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Neurogenetic Disorders (PHAKOMATOSES (Tuberous Sclerosis Complex…

- - - - Absent Corpus Callosum
        No axons or parent cell bodies, absent probst bundles
      - Partial Absence of the Corpus Callosum
        Axons form but do not cross the midline, leaving large, aberrant fiber bundles called PROBST BUNDLES along the medial hemispheric sides
      - Corpus Callosum
        Present
    - - Increases by 2-3% in patients with developmental issues
  - - - Microcephaly vera/Seckel Syndrome
        
        On a continuum
        Microcephaly at birth
        Absent visceral malformations Imaging: small brain, can have some malformations with certain genes (WDR62)
        Low to normal severe cognitive impairment
        Short stature (significant in Seckel) Secondary craniosynostosis
        Facial features: "bird face"
        Multiple loci, most are AR
        
        IUGR, small size
        Microcephaly, pachygyria
        ID
        Large eyes, narrow jaw, beaked nose, sloping forehead
        Skeletal abnormalities
        Pancytopenia
        AR: ATR, RBB8, CEP152, NIN, DNA2, CEP63, CENPJ, TRAIP, NSMCE2
    - - Lissencephaly
        
        Absent gyri Smooth brain
        
        Cannot diagnose until 20 weeks
        
        Seen in:
        Miller Dieker 17p13.3del
        LIS1, TUBA1A, NDE1
        RELN (Norman-Roberts)
        ARX (XL)
        XL DCX
        (doublecortin; leads to lissencephaly in males and double cortex in females)
      - Heterotopia
        
        Areas of neurons which have not migrated to normal location
        
        Double Cortex
        
        Nodular Heterotopia
        
        Periventricular Nodular:
        FLN1 (XL)
        ERMARD (AD)
        ARFEF2 (AR)
    - - Pachygyria
        
        Larger Gyri
        
        Baraitser Winter Syndrome
      - Polymicrogyria
        
        Large number of small gyri
      - Schizencephaly
        
        EMX2
        SIX3
        SHH
  - - - mildest form: bony inlet of the nose formed by the maxillary and nasal bones
    - - Ocular hypotelorism and single maxillary incisor
      - Cyclopia with proboscis
    - - Separated ventricles
        Incomplete frontal cortical separation
        Milder variant: 'middle interhemispheric variant' (MIHV) with incomplete separation of the posterior, frontal, and parietal lobes and hypoplastic corpus callosum
    - - Partial cortical separation with rudimentary cerebral hemispheres and a single ventricles
        Most common in those who survive
    - - Most severe
        Single ventricle
        No interhemispheric fissue
        Absent olfactory bulbs and nerves
        (no sense of smell)
        Absent corpus callosum
    - - Careful physical examination, history for syndromic forms, imaging
        Karyotpe, CMA
        HPE gene panel, deletions
        Parental testing as appropriate
        Genetic counseling depending on results: without clear etiology --> recurrence risk generally low but may take into account germline mosaicism
- - - - AD
        1:4000
        CAL spots
        neurofibromas
        optic glioma
        skeletal dysplasia
        learning disability
        Tumor Suppressor Gene (NF) codes for neurofibromin on chromosome 17q11.2
        Gene inactivation in Schwann cells
        50% de novo
        5-10% microdeletions, see more neurofibromas, LD, cardiovascular malformations, dysmorphisms
        
        Learning Disability:
        Verbal and non-verbal
        Lower IQ Scores
        ADHD
        Large deletions associated with severe LD
        On MRI, you will see enhanced T2 signals in the basal ganglia, cerebellum, internal capsule. Still determining if this has a relationship with learning disabilities
      - Diagnostic criteria:
        At least 6 CAL spots (5mm prepuberty; 15mm post puberty)
        skin-fold freckles
        2+ neurofibromas/1 plexiform neurofibroma
        2+ iris Lisch nodules
        Optic glimoa
        Characteristic Skeletal dysplasia (tibia and orbit)
        Affected 1 degree relative
        
        Lisch Nodules in the Iris; melanocytic hamartomas; highly specific to NF1
        
        CAL Spots
        
        Armpit Freckles
        
        Neurofibroma
        
        Optic Glioma
        
        Tibial Dysplasia
        
        Manifestations of NF1:
        Plexiform neurofibroma
        Learning Problems
        Epilepsy
        Hydrocephalus
        Malignancy
        CNS Tumor
        Tibial Dysplasia
        GI Neurofibroma
        Renal Artery Stenosis Scolisis
    - - AD
        1:40000
        vestibular schwannoma
        meningioma
        cataract
        merlin/schwannomin on chromosome 22q12.2
      - Diagnostic Criteria:
        Bilateral vestibular schwannomas
        First degree relative with NF2 and Unilateral vestibular schwannoma
        First degree relative with NF2 and any two of: meningioma, schwannoma, glioma, neurofibroma, subcapsular lenticular opacities or cortical wedge cataract
        Unilateral vestibular schwannoma and any two of meningioma, schwannoma, glioma, neurofibroma, subcapsular lenticular opacities or cortical wedge cataract
        Multiple meningiomas and unilateral vestibular schwannoma
        Multiple meningiomas and any two of glioma, schwannoma, neurofibroma, subcapsular lenticular opacities or cortical wedge cataract
  - - - Skin Signs in TSC (Epiloia)
        
