Peds Flashcards
inborn errors metabolism
energy metabolism/catabolism-present acutely
intoxication - Sx free then present acutely - urea cycle
complex molecules/anabolism - not acute presentation
Galactosemia
-Galactose-1-P UDT deficiency MCC - classic galactosemia w/ intellectual disability
AR, GALT/GALK/GALE genes ; newborn screen,
-present at birth, vomiting, diarrhea, jaundice; cataracts b/c galactitol
Dx: reducing substances in urine
-Tx: no lactose (can’t break down), no galactose (no cataract, hepatomegaly but still CNS Sx)
PDH deficiency
PDH: oxidative decarboxylation: pyruvate to Co2 + acetyl CoA
-low lactate:pyruvate ratio, elevate lactate ad pyruvate; buildup alanine
-neonatal acidosis, lactic acidosis or present later
ataxia
-can trigger exacerbations by high card meal
-cytic lesions: white matter BG +/- corpus callosum
-MCC X-linked E1 (less common AR)
Tx: acetyl CoA, ketogenic diet, carnitine, coQ10, biotin, acetazolamide-ataxia
NF1
Diagnostic criteria: 2 or more:
-6 cafe au lait
-inguinal/axillary freckling
-2 cutaneous neurfibromas or 1
-plexiform neurofibroma - (Schwann cells, fibroblasts; peripheral nerves - can come from DRG + invade spinal cord; GI track-intestinal hemorrhage ; can be malignant)
-2 Lisch nodules
-Optic path glioma - anywhere along tract - low grade (can present precocious puberty) ; serial imaging over time
-bony lesion (sphenoid wing dysplasia, thinning bone cortex)
-child of parent with NF1
mild developmental delay
-renal A stenosis from renal A dysplasia-> HTN
-pheochromocytoma
-Moyamoya syndrome
-cerebral ansuerysms
-macrocephaly independent of hydrocephalus
-pathologic fracture, scoliosis, sphenoid wing dysplasia
Cafe au lait,
autosomal dominant neurofibromin- chr 17 - variable expression, complete penetrance
DDx Legius syndrome - SPRED1 gene AD - cafe au lait and axillary/inguinal freckling but no Lisch nodules, no other NF findings
NF1-tumor suppressor-regulates RAS proto oncogene - can get astrocytoma, leukemia
GLUT-1 deficiency
-GLUT1 encoded by SLC2A1 de novo or ADDeVivo syndrome
low CSF glucose, normal serum glucose
-epileptic encephalopathy if early, or episode invoultary movements/ataxia, paroxysmal exertional dyskinesias
-Tx: ketogenic diet
Phenylketonuria PKU
Phenylalanine hydroxylase deficiency (phenylalanine to tyrosine); -if tetrahydrobiopterin deficiency (cofactor of phenylalanine hydroxylase)
-accumulate phenylalanine —> metabolized phenylacetic acid causing musty odor
autosomal recessive
-normal at birth after feedingrise phenylalanine levels; early normal Neuro development
-no acute metabolic encephalopathy
-microcephaly, seizures, fair with blond hair/blue eyes - no tyrosine and no melanin pigment production
-avoid phenylalanine
-newborn screen: detects hyperphenylalanemia-high phenylalanine in blood
Dx: reduction phenylalanine in blood and urine after BH4 given
Tx: low protein, phenylalanine free diet
Maple syrup urine disease
autosomal recessive
-branched chain a-ketoacid dehydrogenase complex deficiency (leucine, isoleucine, valine)
I Love Vermont maple syrup from maple trees
(with B1ranches). - Isoleucine, Leucine, Valine
decreased branched-chain α-ketoacid dehydrogenase (B1). Causes increased α-ketoacids in the blood, especially those of leucine.
