Precise molecular diagnosis of individuals with developmental delay is important to guide management and future prognostication. Lucas‐Del‐Pozo and colleagues describe a patient with cerebral palsy (CP) diagnosed in adulthood with galactosemia highlighting the power of genomic sequencing to identify previously unsuspected metabolic disorders.1
Classic galactosemia is an inborn error of metabolism leading to toxic accumulation of galactose and derived metabolites. This condition usually presents within days of ingesting milk with failure to thrive, hypoglycemia, bleeding diathesis, and jaundice. Left untreated, complications occur including liver failure and sepsis, resulting in neonatal fatality.2 Early institution of a lactose‐restricted diet may eliminate these systemic features, although children remain at risk for developmental motor and speech delays, cataracts, poor growth, female reproductive abnormalities, impaired intellectual functioning, and motor deficits including ataxia and extrapyramidal abnormalities.2 Many of these features are evident in retrospect in this case.
Clues in adulthood to potential metabolic disorder include a history of early neonatal difficulties and hyperbilirubinemia improved with dietary manipulation as well as later onset progression of symptoms associated with an evolution of brain magnetic resonance imaging findings. In addition, this patient, diagnosed previously with CP, displays an ataxic phenotype. Although acquired etiology is reported, the underlying genetic etiology is frequent for this CP subtype.
Appropriate evaluation including metabolic screening identified abnormal sialotransferrins suggesting a congenital disorder of glycosylation (CDG). Galactosemia, although not a primary disorder of glycosylation, shares many clinical characteristics with CDG. Although the exact pathogenic mechanisms are not fully understood, the toxic buildup of galactose intermediates or a shortage of metabolic end products is hypothesized to interfere with glycosylation.3, 4 Persistent defects in glycosylation are thought to contribute to poor neurologic outcomes despite dietary galactose restriction. Better understanding of the links between these 2 pathways and the persistence of glycolytic abnormalities in galactosemia patients may lead to the development of improved therapeutic approaches in the future.3
Video 1.
Full video from the 2020 Video Challenge discussion of this case.
Author Roles
(1) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
J.F.: 1A
S.L.‐D.‐P.: 1B
David Moreno‐Martinez: 1B
M.C.‐G.: 1B
Daniel Moreno‐Martinez: 1B
J.H.‐V.: 1B
M.A.K.: 1B
Disclosures
Ethical Compliance Statement
The authors confirm that neither informed patient consent nor the approval of an institutional review board was necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
M.A.K. is funded by an NIHR Research Professorship, the Sir Jules Thorn Trust and Rosetrees Trust. The other authors declare no funding sources or conflicts of interest.
Financial Disclosures for the Previous 12 Months
J.F. Participates in Clinical Trials with Biogen (Angelman's Syndrome) and J.F.'s spouse is Founder and Principal of Friedman Bioventure, which holds a variety of publicly traded and private biotechnology interests. The other authors declare no financial disclosures.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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