nemoci-sympt/METABOLISMUS/downuv-syndrom/00-fenotyp
Fenotyp DS - různě závažný
- Physical growth delays
- Characteristic facial features
- Congenital heart disease
- Neurodevelopmental problems
- Progressive intellectual disability
- At later stage of life Alzheimer-syndrome-like state
- Recent classifications consider DS as a "congenital form of Alzheimer’s disease"
- Airway, pulmonary and hearing disorders
- Hematological, oncological and autoimmune diseases
- [(Bull 2020; Antonarakis et al. 2020; Lagan et al. 2020]
- molmed.biomedcentral.com/articles/10.1186/s10020-020-00225-8
Cystathionine beta-synthase (CBS)
- Homocysteine/folate/transulfuration pathways (Iacobazzi et al., 2014);
Cysteine, cystathionine, choline, and dimethylglycine
- Changes in the levels of metabolites involved in the methylation cycle
Dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1 A (DYRK1A)
- Involved in brain development and learning and memory (Altafaj et al., 2001; Park et al., 2009);
Fenylketonurie
Dieta
- Při včasném nasazení diety se jedinec vyvíjí zcela normálně.
- phenylalanine, which is found in almost all foods containing protein, must be avoided
- Many food items that are not thought of as sources of protein (such as fruits and vegetables) still have small traces of phenylalanine and must be avoided to maintain brain health in the patient with PKU.
- Who stay on the diet for life are good
- Restrictive, low protein diet with reduction of phenylalanine
- Addition of vitamins and minerals that are necessary for body metabolism
- Requires special medical formula
- Modified to remove phenylalanine
- The special formula alone can cost $500/month or more.
- Special low-protein medical foods may need to be used to satisfy hunger and caloric needs.
Saproterin (brand name Kuvan)
- A medication approved by the FDA in 2007
- Shown to increase phenylalanine tolerance in about 25% of patients
Pegvaliase-pqpz (brand name Palynziq)
- An enzyme therapy drug approved by the FDA in 2018
- Used to aid adults with PKU with uncontrolled blood levels
- Many other therapies are in the trial phase.
Relaxation of diet is linked to
- Executive function problems,
- An increased risk of attention deficit disorder,
- Problems in school
- Metabolismus AMK u nemocných snižovat cerebrální funkce, a to v důsledku poruchy metabolismu neurotransmiterů
Kontroly
- Regular daily tracking of food and phenylalanine intake is necessary
- Blood tests, anywhere from weekly to monthly, are required to properly monitor blood phenylalanine levels
- Regular appointments and conversations with a metabolic dietitian
Kojení
- It is often possible to breastfeed an infant with PKU
- Should be discussed in detail with the metabolic genetics team
- Many mothers with PKU babies have successfully breastfed in tandem with metabolic formula and close monitoring of blood phenylalanine levels,
- Nursing mothers with PKU do NOT need to adhere to a low protein diet to accommodate their child with PKU (??)
Příčiny
- PKU is caused by a defect in a gene that codes phenylalanine hydroxylase
- Changes phenylalanine to tyrosine
- Leading to a toxic build-up of phenylalanine
- phenylalanine hydroxylase (PAH) which is located on chromosome 12
- Ale míra jeho aktivity může být regulována proteiny/miRNA z jiného chormozomu
Without treatment, symptoms in classic PKU begin by about 6 months of age
- The first symptoms may include:
- A musty or "mousy" odor of the body and urine
- Developmental delays in sitting, crawling, and standing
- Microcephaly (small head size due to decreased brain growth)
If children remain untreated, they may develop:
- Decreased skin and hair pigmentation (due to lack of tyrosine)
- Eczema
- Seizures
- Anxiety, depression, problems with concentration and other aspects of executive function
- Profound intellectual disability
Diagnostika
- Most children with PKU are found by the newborn screening test
- A heel prick done to all babies
- If suspected after the newborn period - blood test
- DNA testing can be used
- To confirm the diagnosis
- Determine the specific gene mutation
- www.medicalhomeportal.org/living-with-child/diagnoses-and-conditions---faqs/phenylketonuria
Formy PKU
- Vary in their blood levels of phenylalanine and their tolerance of protein in their diet
- Age is also important
- Infants and young children require more protein, including phenylalanine, for growth
- Protein intake should be guided by blood levels of phenylalanine
Benign hyperphenylalaninemia - HPA
- Can tolerate the most protein
- Hyperfenylalaninemie, benigní
- Aktivita fenylalaninhydroxylázy je na rozdíl od klasické PKU v rozmezí 1 až 35 %
- Děti s h. b. jsou podchycovány v rámci standardního screeningového testu novorozenců
- Jsou asymptomatické, vyvíjejí se normálně
- Mírné omezení přísunu proteinů, popř. i restrikce fenylalaninu, a systematické sledování těchto dětí je nezbytné, stejně jako vyloučení hyperfenylalaninemie.
