Transcript 10. Hereditary diseases

Hereditary
diseases of
nervous system
Diseases with involvement of
nervous – muscle synapse:
– Myasthenia
– Myasthenic syndromes
Myasthenia gravis (MG)
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Etiology How the autoimmune disorder
starts is not known
In about 15% of patients there is an
encapsulated benign tumor - thymoma.
There are few familial cases of the disease,
but disproportionate frequency of some HLA
haplotypes (B8, DR3, DQB1) in MG patients
suggests that genetic predisposition may be
important
Myasthenia gravis (MG)
is caused by a defect of neuromuscular
transmission due to an antibodymediated attack on nicotinic
acetylcholine receptors (AchR) at
neuromuscular junctions. It is
characterized by fluctuating weakness
that is improved by inhibitors of
cholinesterase.
Pathogenesis
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Loss of receptors due to complement-mediated lysis
of the membrane and to acceleration of normal
degradative processes (internalization, endocytosis,
lysosomal hydrolysis) with inadequate replacement
by new synthesis
Loss of AChR and the erosion and simplification of
the endplates
Abnormally sensitive to the competitive antagonist
curare
Most AChR antibodies are directed against antigenic
determinants other than the ACh binding site
Destruction of the receptors
Clinical features
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According to the course of the disease:
– Progressive
– Stationary
– Mysthenic episodes
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Clinical forms:
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Ophthalmic
Bulbar
Skeletal
General
Typical features:
Asymmetric lesion
 Dynamic symptoms (the signs increase in the evening)
 Ophthalmoplegia is a very common symptom. The
other ones are:
- Weakness of mimic muscles – especially oral muscles.
- Weakness of chewing muscles.
- Weakness of pharyngeal, laryngeal muscles and
muscles of tongue
- Tongue muscles function disorders
- Breathing disturbances
- Extremities function disturbances (especially proximal
parts)
- Neck muscles weakness – hanging of the head
- Body muscles weakness that leads to duck – like gait
 Sensory and pelvic disorders usually are not observed.
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Eyes movemens disorders
Left side ptosis
Myasthenia gravis . Bilateral ptosis,
hypomimia
Myasthenia gravis.
Weakness of neck musles
Tests for disease revealing
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The patient is asked to look upwards or inside during 30
seconds in order to cause ptosis
He is asked to read text aloud in order to cause
dysarthria
The patient is asked to make 100 chewing movements
in order to reveal the weakness of these muscles
Proserine test. Proserine is introduced in dose 1.5 – 3
ml s/c, sometimes Atropinum is used in order to prevent
side effects. In 20–40 min all the signs of myasthenia
disappear. In 2–3 hours all the symptoms appear again
Diagnosis
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EMG – myasthenic reaction. Test is
positive in 85% of patients with
skeletal form.
Muscle biopsy – muscle atrophy and
signs of degeneration.
CT reveals timoma signs. In 90% of all
patients antibodies to ACHR are found
Thymoma (CT-scan)
Thymoma (X-ray)
Differential diagnosis
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Botulism
Neurasthenia
LAS
Polineuropathy
Muscles dystrophy
Inflammatory myopathy
MS
Stroke in v/b region
Brain stem tumor
Bothulism
Myastenic syndrome Of
Lambert-Ithon
Treatment
Anticholinestherase medicines:
- Caliminum – 30 mg 3 times per day.
- Proserinum – 0.5 – 1.5 mg s/c
 K drugs 3 – 4 g per day.
 Corticoids – we start from 15–20 mg a day, than
increase gradually on 5 mg every 3 day
 Anabolics – Retabolil 50 mg once every 3 days, 5
– 6 injections
 Immune suppressors – Asatioprinum in dose 50
– 150 – 200 mg per day
 Plasmapheresis - at acute and progressive form
 Radiation therapy of thymus
 Methabolic drugs
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Myasthenic crisis:
– Plasmapheresis
– Ig i/v (2 g per kg 2 – 5 days)
– Corticoids (100 mg prednisonum)
– Proserinum 1 – 2 ml i/v
– SLV, oxygen
– Halloperidolum at excitation
Cholinergic crisis
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There fasciculations, seizures,
bradycardia, salivation, hyperhydrosis
and abdominal pain.
