Tegay - Neurogenetics

Holoprosencephaly

Incomplete division of embryonic forebrain (prosencephalon) into lateral hemispheres

• - 1:250 conceptions/1:10,00 live births —> one of the most common embryonic abnormalities, but most are lethal in utero

• - Assoacted with dysmoprphic features related to laterality: cylopia, probisoicus, hypertelorism, SCMI (a tooth thing?)

• “Face preditcs the brain” : mental retardaiton, seixures, pituitary insufficney, FTT

Holoprosencephaly Eitology

- 90% genetic

• Half are Chrsome Abnormalities: OVERWHELMINGLY Trisomy 13 (Patau)

• Half are Monogenic disorders: Mutations in SHH (Non-syndromic) autosomal domaint

HPE and Patau syndrome

HPE occurs with facial clefting, CHD, PKD, Omphalocele

Sever mental retardation

3% Survival at 1 Year

Recurrence risk: 1%

HPE and SMith-Lemli-Opitiz Syndrome

HPE wit hcleft palate, CHD, GU anaolmay, low set eares a

Variable lntellcualt dialbity, grow retardation and life span

Etiology: 7-Dehydrocholestrol Reductase (7-DHCR) Gene Mutation

Recurrence Risk: 25% (Autosomal Recessive)

HPE and Sonic Hedhog (SHH) Pathway gene mutation

HPE is isolated and with variable mental retardation

Etiology: SHH gene mutation

Recurrence risk: 50% for affected Indvidual (Autosomal Dominant)

→minimal recurrence risk if parent unaffected, but variable expressivity so test parents

Lissencephaly

• malformation characterized by the absence or significant reduction of the normal folds and grooves (gyri and sulci) on the surface of the brain

• Can be diffuse(classic) or patchy (cobblestone)

• Evident at >24 weeks

• Invariable will cause some degree of Intellectual Disability

• Associated syndromes: MillerDieker Syndrome, Muscle-Eye-Brain Disease

Miller-Dieker Syndrome

Microdeletion syndrome in 17p13.3

#1 Cause of Lissencephaly

50 genes in region

• Lis1→ Lissencephaly

• YWHAE→ greater intellectual severity

• Other genes→ Dysmorphic features (midline forehead crease, etc.)

Essentially Always De Novo (not inherited):

Prognosis: severe growth and Mental retardaiton, life exptnacy <2 years

Muscle-Eye-Brain Diseases

3 Types from most to least severe

• POMT1 Gene (Walker-Warburg)

• Fukutin Gene (Fujuyama CMD)

• POMGT1 Gene (Finnish MEB disease

All have varying degrees of

• Progressive muscular dystrophy (muscle disease)

• Micorpathalmia (Eye diease)

• Cobblestone Lissencephaly (Brain diease)

Prognosis

Inheritance: All Autosomal Recessive

Hydrocephalus

Fairly common: incidience 1:500

Etiology: Often Non genetic in orgin (Post-viral, intraventicualr hemorrage, mass obstrution) → treatment = normal IQ, low recurrence risk

Genetic Basis: “X-linked Recessive Hydrocephalus”

• L1CAM Gene Mutation (located on X-chromosome): Hydrocephalus+abducted thumbs+ Intellault diablity (depsite treatment)

Hydranencephaly

During devleopment, when brain structures do not get proper vascualrazation, they will not delvope and simply liquify: this iswhat happens (holy shit)

Clinical: prentatl liquication necrosis of coritcal sturcutres (instead of a brain/coritcal strucutres there is just fluid)

Etiology: pirmality vascualr disrution (never a fetal gene error)

Recurrence Risk: Very Low- tends not to be genetic, but RARE cases of Autosomal Recessive families

Joubert Syndrome

“Molar Tooth” sign (pocket in the midline posterior brain)

• CVH, Deep interpeduncular Foss, Elongated

Dysmorphic Facial Features

Neurological Features: Mental retardation, hypotonia, ataxia, nystagmus, seizures,

1:100,000

Etiology: Autosomal Recessive and X Linked Recessive Gene

Dandy Walk Malformation (DWM)

( *** NOTES FOROM SLIDES HAD NO AUDIO***)

Etiology is Heterogenous: multiple genetic syndromes associated with it

A 32yo G1P) Femal with gestational diabetes has a level II fetal ultrasound at 22 weeks gestion which shows ventricular enlargement.

