Expanding Phenotypes of Female Heterozygotes in X-Linked Neurogenetic Conditions OnDemand-Expanding Phenotypes Presentation

Video Transcription

Video Summary

The 2025 ACMG Education Webinar on X-linked disorders addressed the complexities of female presentations in several genetic conditions, emphasizing updated terminology and clinical management.<br /><br />Dr. Andrea Grobman discussed ornithine transcarbamylase (OTC) deficiency, highlighting that females, previously considered asymptomatic carriers, often exhibit symptoms due to random X inactivation and varying enzyme activity. Neuroimaging and spectroscopy have revealed biochemical brain changes even in "asymptomatic" females, with cognitive impacts on attention and executive function. Functional assessments, including driving simulations, correlate these findings with real-world difficulties.<br /><br />Dr. Steve Krasnowski focused on dystrophinopathies, cautioning against calling females "carriers," given that up to 20% exhibit neuromuscular symptoms and up to 17% develop cardiac issues. He emphasized lifelong cardiac and neuromuscular surveillance with early intervention, including baseline cardiac MRI to detect silent fibrosis. Newborn screening for Duchenne muscular dystrophy is expanding but not yet nationally recommended.<br /><br />Dr. Jerry Bedoyan presented on pyruvate dehydrogenase complex deficiency (PDC), particularly PDHA1-related forms, an X-linked mitochondrial disorder causing neurological impairment and lactic acidosis. Females show variable phenotypes due to enzymatic mosaicism; diagnosis requires sensitive fibroblast assays, as lymphocyte tests may be normal. Some cases respond to thiamine supplementation and ketogenic diet, highlighting personalized treatment needs.<br /><br />Dr. Nishita Pillai reviewed X-linked adrenoleukodystrophy (ALD) in females, noting that symptoms often manifest in adulthood with myelopathy and neuropathy. Elevated C26-lysophosphatidylcholine is a superior diagnostic marker over very long chain fatty acids (VLCFA). Treatment remains supportive, focusing on symptom management.<br /><br />The webinar underscored evolving concepts in X-linked disorders, advocating terminology that acknowledges female disease manifestations rather than "carrier" status, and emphasized multidisciplinary lifelong surveillance and early therapeutic intervention. Questions addressed newborn screening policies, genetic testing age recommendations, and international incidence considerations.

Keywords

X-linked disorders

female presentations

ornithine transcarbamylase deficiency

dystrophinopathies

pyruvate dehydrogenase complex deficiency

X-linked adrenoleukodystrophy

neuromuscular symptoms

cardiac surveillance

newborn screening

genetic testing