-with feeding, present as neonate
Day 2-3 of life - progressive encephalopathy
opisthotonus arched back posture (like an arched tree)
Urine: maple syrup, esp during exacerbations
Tx: low protein diet
X linked disorders
All Oblivious Females Can Pass Her Boys X-Linked Disorders
All-Aicardi (dominant) + X-linked adrenoleukodystrophy (ABCD1); acqueductal stenosis
Oblivious-ornithine
transcarbamylase deficiency ; oculocerebrorenal syndrome - OCRL1 (-Lowe syndrome )
Females-Fabry + Fragile X (trinucleotide repeat)
Can/Kan-CMTX ; KAllman’s; Kinky hair syndrome - Menkes (ATP7A Copper transporter); Kennedy disease (spinobulbar muscular atrophy-CAG repeat in androgen R)
CDKL5
Pass -PDH deficiency (MCC), pigmentia (incontinentia-pustular lesions-NEMO), periventricular nodular hetertopia (FLNA), Pelizaeus-Merzbacher
Her ett-Hunter (Hurler AR)
RETT - MECP2
Boys-BPAN-beta propeller protein associated neurodegernation (mostly female)
X-Linked-McLeod’s syndrome-XK disease+ Lesch-Nyhan + XL Lissencephaly (DCX)
Disorders-muscular Dystrophy (Emery-Dreifuss-Emerin mutation, Becker, Duchenne)
Neurulation
Differentiation
Specification
- neuralation (3-6 wks) - Neural plate - ectoderm ->to neural tube via notorcord (mesoderm “make note”)
- Notochord - mesoderm becomes vertebral column
-induces neuralation neural plate - forms midline groove with fusion starting in center,->
by week 4: anterior neuropore then posterior closes
->3. neural tube formed-> differentiation
-ventral: notorcord signals via sonic hedge hog
-dorsal: lateral ectoderm signals - 5-6 wks - Specification: Neural tube->3 vesicle segmentation
-Prosencephalon = telencephalon (cerebral hemispheres) + diencephalon (hypothalamus, thalamus)
-Mesencephalon - midbrain
-Rhombencephalon - pons, medulla, cerebellum
-Specification problem - septo-optic dysplasia
Neural crest cells
PNS , autonomic ganglia+ cromaffin cells adrenal medulla + melanocytes
neural tube defects-anterior
NTD: risk: more common in females, retinoids, VPA, carbamazepine? , hx infant NTD
-supplement 0.4 mg folate
-Dx: prenatal US, alpha-FTP +Achesterase elevated (in serum+amniotic fluid); can get prenatal MRI; if positive screen for trisomy 13 and 18 (encephalocele)
-anencephaly (no cerebral hemispheres, cranial vault b/c no mesoderm diffferentiation), Anterior neuropore prob
-encephalocele (hernation neural tissue into midline skull-occipital (more severe, more common)>frontal; fluntuant mass, can still live but microcephaly) -anterior neuropore
-trisomy 13, 18
Holoprosencephaly:
-no prosencephalon to telencephaphon (cerebral hemispheres + BG+ olfactory) + diencephalon (thalamus+hypothalamus)
-no telencephalon to 2 cerebral hemispheres + BG
-alobar -most severe; vs semilobar vs arrhinecephaly
Holoprosencephaly
Trisomy 13, 18, Sonic HH, cholesterol synthesis (Smith Lemli Opitz-7 dehydrocholesterol reductase)
ALobar- cyclopia, endorine problems, hydrocephalus
semilobar -partial agenesis corpus callosum (commissural plate); splenium + genu preserved)
Arrhinecephaly - agenesis olfactory bulb + tract
-Kallmann’s X linked dominant - anosmia + hypogonadims
-septo-optic dysplasia - Specification problem -HESX1, homeobox, SOX endocrine deficiency, no septum pellucidum, hypoplastic optic nerve
+/- arrhinencephaly, hypothalamic hamartomas
-ataxia
cavum septum pellucidum - normal
neural tube defects - posterior
-meningocele (only leptomeninges, CSF herniate) vs occipital encephalocele ; no neurological deficit vs myelomeningocele
Myelomeningocele - SC, nerve root, meninges protrude, Chiari II ; hydrocephalus, bowel/bladder dysfunction
-sacral agensis- absence sacrum, not sacral SC ; range clinical Sx
-GI, urogenital, SC prob
-maternal IDDM risk
-homeobox gene mutations, AD
Diastematomyelia - splitting SC into 2 by midline septum
-diplomyelia - duplication of SC - two central canals each with gray and white matter like a normal SC (vs diastematomyelia)
Posterior neuropore prob - spina bífida
-occult spinal dysraphism - tuft of hair + neuro dysfxn - tethered cord, epidermoid cysts
spinal bifida occulta - no neuro dysfxn
tuberous sclerosis complex
TSC1 mutation on chromosome 9 or TSC2 mutation on chromosome 16. (1 Hamartin for 9 or 2 Tuberin for 16 on sale) - sporadic - form TSComplex which inhibits mTOR pathway
Tumor suppressor genes. Autosomal dominant, variable expression.
