Neurodegenera*vediseases:

MałgorzataBilskaDepartmentofChildNeurologyWarsawMedicalUniversity

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