Which is the possible diagnosis?

Hydranencephaly

Hydrocephaly

Holoprosencephaly

Lissencephaly

Any of the above

Any of the above

A 32yo G1P) Femal with gestational diabetes has a level II fetal ultrasound at 22 weeks gestion which shows ventricular enlargement. AND

She reports no medication or drug use asiade from prenatal vitamins, there is no family history of hydrocephalus and she had a normal ‘triple screen’.

Fetal Skull, XRAY, Head CTScan, Brain MRI, AMinocetisis or Chrsome Microarray?

Fetal Brain MRI

A 32yo G1P) Femal with gestational diabetes has a level II fetal ultrasound at 22 weeks gestion which shows ventricular enlargement. AND

She reports no medication or drug use asiade from prenatal vitamins, there is no family history of hydrocephalus and she had a normal ‘triple screen’.

On tkaing a family history the mother has leanring diablties and didn;t graduate high school. When she smiles you notice she has one centeral maxillary incisor.

This suggest her recurrence risk in the futre pregencies is closest to:

0%

1%

25%

up to 50%

100%

Up to 50%: since she has (ID + Incisor) suggest a mild form of HPE, which does not indicate syndromic HPE. So, she probably has the form from SHH pathway mutations ,which are Autosomal Dominant —> thus, 50% recurrence to have another child with HPE

Developmental Disalbites

Structurally normal brain (no Malformation), but does not function as normal

CNS disfunction

• Developmental delays

• Intellectual disability

• Autism

• Stuttering

• Hearing/Visual impairment

• ADD/ADHD

• Cerebral Palsy

• Seizures

Criteria for Intellecual disalbity “Mental Retardation”

• Deficits in Intellectual functions:

• Deficits in Adaptive function

• Onset of Deficits

Autism Spectrum Disorder

• reorganization of multiple disorders under one (

  Criteria

• Deficits in social communication and social interaction

• Restricted, repetitive patterns of behavior, interests or activities

• Onset of symptoms in infancy/early childhood

• symptoms limit and impair everyday functioning

Exclude contirubting condtions for Autism

• lead intoxicaiont

• Hypothyroidism

• Deafness/Hearing loss

• Extreme impoverished environment

• Prenatal/Birther history (toxins, infections, prematurity) + Brain trauma

Autism Incidence

Male: Female Raito of 4:1

Autism Heritability:

• Familial Autism recurrence rate: 5-10% if one child affected, 25% if two children affected

• Heritability Factor (Genetic Cause): 37-90%

Common single Gene Autism-related Disorder

• Fragile X (FMR1 gene, XL): 2%

• Ret Syndrome (MECP2 Gene, XLD): 1%

• PTEN Related (PTEN gene, AD): 1% (15% if macrocephaly)

• Tuberous Sclerosis (TSC1-4 gene, AD): 1% (5-15% if epilepsy)

• Neurofibromatosis Type 1 (NF1 gene, AD): 1%

Fragile X Syndrome

Typical Dysmorphology (features not universal)

• Long Face, prominent ears, macrocephaly, high forehead

FMR1 Gene mutation: CCG Repeats

• Pre carrier 60-200 repeats

• Mutation: >200 repeats

Mental Retardation

Seizures (25-40%)

Behavioral Phenotype

• 80% autistic features, >90% ADHD

Rett Syndrome

Neurodegenerative, Female only disorder (males lethal)

AUTISM!!

