Neurologic disorders Flashcards
X-LINKED ADRENOLEUKODYSTROPHY
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Responsible gene:ABCD1
Protein: ATP-binding cassette sub-family D member 1
Cytogenetic locus: Xq28
Inheritance: X-LR
Clinical Features and Diagnostic Criteria:
a. Childhood cerebral: ADHD->total disability within 2 yrs
b. Adrenomyeloneuropathy: late 20’s progressive paraparesis, sphincter disturbance, adrenocortical dysfunction
c. Adrenocortical insufficiency (only); majority by age 7.5 (seen in 20% carrier females
Clinical Tests: Brain MRI, VLCFA (not reliably abnlin carrier females)
Molecular Tests:ABCD1 seq(92%);ABCD1 del/dup (6%)
Disease Mechanism: Peroxisomal disorder, accumulation of saturated VLCFA
Treatment/Prognosis: Corticosteroid replacement, BMT if diagnosed after changes visible on brain MRI but before significant neuropsychproblems develop (Lorenzo’s Oil)
EARLY ONSET FAMILIAL ALZHEIMER DISEASE
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What to do for Finnish population?
Note: late onset (>65 years) gene is APOE
Responsible genes: PSEN1, APP, PSEN2
Proteins: Presenelin-1, Amyloid beta A4, Presenilin-2
Cytogenetic loci: 14q24.3, 21q21, 1q31-q42
Inheritance: AD
Clinical Features and Diagnostic Criteria: Dementia, confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Early onset: <age 60
Clinical Tests: Gross cerebral cortical atrophy. Post mortem neuropath: A beta-amyloid neuriticplaques, intraneuronal neurofibrillary tangles, and amyloid angiopathy
Molecular Tests:Seq.: PSEN1 (20-70%), APP(10-15%), PSEN2 (rare)
Disease Mechanism: ?chromosomal instability and breakage at nonrandom sites? Triple dose of APP may explain Alzheimer’s in Tri 21.
Treatment/Prognosis: Death from general inninition, malnutrition, and pneumonia. Clinical duration 8-10 yrs(range 1-25 yrs)
EOFAD1-6% OF ALL Alzheimer’s, 60% of which is familial, and 13% inherited in an AD manner. (<2% of all Alzheimer’s)
LOFAD: Appears to be an assocwith APOE e4 but not sensitive or specific-supports the dx. APOE e2 may be protective, e3 most common in general population, e4 risk factor
If patient is Finnish: test should be MLPA for a 4555-bp deletion spanning exon 9 of PSEN1 has been found in the Finnish population with founder effect; this mutation is rarely observed in other populations
ANGELMAN SYNDROME
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Responsible gene: UBE3A
Protein: Ubiquitin protein ligase E3A
Cytogenetic locus: 15q11-q13
Inheritance: loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region
Clinical Features and Diagnostic Criteria: severe developmental delay or ID, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability, microcephaly and seizures
Clinical Tests: acquired microcephaly by age two years,
Seizures before age three, abnlEEG: large amp. slow-spike waves
Molecular Tests:4-6 Mb del (65-75%),UBE3A mutation (11%), imprinting defect (2.5%), unbalchromtransloc(<1%), Pat UPD 15 (<1%), del of imprinting center (0.5%)
Disease Mechanism: Disruption of E6AP ultimately causes an abnormality in the ubiquitin protein degradation pathway, but no clear AS-causing target protein yet identified
Treatment/Prognosis: Typical care for medical issues, PT, OT, ST, and individualized education and behavior program.
CADASIL
(Cerebral Autosomal Dominant Arteriopathywith
Subcortical Infarcts and Leukoencephalopathy)
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Responsible gene: NOTCH3
Protein: Neurogenic locus notch homolog protein 3
Cytogenetic locus:19p13.2-p13.1
Inheritance: AD
Clinical Features and Diagnostic Criteria: Stroke-like episodes before age 60, cognitive disturbance, behavioral abnormalities, migraine with aura
Clinical Tests: Skin BxEM: e-dense granules in media of arterioles. Brain MRI: T2 signal abnormalities in the WM of the temporal pole and external capsule, subcortical lacunar lesions (groups of rounded lesions at the junction of GM and WM. WM changes seen as early as age 21 yrs.
