neurogenetics_acmg
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Phakomatosis- definition and conditions | Definition: disorders of central nervous system that additionally result in lesions on the skin and the eye
Conditions: Neurofibromatosis, Tuberous sclerosis, von Hipple Lindau
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3 types of Neurofibromatoses | 1.NF1
2.NF2
3.Schwannomatosis
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Neurofibromatosis type 1 (NF1) inheritance frequency features gene/protein function | AD (complete)
1/3000 (most common NF)
neurofibromas, cafe-au-lai macules, learning disabilities, skeletal dysplasia, gliomias, malignant peripheral nerve sheath tumors
NF1 (chr17)/neurofibromin: GTPase activator (tumor suppressor- Ras signalling)
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Neurofibromatosis type 2 (NF2) inheritance frequency features gene/protein function | AD (complete)
1:25,000
vestibular schwannomas; other schawannomas; meningiomas; ependymomas; cataracts
NF2 (chr22)/merlin/schwannomin: cytoskeletal protein
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Schwannomatosis inheritance frequency features gene/protein function | AD (incomplete)
unknown
schwannomas
INI1/SMARCB1/ chromatin remodelling protein
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NF1 diagnostic criteria | 1.at least 6 cafe-au-lait macules
2.skin-fold freckles
3. 2 or more NFs/1 plexiform neurofibroma
4. 2 or more iris Lisch nodules
5. optic glioma
6. skeletal dysplasia (tibia , orbit)
7. affected 1st deg relative
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Legius syndrome: clinical manifestation gene | multiple cafe-au-lait
SPRED1 gene
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NF2 diagnostic criteria | 1.Bilateral vestibular schwanommas, or
2.1st deg relative w/ NF2 and (2 of the following)
3.meningioma
4.ependymoma
5.schwannoma
6.juvenile cataract/lens opacity
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NF2 treatment | surgery
clinical trials with bevacizumab
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Tuberous sclerosis diagnostic criteria (major) | Major: 1.angiofibromas 2.ungual fibromas 3.hypomelanotic macules 4.shagreen patch 5.retinal hamartomas 6. astrocytoma 7.supependymal nodules 8.cortical dysplasias 9.cardiac rhabdomyoma 10.renal angiomyolipoma 11.lymphangioleiomyomatosis
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Tuberous sclerosis complex inheritance frequency genes/protein function | AD (complete)
1/6,000
TSC1 (chr 9q34)/hamartin; TSC2 (chr16p13)/tuberin: tumor suppressor-mTOR inhibition
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Tuberous sclerosis surveillance treatment | surveillance: development, seizures, SEGA, renal, pulmonary, eye
treatment: everolimus for progressive SEGA or AML
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Von Hippel Lindau clinical features | 1.Hemangioblastoma (cerebellum, retinal, spinal cord)
2.Pheochromocytoma
3.Renal cell carcinoma
4.Endolymphatic sac tumor
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Von Hippel Lindau surveillance | 1.Opthalmology: annually till 10 yrs, then 6mo
2.Hearing: 2-3yrs to 10, 1-2yrs
3.brain:MRI w/gadolinium 1-2 yrs
4.kidney: abdominal imaging 1-2yrs 1
5.Pheochromocytoma: annual test catecholemines and metanephrines in 24 hr urine or blood
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Von Hippel Lindau frequency inheritance gene/protein function treatment | 1/36,000
AD (20% de novo)
VHL/tumor suppressor-vascular response to hypoxia
some clinical trials (angiogenesis inhibitors
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Channelopathies: channel types | 1.Nicotinic AchR
2.K channel
3.Na channel
4.GABA(A) receptor
5.Cl channel
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Bradykinesia | slow movements
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Dystonia | sustained muscle contraction resulting in abnormal posture
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Chorea | sudden involuntary movement
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Myoclonus | muscle jerking
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Tremor | rhythmic oscillatory movement
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Tic | sudden stereotyped motor movement or vocalization
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Parkinsons 1.clinical 2.inheritance/genes | 1.tremor, rigidity, bradykinesia
2.sporadic (most cases)/glucocerebrosidase
-AD (rare)/ alpha-synuclein, LRRK2
-AR (rare)/ parkin, PINK1, DJ1,ATP13A2, PLA2G6, FBX07
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Fragile X tremor syndrome (FXTAS) 1.clinical features 2.inheritance 2.mechanism | 1.ataxia,intention tremor,short term memory loss, dementia,parkinson symptoms, >50 yrs
2.X-linked (premutation of repeat expansion)
3.FMR1 gene, CGG repeat expansion in 5'UTR results in sequestration of rCGG binding protein
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Dystonia genes/inheritance | could be AD/AR/XL
DYT1 (Torsin A on chr9q34): AD, GAG deletion most common, focal to generalized dystonia
DYT5 (GTP cyclohyrolase l/tyrosine hydroxylase), AD inheritance, DOPA-responsive
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Pantothene Kinase Associated Neurodegeneration 1.clinical 2.genetics | 1.movement disorder (dystonia, choreoathetosis, rigidity); eye (RP, iron accum in basal ganglia)
2.AR, PANK2 mutation (kinase)
