Genetic Disease of the Nervous System

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???? ???????

• Genetic Disease of the Nervous System
• Department of Neurology
• Second Affiliated Hospital
• Harbin Medical University

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• Genetic disease of nervous system
• 1? Introduction
• 2? Friedreich Ataxia
• 3? Spinocerebellar Ataxia(SCA)
• 4? Charcot-Marie-Tooth Disease
• ??
• 1?Friedreich??????????????????
• 2????????????????????????

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• ??
• 1?Friedreich??????????????
• 2???????????????????
• 3???????(CMT)????????????? ?

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??? General Introduction

• 1. Conception
• Genetic disease of the nervous system
  ????????( germ cell)????( zygote)?????????????????
  ???,???????????????(deficiency)???????????
• Congenital Disease
• Family Disease

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Classification and Genetic pattern

• Monogenic Disorders
• Polygenic Disorders
• Mitochondrial Disorders
• Chromosome Disorders

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• 1.Monogenic disordersThe base replacement,
  Insert, Deletion, repeat or abnormal expansion of
  single gene. Autosomal dominant disorders
  Autosomal recessive disorders
  X-linked dominant disorders
• X-linked recessive disorders
  ???????Common Diseases Charcot-Marie-Tooth,
  Duchenne muscular dystrophy, Wilson Disease,
  Hereditary Ataxia

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• 2. polygenic disorders are influenced by genes
  in complex ways which are poorly understood but
  involve the interaction of multiple genes and
  interactions between genes and environmental
  factors
• The common polygenic disorders
• Epilepsy, migraine and arteriosclerosis.

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• 3. ??????(mitochondrial disorders )
• Mitochondrial disorders are caused by mutation
  of mitochondrion (number or structure),They are
  maternal inheritance.
• optic atrophy and mitochondrial
  encephalomyopathy.
• 4.Chromosome disorders
• Chromosome disorders are caused by the number or
  construction abnormalities of chromosome. for
  exampleDownsyndrome

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Symptoms and physical signs

• Clinical features are of diversity, include
  common and specific symptoms
• Common symptoms
• Specific symptoms

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• 1.Common symptoms
• Mental retardation and Disturbance of behavior
• Language dysfunction, dementia
• Seizure?Nystagmus, Paraesthesia (????)
• Involuntary movement(?????)?
• Ataxia and Dystonia(?????)
• Muscle atrophy
• ?????????????????(?)??????????????

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• 2.Specific symptom
• ??????K-F??
• ????????????????????
• ????????????
• ????????????

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• 4. Diagnosis
• (1). ??????????????????????????,??????
• (2). ????(pedigree analysis)?????????????
• (3). ?????? Include biochemistry,
  Electrophysiology, Imaging studies and
  Pathology??????????????,
• ????????????????????????????????
  ?????????? ?????????,???????????MRI

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• (4). genetic diagnosis
• 1) ?????(karyotype analysis)
• ???????
• ???????(constructive aberration)
• 2) ????(gene detection)
• ???? Southern Hybridization,PCR
• 3) Gene production detection
• ?????????--?????????????(dystrophin)

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• 5. treatment and Prevention
• No effective treatment
• ????(gene therapy)?????????????????????,??????????
  ?,????????????
• ??????Operation medicine therapyDiet
  therapysymptom therapy rehabilitation?

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• Preventionimportant
• ????(genetic counseling)
• ??????
• ?????(carrier detection)
• ????
• ???????(selective abortion)

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??? hereditary ataxia

• 1. Conception
• Hereditary ataxia is a group of inherited and
  degenerative disorders of CNS.
• Characterized by slowly progressive ataxia.
• These disorders show considerable clinic
  variability. But, genetic background, ataxia and
  spinocerebellar lesion are mainly clinical
  features of them.

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• 2. Classification
• Traditional classification by pathologic
  findings Spinal Ataxia
• Spinocerebellar Ataxia
• Cerebellar ataxia
• New classification by the onset of age, clinical
  features, Genetic pattern and location of gene
  mutation(???16-1)by Harding (1993 ) p.270
  
  
  
  
  
  

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• Friedreich ?????
• Friedreich report this disease firstly in
  1863,Its incidence rate is 2 /100000,It is a
  early-onset ataxia and transmitted by autosomal
  recessive inheritance

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• 1. Etioligy and Pathogenesis
• Friedreich ataxia(FRDA)????9??????(9q13
  -21.1)???????95??????????18????( intron
  )GAA????(661700?),???GAA??42???,???GAA???????????
  ?????(gene transcription)?
• Friedreich?????????Frataxin??????spinal
  cord? Skeleton muscle?heart and liver
  ?????(mitochondrion )???,??????????????