Molecular Tests:NOTCH3 sequencing (>90%)
Disease Mechanism: NOTCH genes encode transmembrane receptors involved in cell fate specification during development. The functional consequences of NOTCH3mutations in the abnormal protein are not known.
Treatment/Prognosis: supportive care, angiography and anticoagulants may precipitate CVA, smoking increases risk of stroke. Mean age to walk with asst.: 60yrs, bedridden by 64yrs, med. age of death 68 yrs.
CANAVAN DISEASE
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Responsible gene: ASPA
Protein: Aspartoacylase
Cytogenetic locus: 17pter-p13
Inheritance: AR
Clinical Features and Diagnostic Criteria: Macrocephaly, lack of head control, developmental delays by age 3-5 mos, severe hypotonia, never sit, walk, or speak. Hypotonia evolves to spasticity.
Clinical Tests: High urine N-acetyl aspartic acid (NAA)
Molecular Tests:3 common mutations account for 99% of disease-causing alleles in Ash. Jewish, 50-55% in non-jewish.
Disease Mechanism: Absence of aspartoacylase leads to build up of NAA in the brain leading to demyelination
Treatment/Prognosis: Supportive care: nutrition, hydration, managing infectious disease, protecting airway. Life expectancy to the teens.
FRAGILE X
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Responsible gene: FMR-1
Protein: FMRP (Fragile X Mental Retardation Protein)
Cytogenetic locus: Xq27.3
Inheritance: X-linked triplet repeat
Clinical Features and Diagnostic Criteria: Delayed motor and verbal development, ID (mod-severe in boys, milder in girls), prominent jaw and forehead, high activity, autistic features. Carrier females: anxiety, OCD, depression, 20% have POF. Carrier Males: (>30% of males >50y), progressive intention tremor, ataxia, parkinsonism, and autonomic dysfunction. Two other loci: FraXE: only ID, FraXF: no phenotype
Clinical Tests: None
Molecular Tests:CGG triplet repeat detection. Southern Blot: good for small or large expansions, doesn’t give repeat #. PCR: Better quantification of repeat number, subject to allele dropout with large expansions. NL: 5-44 repeats, Intermediate: 45-58 repeats (gray zone), Pre-mutation: 59-200 repeats, Mutation: >200 repeats
Disease Mechanism: >200 repeats leads to silencing by methylation. POF and ataxia thought to be due to toxic gain of function.
Treatment/Prognosis: No specific treatment.
HUNTINGTON DISEASE
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Responsible gene: HD
Protein: Huntington
Cytogenetic locus: 4p16.3
Inheritance: AD
Clinical Features and Diagnostic Criteria: progressive motor disability involving both involuntary and voluntary movement (chorea, dysarthria, dysphagia progress to bradykinesia, rigidity, and dystonia) , cognitive decline (problems with planning or organization), psychiatric disturbances (personality change, affective psychosis, or schizophrenic psychosis. Mean age of onset 35-44 yrs(juvenile onset <20yrs ~10%).
Clinical Tests: CT or MRI: characteristic atrophy of caudate and putamen. PET scan: decuptake and metab. of glucose in the caudate nucleus (often abnlbefore MRI or CT).
Molecular Tests:Targeted mut. analysis: trinucleotide CAG repeat expansion >36. 27-35: no symptoms but, if male, risk of expansion in children (6-10% risk of expansion with 35 repeats). 36-39: reduced penetrance, may never develop symptoms. >40: fully penetrant. >60 repeats: juvenile onset.
Disease Mechanism: Unknown
Treatment/Prognosis: Txis symptomatic: neurolepetics, benzo’s, psychotropics, Median survival time: 15-18 yrsafter onset, average age of death is 55 yrs. Suicide in 12%.
KRABBE DISEASE
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Responsible gene: GALC
Protein: Galactocerebrocidase
Cytogenetic locus: 14q31
Inheritance: AR
Clinical Features and Diagnostic Criteria: Infantile form: irritability to sensory stimuli, muscle hypertonicity, progressive neurologic deterioration, peripheral neuropathy, white matter disease, elevated CSF protein. Later onset (6 mosto 5thdecade): weakness, vision loss, intellectual regression.
