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CHRONIC POLYNEUROPATHY

- A polyneuropathy that advances slowly over 10 years or more is almost invariably genetic in origin.
- The time of onset of these very chronic neuropathies is usually in early life but often cannot be dated with certainty by the patient or family.
- INFANTS: mistaken for muscular dystrophy or infantile muscular atrophy until sensory testing becomes possible.
- DEVELOPING CHILD: musculature naturally increases in power and volume with age, it may be difficult to decide whether the disease is progressive but
typically, there is trouble running or walking making it difficult to keep up with other children, repeated ankle injuries, toe catching,
labeled as clumsiness," or falls.
- Strongly indicative of one of these conditions at any age are pes cavus, hammertoes, and, in extreme forms, talipes equinus.
- ADULT: some of the inherited neuropathies are manifest as trophic changes of skin and bone in distal parts of the limbs indicate involvement of small
(pain) fibers and the presence of deformed and degenerated joints (Charcot joint)
- . The mutilating effects are the result repeated injury to analgesic parts and to a lack of autonomic vascular reflexes. Atrophy of muscle and trophic
changes in the skin are generally more marked than in the acquired forms of polyneuropathy.
- Charcot-MarieTooth (CMT) disease (type 1) shows slowed nerve conduction as a consequence of a disorder of myelin.
- A distinctive feature of hereditary neuropathy is the uniformity of the electrophysiologic changes, e.g., a similar degree of slowing of nerve
conduction velocity in all
the nerves, a feature that distinguishes this group from most acquired neuropathies.
- Demyelinating vs Axonal types of Inherited Neuropathies is based on the motor nerve (typically ulnar or median nerve) conduction velocities in the
arms
o Demyelinating category: slowing to velocities below 38 m/ s defines the demyelinating category.
INHERITED POLYNEUROPATHIES OF MIXED SENSORIMOTOR-AUTONOMIC TYPES
Description Features/Manifestations Diagnosis Treatment

HEREDITARY - Autosomal dominant Age of onset: usually 10-20 yo HALLMARK:


MOTOR SENSORY - Most common forms of inherited No specific
NEUROPATHY peripheral neuropathy and among Children 1. Genetic treatment
the most common of all inherited - clumsiness and athletic transmission (Because it is
neurologic diseases 2. Complete genetic. We only
imprecision
- foot deformities of high arches and symmetry do symptomatic
CMT1 CMT2 hammer toes. (sometimes treatment)
Onset 1st decade 2nd decade - ankle fractures, foot-drop, medical plantar unilaterally)
Mean Decreased Normal foot 3. Very slow Regular exercise
conduction < 38 m/sec calluses and a need for podiatric treatment progression
velocity 4. Loss of myelin
Amplitudes Reduced Reduced at an early age,
disproportionate to
of sensory painless or foot ulcers
and action axons
potentials Adolescence
Genetics Duplciation Mutation for - "inverted champagne bottle" appearance PATHOLOGIC FINDINGS: Light braces or
of PMP 22 connexin- of the forelegs may shoes with
gene 32 gene 1. Depletion of axons,
(Autosomal (X-linked)
springs (to
Domiant)
Difficulty in running, frequent weakness, myelin sheaths, prevent foot drop)
Enlargeme Yes No sprains of ankles, stumbling and slapping sensory and motor
nt of of feet (First complaint is usually loss of fibers Arthrodoses to
nerves 2. Nerves may be stabilize ankles
balance, because of involvement of
posterior column and destruction of myelin enlarged with onion (weak ankles)
sheath) bulb formations of
Kyphoscoliosis- occur in severe cases due Schwann cells and
to unequal weakness fibroblasts
Pes cavus (Friedreichs foot)
Pied en griffe (giraffe foot) (High arches Good Prognosis
and hammertoes extensor hallucis,
digitorum longus, peronei and intrinsic feet
muscles )
Foot drop (Atrophy of calf muscles)
Champagne glass or stork-like legs
(smaller legs as compared to thigh, this is
the most common appearance)
Impaired motor, vibration and joint position
sense
Tremors (occasional)
Paresthesias, cramps, sensory loss
Atrophy
Claw hand (If with atrophy of thenar
muscles)
HEREDITARY Multiple recurrent focal neuropathies Pressure on the nerves can cause tingling 1. Nerve biopsy (+)
NEUROPATHY and plexopathies often provoked sensations, numbness, pain, weakness, muscle localized nerve sheath
WITH PRESSURE by compression atrophy, and even paralyzation of affected area. thickening with
PALSIES Deletion of the PMP22 gene at half duplication of myelin
normal level (disorders arise lamellae (tomaculae
because the total amount of the sausage shaped)
protein is abnormal 2. EMG mild slowing of
Usually non-painful conduction of distal
Often with underlying chronic but sensory and motor
slowly progressive mild nerves
demyelinating sensorimotor
neuropathy
HYPERTROPHIC Autosomal recessive Walking is delayed in onset and progressively NCV: markedly reduced (10
NEUROPATHY OF Onset: early childhood or infancy impaired m/s) even when there
INFANCY Pain and paresthesias in the feet are early is no or little functional
( DEJERINE- symptoms followed by symmetrical impairment
SOTTAS DISEASE) weakness and wasting of distal extremities CSF protein: persistently
All sensory modalities are impaired increased because of
Areflexia enlarged spinal roots
PATHOLOGY:
OTHER MANIFESTATIONS: segmental demyelination
1. Kyphoscoliosis Thickening of nerves
2. Deformities of hands and feet onion bulb
3. Miotic, unreactive pupilsNystagmus Mononeuritis multiplex
4. Hypertrophy of nerves
5. Severe motor deficit
PROGNOSIS: Poor;
6. Severe sensory deficit (pseudoataxia /
wheelchair bound at early
pseudoathetosis)
age
INHERITED POLYNEUROPATHIES OF PREDOMINANTLY SENSORY TYPE
Description Features/Manifestations Diagnosis