        Angiofibromas (adenoma sebaceum)
        
        Ashleaf spots
        
        CAL Spots
        
        Periungual and Subangual fibromas
        
        Shagreen Patch
      - Retinal Hamartoma
      - Cortical Tuber - tumors within the cortex itself 90%
      - Subependymal Nodules
        80%
      - Subependymal Giant Cell AStrocytoma ~10%
        
        With this finding, you'll see hydrocephalus, seizures, focal neurological deficits
      - Renal Angiomyolipoma
  - - - CCND1 (cyclin D1 gene) may be a modifier
    - - 80% familial
  - - - Abnormal sensitivity to radiation
        Other tumors: cardiac fibromas, ovarian fibromas
        Somatic mutations in PTCH2 gene in BCC and medulloblastoma
        Treatment: surgical treatment, vismodegib (SHH inhibitor) for severe BCC
- - - - Many different forms
        Classified by age of onset, location (focal, segmental, multifocal, hemidystonia, generalized), temporal pattern, and other features: isolated, combined (another movement disorder such as myoclonus, Parkinsonism), complex (other neuro features)
        Some are DOPA responsive
    - - Movement disorder featuring dystonia
        choreoathetosis
        rigidity
        Opthalmologic signs
        Retinitis pigmentosa
        Optic atrophy
        Progressive
        Due to iron accumulation in the basal ganglia
        AR
        PANK2 mutations
    - - Many different forms
        Gait and finger/hand movement disorders, dysarthria, nystagmus
        Distinguish from
        non-genetic causes of ataxia
        
        Autosomal Recessive
        
        Ataxia Telangiecstasia
        
        Ataxia
        Telangiecstasia
        Immune deficiency
        Cancer
        Increased AFP
        Abnormalities on 7 and 14
        ATM mutations
        
        Friedrich Ataxia
        
        Ataxia, impaired position and vibration sensation
        Loss of deep tendon reflexes; pes cavus; extensor plantars
        Hypertrophic cardiomyopathy; diabetes mellitus
        GAA repeat 7-22 = normal
        tens to hundreds = pathological point mutations also possible
        Impaired mitochondrial Fe metabolism
        
        Autosomal Dominant
        
        Spinocerebellar Ataxia
        
        SCA 1-42, plus some more complex forms
        DRPLA mimics HD
        SCA1,2,3,6,7 and DRPLA: CAG expansions
        SCA8: CTG expansion
        Differ in age of onset and associated features
        SCA3 most common (Machado Joseph) then, SCA1, 2, 6, 7
        Progressive
        Adult-onset
    - - OVERVIEW
        Variable age of onset, 30's-40's, mean = 45y
        Clinical features
        psychiatric: depression, mood wings, psychosis
        cognitive: dementia
        motor: chorea, bradykinesia dysarthria, dysphagia
        Paternal anticipation - earlier onset with rigidity when inherited from father
        pathology: caudate, putamen, and cerebral cortex atrophy
        
        GENETICS
        CAG triplet repeat (polyglutamine) repeat expansion general population 10-26 repeats intermediate 27-35 repeats, risk for instability HD 36-121 repeats (arise from intermediate, more often in sperm) reduced penetrance 36-39 repeats Correlation with age of onset and number of repeats Modifiers Promotor variant on normal allele leads to earlier onset Promoter variant on abnormal allele leads to later onset
        
        Huntington Disease-like 1 and 2
        HDL1L:
        AD
        Early onset
        Slowly progressive
        Overlaps with HD
        Prion disease
        specific mutation in PrP gene
        (3 extra octapeptide repeats)
        
        HDL12:
        AD
        prevalent among Africans
        Clinically indistinguishable from HD
        Present in midlife
        CTG/CAG repeat in junctophilin3
        (JPH3 gene)
    - - 2nd most common neurodegenerative disease
        1% of adults over age 50
        Tremor, muscle rigidity, slowed movements (bradykinesia), dementia in ~25%
        Loss of dopaminergic neurons
        Most cases sporadic: environmental/genetic components
        
        Rare AD: SCNA, LRRK2, VPS35
        Rare AR: PARK2, PINK1, PARK7, DJ1, ATP13A2, FBX07, SLC6A3
        Susceptibility genes in expanded triplet repeats causing SCA (ATXN2, ATXN3, ATXN80X)
        Rare XL
        Mitochondrial