RAPAMYCIN (mTOR inhibitor)
HAMARTOMAS
-Hamartomas in CNS, lymphangiomyomatosis, retina, skin-mulberry lesion
-hamartomas - not malignant and don’t grow; make of abnormal cells - T2 hyperintense hazy patches on MRI; correlate with neuro deficits; TX with rapamycin
-Angiofibromas+fibrous cephalic plaque ; ungual fibromas
-Mitral regurgitation
-Ash-leaf spots +Shagreen patches (raised)
-can see under Wood’s lamp UV light
-cardiac Rhabdomyoma-can regress over time
-autosomal dOminant;
-Mental retardation (intellectual disability);
-renal Angiomyolipoma
-Shagreen patches (connective tissue hamartomas),
-dental enamal pits
-Subependymal giant cell astrocytomas - specific for TSC, low grade; surgery curtative; or Tx Rapamycin
-ENHANCE vs calcified nodules
-subependymal nodules - hyperdensity on CT scan; calcified; can grow
-don’t correlate with intelligence or seizures vs cortical hamartomas
-MCC infantile spasms - vigabatrin
-burden tubers correlates with seizures
-angiomyolipomas
lymphangiomyomatosis -pulmonary disease in females >males- dyspnea, hemoptosis, pneumothorax - Tx - tamoxifen-fatal yrs after under; Dx chest imaging
Fabry
only x-linked sphingolipidosis
alpha galactosidase defect
‘Fabry is a gal (galactosidase) who tries ceramics’
(build up of ceremide trihexaside)
Throwing pottery (hands+feet on pedal-small fiber neuropathy) + splatter (angiokeratomas trunk, LE) + round clay clogging arteries->strokes (dolioectatic) + cardiomyopathy + ESRD + cloudy corneals
-ESRD, birefringent lipid deposits, lamellar deposits
Tx: enzyme replacement alpha galactosidase
propionic acidemia - branched chain organic acidemia
AR, deficient propionyl-CoA carboxylase
-accumulate propionyl-CoA+glycine; normal MMA levels
-makes D methylmalonyl CoA from propionyl CoA; (then Methylmalonyl-CoA mutase makes succinyl coA for Krebs)
need biotin B7 as cofactor
-normal at birth; episodic hyperammonemia
-movement disorders - BG involved
-pancytopenia, bleeding, ICH
-on newborn screen
Tx: biotin, carnitine; ABx-metronidazole - decrease propionate by gut bacteria
methylmalonic acidemia
Methylmalonyl-CoA mutase deficiency
-makes succinyl-CoA->Krebs cycle
-B12 cofactor
-present first week life
-ketoacidosis, hyperglycinemia, hyperammonemia, elevated MMA in blood and urine ( vs propionic acidemia)
Tx: low protein, can respond to B12, carnitine, ABx to reduce gut flora propionic acid
Lesch Nyhan
deficient hypoxanthine guinane phosphoribosyltransferase - purine metabolism salvage (HPRT1 gene)
-accumulate purines - increase uric acid
-choreoathetoid movements, gout, nephrolithiasis
Niemann Pick
sphingomyelinase deficiency->accumulate sphingomyelin
(cherry Pick the liver, knee on a springboard)
AR
-type A: severe, infant, cherry red spot
Type B - visceral - no CNS effects; Hepatosplenomegaly + interstitial lung disease
Bone marrow biopsy: foam cells
Type C: NPC1- Chr 18
-cholesterol trafficking problem;
+ Filipin test - unesterified cholesterol accumulates in lysosomes
-fibroblasts can’t esterify cholesterol
-EOM abnormalities
metachromatic leukodystrophy
snowman without arms + legs + egg on head
-cerebroside sulfate buildup
Arylsulfatase A deficiency
-late infantile, juvenile, adult
-confluent white matter spares U fibers
-
Chiari I vs II, III
Dandy Walker
I - cerebellum+tonsils displaced -
-if <1 cm displaced, Pt can be ASx
-brainstem Sx, Ha, ataxia, syringomyelia (separate from central canal, lined by gliotic tissue)
-2/2 posterior fossa hypoplasia - overcrowding?
II = Arnold Chiari-vermis + myelomeningocele
-hydrocephalus-4th ventricle compressed
-Tx: shunt, suboccipital crani
Chiari III - cerebellar heniation into cervical/occipital encephalocele
syringomyelia - pressing on central canal
vs hydromyelia - central canal enlarged, lined by ependyma
Dandy Walker: Agenesis of cerebellar vermis leads to CYST enlargement of 4th ventricle
-chromosomal abnormalities
-facial hemangiomas
-noncommunicating hydrocephalus, spina bifida.
Sialidosis
glycoproteinoses - lysosomal storage disorder-deficient alpha-N-acetyl neuraminidase
-AR
-Type I - adolescent- cherry red spot + myoclonic epilepsy - no dysmorphism
Type II - kids - cherry red spot + myoclonic epilepsy + coarse facial features, psychomotor retardation
neonatal form - hydrops fetalis
Tx: -increased urinary excretion sialic acid containing oligosaccharides
-vacuolated lymphocytes, membrane bound vacuoles
Joubert’s syndrome
ciliopathy ->resp problems
molar tooth sign
-cerebellar vermis hypoplasia
ataxia, developmental delay, EOM abnormal
-central apnea
-renal failure