MECP2 Mutation

• Normal development 6-18months

• Regression between 1-4yo: Head growth slows

• Stabilization period 2-10yo: Awareness and minimal verbal communication

• Late motor deterioration after 10yo: Early death from infection

Almost always De Novo mutation (Males lethal and Females don’t make it maturity to pass on), with rare gonadal mosaicism in some females

Autism with Macrocephaly

Autosomal Dominant PTEN Gene mutations (PTEN also related to the hereditary cancer syndrome Cowden, but autism and cancer mutations may differ)

17% of macrocephalic autistic children have PTEN mutations

ANYONE WITH AN ABNROMALY LARGE HEAD CIRCUMFRANCE SHOWED BE TESTED FOR PTEN MUTATIONS

Tuberous Sclerosis

A common clinical Triad

• Adenoma Sebaceum (50-80%)

• Epilepsy (75%)

• Mental Retardation: (50%)

  AUTISM!!!!?

Autosomal Dominant TS gene mutation (4 Genes)

• De Novo 75% of cases/Inherited in 25% of cases

Major Diagnostic Features (need >1)

• Skin: Facial Angiofibroma’s, perunigal fibroma

• Eye: Retinal Hamartomas

• Brain Subependymal nodule, coritucal tubers, SEGA’s (?)

• Heart: Congenital heart ****RHABDOMYOMA****

• Lung: Lymphangiomyomatosis

• Kidney: Renal angiomyolipoma

20-50% have Autisic Features

Neurofibromatosis Type 1 (NF1)

Autosomal Dominant Neurofibromin Gene Mutation: 50% Devo / 50% Inherited

Major Diagnostic Features (Need >1)

• Cafe-Au-Lait Skin spots

• Neurofibromas

• Axillary/Inguinal Freckling

• Optic Glioma

• Lisch Nodules (Iris hamartomas)

Major Morbities

• 50% have learning Disability (AUTISM, ADHD but normal IQ)

• Increased rare cancer rate (Pheochromocytoma, juvenile myelomonocytic leukemia)

• Resistant Hypertension in >50%

• Neurofibroma mass

Mowat-Wilson Syndrome

ZEV2 Loss of function mutation or deletion: Always De Novo (NEVER INHERITED)

Clinical features:

• Facial dymorphism

• Birth defects

• Mod-Sever intellectual disability: Minimal speech, happy demeanor, frequent laughter (OFTEN CONFUSED WITH ANGELMAN SYNDROME “Happy puppet”

Rubenstien-Taybi Syndrome

• Autosomal domain CREBBP LOF mutation or deletion: ALWAYS DE NOVO (NEVER INHERITED)

• Clinical Features

  • Facial Dysmorphism

  • Birth Defects

  • Mod Intellectual disability: 40% autism; Wide variability of effect

Cornelia de Lange syndrome

• Autosomal domain NIPBL, RAD21, SMC3, BRD4 LOF mutation

• X-linked HDAc8 or SMC1a hemizygous

• Mostly De Novo, 1% inherited

• Clinical features

  • Facial Dimorphism

  • Birth Defects

  • Mod-Mild Intellectual Disability: IQ range 30-102

Developmental Epileptic Encephalopathies

Etiology:

• 50% genetic cause Whole Exome/Genome sequencing recommended (hug gene heterogeneity, >900 genes associated)

• Most common gene SCN1a Mutation associated Dravet Syndrome

• Prevalence 1:600-1,000

Clinical Features

• Seizures, slowed development and regression, onset infancy or childhood

• overlapp with many differnet epileptic syndromic presenations

Chromosomal Autism Associated Disorder

• Down Syndrome (Trisomy 21)

• Klinefelter Syndrome (47, XXY)

• Non-Eponymous Micrcoically Visible Chrsomal Deltaitons, Duplicaitons and Rearragnemnts in Indidual Cases

  All of these will be apart of workup for suspected Autism Disaongis

Microdeltion Autism Assoacted Syndromes

• Digeorge Syndrome (22q11.2 Deletion)