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• 2. Pathology
• Posterior columns and lateral column of
  spinal cord are mainly involved ,the spinal cord
  is thin,especially in thoracal spinal cord?
• Microscope can find that cell loss of
  posterior column,spinocerebellar tract ,
  pyramidal tract degenerate , dorsal root ganglia
  and Clarkes column
• peripheral nerve demyelination and
  gliosis brainstem?cerebellum and brain
  are rarely involved
• Cardiomyopathy and heart cell
  hypertrophy?

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• 3. clinical findings
• (1).The age of onset is 8-15 years older
  commonly, with more expanded repeats correlating
  with earlier onset?
• (2). The initial symptom is progressive gait
  ataxia , followed by ataxia of all limbs within 2
  years. usually,both legs are affected
  simultaneously ,
• difficulty in standing and walking steadily
  the hands usually become clumsy month or years
  after the gait disorder with intention
  tremorDysarthric speech appears after the arms
  are involved (rarely is this an early symptom)?

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• (3).Physical examination
• ??????(horizontal nystagmus),???(vertical)????
  (rotatory)????
• ??????,????(muscle tone decreased),?????(Heel-
  knee-shin)??????(Romberg sign)??
• ???????(vibration sense)??????(joint position
  sense)???????
• ????Babinski sign, Muscle atrophy,occasionally
  , sphincter distubances

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• ?25????????(optic atrophy)
• 75???????(kyphoscoliosis),
• 50????(pes cavus)
• 85??????????
• 1020?????(diabetes)?
• (4).????15????(bedridden),??4050??????????

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• 4. investigative studies
• (1). skeleton film show skeletal abnormalities
• CT?MRI?????,cerebellum and brainstem are rarely
  involved
• (2). ???(electrocardiograph) ??T?????????????
• (3). Echocardiography Hypertrophy
• (4). ?????(visual evoked potential) Amplitude
• decreased
• (5). ???(cerebrospinal fluid) normal protein
• (6). DNA??FRDA??18????GAA??66????

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• 5. Diagnosis and differential diagnosis
• (1). Diagnosis
• Early onset
• Slowly Progressive Ataxia from both legs
  to arms
• Dysarthria, Nystagmus, tendon reflex
  absent and Babinski sign
• loss of vibratory and joint position
  sense
• Kyphoscoliosis,Pes vacus,heart lesion
• MRI??????,?????
• FRDA??GAA????,??????

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• (2)?????????????
• ?????????????(demyelinative disease),
• Charcot-Marie-Tooth Disease
• ???VitE???ß-??????????????,???????VitE?
  ß-???????????
• 6. treatment
• no effective treatment is available
  ,??????????,??(rehabilitation)??????????????????
  ??????????????????
•  

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• ?????????(Spinocerebellar ataxia SCA)
• SCA?????????????,??SCA1-10.
• The common feature onset in middle
  life?autosomal dominant hereditary and ataxia.
• Harding????????(ophthalmoplegia
  )?????(extrapyramidal)??????????(retinal pigment
  degeneration)?????????(?16-1),SCA????????,SCA1-2??
  ???????,??????????SCA3????

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• 1. etiology and pathogenesis
• SCA????????,?????????(exon)CAG???????,?????
  ????(SCA8??),??????,???????????SCA??????????????
• ??,??SCA?????????????,??????????????(?16-1?
  ),SCA????????????,?????????(ophthalmoplegia),?????
  ??????,???????????????,?????????????????,?????????
  ????

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• 2. pathology
• The common pathological lesion of SCA is in
  cerebellum?brainstem,with the degenerative spinal
  cord.
• ?????????,?
• SCA1 loss of neuron in brainstem and
  cerebellum,spinocerebellar tract and posterior
  column are usually involved,??????(black
  matter)?basal ganglia and anterior corn cell
• SCA2 nuclei of inferior olivary. Pons and
  cerebellum
• SCA3 pontine and spinocerebellar tract
• SCA7 Retinal neuron degeneration?

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• 3. clinical findings
• SCA??????????,????????,????,????????
• (1). ???3040?????,????,???????70?????
• (2). ????????????,?????????????????????????
  ???(intention tremor)
• ????, ????????, dementia and distal muscle
  atrophyDystonia, increased tendon reflex,
  pathological reflex, spastic gait and sense of
  vibration and proprioception absent?

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• (3). ????????,????SCA???????????,??????,?SCA??????
  ???????1020????????
• (4). ?????????????,????????????????????
• SCA1?????(ophthalmoplegia),?????????
• SCA2???????????,?????????
• SCA3???????(facial)???(glossal)??(fasciculati
  on)?????????

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• SCA5????????,?????
• SCA6?????????(spasm)????????(diplopia)??????(v
  ertigo)
• SCA7??????????????,???????,????????
• SCA8??????(dysarthria)
• SCA10???????(epilepsy)??

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• 4. Lab studies
• (1). CT or MR show cerebellar and brainstem
  atrophy,especially pons and the middle peduncle
  of cerebellum atrophy
• (2). brainstem evoked potential may be abnormal
• (3). Electromyography show peripheral nerve
  lesion
• (4). normal cerebrospinal fluid
• (5). ?????????????????PCR??,??????CAG?????