- Prognóza je dobrá
Mild PKU
- Mild PKU can tolerate more protein
Classic PKU - homozygotní defekt
- Jakmile začne novorozenec pít mateřské mléko, hladina fenylalaninu v jeho krvi začne stoupat a poškozuje vývoj mozku, během kojeneckého a batolecího věku se postupně rozvíjí mentální retardace, která dále progreduje ve středně těžkou až těžkou.
- Lowest tolerance of protein
- Fenylalanin se u nich nehydroxyluje na tyrosin
- Hromadí se v tělních tekutinách
- Poškozuje myelinizaci vyvíjejících se nervových vláken
- část fenylalaninu je fenylalaninaminotransferasou přeměněna na fenylpyruvát
- Mohutná transaminace fenylalaninu způsobuje vyčerpání 2-oxoglutarátu v citrátovém cyklu
- úbytek energie se projeví nejdříve v CNS
- Fenylpyruvát, fenyllaktát a fenylacetát
- Ve zvýšené míře vylučovány močí,
- Odtud název nemoci fenylketonurie
- Dodávají jí zápach po myšině
- V organismu je méně tyrosinu a produktů jeho metabolismu
- Např. melaninu, proto je pro nemoc typická i slabá pigmentace.
- Mikrocefalie, sklony k ekzémům, záchvaty křečí a pyramidové i extrapyramidové příznaky.
Defekt dihydrobiopterinreduktázy - atypická fenyketonurie
Defekt biosyntézy dihydrobiopterinu (kofaktor fenylalaninhydroxylázy) - atypická fenylketonurie
Hyperfenylalaninemie
- Fenylalanin zvýšený jen do 0,6 mmol/l
- Zvýšené množství fenylalaninu v krvi při normální dietě pacienta
- www.wikiskripta.eu/w/Hyperfenylalaninemie
Těhotenství fenylketonuriček
- Aby se narodilo zdravé dítě, je nutné držet přísnou dietu již před početím a během těhotenství
- Tři měsíce před početím a během těhotenství musí být fenylalaninémie (hladina fenylalaninu v krvi) matky v mezích normy
- Fenylalanin z krve matky by totiž přecházel do krve plodu a jeho vysoká hladina by poškodila vývoj plodu.
- Důsledkem takzvané mateřské fenylketonurie jsou
- Mentální retardace,
- Mikrocefalie,
- Srdeční vady
- Plod je postižen bez ohledu na svůj genotyp (tzv. fenokopie)
- Stejně tak je nutné, aby dietu držely pacientky s HPA, jelikož i u těch by mohla hladina fenylalaninu plod poškozovat
- www.wikiskripta.eu/w/Fenylketonurie
Highly restricted “Down syndrome critical region” (HR-DSCR)
- Studying partial (segmental) trisomy 21 (PT21)
- Demonstrated a highly restricted “Down syndrome critical region” (HR-DSCR)
- Only 34 kb on distal 21q22.13
- Duplicated in all DS subjects
- Not duplicated in subjects without a diagnosis of DS10.