+/- Leber’s congenital amaurosis-rod/cone dystrophy
vs COACH syndrome - Molar tooth + LIVER + PUPIL problems
-cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, coloboma (blotchy pupil), hepatic fibrosis
vs. Leber congenital amaurosis-can get molar tooth
Progressive myoclonic epilepsies
All AR - Tx VPA except for MERRF
1. Unverricht-Lundborg - EPM1 gene - cystatin B - BALTIC SEA
-severe myoclonus
- Lafora body - EPM2A/2B encoidng laforin, malin protein
Partial seizures, dementia
Dx: skin biopsy - MERRF
-deafness, lipomas, optic atrophy, myopathy, neuropathy, severe myoclonus
-elevated lactate levels
-no VPA - Neuronal ceroid lipofuscinosis - CLINGY FAT and CLINGY TP over eyes (blindness), head (dementia), struggling to break free ->seizures/facial dyskinesias as adults + bits of deposits intraneural
blindness, dementia, psychomotor retardation, +/- myoclonic seizures + intraneuronal deposits
CLN1 - PPT1 - infantile - saposins A/D
CLN2 - TPP1 - late infantile
CLN3-Juvenile - 4-10 yrs
-Adult - 30s - dementia, facial dyskinesias
microscopy: lymphocyte vacuolation; fingerprint bodies +other deposits accumulate
- Sialidosis - NEU1 - NEW FARM SILO CHERRY SPOT
Type 1: no alpha-neuraminidase
-adolescence/adult - normal cognition
-ataxia, GTC, vision loss , cherry red spot
Type 2 - deficient alpha-N-acetyl neuraminidase/Beta-galactosialidase
-fundus changes, cherry red spot, neuropathy, dysmorphism, severe myoclonus
(shaky ataxic alcoholic farm hand with fetal alcoholism=dysmorphism)
Dx: urinary sialyl oligosaccaride + leukocyte enzyme deficient
-lymphocyte vacuolation
congenital aqueductal stenosis
btw 3rd + 4th ventricle
(foramen of Monro-lateral+3rd)
1. neurulation disorder -abnormal midbrain development
2. X linked - gyria +/- holoprosencephaly/Chiari II
2. CMV, mumps
3. tumors: ependymomas, hamartomas - or secondary compression on aqueduct
Sx: macrocephaly, sundowning of eyes, hydrocephalus
Peroxisomal disorders
- Zellweger’s - PEX mutation (Pachy Poly PEX)-AR
-chondrodysplasia, calcific stippling patella, dysmorphic faces, normal head circumference, liver/kidney disease, hearing loss
-pachygyria/polymicrogyria; white matter involved
Dx: -VLCFA in serum, decreased RBC plasmalogens, decrease hepatic peroxisomes
-die early - neonatal adrenoleukodystrophy - NO pachygyria
+heterotopia, cerebellar dysplasia, spares U fibers
-cirrhosis, adrenocortical atrophy
-VLCFA in serum - infantile Refsum’s - phytanic acid increased
A dominant PHYTING the REF; punching in chest (cardiomyopathy); socks and gloves on-neuropathy
AD Autosomal dominant;
-motor delay, hearing loss, anosmia,
retinitis pigmentosa
-cardiomyopathy
-large fiber neuropathy (vs KSS-no neuropathy)
-short 4th toes
-mild, can live to adult
-no peroxisomes
Stroke in young
Hereditary hemorrhagic telangiectasia+Osler-Weber-Rendu - autosomal dominant - multiple AVMs
pseudoxanthoma - thrombosis
Ehlers-Danlos - aneurysm, dissection
Fabry - ectasia, thrombosis
MELAS-infarcts not correlating with vascular territories
xeroderma pigmentosum
peripheral neuropathy, ataxia, hyperkinetic, cog decline
adrenoleukodystrophy
XL ABCD1 gene - peroxisome membrane transport
- childhood onset cerebral type - 4-8 yrs
ADHD behavior problems, aggression
-spasticity, incoordination, bulbar dysfxn
-no pachygyria; SPARES U fibers
-rim of enhancement posterior white matter - differentiate (except Alexander’s - contrast enhancement on MRI)
-neonatal adrenoleukodystrophy - NO pachygyria
-heterotopia, cerebellar dysplasia
-cirrhosis, adrenocortical atrophy
-adrenal cortex, Leydig cells testis
-brain biopsy: perivascular cuffing, +T cells
-risk adrenal crisis
-die early - adrenomyeloneuropathy-age 20, sensory neuropathy, sex dysfxn, sphincter control problem, peripheral nerve demyeliantion, no inflammation
-can have adrenal insufficiency
-female carriers mild Sx - pure adrenal insufficiency
-Addison crisis
elevated VLCFA, elevated ACTH 2/2 adrenal insufficiency
Tx: Lorenzo’s oil - 4:1 glyceryl trioleate-glyceryl triercate - if young + ASx
BW transplant
Leigh’s
subacute encephalomyelopathy-mitochondrial dysfxn from respiratory chain
-sporadic or familial, maternal inheritance; mutation in mitochondrial/nuclear DNA encoding resp chain subunits
-onset within 1 year: hypotonia, loss of head control, poor suck, vomiting, myoclonic jerks
-onset >1 year: respiratory prob, apneas, periodic hyperventilation, nystagmus, ophthalmoplegia
-lactate elevated in blood+CSF; lactate + pyruvate elevated during exacerbations
-hyperintense BG, substantia nigra, inferior olive, periqueductal gray
Tx: thiamine, if responsive better prognosis
