Physiology and Pharmacology in the Care of Patients with Rett Syndrome

Physiology and Pharmacology in the Care of Patients with Rett Syndrome

• Author
• Karoliny França Farias
• Abstract

•  

  Physiology and Pharmacology in the Care of Patients with Rett Syndrome

   

  Karoliny França Farias¹; Jamilly Kelly Oliveira Neves²

   

  ¹ Graduanda em Farmácia – UNIFACISA – karoliny.farias@maisunifacisa.com.br

  ² Mestre em ciências farmacêutica – UEPB – Jamilly.Neves@maiunifacisa.com.br

   

  INTRODUTION:

  The development of Rett syndrome primarily occurs in females and is characterized by pathological consequences linked to a significant array of neurological and orthopedic alterations. These include hypotonia, ataxia, irregularity in transitional movements, scoliosis, spasticity, loss or alteration of gait and hand voluntary function, as well as deformities in the feet, and reduced cardiovascular capacity. Rett syndrome is also associated with the development of severe intellectual disability (References 26,27). Furthermore, the neurophysiology of the pathology is responsible for the deceleration of cerebral growth in the syndrome, beginning after birth. However, when examining the development and growth of the heart, kidneys, liver, and spleen in research, they grew at a normal rate until between 8 and 12 years of age. There was deceleration, but continuity existed, adapting the weight of the organs to height, which was also reduced. From a genetic perspective, RTT is attributed to pathogenic variants in the MECP2 gene, which is located on Xq28 and encodes the methyl-CpG binding protein 2 (MeCP2) (3). The expression of MeCP2 occurs in all tissues but is predominantly in the brain, making it likely to be more sensitive to abnormal MeCP2 than other tissues. The detection of pathogenic variants in MECP2 has been identified in approximately 95% of classic cases of Rett Syndrome (RTT) in sporadic cases and 75% of atypical cases, caused by pathogenic variations in the CDKL5 or FOXG1 genes, with phenotypic presentation of neurodevelopmental disorders in separate conditions. The treatment of the pathology is developed through an approach that favors the individual with the syndrome, while also preparing the caregivers, creating space for multiprofessional care in which the patient is comprehensively and individually attended to. In this context, pharmacological treatment is achieved through trofinetide. Its mechanism of action includes anti-inflammatory, antioxidant, and trophic effects, with the goal of stabilizing dendritic morphology, synthesizing synaptic proteins, and neuronal signaling [6,7]. A synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1, it has been approved by the United States Food and Drug Administration (FDA) for the treatment of Rett syndrome (RTT) in patients aged two years or older [1]. Its mechanism of action is not fully understood, but purported actions include anti-inflammatory, antioxidant, and trophic effects that stabilize dendritic morphology, the synthesis of synaptic proteins, and neuronal signaling [6,7]. Looking at the individual as a whole, it is worth noting that they may experience nutritional, gastrointestinal, and motor problems, as well as reproductive issues, motor dysfunction, sleep disturbances, cardiac anomalies, respiratory disorders, seizures, scoliosis, bone quality, and fractures, necessitating support from professionals such as physiotherapists, physical educators, psychologists, physicians, and pharmacists, for example.

  Keywords: Trofinetrida, Multidisciplinary, Pathology, Treatment

  AIMS :

  The present summary aims to provide guidance to caregivers and the professional team regarding the pathology, with the intention of disseminating knowledge that can be helpful during treatment. Primarily, it aims to convey these insights from a scientific perspective: specifying the role of the multiprofessional team, the disease's pathophysiology, and how to administer treatment, with particular emphasis on the pharmacological aspects of medications.

  METHODS:

  The research development strategy was based on information collected from the PubMed, UpToDate, Google Scholar, and Scielo databases, using keywords such as Rett Syndrome, pharmacology, trofinetide, and pathophysiology. In this way, the study takes on a descriptive and exploratory nature, aiming to identify evidence related to Rett Syndrome that can contribute to the development of a utilitarian understanding of the pathology and its treatment.

                 

  RESULTS AND DISCUSSION:

  The occurrence rate of Rett Syndrome is approximately one girl in every 10,000 - 20,000 individuals, with evidence of occurrence in boys as well, though at a much lower rate. The context of this pathology has a sudden impact on affected individuals, families, and caregivers. Therefore, as a first step, a qualified professional diagnosis is necessary to guide the patient and their caregivers in the best possible way, with a focus on their well-being and quality of life. Individuals with Rett Syndrome are dependent on assistance for all activities throughout their lives. This places a significant burden on their family members and caregivers, and there are limited studies investigating the best methods for the healthcare team to support these caregivers. This has been associated with lower scores in their physical and emotional well-being [4]. It is important to assess how the physical and mental health of RTT caregivers is maintained, and it is advisable to provide regular days off and self-care to a significant extent to ensure their well-being and quality of life. In today's society, with the help of media resources, this support is crucial.