Treatment – Atropinum 1 ml 0.1 % s/c
or i/v.
Diseases with involvement
of pyramidal system:
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Hereditary Spastic paraplegia of
Shtrumpel
Family spastic paralysis with
amyotrophy, oligophrenia, retina
degeneration (described by Kellin)
Family spastic paralysis with
ichthyosis and oligophrenia
Spastic paraplegia of Shtrumpel
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This disease is the result of pyramidal tracts and
cerebellar connections degeneration.
Transmission: genetically recessive in most cases but in
some families it show dominant inheritance
Clinical features:
The first signs are observed at the age of 10–15
Lower spastic paraplegia with increased muscle tonus,
high stretch reflexes, pathological reflexes
Lesion of lower extremities is symmetrical
Sometimes motor disorders can be developed in upper
extremities.
In some cases pseudobulbar symptoms are joined
The typical signs of the disease:
The dominance of spastic tonus over motor disorders
Well preserved abdominal reflexes
The absence of pelvic disorders
Diseases with involvement of
extrapyramidal system:
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Parkinson disease
Hepato – cerebral degeneration
Dystonia
Huntington disease
Double athetosis
Myoclonus – epilepsy
Tourette syndrome
Parkinsonism
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is a chronic progressive neurodegenerative
syndrome that is characterized by motor
disorders as a result of extrapyramidal
system involvement
Parkinson disease (PD) – is a chronic
progressive degenerative disease of CNS
that manifest as voluntary movements
disorders.
Etiology
Primary Parkinsonism:
 Parkinson disease
 Younger parkinsonism
Secondary Parkinsonism:
 Cerebral vessels sclerosis
 Long lasting usage of neuroleptics, reserpinum medicines
 Toxins
 Viral infections
 Metabolic encephalopathy
 Severe cranial trauma
 Tumors, hydrocephalus
Parkinsonism as syndrome of other hereditary
diseases
Clinical features
 Hypokinesia
 Rigidity
 Resting
trembling
 Loss of postural reflexes
Parkinson’s disease
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In 1817 – James
Parkinson described the
major manifestation of
this syndrome
In 1874 – this disease
was called after James
Parkinson – Parkinson’s
disease
In 1920 – Tretiakov
noticed that the greater
cell loss in substantia
nigra, the lower
concentration of
dopamine is in striatum
and more severe the
degree of clinical
Parkinsonism.
Death of the neurons of black
substance in patient with
Parkinson disease
Normal
Parkinson disease
PGS
CGS
A8
A8
rn
SNpl
SNpc
cp
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SNpl
SNpc
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Rest tremor
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at a frequency of 4 to 5 Hz is present in the
extremities, almost always distally
the classic "pill-rolling" tremor involves the thumb
and forearms
disappears with action but reemerges as the limbs
maintain a posture
common in the lips, chin, and tongue
tremor of the hands increases with walking and
may be early sign when others are not yet present
stress worsens the tremor
Rigidity
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increase of muscle tone that is elicited when the
examiner moves the patient's limbs, neck or trunk.
this increased resistance to passive movement is
equal in all directions and usually is mat by a
ratchety "give" during the movement.
so-called cogwheeling is caused by the underlying
tremor even in the absence of visible tremor.
Cogwheeling also occurs in patients with essential
tremor.
rigidity of the passive limb increases while another
limb is engaged in voluntary active movement
Parkinson’s Disease
Paralysis Agitans
Clinical Feature (2)
Resting Tremor
Parkinsonian Posture
Rigidity-Cogwheel Rigidity
Parkinson's disease. Facial
appearance
Parkinson's disease.
Micrographia
Parkinson's disease. Stooped
posture.
Test of knee flexion
Flexed posture
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The commonly begins in the arms and spreads to
involve the entire body.