Kearns Sayre
Usually sporadic - mitochondrial DNA deletion or duplication
KISS- eyes half closed, not moving, heart stops, ataxic, short
HIGH PROTEIN in CSF
opthalmoplegia + onset <20 + short stature/pigmentary retinopathy/cerebellar ataxia/heart block/ increased CSF protein
-pacemaker b/c heart block
-no neuropathy vs Refsum
path: ragged red fibers in muscles, white matter with spongy myelopathy
congenital disorders of glycosylation
AR
Type I CDG - abnormal glycan synthesis- developmental delay, liver problems, ataxia, retinitis pigmentosa, stroke like episodes, hypogonadism,
carbohydrate deficient transferrin -serum+CSF
lipodystrophy: fat pads in buttocks, inverted nipples
Dx: serum transferrin isoforms
Tx: supportive
cortical development
- cerebral hemispheres : single epithelial layer around lateral ventricles-> ventricular zone; radially oriented
- marginal layer forms above ventricular zone; subventricular below
-radial glia in ventricular zone sends processes to pia cortex surface and new neurons migrate on scaffold made by radial glia to cortical plate
-marginal zone: Cajal-Retzius cells-express Reelin, for migration
- cortex forms inside out - cells migrating earliest form deepest layers first
-neuronal progenitor cells: ventricular, subventricular zones
-radial glia toward cortical plate-neurons migrate
neuronal cell: pyramidal, stellate /cortical granular, Betz (5th layer motor cortex)
glial cells: astrocytes, oligodendrocytes, ependyma, microglia
all 6 layers of cortex by 27 wks gestation
-peak migration 12-20 weeks
gyri, sulci: 20-36 wks
-most cortex neocortex (isocortex) = 6 layers
[vs. primitive cortex - fewer layers - archicortex - hippocampus; paleocortex - olfactory, limbic]
Layer I - most superficial - pia covers-molecular layer
II - external granular cell
III - external pyramidal cell - corticocortical efferents (project to II and III layers)
IV-internal granular cell
V-internal pyramidal cell (Betz) - corticostriate
VI - multiform overlies white matter - corticothalamic (cortex to thalamus)
Thalamic efferents: thalamus to cortex - I, IV, VI
pyramidal cells - III and V: glutamatergic-largest + cortical neurons
stellate/granular neurons-II and IV- smaller interneurons
Corpus callosum dysgenesis
commissural plate-bridge over which axons run ; problems = corpus callosum dysgenesis/agenesis
-Aicardi, nonketotic hyperglycinemia
-hypertolorism
-coronal MRI: racing car sign
Phakomatoses/neurocutaneous disorders of ectoderm
- Neurocutaneous melanosis - leptomeningeal melanoma + giant hair pigmented nevi, congenital melanocytic nevi; risk melanoma
-from melanoblasts origin in pia matter)
-brain base, brainstem, cerebellum
-hydrocephalus - Parry Romberg - hemifacial atrophy - loss facial tissue, cartilage, bone, hair (ROMBERG fall TO ONE SIDE - hemifacial)
-HA, Horner’s, seizures, hemiparesis
-DDx scleroderma, lipodystophy -
Maffucci’s - enchondromas (cartilage tumor) and hemangiomas - vitiligo, hypergimentation
-CNS tumors, compression by enchondromas - Incontinetia pigmenti - vesiculobulous lesions at birth, verrucous lesions 6 weeks, HYPERpigmented lesions following Blaschko lines of skin development
-NEMO gene mutation-encodes protein in NF k B pathway (sounds like fish species name)
-X linked
- +/- neuro delay - VHL - retinal, cerebellar, spinal hemangioblastoma - renal cell carcinoma, no skin findings
-AD mutation on VHL gene chromosome 3 - tumor suppressor protein - Hypomelanosis Ito - hypopigmented streaks following skin lines (Island of Ito - have to look for it in a map)
-cataracts, macrocephaly+eye abnormalities seizures,
-lissencephaly, hemimegalencephaly
-detect lines with UV light - epidermal nevus syndrome -types include Proteus syndrome (asymmetry; hypertrophy soft tissue + bones), Becker nevus (high plague, breast hypoplasia, rib defects)
others: sebaceous, phakomatosis pigmentokeratotica, CHILD syndrome
-nevi over face predict CNS involvement; can get hemimegalencephaly ipsilateral to facial nerve nevus +contralateral hemiparesis ; other cortical development problems
-risk malignancy -basal cells carcinoma, risk astrocytoma
-iris colobomas
Glycine encephalopathy/
Nonketotic Hyperglycinemia
hiccups in utero, myoclonic jerks
-present within hours of birth, irritable, poor feeding, hiccups
burst suppression EEG + hypsarrhythmia
-agenesis corpus callosum
-can’t break down glycine - defects in the genes (GLDC P proteinand AMT) that encode glycine cleavage enzyme system resulting in decreased enzyme activity
-enzymes = AR (proteins, membrane transporter AD)