HEREDITARY SENSORY AND Mutilating Hereditary Polyneuropathy in Begins with subtle loss of pain and PATHOLOGY:
AUTONOMIC NEUROPATHY Adults temperature sensation in the feet
TYPE I later of the fingers 1. Slowly progressive sensory distal
Autosomal Dominant Calluses, later blistering, ulceration of axonal degeneration and segmental
Onset: Second decade or later feet demyelination affecting non-
Osteomyelitis and osteolysis myelinated and small myelinated
also entails progressive, disabling, distal Shooting pain and sensory loss fibers
motor weakness, a consequence of Mild muscle weakness 2. Loss of function of enzyme serine
ongoing axonopathy and denervation Hypo/areflexia palmitoyl transferease (rate limiting
HSAN1 is a consequence of a loss of Loss of sweating step in biosynthesis of sphingolipids )
function of the enzyme serine Sensory nerve conduction: absent or
PROGNOSIS: Good
palmitoyltransferase, which is the slowed
ratelimiting step in the biosynthesis of
sphingolipids.
RECESSIVE MUTILATING Autosomal recessive Walking is delayed
SENSORY POLYNEUROPATHY Onset: Infancy and early childhood Ataxia
OF CHILDHOOD Ulceration of tips of toes and fingers
Some of the infantile hereditary sensory Areflexia
neuropathies are a result of a Impaired sensory modalities distal
disruption of molecular signaling part of the limbs but also over trunk
pathways for neurotropic Disruption of nerve growth factors
substances, such as nerve growth (Destruction of all sorts in the lower
factor, that are critical to neural extremities)
development
HSN II (MORVANS Autosomal recessive (Increase in size of Distal sensory deficit Prognosis: Poor; does not reach
SYNDROME, INFANTILE CENTRAL CANAL of spinal cord; Can adulthood
SYRINGOMYELIA, spread to the anterior part and affect
CONGENITAL SN) motor activity; If severe enough can
affect sensory part)
Onset: Infancy
HSN IV (CONGENITAL SN W/ Autosomal recessive High fever due to absence of
ANHYDROSIS / CONGENITAL Onset: infancy sweating mechanisms
INSENSITIVITY TO PAIN) Mental retardation
Short stature
Insensitivity to pain
Absence of neurons in dorsal root
ganglia, Lissauers tract and
decreased size of descending tract
of CN V (Patient has autonomic
dysfunctions. Patient may not
reach up to 5 years old)
HSN WITH FAMILIA Autosomal recessive Congenital absence of autonomic and HISTOPATHOLOGY: Diminished
DYSAUTONOMIA Ashkenazic Jewish families dorsal root ganglia sensory neurons myelinated and unmyelinated fibers,
(RILEY-DAY SYNDROME) Autonomic neuropathy (fluctuating and sympathetic and parasympathetic
Familial dysautonomia is usually body temperature, no tears, ganglion cells
manifested soon after birth: postural hypotension, dry mouth,
- poor sucking impaired taste sensation w/ PROGNOSIS: Poor (die at age 15 or
- failure to thrive strikingly smooth tongue, poor suck, below) due to autonomic dysfunction
- unexplained fever failure to thrive episodes of
- episodes of pneumonia TREATMENT: Symptomatic relief of GI
Later in life: neuropathy becomes pneumonia) symptoms and orthostatic fainting
overshadowed by other Main manifestations: Loss of pain and
manifestations of the disease, temperature sense with
notably repeated infections and preservation of pressure and tactile
abnormalities of the autonomic sense
nervous system Absent reflexes, hyporeflexia
Motor functions slightly affected
shown more effectively by reduced
motor conduction velocity in
peripheral nerves than it is by
weakness
Corneal ulceration, fixed pupils,
blotchiness of skin, excessive
sweating, difficulty in swallowing,
esophageal and intestinal dilatation,
emotional instability, recurrent
vomiting, stunted growth