The head is bowed
the trunk is bent forward
the back is kyphotic
the arms are held in front of the body
the elbows, hips, and knees are flexed
Deformities of the hands include ulnar deviation of
the hands, flexion of the metacarpal-phalangeal
joints, and extension of the interphalangeal joints
(striatal hand)
Inversion of the feet is apparent, and the big toes
may be dorsiflexed (striatal toe)
Lateral tilting of the trunk is common.
Akinesia
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Bradykinesia (slowness of movement, difficulty initiating movement, and loss of
automatic movement) and hypokinesia (reduction in amplitude of movement,
particularly with repetitive movements, so-called decrementing)
The face loses spontaneous expression (masked facie: hypomimia) with
decreased frequency of blinking.
Poverty of spontaneous movement is characterized by loss of gesturing and by
the patient's tendency to sit motionless.
Speech becomes soft (hypophonia, and the voice has a monotonous tone with
a lack of inflection (aprosody).
Some patients do not enunciate clearly (dysarthria) and do not separate
syllables clearly, thus running the words together (tachyphemia).
small and slow handwriting (micrographia) and in difficulty shaving, brushing
teeth, combing hair, buttoning, or applying makeup.
Playing mi instruments is impaired.
Walking is slow, with a shortened stride length and a tendency to shuffle;
swing decreases and eventually is lost.
Difficulty rising from a deep chair, getting out of automobiles and turning in
bed are symptoms of truncal bradykinesia.
Drooling saliva results from failure to swallow spontaneously, a feature of
bradykinesia, and is not caused by excessive production of saliva.
The main clinical forms
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Trembling
Rigidity
Mixed
Severity stages:
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I – loss of activity, but that doesn’t influence
on professional activity and working ability
II – moderate loss of professional activity
III – the patients need someone to look
after him
Drug Therapy
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Carbidopa is listed as the peripheral dopa
decarboxylase inhibitor, but in many
countries benserazide is also available
Amantadine, selegiline, and the
anticholinergics are reviewed in following
sections
Antidepressants are needed for treating
depression
Triatment
Basic therapy:
 Nootrops
 Cinnarizini
 Cavintoni
 Adequate dose of antiparkinsonic drugs
Surgery therapy:
 Stereotaxis operations
 Deep electrostimulation of brain structures
 Method for case of no effective of drug therapy
PET*
Early
stage of
PD
Early-Stage
PD
Контроль
Later
stage of
Late-Stage
PDPD
OPEКТ‡
КControl
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Later stagePD
of PD
Middle stage
Early stage of
PDof PDLate-Stage
Early-Stage
PDPD Mid-Stage
Hepatocerebral dystrophy (HCD)(
Wilson – Konovalov disease)
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This disease is connected with disorders of
ceruloplasminum metabolism.
Ceruloplasminum is a blood protein
responsible for Cu transport. It is produced
in liver. Pathologically there is
accommodation of Cu in subcortical
ganglions (especially n. Lenticularis), brain
cortex, cerebellum, liver, spleen, iris.
Transmission: genetically autosomal –
recessive. And it is observed in male and
female with the same frequency.
Clinical signs
The first signs of the disease are observed in early
childhood.
 neck stiffness
 different hyperkinesis and psychiatric changes
 Sometimes seizures can be observed
 liver enlargement.
 Kaizer – Fleishner ring in the iris.
Konovalov classification types of the disease:
 Rigid – arythmokinetic
 Trembling – rigid
 Trembling
 Extrapyramidal – cortical
 Sometimes the disease manifests only as liver
insufficiency and neurological signs are joined later.
Diagnosis
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Family history
The typical signs of the disease – Kaizer –
Fleishner ring, lesion of liver, low quantity of
ceruloplasminum in the blood, increased
quantity of Cu in urine.
Differential diagnosis
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Huntington disease
MS
Chronic stage of epidemic encephalitis
Torsion dystonia
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The pathology of the disease includes
degenerative changes of subcortical
ganglions, subthalamic nuclei and n.
Dentatus of cerebellum as a result of
neuromediators production and metabolism
disturbances.
Hyperkinetic form of the disease has
autosomal – dominant type of inheritance.
