Clinical and genetic analysis of a Chinese pedigree affected with Charcot-Marie-Tooth disease presenting as childhood-onset encephalopathy

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DNA-based screening and personal health: a points to consider statement for individuals and health-care providers from the American College of Medical Genetics and Genomics (ACMG)

The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have introduced an internationally shared framework for variant classification in genetic disorders. FVII deficiency is a rare inherited autosomal recessive bleeding disorder with sparse data concerning ACMG classification. To develop an approach which may improve the utility of molecular genetic test results, 129 patients with FVII deficiency were retrospectively assigned to six subgroups for exploratory analysis: F7 gene wildtype (group 1), ACMG 1 (benign variant) or ACMG 2 (likely benign variant), only (group 2), ACMG 3 (variant of uncertain significance) ± ACMG 1-2 heterozygous or not classified variant (group 3), ACMG 4 (likely pathogenic variant), or ACMG 5 (pathogenic variant) single heterozygous ± ACMG 1-3 single heterozygous (group 4), ACMG 4-5 homozygous or ≥2 ACMG 4-5 heterozygous or ≥1 ACMG 4-5 heterozygous plus either ACMG 1 c.1238G>A modifying variant homozygous or ≥2 ACMG 1-3 (group 5), FVII deficiency and another bleeding disorder (group 6). Eleven of 31 patients (35.5%) in group 5 had abnormal ISTH-BS (n = 7) and/or history of substitution with recombinant factor VIIa (n = 5) versus 4 of 80 patients (5.0%, n = 1 abnormal ISTH-BS, n = 3 substitution) in groups 1 (n = 2/22), 2 (n = 1/29), 3 (n = 0/9), and 4 (n = 1/20). Four of 18 patients (22.2%) with FVII deficiency and another bleeding disorder (group 6) had an abnormal ISTH-BS (n = 2) and/or history of substitution with recombinant factor VIIa (n = 3). Patients with a homozygous ACMG 4-5 variant or with specific combinations of heterozygous ACMG 4-5 ± ACMG 1-3 variants exhibited a high-risk bleeding phenotype in contrast to the remaining patients without another bleeding disorder. This result may serve as a basis to develop a genotype/phenotype prediction model in future studies.

NEWS updateN oninvasive prenatal tests used to screen for trisomies 13, 18, and 21 have specific advantages and limitations that should be thoroughly explained to pregnant women so they can carefully consider this option, according to a recent policy statement from the American College of Medical Genetics and Genomics (ACMG).The recommendation from ACMG is the fifth guidance statement about these tests, which are marketed in the U.S. by four companies.It follows statements from the American College of Obstetricians and Gynecologists (ACOG)/Society for Maternal-Fetal Medicine (SMFM), two from the International Society for Prenatal Diagnosis (ISPD), and the National Society of Genetic Counselors (NSGC).While the ACMG generally agrees with advice from these other groups, their statement makes important departures.Namely, the ACMG calls these tests-which detect cell-free fetal DNA (cfDNA) in maternal blood-"noninvasive prenatal screening" (NIPS) tests to emphasize that they are not diagnostic.Likewise, the ACMG statement places no limits on who should be offered NIPS and goes into greater detail about what patients should know about it [Gregg et al., 2013]."ACMG's statement emphasizes that NIPS is a screening test, not the be-all and end-all.There are certain caveats with [these] tests," says

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American College of Medical Genetics and Genomics: revised scope of practice and strategic plan

Love in the time of COVID-19.

To analyze the phenotype and genotype of CMTX1 patients with episodic transient reversible white matter involvement, and delineate the features of brain MRI in the episode and the possible mechanisms. Three Chinese probands and their family members were sequenced in the coding regions of GJB1. With the other 16 reported CMTX1 patients with episodic transient reversible white matter involvement, the clinical feature of the episodic central nervous system symptoms and the genotypes were reviewed. Missense mutations in GJB1 were identified in all 3 probands. In 19 patients with transient reversible white matter involvement, the episodes were manifested as weakness of the limbs, dysarthria, and dysphagia, without disturbance of consciousness or seizures. The episodes lasted for 13 hours (10 min-72 hours) with complete remission in all patients; There were multiple episodes in 9 patients. During the episode, brain MRI showed symmetrical high signals in T2 weighted, Flair and DWI images in periventricular white matter, with predominance in posterior region including splenium of corpus callosum. These changes in imaging were most prominent during or within 1 week after the clinical episode.Significant improvements occurred within 1 month, with complete remission within 4-6 months.No specific locations of mutant amino acids in GJB1 protein were found in these patients with episodic transient reversible white matter involvement. Episodic transient reversible white matter involvement may present in a small number of patients with CMTX1. Transient edema of oligodendrocytes due to the dysfunction of gap junction may be involved in the pathogenesis. There is no correlation between the location of the mutant amino acids in GJB1 and the occurrence of the episodes.

<h3>Objective:</h3> NA <h3>Background:</h3> CMTX1 is an X-linked dominant form of hereditary sensorimotor polyneuropathy. It is caused by mutations in the gap junction protein beta 1(GJB1) gene on chromosome Xq13.1, which encodes connexin 32 protein. CNS can be affected and lead to transient or persistent CNS symptoms including dysarthria, dysphagia, hemiparesis or quadriparesis, ataxia, aphasia, and encephalopathy. <h3>Design/Methods:</h3> <h3>Case Report:</h3> A 22-year-old man presented with acute onset left facial droop, dysarthria and left upper extremity weakness. Two weeks prior he experienced a one-day episode of gastroenteritis. Neurological examination showed weakness in the left lower face, distal muscle weakness in toe extension, ankle dorsiflexion and hand intrinsic muscles, absent lower extremity reflexes, diminished vibration and temperature senses in length-dependent pattern, high-arched feet and hammertoes. Family history of early onset polyneuropathy, never genetically tested. Brain MRI showed marked and symmetric restricted diffusion lesions involving bilateral fronto-parietal white matter, corpus callosum and posterior limb of internal capsule without contrast enhancement. CSF analysis was unremarkable. The patient was given pulse steroid therapy for possible demyelinating disease, his symptoms completely resolved within 48 hours. Two prior similar symptoms, one was diagnosed as acute disseminated encephalomyelitis (ADEM) and treated with steroids. Brain MRI of these two episodes showed similar restricted diffusion abnormalities. Repeat brain MRI seven months after the second episode showed complete resolution of restricted diffusion lesions. Leukodystrophy genetic panel was negative. Genetic testing showed hemizygous pathogenic mutation c.491G&gt;A in GJB1 gene, associated with X-linked Charcot-Marie-Tooth disease - CMTX1. <h3>Results:</h3> NA <h3>Conclusions:</h3> Young patients with history of polyneuropathy presenting with acute CNS symptoms with bilateral white matter and corpus callosum lesions, CMTX1 should be included in the differential diagnosis. Upon confirmation of CMTX1 diagnosis, patient reassurance is important as well as education regarding potential provoking factors that lead to CNS involvement. <b>Disclosure:</b> Dr. Altarazi has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Sankaraneni has nothing to disclose.