• Williams syndrome (7q11.23 Deletion):cocktail party

• Prader-Wili Syndrome (Paternal 15q11-13 deletion/imprinting): Hungry

• Angelman Syndrome (Maternal 15q11-13 deletion/imprinting): happy puppet

• Smith-Magenis syndrome (17q11.2 Microdeletion): stuff in ass+ Self injusry disoer

Genetic Evaluation of Autism

Look for Underlying Etiology

• Physical+ History, Fam Hx, Morphologic Skin Exam (Wood Lamp),

• Audiology, Lead and thyroid testing in all, MRI/EEG as indicated

Based on what you find: Syndrome Specific Genetic Testing if Indicated

• PTEN gene testing if macrocephalic, TS or NF1 testing if neurocutaneous signs

Empric Genetic Testing if Cause is Unclear

• chrsome microarry analysis nd karotype for all

• Fraifle X DNA testing for all males and females

• Rett syndrome MECP2 gene testing for all females

Newer ASD Gene Testing

• Autism/ID gene panels

• Whole Exome/Whole Genome Sequencing (WES/WGS)

Inherited Neurodegenerative Diseases

• Pathological conditions primarily rooted in the genetically determined premature loss of structure or function of previously normal neurons and neuronal structures

• including

  • Alzhimers’s Disease

  • Parkinson’s Disease

  • Amyotrophic Lateral Sclerosis

  • Huntington’s Disease

Most Common Neurodegenerative Diease

Alzheimer’s Disease: also most common irreversible cause of dementia

Alzheimer’s Diease: Risk

• Age is the greatest for all: lifetime 10% (slightly more for men) - 65y=1%; 85y=20%; 95y=45%

• Early Onset: 65yo

• Familial AD

  • 10-25% of patients have a paotive family history

  • 60% of Early onset cases have a postive family history

  • Life time risk for 1st degree relatives of affect indiduals: 20-25%

Alzheimer’s Disease: Clinical features

• progressive impairment of

  • memory

  • judgment

  • decision-making

  • orientation to physical surroundings and language

• Pathological Hallmarks: need to distinguish from other neurodegenerative disease

  • neuronal loss (cortex and hippocampus)

  • Extracellular amyloid plaques

  • Intracellular neurofibrillary tangles

• NO PROVEN TREATMENTS: But MIND Diet can reduce risk 30-50% over 10 years

Alzheimer’s Disease Genes

• Early onset Alzheimer’s Disease Genes (at or before 65yo)

  • APP, PS1, PS2

  • production or splicing of amyloid protein

  • All HIGHLY PENETRANT

  • Autosomal Domiant

• Late Onset

  • ApoE4 : Shuttle LDL though the bloodstream

  • 3 Major isoforms (alleles): E2, E3, E4

  • Most people E3 Homo.

  • E2 alleles might lower risk: those who carry will be below general population risk

  • E4 assonated with higher risk late-onset AD (each E4 allele shift age of onset 5-10 years earlier)

    • 1 E4, 40%, 2 E4 70-90%

APOE4 Allele Genotyping

• Not sensitivity or predictive for late onset AD

  • Low Negative predictive value for AD: >50% of AD patient has no E4 allele

  • Incomplete PPV for AD: most people with 1 E4 allele do not develop AD

  • Unclear clinical benfit to knowing ApoE status

Parkinson’s Diesease

• Most common neurodegenerative movement disorder: 2nd most common N.D. disorder overall

• lifetime risk: 1.5% (3-7% if 1 degree relative w/ PD)

• Average age of onset 40-70

  • early onset: 20-40 years

• Majority of cases are “sporadic”: 90-95% hve no family history

Parkinson’s Disease: Clinical Features

• Major features:

  • Resting Tremor

  • Rigidity

  • Gait Ataxia

  • Bradykinesia

• Other associated features: Dementia, Depression, Sleep disturbances, ( XXX)

