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Metabolicdiseases:Inborndefectsofcarbohydratemetabolism:
GalactosemiaFructosemia
UDPGdeficiency(galactose-1-phosphateuridylyltransferase)aldolaseBdeficiency
Thesymptomssoona@erbirth-vomiCng,diarrhea,hepatosplenomegaly,CNSdamage,tubulopathy,cataract
Glycogenstoragediseases Deficiencyofenzymesinvolvedinthesynthesisandmetabolismofglycogen
Symptomsindifferentages:-hypoglycemiaintracellularaccumula*onofglycogen:hepatomegaly,cardiomegaly,developmentaldelay,neurodegenera*on
Aminoacidmetabolicdisorders:phenylketonuria phenylalaninehydroxylase
deficiencyEarlysymptoms:vomiCng,eczema,lightskin,thesmellofmouseurine,seizures,mentalretardaCon,
maplesyrupdisease(MSUD)
branchedaminoacidsmetabolismdisorder
Early:hypoglycemia,severegeneralcondi*on,coma,caramel-scentedurine
nonketo*chyperglycinemia
Inbornerrorofglycinemetabolism
Hypotonia,tremor,myoclonus,developmentaldelay
Hyperammonemia:
• Congenitalenzyma*cdefectsofureacycle,• ThemostcommontypeIIhyperammonemia-congenitaldeficiencyofornithinetranscarbamylase(OTC)X-linkedrecessiveinheritance(themostcommonsymptomsinboys)
• ToxicammoniariseSymptomsofintoleranceofdietaryproteinvomi*ng,psychiatricandneurologicalsymptoms(convulsions,disturbanceofconsciousnessuptocoma)
Mitochondrialdiseases:
• Defectsintherespiratorychaincomplexenzymes;muta*onsacquiredorinherited,inmitochondrialDNAorinnucleargenesthatcodeformitochondrialcomponents.
Symptoms:lac*cacidosis,increasedalanine(blood,CSF).Leighsyndrome(vomi*ng,suppressionofgrowth,seizures,hypotonia,nystagmus)Lebersyndrome(blindness,myoclonus,impaireddevelopment)MERRF(myoclonalepilepsy,raggedredfibers)WolframsyndromeDIDMOAD(diabetesinsipidus,diabetesmellitus,op*catrophy,deafness)MELAS–encephalopathy,lac*cacidosis,stroke-like–episodesAlperssyndrome–myoclonus,hypotonia,liverdamage,
Lysosomaldiseases:
• Thediseasesassociatedwithadeficitofenzymesinvolvedinthesynthesisanddegrada*onofsubstancesgeneratedinthelysosomes:gangliosides,mukolipides,sphingolipides,cerebrosides
Mucopolysaccharidoses:MPSI(Hurlersyndrome)MPSII(Huntersyndrome)
iduronidasedeficiencydeficitofidursulfase
ProgressiveneurodegeneraCon,dysmorphia,dwarfism,bonedefects,deafness,hepatosplenomegaly
MPSIII(Sanfilipposyndrome)
neurodegenera*on
Lipidoses:Niemanna–Pickt.Cdisease
Intracellulartransportofcholesterolimpairment
ProgressiveneurodegeneraCon,epilepsy,hepatomegaly
GauchertypeIIiIIIdiseaseKrabbedisease
Impairmentofceramidedegrada*onBetagalactosidasedeficiency
Neurodegenera*on,hepatosplenomegalyNeurodegenera*on,epilepsy,deafness,blindness,leukodystrophy
Sulfatydoses:• MetachromaCcleukodystrophy(deficitofsulfatasecerebroside)-
peripheralneuropathy,demyelina*on,op*catrophyGangliosydoses:Neurodegenera*on,epilepsy,deafness,hepatosplenomegaly• GMI(betagalaktosydasedeficiency)• GMIITay–Sachsdisease(deficiencyofheksozamidase)Glykoproteinoses:• Neuronalceroidlipofuscinosis(TPPIdeficiency)enzymuTPPI)Symptoms:Neurodegenera*on,epilepsy,Op*catrophy