  For the evaluation of Rett Syndrome, parameters for identification and assessment are used through a medical history (anamnesis), and DNA analysis with an observation of pathogenic variants in MECP2. Other studies that support the evaluation include the following criteria: Brain Magnetic Resonance Imaging (MRI), serum amino acids, organic acids in urine, genetic tests for phenotypes similar to Rett, including Angelman syndrome and Angelman-like syndromes and/or Pitt-Hopkins syndrome if there is clinical suspicion, white blood cell enzymes (if there is regression), hearing tests, and ophthalmological evaluation.

  A patient may be considered to have RTT without a MECP2 variant if these studies are not diagnostic, clinical criteria for RTT are met, and genetic analysis has not identified an alternative diagnosis. However, this "functional diagnosis" should be periodically reviewed with repeated genetic/genomic analyses as genetic testing improves. Electroencephalography can identify changes, but it does not serve as a diagnostic tool; it serves as a supplementary tool. Staging also has limited diagnostic utility, functioning by tracking the clinical course of the pathology and anticipating potential problems.

  The development of Rett Syndrome is reflected in four stages. The first stage, called early stagnation, begins between 6 and 18 months, characterized by stagnation of development, slowing down the growth of the head circumference and tendency to social isolation, lasting a few months. The second stage is known as rapidly destructive, it begins between the first and third year of life, with time lasting from weeks to months depending on the case. At this stage, there is a visible psychomotor regression, aligned with unmotivated crying, irritability, acquired speech loss, autistic behavior and stereotyped hand movements, with the loss of their function practice. Respiratory distress (apnea during wakefulness and episodes of hyperventilation, among others) and epilepsy may be present. The stage subsequent, is the pseudo-stationary, occurs between two and ten years of age and characterized by a gradual improvement in some of the signs and symptoms, especially in the it concerns social contact. From the motor point of view, ataxia and apraxia, spasticity, scoliosis and bruxism are present, as well as episodes of loss of breath, aerophagia, forced expulsion of air and saliva. The fourth stage, that of late motor deterioration beginning at around ten years presenting as a slow progression of motor impairments, by occurrence of scoliosis and severe cognitive impairment. Choreo-athetosis, dystonia and disorders of peripheral motor neurons may exist. From this perspective, the difficulty of development development of gait happens in Girls able to walk independently and usually they will need a wheelchair.6 even if the accepted diagnostic criteria currently suggest that children with SR have normal development during early in life, recent evidence suggests that there are subtle signs of some abnormality already at a very early age, including discrete motor retardation, presence of muscle hypotonia and other motor changes. Clear identification are serious impairments of talk. In fact, most of these children do not speak; although some of them acquire some speech, they lose this ability in the regression phase. A small percentage of girls are able to speak, so that this form of SR was termed SR with preserved speech.7 the occurrence of epilepsy is frequent and can present under various types of seizure, which can be well resistant to medication. The electroencephalogram shows normal records in the early stages disease, but it becomes more slowed down as the condition progresses. Can appear sharp waves in the central-parietal regions. Later, in phase 3, discharges in spike-waves can occur and are most easily observable in the record during sleep. In step 4, there may be an improvement in the electroencephalogram, with a reduction in epiletiform elements (rhythmic and periodic patterns of brain activity similar to epileptic seizures). Survival in SR may be reduced and death occurs, in general, as result of infectious causes and respiratory complications, possibly related to severe scoliosis or during sleep (sudden death)

   The diagnosis of Rett Syndrome should be considered through the observation of postnatal deceleration of head growth, along with the following signs: Partial or total loss of acquired intentional hand skills; Partial or total loss of acquired spoken language; Abnormalities in gait: impaired (dyspraxia) or lack of ability; Stereotyped hand movements, such as wringing/squeezing hands, clapping, talking with the mouth, and washing/rubbing automatisms.

  Supporting criteria include respiratory disturbances when awake; Bruxism when awake; Impaired sleep patterns; Abnormal muscle tone; Peripheral vasomotor disturbances; Scoliosis/kyphosis; Growth retardation; Small and cold hands and feet; Inappropriate spells of laughter/screaming; Diminished response to pain; Intense visual communication.

  Trofinetide is one of the most frequently mentioned medications for the treatment of Rett Syndrome, and it was approved by the FDA in the United States in March 2023 for the treatment of RTT in children and adults aged two years and older [5]. The medication received approval for use based on the results of the LAVENDER trial. It's important to note that diarrhea and vomiting are reported as potential adverse effects. It is recommended that trofinetide be administered on an individualized basis under the guidance of caregivers and family members.

  Its medicinal composition is based on trofinetide, which is a synthetic analogue of glycine-proline-glutamate (GPE), the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1). While its mechanism of action is not fully understood, purported actions include anti-inflammatory, antioxidant, and trophic effects that stabilize dendritic morphology, synthesize synaptic proteins, and facilitate neuronal signaling [6,7].