• PD diagnosis is made clinically

Parkinson Disease: Pathology

• Dopaminergic neuron loss

• Lewey bodies: but not universally present in PD, not unique to PD

Overlap of Parkinson and Other Diease

• 1st Degree

  • Lewy Body Dementia

  • Alzheimer’s Disease

  • Wilsons disease

  • Dopa-responsive dystonia

• 2nd Degree

  • Drug induced

  • Toxic exposures

  • Dementia Pugilistica

Parkinson’s Disease Genes

• Mutiple and Heterogenous: many different genes

  • But Cluster along certain pathways: removal of proteins form the brain, mitochondrial removal, oxidative stress (important for dopamine production)

• Usually Autosomal Dominant

• One x-linked

  • PARKIN: Juvenile Onset - Very slow progression, no Lewy bodies (Recessive)

  • SNCA: Early onset - typical progression, dementia, Lewey Bodies (Dominant)

  • LRRK2: Adult onset - typical progression, no dementia, No Lewey bodies (Dominant)

Huntington Diease

• Trinucleotide CAG repeat disorder: Expansion in HTT gene

  • Normal: </= 26

  • Intermediate: 27-35

  • Reduced penetrance: 36-39 (rarely asymptomatic, expands)

  • Fully penetrant: >40

• Higher CAG repeat # = higher severity and onset

• COMPLETE PENTRANCE

• Incidence 1:10,000

• Onset 35-44 yo

• NO DRUGS FOR TREATMENT

Huntington’s Disease Clinical Features

• Initial (10 years preceding): mild motor, behavioral, psychiatric

• Chorea

• Dementia

• Rigidity

• Seizures

Spinocerebellar Ataxias

• Dozens of types

  • All are Trinucleotide Repeat Disorders

  • All are Autosomal Dominant (+FamHx)

• Present with various degrees of difficulty with:

  • Gait

  • Balance

  • Speech

  • Fine motor skills

Friedreich’s Ataxia

• Early onset: first two decades of life

• Autosomal recessive trinucleotide repeats expansion (GAA): Frataxin protein

  • Need to have BOTH parents with expansions

• Limb ataxia, cerebral dysarthria, lack of deep-tendon reflexes

Amyotrophic Lateral Sclerosis (ALS)

• Most common neurodegenerative motor neuron disorder

• average onset: 56yo (40-60 years of age)

• Motor Neuron degeneration:

• Survival: 95% live 3-5 years after diagnosis

• 90% simplex, 10% Familial

  • C9ORF72 hexanucleotide repeats (AD)

  • SOC1 (AD)

Amyotrophic Lateral Sclerosis (ALS) Genetics

• 90% are simplex (No family history)

• 10% family ALS: most common single genes

  • C9ORF72 AD hexanucleotides expansion in 45%

  • SOD1 AD or AR mutation 15-20%

Myopathy

• any disorder of muscle, genetic or nongenetic

• Weakness

• can be congenital or late onset

• usually progressive (gets worse)

• Suggestive test

  • Serum CPK / Aldolase (released in muscle breakdown)

  • Electromyography:

  • Muscle biopsy (immunohistochemsitry)

Neuropathy

• Disorder of peripheral nerves

• presents with weakness, pain, abnormal sensation

• congenital or late onset

  • motor nerves

  • sensory nerves

  • autonomic nerves

• suggestive tests

  • Electromyography

  • Sudoscan (low voltage sweat gland activation)

  • Nerve Biopsy

Congenital Hypotonia

• Low tone in babies: “Floppy” Newborn

• Tone= the involuntary positioning in the body

• strength = involuntary muscle activity

Prader-Willi Syndrome

• Profound Hypotonia: MAGEL2 gene associated

• the 5 H’s

  • hypotonia

  • Hyperphagia

  • Hypomania

  • Hypopigmentation

  • Hypogonadism

• Chromosome 15q11-13 microdeletion or paternal methylation defect

Congenital Myopathies

Myotonic Dystrophy 1

• Autosomal dominant DMPK

  • Trinucleotide repeat disorder: increased repat = increased severity/earlier onset