-high glycine in CSF;
CSF/plasma glycine concentration >0.6
cortical malformations
proliferation: focal cortical dysplasia; megalencephaly
-Focal cortical dysplasia: dysmorphic enlarged cells, balloon cells, abnormal lamination
+/- tuberous sclerosis
migration: lissencephaly, periventricular nodular heterotopia, pachygyria, subcortical band heterotopia
organization: polymicrogyria (NOT migration), schizencephaly, microdysgeneiss, focal cortical dysplasia with normal cell types
microcephaly/macrocephaly
microcephaly: can be benign + hereditary
macrocephaly: HC > 2 SD above mean
-also can be benign+hereditary
-2/2 hydrocephalus
-or 2/2 megalencephaly - oversized brain-weight >2 SD
-Tay sachs, mucopolysaccaridoses, Canavan, Alexander’s
-also could be benign familial
hemimegalencephaly - enlarged hemisphere - hamartomatous growth - abnormal proliferation
-hemiparesis, seizures
-Tx. hemispherectomy
Lissencephaly type 1 - LIS1, DCX
Miller Dieker syndrome -4 layer classic lissencephaly type 1 (smooth MILLER LIGHT (LIST) beer bottle)
-microcephaly, micrognathia, low set ears
-LIS1 gene-chromosome 17 - problem with microtubule directed migration
X linked lissencephaly - DCX gene-doublecortin in males
(DOUBLE COATING)
-if abnormal genitalia - ARX gene- + BG abnormal - type I lissencephaly
Subcortical band heterotopia - all 6 layers cortex; doublecortin (microtubules)
-DCX gene in females (lyonization- random X inactivation) - neurons with normal gene can migrate into cortex
-or mosaic mutations
Lissencephaly type 2
cobblestone lissencephaly- type 2 -no cortical layers
-hydrocephalus +muscular dystrophy+eye problems (optic n atrophy, retinal hypoplasia, glaucoma, cataracts)
Cobble stone + alpha-Dystroglycanopathies
-AR; POMT1, POMT2, LARGE, FKTN
- muscle-eye-brain disease - eyes less affected+less cortical change vs Walker-Warburg
- Walker-Warburg -most severe lissencephaly inc. brainstem- brain, eye, muscle dystrophy, elevated CK, cataract, corneal opacity
- Fukuyama: AR , FKTN gene, fukutin mutation ; more severe muscular dystrophy— frontal white matter changes - weakness, ocular problems , CNS abnormalities, contractures , seizures, intellectual disability
biopsy: dystrophic; reduced alpha-dystroglycan
homocystinuria
cystathionine synthase deficiency (enzyme so AR)
-CBS gene on chr 21
-elevated blood, urine homocysteine + high methionine
“tall sissy homo high on meth”
-ectopia lentus (down and in vs. Marfan up and fans out), Marfanoid habitus
-intimal thickening, thromboembolism, stroke
-variants: pyridoxine response vs not responsive
Tx: B6, B12, low protein diet, low methionine diet, cystine supplementation (month of June is 6); betaine Tx alternative pathway to convert homocysteine to methionine
colobomas
COACH syndrome
CHARGE syndrome (coloboma, heart defects, atresia choanae, GU, ear abnormalities)
Epidermal nevus syndrome
Patau - trisomy 13
Heterotopia
Normal morphology neurons, wrong location->never migrated, remained in periventricular area
-periventricular nodular/subependymal most common
-FLNA gene-X linked - cytoskeleton stabilization - can’t attach neurons to radial glia scaffold
-affect females-X linked dominant
Urea cycle disorders
Newborn presentation common except arginase deficiency
Ornithine transcarbamylase deficiency
only X-linked disorder
All others AR - carbamoylphosphate synthetase I deficiency
hyperammonemia + encephalopathy + respiratory alkalosis, no AG, normal glucose, no organic acidemia
high glutamine=edema,astrocyte swelling encephalopathy
glutamine accumulation ->astrocyte swelling, brain edema
NO organic acidemia, no anion gap
Tx: no nitrogen, no protein,
-sodium benzoat during acute episodes; mannitol for edema
schizencephaly
pial to ventricle, lined with gray matter cortex
closed lip: cortex in contact
open lip: cortex separated by CSF
vs porencephaly - lined with white matter; from CSF cysts acquired in utero, not development
polymicrogyria
CMV
Zellwegers peroxisome
NF2
Dx: one of
-BL vestibular schwanomas
-2 of:
unilater vestibular schwannoma +/-
1st degree with NF2 +/-
2 of neurofibroma, schwanomma, meningioma, glioma, posterior subcapsular lenticular opacities
-muliple meningiomas + unilateral vestibular schwanomma or glioma/neurofibroma/schwanomma/cataract
schwannomatosis
ependymoma
meningioma
Chr 22 - merlin/schwannomin-AD
DDx -
autism spectrum disorder
underdevelopment limbic system, reduced cerebellar Purkinje cells
Down’s syndrome
frontal lobes small, underdeveloped
-superior temporal gyri small
-Brushfield’s spots - white spots in iris
