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The Neurologic Disorders in Film
Published in Eelco F. M. Wijdicks, Neurocinema—The Sequel, 2022
Finding a cure for another devastating neurologic illness is the theme of Extraordinary Measures (2010) , starring Brendan Fraser, Harrison Ford, and Keri Russell and directed by Tom Vaughan. Brendan Fraser is John Crowley, a biotechnology executive with three children affected by Pompe disease (first described by a female Dutch pathologist in 1932). Pompe disease is a result of a deficiency of the lysosomal enzyme acid alpha-glucosidase, which breaks glycogen links.143 The film immediately confronts the viewer with a child in a motorized wheelchair and another severely paralyzed. Both are tracheostomized and fed through a gastrostomy. Megan’s eighth birthday party is the setup of the story. An underlying respiratory infection brings Megan to the ICU, and in an accurately portrayed physician–parent interaction, the physician tells the family that nothing more can be done and she is already past the normal life expectancy (classic Pompe rarely survives the first infantile year). After a successful resuscitation, the parents feel something needs to be done. Contact with an expert, Dr. Stonehill (Harrison Ford)—representing a fictional composite of scientists—leads to the discovery of an enzyme that halts progression.
Risk and Causality by Genetics, Gender, and Age
Published in Susmita Chowdhuri, M Safwan Badr, James A Rowley, Control of Breathing during Sleep, 2022
Moshe Y Prero, Nardine Zakhary, Sally Ibrahim, Kingman P Strohl
There are relatively strong genes that can be found in adult OSA cohorts but many were first discovered in childhood congenital disorders and then examined for effect in adult relatives, finding effects with variable or dependent penetrance, or taking some time for its actions to come to clinical attention. Table 9.1 presents some of the known genetic syndromes that could present at birth; however, once identified, some mild childhood conditions appear in adulthood. One pathway, PHOX2b, was identified originally through an unbiased association of genetic polymorphisms to disease traits in childhood and led to the identification of parental phenotypes of sleep apnea and hypoventilation after the diagnosis of the child (42). Now parents of such patients are found to have apneas and hypoventilation with shorter polyalanine repeats. Other genetic syndromes, like Pierre Robin Prader-Willi, and Down syndrome, while recognizable at an early age, can appear with symptomatic sleep-disordered breathing in young adulthood or even later (43, 44). Pompe disease can be noticed in childhood; however, there are those who present in early adulthood, and this condition should be part of the differential diagnosis of adult hypoventilation syndromes. The recognition of Pompe disease is important now that there is enzyme replacement therapy (45, 46). Ehlers-Danlos syndrome, especially in its more mild presentations, may go undiagnosed in childhood (47).
Metabolic Myopathy
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Pompe disease is the most common glycogen storage disease in clinical practice that is characterized clinically by spinal muscular atrophy-like disease, floppy baby syndrome, and facial dysmorphism. Patients can also present in late adulthood with variable weakness distribution ranging from proximal weakness to limb-girdle muscular weakness. The disease may progress to involve organs such as liver, spleen, lungs, and, rarely, heart. The disease is inherited as autosomal recessive and associated with GAA gene mutation, which causes deficiency of acid maltase or α-1, 4-glycosidase enzyme.
Addressing the Burdens That Newborn Screening Imposes on Underserved Communities
Published in The American Journal of Bioethics, 2023
Meghan E. Strenk, Courtney Berrios, Jeremy R. Garrett
In 2013, Missouri was at the forefront of expanded NBS when it became the first US state to screen newborns for four lysosomal storage disorders (LSDs): Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis, type 1 (MPS1). Two of these LSDs—Pompe disease and MPS1—were later added to the RUSP in 2015 and 2016, respectively (HRSA. Previously Nominated Conditions. 2023). As screening for these two conditions began, several unexpected outcomes came to light. Here, we will focus on an outcome that disproportionately has affected underserved communities: namely the identification of enzyme pseudodeficiency alleles, which yield low enough enzyme levels to give positive NBS results but do not cause disease. While one MPS1 pseudodeficiency allele had been identified prior to the start of MPS1 newborn screening (Aronovich, Pan, and Whitley 1996), three additional alleles were identified during the pilot phase of Missouri’s expanded NBS program (Pollard et al. 2013). Pseudodeficiency alleles also have been identified in Pompe disease (Tajima et al. 2007).
Body composition and 6 minute walking ability in late-onset pompe disease patients after 9 years of enzyme replacement therapy
Published in International Journal of Neuroscience, 2022
Gerasimos Terzis, Georgios Papadimas, Argyro Krase, Eleni Kontou, Ioannis Arnaoutis, Constantinos Papadopoulos
Pompe disease is an inherited autosomal recessive glycogen storage disease caused by total or partial deficiency of acid α-glucosidase (GAA) [1]. Deficiency of this enzyme results in the accumulation of glycogen in the lysosomes of skeletal muscles, heart, liver and other tissues with variable clinical symptoms which are often related to the age of disease onset [2]. The infantile form of the disease is the most severe and fatal and it is characterized by hypotonia, muscular weakness, cardiac hypertrophy and hepatomegaly [3, 4]. The adult- or late-onset form of the disease (LOPD) presents various clinical features and the first symptoms may be manifested between early adulthood to even the seventh decade of life. Proximal lower limb weakness predominates, leading to difficulties in everyday activities such as climbing stairs or rising from a chair while there may be also respiratory involvement due to diaphragmatic weakness [4–6]. The course of the disease is usually slowly progressive and variable. Some patients may become wheelchair-bound while others remain independent for long [7]. Respiratory muscle involvement may inevitably call for mechanical ventilation [8].
New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges
Published in Expert Review of Clinical Pharmacology, 2019
Federica Ricci, Martina Vacchetti, Chiara Brusa, Liliana Vercelli, Chiara Davico, Benedetto Vitiello, Tiziana Mongini
Since 2006, the standard care of Pompe disease has been enzyme replacement therapy (ERT). ERT dramatically changed the natural course of the disease in infants, resulting in a much longer survival. The most reliable effect of ERT in infant has been demonstrated on cardiac pathology and motor functions; in adults, motor performances and respiratory parameters, although less impressively, were improved or maintained [72,73]. In treated IOPD patients, a new phenotype, mainly myopathic, is emerging [74]. Some factors have been related to treatment ineffectiveness in some cases, including later age at diagnosis, worse clinical picture at the beginning of treatment, cross-reactive immunologic material (CRIM)-negative status, and development of immune response against recombinant human GAA. As for the latter, immune tolerance protocols were proposed to prevent the formation of antibodies against the recombinant enzyme [75,76].