• Mild (50-150 repeats) adult onset mild myotonia

• Classical (150-1000 Repeats) adult onset

• Congenital (+1000 Repeats) congenital hypotonia

Muscular Dystrophies

• Highly heterogenous

• But some are simple and monogenic like Duchenne/Becker Muscular dystrophy

Duchenne/Becker Muscular Dystrophies

• Incidence

  • DMD: 1:3,500 male births (more severe)

  • BMD: 1:18,000 male births

• X-linked Recessive Dystrophin Gene Mutations

  • DMD typically larger deletions/ rearrangement/frameshift

  • BMD typically missense/smaller deletions

• 1/3 Sporadic

• 2/3 Mother is a carrier

Duchenne Muscular Dystrophy - Clinical presentation

• more severe form of

• Progressive muscle weakness 3-5 years, shoulder and hip muscles affected

  • Gower Sign: use arms to stand up

• Progressive: wheelchair, then death form cardiac respiratory failure

• Dystrophin protein ABSENT in muscle biopsy

Becker Muscular Dystrophy - Clinical Presentation

• Milder form

• Later onset muscle weakness, cardiomyopathy, longer life span (40s yo)

• Dystrophin protien present in muscle biopsy

Facioscapulohumeral Muscular Dystrophy (FSHD)

• Slowly progressive skeletal muscle weakness and atrophy

  • Face musclar, shoulders, upper arms, hips

• Sensory Nural Heraing loss (60%)

• Most prevalent Muscalr Dystrophy (1:10,00)

• Rarely have life threatening issuesP

Facioscapulohumeral Muscular Dystrophy (FSHD) - Genetics

• Autosomal dominant:

  • 1/3 De Novo

• FSHD1: Deletion of D4Z4 repeats

  • 95% patients have <11 repeats

• FSHD2: Methylation pattern of D4Z4 repeats

  • 5% of patients

Spinal Muscular Atrophy (SMA)

• Autosomal Recessive (25% recurrence risk)

• Progressive muscular weakness: Skeletal + Respiratory

• Lack of Reflects = Diagnostic

• Normal IQ

Spinal Muscular Atrophy (SMA) - Genetics

• Survival Motor Neuron 1 (SMN1) Gene mutation

  • 95-98% homozygous SMN1 exon 1 deletion

  • Severity modified by SMN2 pseudogene: having more copies can help protect against the severity of SMA (increases age of onset)

Hereditary Neuropathy

Charcot-Marie tooth (CMT)

• Hereditary Neuromyopathy,

• Dramatically heterogenous grouping of disorders with:

  • distal weakness, pain, loss of sensation

• Varying genes, modes of inheritance, age of onset and severity

CMT1

• Most common type

• Autosomal Dominant

  HIGH FOOT ARCHES!!! (Pes Cavus)

  • Demylating- nerve condcution slowed siginficnagly

• Adult onset

• CMT1-A most common CMT1 - PMP22 gene

CMT2

• Autosomal Axonal HMSN

  HIGH FOOT ARCHES!!! (Pes Cavus)

• does not slow nerve conduction velocity

• Affects Axons

• Loss of sensation

• Peripheral weakness

• sometimes early onset (recessive forms)

CMT 4

• Autosomal Recessive HMSN (same genes of CMT1- homzygous CMT1 gene defects)

  • Demyelinating = very slow nerve impulses

• Early onset, more sever phenotype

CMTX

• X-linked recessive and Dominant Demyelinating

• CMTX1 - 10% of all cased of CMT (2nd most behind CMT1-A)

Trinucleotide Repeat Disorders

• Huntingtons Diease (CAG)

• Spinocerebellar ataxia (CAG)

• Friedreich’s ataxia (GAA)

• Fragile X Syndrome (CGG)

• Myoyonic dystrophy (CTG)

Patient with MECP2 positive mutation, what is the ocndtion? What is the mode of inheritance and recurrence risk?

• Rett Syndrome

• X Linke Dominant: means all males lethal.

  • Recurrence Risk very low: Father

Re