APP-Chr 21 - amyloid precursor protein (beta-amyloid) - early dementia
Leukemia
Atalantoaxial instability
kleinfelter
XXY - two X chromosome in male
-intellectual disability, gynecomastia, wide arm span
RETT
Cri du chat
RETT: X linked dominant (all oblivious females can pass herRETT boys X linked disorders)
-arrest of head growth->microcephaly
MECP2 - binds methylated DNA
DDx-CDKL5
-earlier seizures - X linked
CRI-DU-CHAT - chr 5 - cat cry, micrognathia; intellectual disability
Fragile X
MCC intellectual disability
-CGG repeats (child with giant gonads) on FMR1 gene (familial mental retardation 1 gene)
-RNA binding protein
-random X inactivation (lyonization) in females->less severe
-long face, protruding ears (Peter II)
Prader Willi
Angelman’s
Chr 15q11p13 microdeletion
Prader Wili - paternally inherited-Maternally derived genes are silenced (imprinted)
failure to thrive as infant, hypotonia
-wide mouth, small feet, hypogonadism
-hyperphagic when older
DDx LAURENCE MOON - obesity + intellectual disability
Angelman’s - Paternally derived UBE3A gene is silenced (imprinted); Maternal allele is deleted or mutated
-microcephaly, epilepsy, ataxia, happy puppet, flailing arms
in utero insults
CMV, Rubella: perventricular calcification
1st tri radiation -> intellectual disability
fetal valproate syndrome+ hydantoin (phenytoin) syndrome - intellectual disability
fetal alcohol-congenital heart disease
Biotinidase deficiency
-enzyme recycles B7 + processes dietary biotin
AR inheritance, BTD gene
alopecia-TIN ROOF Smooth and shiny
-hearing, vision loss, seizures, ataxia
ketoacidosis, hyperammonemia, organic aciduria
partial deficiency-10-30% normal enzyme activity, severe <10%
Tx: free biotin supplement, can prevent disability if early
-once impaired, cannot repair deficits
Gaucher
Oscar the grouch with chocolate bar on head
-glucocerebrosidase deficiency-can test in amniotic fluid
-accumulation glucocerebrosides
-GBA gene mutation Chr I
Type I - most common- HSM, anemia, pulm infiltrates; risk Parkinson’s disease otherwise no early CNS effects
Type 2 - onset before 2, most severe, die early
Type 3 - after 2 yrs, progresses slowly; oculomotor involvement - can Tx with bone marrow transplants
wrinkled tissue paper cells
Tx: enzyme replacement - imiglucerase, taliglucerase lapha, velaglucerase alpha
Pompe
tx: alpha-glucosidase
GM2 gangliosidosis
Tay Sachs - hexosaminidase A deficiency - HEXA gene - ONLY CNS affected
-increased startle response, motor repression, blindness
-cherry red spot, macrocephaly
-die before age 5
Sandhoff’s disease - hexosaminidase A B deficiency - HEXB gene - CNS + other organs affected ->HSM
-rare in Ashkenazi Jews
Canavan’s disease
Megalencephaly
AR
—symmetric white matter disease + U fibers
deficiency aspartoacylase - >accumulate N-acetylaspartic acid (MR spec: peak N acetylaspartic acid)
-Ashkenazi Jews
-ASPA mutation chr 17
-present 2 months of life; no Tx; death in 20s
-Adrenoleukodystrophy: rim of enhancement posterior white matter - differentiate (except Alexander’s - contrast enhancement on MRI)
Krabbe
globoid cell leukodystrophy
galactocerebrosidase deficiency (eyes on top of head), AR
“galacto boobs globoid” cerebro on head, nothing behind eyes = optic atrophy
-demyelination + U fibers spared
-accumulate galactocerebrosides in macrophages->globoid cells
-peripheral neuropathy
Infantile - present 4 months (maple syrup urine=at birth); regression
-hypersensitivity to stimuli->increase hypertonicity->opisthotonus, low grade fevers, optic atrophy
Juvenile - 3-10 yrs
Adult - 30s-50s
-path: PAS+ globoid macrophages - cytoplasm accumulation galactocerebroside
CSF: high protein
Sturge Weber
GNAQ chr 9, sporadic
tram track calcifications -parietal, occipital -from angiomatosis
port wine stain - trigeminal distribution
-encephalotrigeminal angiomatosis - gyral calcifications from angiomatosis - leptomeninges, brain
-CNS involvements more likely is angiomas on face- esp if V1, near eye (no cataracts)
-can get enlargement of eye; hemiATROPHY of brain
-sporadic inheritance; GNAQ gene mutations
Cobb’s syndrome - cutaneomeningospinal angiomatosis - rash over spinal dural angioma
Risk: venous stasis, AVMs, venous thrombosis, capillary venous malformation
GM1 gangliosidosis
lysosymal B galactosidase deficiency, AR GLB1 gene
accumulate GM1 gangliosides - brain+organs
-lipid, neuronal ballooning, atrophy
BE ONE Gangly gargoyle gal with red eyes
Like Hurler with cherry red spot + gargoyle faces
-no mucopolysacchariduria
mucopolysaccaridoses
accumulate glucosaminoglycans - disaccharides-in lysosomes, extracellular matrix