Rigid form of the disease is characterized by
autosomal – recessive type of inheritance.
Clinical features
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The disease begins in early childhood
permanent progression
hyperkinesis that increases with every movement.
hyperkinesis may have a look of tonic body and
extremities muscle straining
Spastic torticollis is one of the earliest symptoms of the
disease.
There are no mental disorders in typical cases.
There are generalized form of the disease and local
ones, such as spastic torticollis and chirospasm.
Diagnosis
Family history and the evaluation of pathological process
dynamics are necessary for the diagnosis putting.
Differential diagnosis
Atypical form of Economo encephalitis
Huntington disease
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It is a progressive hereditary disorder
that usually appears in adult life. It is
the result of systemic degeneration of
extrapyramidal structures and brain
cortex.
It has autosomal – dominant type of
inheritance.
Clinical features
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Appears in adult life and it is very rare in children
Male and female can suffer from this disease.
Choreic movements
Extrapyramidal rigidity
Slowly progressive dementia
Rare forms are:
Akinetic – rigid syndrome
Extrapyramidal immobility in children
Epileptic attacks
Myoclonia
Diagnosis
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Clinical and genetic analysis
CT and MRI of brain (atrophic changes of
brain hemispheres)
EEG
DNA – analysis
Differential diagnosis
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Chorea
Hepato – cerebral degeneration
Hereditary ataxia
– Spinal ataxia of Fridreich
– Hereditary cerebellar ataxia of
Pier – Mary
– Olivo – ponto – cerebellar
degeneration
Spinal Fridreich ataxia
The disease is characterized by spinal cord degeneration and
degenerative – dystrophic changes in posterior and lateral columns.
Transmission: by autosomal – recessive type of inheritance.
Clinical features :
 The disease begins at the age of 10 – 12
 slowly progresses
 sensitive – cerebellar ataxia, nystagmus
 muscle hypotonia and areflexia
 gait disorders
 At the beginning of the disease there is deep sensation disorders
according to the conductive type on lower extremities.
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In the course of the disease coordination disorders, scan speech,
body and upper extremities ataxia appear.
 some bone abnormalities
 cardiomyopathy
 mental disorders
 symptoms of lesion of pyramidal tracts
Hereditary cerebellar ataxia of Pier–Mary
The main signs of the disease are:
 The beginning at the age of 30 – 50
 Cereballar ataxia
 Dysarthria
 Hyperreflexia
 Spastic muscle hypertonia
Transmission: by autosomal – dominant type.
Clinical feature:
 begins gradually with gait disorders
 disorders of coordination, nystagmus, dysarthria
 high reflexes, increased muscle tonus spastic type
(mainly in lower extremities), pathologic reflexes
 eye movements disorders
 mental, memory and emotional disorders
 the course of the disease is progressive
Olivo-ponto-cerebellar degeneration
It is the group of the diseases that are
connected by system lesion of
cerebellar cortex, pons and lower
olives. Sometimes the neurons of
anterior horns of the spinal cord and
basal ganglia are involved.
 The inheritance of the disease is
autosomal – dominant.
Clinical features
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Begins at the age of 15 – 20, sometimes 30
years
Cerebellar symptoms dominate
also extrapyramidal and pyramidal
symptoms
peripheral polineuropathy
Sometimes retina is involved in pathological
process
Mental disorders are often observed
Diseases with involvement of neuro
– muscular junction:
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Progressive muscular dystrophy
– Dushen pseudo – hypertrophic muscle
dystrophy
– Late Bekker pseudo – hypertrophic
muscle dystrophy
– Shoulder – scapula – facial form of
Landuzi – Degerina
– Erba dystrophy
Amyotrophy as a result of
peripheral neuron lesion
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Spinal amyotrophy of Werding –
Hoffman
Proximal amyotrophy of Kukelberg –
Welander
Sharkot – Marie – Tooth disease
Family – hereditary myotonia:
– Myotonia Tomsena
– Atonic myotonia
Hereditary diseases with paroxysmal
states:
– Paroxysmal family myoplegia
– Episodic hereditary adynamia