Peroksysomaldiseases:
• Zellwegersyndrome(cerebro-hepato-renalsyndrome),cataracts,bonedefects,re*ni*spigmentosa
• X–linkedAdrenoleukodystrophy:progressiveleukodystrophy,adrenalinsufficiencyDiagnos*cs:increaseVLCFAinblood
Metalrelateddisorders:
• Wilsondisease(hepato–len*culardegenera*on)defectoftransmembranetransportofcopperinvolvesliverandCNS,autosomalrecessiveinheritance
Symptoms:liverfailure,slurredspeech,tremor,Kayser-Fleischerring,hemoly*canemiaDiagnosis:MRI,Cuandceruloplasindecreaseinserum,increasedurinaryexcre*onofCu• Menkesdisease:X-linked
inheritance,malabsorp*onofCuSymptoms:decreasecopperandceruloplasmininserum,neurodegenera*on,laxity,„kinky”hair
Metalrelateddisorders:
• NBIA(formerlyHallervorden–Spatzdisease)-deficiencyofpantothenickinase,irondeposi*onintheglobuspallidus"*gereye"Symptoms:neurodegenera*onop*catrophy,dystonia
Biotynidasedeficiency:
• Biotynidase-involvedinthecyclicreproduc*onofbio*n(vitaminH)Symptoms:muscularhypotonia,developmentaldelay,seizures,eczema,hairloss,ataxia,blindness,deafnessTreatment:Bio*n(vitaminH)
NeurodegeneraConwithataxia:• Friedreich'sataxia;ARinheritance,genecodingfrataxine(increasednumberof
repe**onsofGAA,mitochondrialprotein)Symptomsinadolescence:-Gaitandlimbsataxiaandlimbs,hollowedfeet-Lackoftendonreflexes-Babinskisign(+)-dysarthria-Numbnessdeep
• Ataxiatelangiectasia;ARinheritance,geneATM(involvedinregula*onofDNArepair)Symptoms:1-4yearsofage-cerebellarsymptoms:-apraxia,ophtalmoplegia(nystagmus,dysmetria)-blurredspeech-hipomimia-telangiectasias-Igdeficiencies(IgA,IgG)-increasedconcentra*onofAFP
Neurodegenera*onwithmovementdisorders:
HunCngtondiseaseAD,increasednumberofCAGrepeats,muta*onofhun*ng*nproteinSymptoms35-40yearsold(alsojuvenileform):-involuntarymovements(choreiform)-personalitydisorders,-demen*aParkinsondisease-themostcommongenePARK1(proteinα-synuclein),PARK2(parkin)Symptoms:-movementdisorders(res*ngtremor,rigidity,hypokinesia,stoopedposture,freezing,slurredspeech)-aken*ondeficit,-personalitydisorders-bradyfrenia
Neurodegenera*onwithdemen*a:• Alzheimer'sdiseaseAD?,
depositsofβ-amyloidinbrain
Symptoms:-recentmemorydisturbances,-disturbancesofabstractthinking,-depression-ini*allywithoutotherneurologicaldisorders(thenextrapyramidalsymptoms,abnormalposture,gaitproblems)
Neurodegenera*on–diagnos*c:
• Metabolicscreeninganerbirth:TANDEMMS-profileofacylcarni*nesinthebloodOther:AAserum
• Cerebro-spinalfluidexamina*on(lactateconcentra*on)• GCMS-profileoforganicacidsinurine• Ammoniaconcentra*onintheblood• Oligosaccharidesinurine• Biotynidasedryblooddrop• Lysosomalenzymesintheblood• VLCFA(verylongchainfakyacidsintheblood)• Gene*cdiagnosis• Neuroimaging(MRIhead,spinalcord)• Ophthalmologicalexamina*on