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• 5. diagnosis and differential diagnosis
• ?????????
• ??(magnetic resonance imaging
  MRI)???????????
• ???????????????????
• ??????????CAG????????golden standard?

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• ????????????(multiple sclerosis)?CJD?????????
  ????
• 6. treatment
• No specific treatment available until now.
  ?????????????

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• ??? ??????(Charcot-Marie-Tooth Disease CMT)
• Introduction
• CMT or hereditary motor sensory
  neuropathy(HMSN). Charcot. Marie and Tooth report
  it firstly in 1886, It is the most common type of
  hereditary motor sensory neuropathy. the
  incidence rate is 1/2500?

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• Classification
• I? nerve conduction velocity less than
  38cm/s. include 3 subtypes 1A, 1B and 1C by gene
  location.
• II? nerve conduction velocity normal or
  nearly normal?Include 4 subtypes 2A?2B?2Cand 2D.
• ?CMT1A?????

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• 1. etiology and pathologenesis
• The majority of CMT is autosomal dominant
  heredity,The minority of it is transmitted by
  other hereditary patterns .
• (1). CMT1A???????17p11.2-12,?????????????22
  (PMP22),????????PMP22??????(over-expression),?????
  ??(myelin protein )???????????????????PMP22??????
  ,????PMP22?????
• (2). CMT2?autosomal dominant
  heredity,????????????????,????1,3,7?????.

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• 2. Pathology
• The axon and myelin sheaths of peripheral
  nerve are involved,the distal parts of nerve
  more than the proximal?
• I???????????????,??????,Schwann???????,?????
  (onion-bulb)???,???????????????
• II??????(axon degeneration),?????????????
  ???????(anterior horn cell)??????,The muscles
  occur group atrophy (????)???????????,??????????t
  he autosomal nervous system remains relatively
  intact?

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• 3. clinical findings
• CMT I?(????)
• (1) the age of onset is late childhood and
  adolescence.
• the symmetrical chronic
  degeneration of peripheral nerve result in
  distal muscle atrophy,???????????,???????????????,
  extensors are involved early, Flexor is normal,
  ???????????(claw foot)??,foot drop??????????????

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• (2) ????
• ????????,?????????1/3??(the lower third of
  the thigh muscle weak and atrophy),just like
  stork leg or inverted champagne
  bottle,????,???????,???????????????
• The tendon reflex are absent in the
  involved limbs
• ????????????,?????????
• ?????????????????,Rarely, the sensory loss
  is severe,and perforating ulcers may appear?

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• (3) ??????,??????????,????????????????????
  ?,?????????,??????????????,????????????
• CMT II?(???)
• late onset,muscle atrophy occur at
  adult,clinical features are the same as CMT I?.
  But lighter than it
• CSF Protein is normal?

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• 4. Lab studies
• (1).????????(Nerve conduction velocity
  NCV)????????CMT1???NCV????50?/????38?/???,CMT2?NCV
  ?????
• (2).X?????????????????????????,???????????????????
  ??

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• (3).Muscle Biopsy neurogenic atrophy
• (4). Nerve Biopsy
• CMT I????????????????????????onion
  bulb
• CMT II??????????????????????????
• (5).cerebrospinal fluid normal,???????????

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• 5. Diagnosis and differential diagnosis
• ??????
• (1). ??????????????????????
• (2). Stork leg,foot drop, high arches??????
• (3). tendon reflex decreased or absent,commonly
  with paresthesia
• (4). family history
• (5). the slow nerve conduction velocity nerve
  biopsy show neurogenic atrophy
• (6). Gene detection find CMT1A gene repeat?

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• CMT1??CMT2????
• (1). the age of onset1?12???,2?25???
• (2). NCV1?????,2????????(3). ????
• 1??17??????(17p11.2)1.5Mb???(????PMP22??)???
  ?PMP22??????(1A)
• 2??1??????(1p3536)?????(2A)?

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• Differential Diagnosis
• (1) ?????????(distal muscular dystrophy)
• ?????????????????,??CMT?????????,??????????
  ,?????????????
• (2). ??????????(family myeloid polyneuropathy)
• ??????,????????DNA???
• (3). ???????????????(chronic inflammatory
  demyelinating polyneuropathy)
• ??????,CSF??????,??????????

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• (4) ?????????????(chronic progressive spinal
  muscular atrophy)
• ?????????????CMT?,????????,EMG????????
• (5) ???????????(hereditary ataxia with muscular
  atrophy)
• ??Roussy-Lévy???????????,?????????????????
  ???????????????????????????????,????????????CMT??
  ????CMT????

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• 7. treatment and prevention
• (1). No specific treatment is known,????????????,?
  ????????????
• (2).???????????,?????(proband)????,???????????????
  ,???????????????,?????
• 8. prognosis
• This illness progress very slowly .
  ???????????,??????????????