RESUMO
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.
Assuntos
Adenosina Trifosfatases/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Mutação/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
OBJECTIVES: The primary aim of our study was to evaluate gastric emptying (GE) and intestinal transit time (ITT) in children with mitochondrial disorders (MD), and secondarily to evaluate the effect of prokinetics in those with prolonged GE. METHODS: We enrolled subjects 3 to 18 years with MD and having any of the following gastrointestinal (GI) symptoms: abdominal pain, vomiting, constipation, diarrhea, or gastroesophageal reflux. Abdominal pain was scored by visual analog pain scale (1-10). Age-appropriate diet was labeled with radioactive technetium-99 sulfur colloid and its movement tracked along the GI tract. Delayed GE based on our institutional standards was defined as half emptying time >90 minutes for a solid and >60 minutes for a semisolid meal. Prolonged ITT was defined as >4 hours for the tracer to pass from mouth to cecum. A prokinetic was instituted to those with delayed GE, and the study was repeated if possible in 4 to 8 weeks. RESULTS: Of the 26 subjects, 18 (69%) had delayed GE (median GE 99 minutes) and 12 (46%) had prolonged ITT. The study was repeated in 9 subjects after administering a prokinetic for >1 month. GE normalized in only 3 subjects (median GE on treatment 128 minutes). Mean abdominal pain score, which was 4.8 (max 10) in the 9 subjects, did not improve (5.6 after prokinetic therapy). CONCLUSIONS: A high prevalence of delayed GE and prolonged ITT was seen in children with MD having GI symptoms, and these abnormalities were poorly responsive to prokinetic therapy.