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Huntington's disease 1.clinical features 2.genetics | 1.depression, mood swings, dementia, motor (chorea, bradykinesia); early onset (paternal inheritance), peak onset 3rd/4th decades; caudate atrophy
2.huntingtin (chr4p16.3); CAG expansion (polyQ repeat)
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Triplet Repeat disorders 1.Fragile X 2.Friedreich ataxia 3.SCA 4.Huntington disease 5.DRP atrophy 6.Spinal&bulbar atrophy 7.Machado-Joseph disease 8.myotonic dystrophy | 1.CGG (5'UTR)
2.GAA (intron)
3.CAG (coding polyQ)
4.CAG (coding polyQ)
5.CAG (coding polyQ)
6.CAG (coding polyQ)
7.CAG (coding polyQ)
8.CTG (3'UTR)
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Hereditary Ataxias (Name 3) | 1.Spinocerebellar ataxias
2.Friedreich ataxia
3.Ataxia telangiectasia
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Friedreich ataxia 1.clinical 2.genetics | 1.ataxia,loss of DTR's; pes cavus; extensor plantars; HCM; DM
2.AR; GAA repeat (intronic)
5-33 nl; 34-65 premut; 44-66 preclin; 66-1,700 mut
SNVs may occur
results in impaired mitochondrial Fe metabolism
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Ataxia telangiectasia 1.clinical 2.genetics | 1.ataxia, telangiectasia (small, widened blood vessels on the skin.), immune deficiency
2.abnormalities on chr 7 & 14 (Ig chains and T cell receptor
ATM mutations
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Alzheimer Disease 1.inheritance 2.genes | 1.AD
2.APP (amyloid beta A4); PSEN1 (presenilin-1); PSEN2 (presenilin-2); APOE e4 allele (susceptibility locus)
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Prion-Associated Dementia 1.genetics/inheritance 2.Spongiform encephalopathies diseases (3) | 1.PRNP mutations (AD) or infectious
2.Creuzfeld-Jacob disease
Gerstamann-Straussler-Scheinker disease
Fatal familial insomnia
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Cerebrovascular Disorders 1.AD form 2.AR form 3.features | 1.CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and leukoencephalopathy (NOTCH3 gene)
2.CARASIL (HTRA1 gene)
3.small artery occlusions leading to ischemic episodes and strokes
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Hereditary Spastic Paraplegia 1.clinical 2.genetics | 1.progressive weakness and spasticity in lower extremities (bladder disturbance, LE sensory changes, seizures, dementia, movement disorder)
2.can be AD, AR, and X-linked
most common AD due to mutation in Spastin gene
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Anterior Horn Cell 1.clinical 2.genetics | 1.weakness, absent reflexes, fasciculations; neuropathic EMG and muscle biopsy; normal level of alertness
2.can be AD or AR
(SOD gene AD; Alsin, Spartin, optineurin are AR)
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Spinal Muscular Atrophy (SMA)genetics 1.locus 2.gene/protein 3.protein function 4.mutation spectrum | 1.5q11.2-q13.3 (inverted, duplicated segment)
2.SMN/survival motor neuron
SMN1&SMN2 differ in exon7&8 bases
3.protein interacts with RNA-binding protien
4.95-98% hom SMN1 del/trunc; 2-5% cmpd het w/SNV
*increased dosage of SMN2=milder
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Peripheral Neuropathy 1.clinical 2.hereditary conditions | 1.absent deep tendon reflexes, weakness, muscle atrophy; inflammatory demyelinating
2.Charcot-Marie-Tooth (motor and sensory)
Familial dysautonomia (sensory)
Friedreich ataxia
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Familial Dysautonomia 1.Clinical 2genetics | 1.feeding difficulty; episodic vomiting; autonomic neuropathy; insensitivity to pain; absent tearing; absent fungiform papillae; increased sweating
2.IKBKAP (splicing mut in AJs)
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Metabolic Neuropathy Examples | Diabetes
Uremia
Porphyria
Pernicious anemia
Abetalipoproteinemia
Refsum disease
Tangier disease (alpha lipoprotein)
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Hereditary Sensory and Motor Neuropathy 1.clinical 2.genetics | 1.distal weakness, pes cavus, absent DTRs
2.AD,XLR,AR
CMT1: PMP2 dup and SNVs (flanked by 24 kb repeat w/ unequal X-over)
HNPP: PMP22 del/trun
Other: PO EGR2, cxn 32 (XL)
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Myotonic Dystrophy 1.clinical 2.genetics | 1.myotonia, weakness, hairloss, DM, cataract, ECG changes
2.DMPK gene CTG repeat expansion (5-35 nl; 35-50 premut; >50 mut; >2,000 severe neonatal)
DM2: CCTG expansion in ZNF9
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Muscular Dystrophy 1.general features 2.conditions | 1.progressive; high muscle enzymes; loss of muscle cells by biopsy
2.DMD/BMD; Facio-scapulo-humeral dystrophy; congenital muscular dystrophy
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Duchenne/Becker dystrophy 1.clinical 2.genetics | 1.High CPK, prominent calves, (treatment: steriods)
2.XR, dystrophin mutations (DMD gene)
DMD=loss of protein
BMD=abnormal protein
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Facioscapulohumeral Dystrophy 1.clinical 2.genetics | 1.weakness of facial and upper shoulder girdle muscles; retinal vasculopathy 40-60%, SNHL 60%
2.DUX4 gene (abnormal expression)
deletion in D4Z4 3.3 kb repeat (11-100 nl; 1-10 abnormal)
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Metabolic Myopathy conditions | 1.periodic paralysis (SCN4A):hypokalemic or hyperkalemic
2.Thyroid disorders
3.Steroid pathway
4.Glycogen storage disorders
5.Mitochondrial
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