyotype testing showed 45,X/46,X,idic(X). Genetic analysis of SHOX gene testing did not detect any exonic mutations. Interestingly, both alleles of the flanking marker DXYS233, a marker downstream of the 3' end of SHOX coding sequence, were absent with resultant LMD. GH therapy in the mean dose of 0.321 mg/kg/wk was administered for 4 yr (0.287, 0.355, 0.317, and 0.327 mg/kg/week in the first, second, third, and fourth years, respectively). Clinical data were reviewed. RESULT: The growth rates of 3.46, 3.87, 2.3, and 0.7 cm/yr were observed in the first, second, third, and fourth years of the GH therapy, respectively. There was no clinical deterioration of the skeletal deformities. CONCLUSION: There was a failure to achieve growth improvements with GH therapy for 4 years, but there was no worsening of the skeletal deformities. We conclude that GH therapy may not be beneficial in severe short stature due to combined TS and LMD resulting from homozygous SHOX deficiency.