Clinical Tests: CT: nonspecific-diffuse cerebral atrophy of grey and white matter. MRI: demyelination of the brainstem and cerebellum. Dec GALC enzyme activity (0-5% of normal activity). AbnlEEG, low nerve conduction velocity,
Molecular Tests:GALCtargeted mutation analysis: GALC 30-kb deletion (45% of Europeans, 35% of Mexicans); 809G>A mutation (50% of late onset Krabbe). GALCsequencing (virtually 100%)
Disease Mechanism: Missense mutations result in unstable protein that is rapidly degraded
Treatment/Prognosis: Hematopoietic stem cell transplant decreases morbidity and mortality when given to infants before they show symptoms. Supportive care to control irritability and spasticity if diagnosed when symptomatic. Infantile form: average age of death is 13 mosdue to infections or respfailure.
NEUROFIBROMATOSIS TYPE I
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Responsible gene: NF1
Protein: Neurofibromin
Cytogenetic locus: 17q11
Inheritance: AD
Clinical Features and Diagnostic Criteria: 2 or more of: 6x5mm (prepubertal) or 6x15mm (postpubertal) café au lait, 2 or more neurofibromas, one plexiform neurofibroma, axillary or inguinal freckling, optic glioma, 2 or more Lischnodules, sphenoid dysplasia or thickening of long bone cortex, 1stdegree relative with NF-1
Clinical Tests: x-ray, eye exam, brain MRI
Molecular Tests:>500 mutations reported, usually unique to a particular family
Disease Mechanism: Loss of function mutations impair rasGTPasemediated cellular proliferation and tumor suppression
Treatment/Prognosis: The majority live normal lifespan. Surgery for bone malformations or painful or disfiguring tumors; clinical trials and use of MEK inhibitors
PARKINSON DISEASE
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Responsible gene: Multiple, main gene PARK2
Protein: Parkin
Cytogenetic locus: 6q25.2-q27
Inheritance: AD, AR, multifactorial
Clinical Features and Diagnostic Criteria: bradykinesia, rigidity, and tremor, asymmetric limb involvement. Juvenile OnsetAR PARK2mutations, typical features, onset 20-40yrs.
Clinical Tests: Good response to L-Dopa
Molecular Tests:PARK2sequencing
Disease Mechanism: Unclear but thought to be due to loss of function by absent protein or protein inactivation
Treatment/Prognosis: Dopamine therapy, PT, OT, ST. Some patients may benefit from palliodotomyor deep brain stimulation of the subthalamic nucleus.
RETT SYNDROME
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Responsible genes: MECP2
Proteins: MECP2
Cytogenetic loci: Xq28
Inheritance: XLD
Clinical Features and Diagnostic Criteria: ID, developmental regression (especially language and hand use), acquired microcephaly, stereotypical wringing hand movements, hyperventilation, bruxism, paroxysmal laughing, prolonged QT, scoliosis
Clinical Tests: EEG (nonspecific for Rett), ECG
Molecular Tests:MECP2sequencing (>80%), Need to test parents if a novel variant found. MECP2MLPA or quantitative PCR testing for deletion (~16%).
Disease Mechanism: Decreased function of loss-of-function of MECP2. Normally MECP2 binds methylated CpGislands.
Treatment/Prognosis: Seizures are often difficult to manage, SSRI’s for agitation, monitor for scoliosis, periodic ECG to monitor for long QT
Small subset have CDKL5mutations and present atypically with early onset seizures
WILSON DISEASE
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Responsible gene: ATP7B
Protein: Copper-transporting ATPase 2
Cytogenetic locus: 13q14.3-q21.1
Inheritance: AR
Clinical Features and Diagnostic Criteria: Can present age 3-50 yrs. Liver disease: jaundice, self-limited hepatitis-like illness, autoimmune hepatitis, hepatic failure, chronic liver disease. Neurologic presentation: movement disorder, disorganization of personality
Clinical Tests: Kayser-Fleisher rings on corneal exam, low serum Cu and ceruloplasmin, incurinary copper excretion. Liver bx: inccopper storage.
Molecular Tests:ATP7Bsequencing (98%). H1069Q (35-45% Europeans), R779L (57% Asians), H714Q and delC2337 (40% Russians).
Disease Mechanism: Loss of ATP7b function impairs holoceruloplasminbiosynthesis and biliary copper excretion with resultant copper-mediated oxidative damage, activation of cell death pathways, leakage of copper into plasma and eventual tissue copper overload.
Treatment/Prognosis: Chelating agents, liver transplant