  Dosage and administration for Trofinetide are as follows:

  - For patients weighing 9 kg to <12 kg: 5,000 mg twice a day (25 mL twice a day).

  - For patients weighing 12 kg to <20 kg: 6,000 mg twice a day (30 mL twice a day).

  - For patients weighing 20 kg to <35 kg: 8,000 mg twice a day (40 mL twice a day).

  - For patients weighing 35 kg to <50 kg: 10,000 mg twice a day (50 mL twice a day).

  - For patients weighing 50 kg or more: 12,000 mg twice a day (60 mL twice a day).

  Trofinetide can be administered orally, through a gastrostomy tube, or through a gastrojejunal tube if administered via the G-tube. There are no contraindications.

  Studies in mice draw attention to investigational therapies for the treatment of Rett Syndrome, such as glatiramer acetate, which improves walking speed. Glatiramer acetate is characterized by a blend of four amino acid polymers and is approved for the treatment of multiple sclerosis. Further, more specific trials are needed to confirm its effectiveness. Additionally, genetic therapy is mentioned, involving the theoretical insertion of a functional copy of the MECP2 gene into MeCP2-deficient cells, which may improve the signs and symptoms of RTT by increasing protein levels.

  To ensure the patient's well-being, it is essential to emphasize the importance of management beyond pharmaceuticals. Management by a multiprofessional team addresses the patient's issues in a broader context. The patient's nutritional foundation should be strengthened with increased energy, protein, fluids, sodium, potassium, calcium, and vitamin D intake. Potential gastrointestinal dysfunctions, such as belching, vomiting, or irritability related to possible gastroesophageal reflux disease, should be analyzed. Constipation is also a concern. Reproductive problems, motor dysfunction requiring the intervention of a physical therapist, and sleep disorders are factors to consider.

  The presented clinical picture may also influence the development of cardiac anomalies. Medications associated with prolonged QT interval, such as tricyclic antidepressants, are prescribed while avoiding beta-blockers. It's important to address respiratory issues by considering Serotonin Agonists like buspirone as a treatment option, based on mouse studies, in addition to non-pharmacological treatments involving respiratory therapists.

  Lastly, to improve bone health, the following measures are recommended: Increasing physical activity to enhance muscle strength and bone density, calcium supplementation when dietary intake is insufficient, and vitamin D supplementation when levels are below normal.

   

  CONCLUSION:

  Through the present study, the occurrence of Rett Syndrome was verified, highlighting its pathophysiological and pharmacological role. I understand the stages of the syndrome and the reflection of it on the human body. Thus seeking to present the importance of multidisciplinary work in the care of this patient, attributing to it an identification of their needs and complications, developing strategies that enable well-being and quality of life. 

   

  ACKNOWLEDGMENT:

  For the development of this work, I thank God for the opportunity to seek improvement and adaptation day by day. My family provides me with support and encourages me to participate in activities. In addition, I thank the scientific community for allocating opportunities to students who seek academic improvement through congresses and elaboration of topics relevant to the population.

   

  REFERENCES:

  (3) Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, which encodes methyl-CpG binding protein 2. Nat Genet 1999; 23: 185.

  (6) Fehr S, Wilson M, Downs J, et al. CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur Jum Genet 2013; 21:266.

  (6) do trofinetride Glaze DG, Neul JL, Kaufmann WE, et al. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurologia 2019; 92: e1912.

  27. Lotan M, Hanks S. Physical therapy intervention for individuals with Rett Syndrome. SciWorld J. 2006;6(1):1314-38

  5. Neul JL, Fang P, Barrish J, et al. Specific mutations in methyl-CpG binding protein 2 confer different severity on Rett syndrome. Neurology 2008; 70: 1313.

  4. Percy AK, Lane JB, Childers J, et al. Rett syndrome: North American database. J Child Neurol 2007; 22: 1338.

  1. Rett A. [on an unusual brain atrophy syndrome in childhood hyperammonemia]. Vienna Med Wochenschr 1966; 116: 723.

  (7) do trofinetide Silva-Reis SC, Sampaio-Dias IE, Costa VM, et al. Concise overview of glypromate neuropeptide research: from chemistry to pharmacological applications in Neurosciences. ACS Chem Neurosci 2023; 14: 554.

   

  26 Temudo T, Santos M, Ramos E, Dias K, Vieira JP, Moreira A, et al. Rett Syndrome with and without detected MECP2 mutations: an attempt to redefine phenotypes. Brain Dev. 2011;33(1):69-76.

   (7)Wong LC, Singh S, Wang HP, et al. FOXG1-related syndrome: from clinical to Molecular Genetics and pathogenic mechanisms. Int J Mol Sci 2019; 20.

   

   

• Keywords
• Trofinetrida, Multidisciplinary, Pathology, Treatment
• Modality
• Pôster
• Subject Area
• Biology, Pharmacology and Physiology