- Hsa21 gene product excess in a ratio of 3:2 when comparing trisomy 21 and normal cells
- “the goal is to figure out where a link between mental deficiency and trisomy 21 should be sought”
- Some enzymes with increased activities are encoded by genes located on Hsa21
- Superoxide dismutase 1 (SOD1) activity
- Increased by 1.5 times in trisomy 21 children
- Genes located on the other chromosomes - změna v aktivitě také
- Glutathione peroxidase (GPX1)
- Also increased
- Alteration of an enzyme or regulatory gene on Hsa21 propagates its 3:2 effect on subsequent steps of the metabolic chain
- Affecting enzymes located on other chromosomes
- Deep analysis of the recently described HR-DSCR, suspected to contain unknown fundamental genetic determinants for ID in DS
- Size of HR-DSCR is lower than the mean size of a single protein-coding gene
- This mean size is mainly due to introns
- Whose size may also be extremely low
- There is also the possibility that short non-coding or micro-RNA
- Might be encoded in this currently “desertic” region
- Deletion of a single copy of HR-DSCR from trisomic cultured cells via CRISPR/Cas959
- Could also allow the demonstration of phenotypic effects
- Isolation of effects on metabolism in DS
- Due to HR-DSCR from the ones due to Hsa21 genes distant from this critical region
Leptin
- Leptin levels in plasma correlate with adiposity in the general population but also in DS children and adolescents (Magni et al., 2004; Yahia et al., 2012).
- DS fetuses (Radunovic et al., 2003), adolescents (Gutierrez-Hervas et al., 2020), and adults (Proto et al., 2007) show lower leptin levels as compared to matched controls without DS.
- Others have found that DS individuals had higher leptin levels compared to unaffected siblings (Proto et al., 2007; Magge et al., 2008)
- Inherent genetic basis for increased leptin resistance could explain the cases of hyperleptinemia not accompanied by hyperinsulinemia in individuals with DS (Tenneti et al., 2017).
- https://www.frontiersin.org/articles/10.3389/fnins.2020.00670/full
Pentose phosphate pathway
- Parallel to glycolysis
- Exclusively in the cytoplasm
- Alternative pathway is the generation of NADPH
- Production of ribose-5-phosphate
- Synthesis of nucleotides
- Catabolism of nucleosides
- Releasing energy from ribose molecules
- Pentose phosphate pathway is interconnected to the glycolysis
- Through the shared used of glyceraldehyde-3-phosphate and fructose-6-phosphate (Aziz and Mohiuddin 2020)
Regulator of calcineurin 1 (RCAN1)
- Cell growth and immune responses + cognition (Dierssen et al., 2011; Mendez-Barbero et al., 2013);
Superoxide dismutase 1 (SOD1)
- Helps redox homeostasis (Valko et al., 2016).
Svaly
- DS individuals have less-than-normal muscle strength (muscle hypotonia) in their hands and lower extremities
- [Cioni et al. 1994; Croce et al. 1996; Carmeli et al. 2002; Hawli et al. 2009; Bala et al. 2018; Dupre and Weidman-Evans 2017; Coelho-Junior et al. 2019]
- Potential musculoskeletal developmental issues
- Neuromuscular junctional problems
- Decreased manual control
- Perform less physical activity
- May have sarcopenia (Bala et al. 2018; Dupre and Weidman-Evans 2017; Coelho-Junior et al. 2019).
- Skeletal muscle contractions are impaired in DS (Cowley et al. 2012).
- Twitch and tetanus contractile responses were not significantly impaired in DS
- Contractile weakness in DS skeletal muscle is associated with the dysregulation of multiple genes and gene products
- Glucose uptake,
- Lipid metabolism,
- Oxidant/antioxidant balance
- mitochondrial dysfunction associated with DS (Hawli et al. 2009; Cowley et al. 2012, 2017; Cisterna et al. 2014; Brault et al. 2015; Glass and Connor 2016)
Progredující demence typu AD
- Most DS individuals, by their 40s, develop a type of dementia that shares many commonalities with Alzheimer’s disease (AD) (ten už dnes umí léčit Dr. Dale Brednesen = jeho protokol již od narození by mohl lecos zbrzdit)
- Deposition of senile plaques and neurofibrillary tangles (Head et al., 2016).