-AR except Hunter
MPS Type 1-Huler -alpha-L-iduronidase deficiency (A Lazy Idaho Hurler)
dermatan+heparin sulfate elevated
-gargoyle, corneal clouding, aiway obstructuion
megalencephaly; normal at birth; develop Sx over 2 yrs
-mild form: Scheie’s syndrome
-hepatosplenomegaly
-electron microscopy - Zebra bodies
Tx: enzyme replacement (doesn’t treat CNS Sx), stem cell transplant
Hunter - iduronate-2-sulfatase deficiency (Idaho hunter with rotten SULFUR potatoes + tuber skin lesions)
-dermatan+heparin sulfate elevated
-like mild Hurler phenotype + ivory colored lesions on back+arms + aggression
-carpal tunnel; megalencephaly
-X linked
Type III-Sanfilippo - heparan sulfate only-intellectual disability, no dermatan sulfate accumulation
MPS Type IV-Morquio’s syndrome -IQ normal; short, skeletal dysplasia, corneal clouding, cardiac valve, SC compression; GLB1 mutation
-high urine glycosaminoglycan-keratan sulfate
VI-Maroteaux Lamy-normal IQ
VII-Sly’s - hydrops fetalis, intellectual disability
IX-Natowicz-deficiency hyaluroinidase, accumulate hyaluronan
Alexander’s disease
GFAP mutation - AD
-infant: megalencephaly, spasticity, seizures
juvenile - childhood - bulbar Sx
adult - bulbar Sx, hyperreflexia, dysautonomia, ataxia, sleep apnea
-tadpole sign-saggital cervical spine
Rosenthal fibers - long corkscrew pink blobs - eosinophilic fibers- myeline loss-
enhancing white matter lesions -frontal lobe+anterior+U fibers involved
No Tx
Pelizaeus-Merzbacher
hypomyelinating leukodystrophy - X linked recessive
-PLP1-proteolipid protein 1 mutation
-present first months of life
-nodding head, pendular nystagmus ataxia, chorea, athetosis, dystonia
-optic atrophy
-some survive to adults
-thinning corpus callosum, SPARES U fibers
-tigroid MRI (tiger spots demyelination)
peripheral myelin spared
TIGER PELT - pelizaeus, PLP1 gene
Porphyria
Usually AD; during attack increased ALA + PBG
acute intermittent porphyria - PBG deaminase -AD - 6 P’s-PBG deaminase deficiency; painful abdomen, port wine urine, polyneuropathy (motor+axonal, proximal>distal; radial N involved), psych Sx, precipitated by drugs (barbituates), EtOH, starvation
-no skin lesions
-high ALA aminolevulinic acid + PBG porphobilinogenduring attack
-normal coproporphyrin
Tx: hemin, glucose-inhibits ALA synthase
variegate prophyria - protoporphyrinogen oxidase deficiency - like AIP but skin findings ; photosensitivity
-high coproporphyrin III
hepatic coproporphyria -coproporphyrinogen oxidase deficiency
-high coproporphyrin
porphyria cutanea tarda - cutaneous Sx, no CNS Sx
Tangier
AR, mutation ATP-binding cassette transporter protein - ABCA1 gene, 9q31
(retro healthy tangerine has low cholesterol, high TGs; no hands or feet b/c peripheral neuropathy; TG tonsils; listening to cassettes)
-symmetric polyneuropathy-loss pain + temp feet, can mimic syringomyelia
-hand weakness, UE+LE weakness
-or multi focal mononeurpathy
-orange tonsils because TG deposited
-LOW HDL, low total cholesterol, high TG
-bone marrow biopsy: fat laden macrophages, premature atherosclerosis
Histo: foamy macrophages
Dx: clinical + lipid panel
Menkes
Kinky hair syndrome, X linked, copper deficiency in liver and brain (7 MENKES MONKEYS trying to steal copper because they’re deficient - monkeys are APES - 7A)
ATP7A intracell copper transporter deficiency; no copper for enzyme cofactor
(vs Wilson’s copper accumulates-ATP7B-copper high in urine)
coarse kinky hair, light colored hair (pili torti) no eyebrows, hyperelastic skin
subdurals, hygromas, kinked intra+extra cranial vessels, full cheeks, bone fractures (may suspect abuse)
histo: cortex, thalamus, subcortex - loss of neurons, granula, Purkinje cells
-low ceruloplasmin + copper
MELAS
mitochondrial encephalopathy, lactic acidosis + strokes
-mtDNA MTTL1 - encodes mtDNA tRNA
-onset 2-10 yrs
-seizures+migraines+vomiting, anorexia
stroke like episodes: altered consciousness, hemiparesis, cortical blindness
MRI - strokes not corresponding to vascular territory esp. posterior ; cause seizures
lactate: high in blood + CSF
biopsy: rapped red fibers
Tx: CoQ10, L carnitine, L arginine (acutely for stroke IV)
Abetalipoproteinemia
A BETA 12 MIMIC MTTP ; no vitE bc no fat
Bassen Kornweig - AR - MTTP microsomal triglyceride transfer protein
-transports TG, cholesterol ester, PL from surfaces - no fat absorption
-demyelination of posterior columns b/c vit E defect b/c can’t absorb DEAK vitamins
-vomiting, loose stools, cerebellar ataxia
-lose proprioception hands + feet
-Labs: acanthocytosis, no LDL, no apo B, low vit E, anemia
Tx: restrict TGs, supplements DEAK
