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neurogenetics_acmg
| Term | Definition |
|---|---|
| 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 |
| 3 types of Neurofibromatoses | 1.NF1 2.NF2 3.Schwannomatosis |
| 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) |
| 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 |
| Schwannomatosis inheritance frequency features gene/protein function | AD (incomplete) unknown schwannomas INI1/SMARCB1/ chromatin remodelling protein |
| 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 |
| Legius syndrome: clinical manifestation gene | multiple cafe-au-lait SPRED1 gene |
| 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 |
| NF2 treatment | surgery clinical trials with bevacizumab |
| 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 |
| Tuberous sclerosis complex inheritance frequency genes/protein function | AD (complete) 1/6,000 TSC1 (chr 9q34)/hamartin; TSC2 (chr16p13)/tuberin: tumor suppressor-mTOR inhibition |
| Tuberous sclerosis surveillance treatment | surveillance: development, seizures, SEGA, renal, pulmonary, eye treatment: everolimus for progressive SEGA or AML |
| Von Hippel Lindau clinical features | 1.Hemangioblastoma (cerebellum, retinal, spinal cord) 2.Pheochromocytoma 3.Renal cell carcinoma 4.Endolymphatic sac tumor |
| 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 |
| 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 |
| Channelopathies: channel types | 1.Nicotinic AchR 2.K channel 3.Na channel 4.GABA(A) receptor 5.Cl channel |
| Bradykinesia | slow movements |
| Dystonia | sustained muscle contraction resulting in abnormal posture |
| Chorea | sudden involuntary movement |
| Myoclonus | muscle jerking |
| Tremor | rhythmic oscillatory movement |
| Tic | sudden stereotyped motor movement or vocalization |
| 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 |
| 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 |
| 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 |
| 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) |
| 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) |
| 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) |
| Hereditary Ataxias (Name 3) | 1.Spinocerebellar ataxias 2.Friedreich ataxia 3.Ataxia telangiectasia |
| 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 |
| 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 |
| Alzheimer Disease 1.inheritance 2.genes | 1.AD 2.APP (amyloid beta A4); PSEN1 (presenilin-1); PSEN2 (presenilin-2); APOE e4 allele (susceptibility locus) |
| 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 |
| 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 |
| 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 |
| 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) |
| 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 |
| 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 |
| 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) |
| Metabolic Neuropathy Examples | Diabetes Uremia Porphyria Pernicious anemia Abetalipoproteinemia Refsum disease Tangier disease (alpha lipoprotein) |
| 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) |
| 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 |
| 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 |
| 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 |
| 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) |
| Metabolic Myopathy conditions | 1.periodic paralysis (SCN4A):hypokalemic or hyperkalemic 2.Thyroid disorders 3.Steroid pathway 4.Glycogen storage disorders 5.Mitochondrial |
Created by:
amrs
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