- After the age of 50, the risk of developing AD-like dementia rises in DS patients up to 70%.
- The overexpression of APP, an integral membrane protein that is concentrated in neuronal synapses
- Consequent overproduction of amyloid beta (Abeta)-peptide
- One of the major toxic players in the early onset of AD neuropathology in DS population (Hartley et al., 2015; Wiseman et al., 2015).
- Abeta overload involved in the
- Increased production of reactive oxygen species (ROS), elevated oxidative stress, and causes
- Excitotoxicity,
- Disturbance of cellular respiration
- X synaptic functions.
- Accumulation of Abeta in DS brain
- As early as 8–12 years of age
- Increases during the patient’s lifespan (Head et al., 2016).
- Worse performance in semantic verbal fluency test and poorer communication skills
- Associated with higher plasma Abeta concentrations and impaired communication skills (ABAS–II) (Hoyo et al., 2015).
Dýchání
- Exhibit significantly reduced aerobic exercise tolerance (Aguiar et al. 2008; Pastore et al. 2000)
- molmed.biomedcentral.com/articles/10.1186/s10020-020-00225-8
Další vlivy
- Quite a number of genes have been found to play important roles in Down Syndrome, such as.
- AFP, APOE, APP, DHDDS, DHPS, DSCAM, DYRK1A, GATA1, MAPT, MTHFR, NT5E, NTM, NTS, PAPPA, PRPH2, PSEN1, RCAN1, SOD1, TRIM26.
- www.bosterbio.com/diseases/down-syndrome
Omezení studia DS na myších modelech
- Trisomic for different sets of genes of Hsa21
- Animal models do not reproduce the human disease with all its complexities
- Rather model specific aspects of the disease
- no perfect model of DS exists
Ts65Dn mouse
- The most studied
- Best characterized model of DS
- Bears segmental trisomy for a distal region of Mmu16
- Contains approximately 55% of Hsa21 conserved genes (Davisson et al., 1990)
Tedy imituje jen z "55% tíži Downova syndromu"
- Additionally trisomic for approximately 50 genes that are non-hortologous to Hsa21 (Rueda et al., 2012)
- Může imitovat jiné metabolické poruchy, které u člověka nejsou
- During the past 20 years, numerous studies have demonstrated common features between Ts65Dn and humans
- Ts65Dn mouse is, at the moment, the only model of DS used in pre-clinical studies to develop therapies for DS (Gardiner, 2015)
- Ts65Dn mouse
- Lacks numerous Hsa21 orthologous genes
- Has some Mmu17 genes that are non-trisomic in humans
- These genes may confound results of therapeutic interventions
- Males are sterile, mice are generated from Ts65Dn dams
- Trisomic condition of mothers
- Could cause developmental problems of the pups independently from trisomy !
- Embryonic treatments may have beneficial effects on trisomic pups that are secondary to the beneficial effects on the trisomic dams
- Due to these limitations, treatment on Ts65Dn mice may have an unpredictable clinical outcome
- But Ts65Dn mouse has allowed scientists to discover treatments that may also be beneficial in individuals with DS.
- www.frontiersin.org/articles/10.3389/fnbeh.2015.00265/full
Water contamination with the pesticide trichlorfon
- Was reported to cause an outbreak of DS birth incidence
- In a village in Hungary, in 1993
- In Massachusetts in 2003
- Suggesting environmental pollutants have some potential to cause Down Syndrome
- Through pre or post conception teratogenic and mutagenic action
- It is recommended from this study to reduce body levels of heavy metals before pregnancy
- www.theconsciouspod.com/metals-and-minerals-in-down-syndrome/