HEREDITARY AREFLEXIC CMT 3 Sensory ataxia


DYSTASIA Autosomal dominant Pes cavus and areflexia
(ROUSY-LEVY SYNDROME) Mutation of myelin protein gene Some degree of sensory loss:
Onset: infancy / from birth vibratory and position
Atrophy of muscles of legs and
There is no cerebellar degeneration; postural tremors
nevertheless, the shared clinical Relatively benign (Patient may reach
features with Friedreich ataxia are adulthood)
unmistakable and create diagnostic
confusion before genetic testing

INHERITED POLYNEUROPATHIES WITH RECOGNIZED METABOLIC DISORDER


Description Features/Manifestations Diagnosis

NON-FAMILIAL SYSTEMIC primary (nonfamilial) systemic deposition Multiple myeloma Diagnosis - biopsy of sural nerve,
AMYLOIDOSIS of amyloid (termed AL), which is derived rectum / gum
from a circulating monoclonal protein Death cardiac or renal
Generalized symmetrical sensorimotor involvement by amyloid
neuropathy w/ serious autonomic
involvement

FAMILIAL AMYLOID Autosomal dominant- pattern of inheritance FOUR TYPES:


POLYNEUROPATHY in all subtypes a. PORTUGUESE (ANDRADE) TYPE
Males = females Unpleasant, progressive and fatal neuropathy; starts from legs in the
Amyloid- descriptive term; any protein 3rd decade (25-35 years) and runs its course slowly and terminates
deposited in filamentous beta-pleated fatally in 10 or more years (10-15 years)
sheets Numbness, paresthesias, pain in lower extremities
Mild weakness and areflexia; Start at lower extremities (ascending)
Sensory loss (pseudosyringomyelic pattern)
Autonomic involvement
- loss of pupillary light reflexes and
- miosis
- anhydrosis
- vasomotor paralysis with orthostatic
- hypotension,
- alternating diarrhea and constipation
- impotence
Difficulty in walking- areflexia and atrophy of legs
Cranial nerve involvement (facial weakness and numbness, loss of
taste) may occur late
Cardiac enlargement and irregular cardiac rhythm
Anemia
Behavior abnormalities, cerebellar ataxia, bilateral corticospinal signs,
nephrotic syndrome, uremia
CSF normal or increased protein (50-100mg/dL)
Africa, France, Brazil, Japan, Sweden

b. FAMILIAL AMYLOIDOSIS WITH CARPAL TUNNEL


SYNDROME (SWISS TYPE)
Milder, starts from arms w/ Carpal tunnel-like syndrome (median
nerve involvement); Pain in wrist: first complaint
Atrophic muscle weakness in distribution of median nerve
vitreous opacities
Generalized neuropathy starting at 4th and 5th decade., w/ minimal
autonomic involvement
Mutation of protein transthyretin (TTR)
German origin
c. IOWA TYPE
Onset: 30 yrs
Severe sensorimoter neuropathy (arms and legs)
Amyloid deposits in testes, adrenal glands and kidneys-usual cause of
death; General metabolic problem
Fairly severe sensorymotor neuropathy
Mutated apolipoprotein A1
d. CRANIAL NEUROPATHY WITH CORNEAL LATTICE DYSTROPHY AND
FACIAL PALSIES
Finnish type
Onset: 3rd decade with lattice corneal opacities
5th decade facial nerves (upper branches) are affected
Excessive skin folds in face, facial diparesis, dysarthria, spasticity,
dense loss of posterior column function, amyloid deposits from
gelsolin protein
Amyloid virtually found in every organ- mainly in kidneys, blood
vessels and perineurium
Facial diparesis: paralysis of right and left face in short expressionless
face
CEREBRAL LIPOIDOSIS deposition of abnormal lipids in the TWO TYPES: NCV & nerve biopsy
brain Metachromatic Leukodystrophy
- Deficiency of arysulfatase A
- widespread demyelination of brain
- Intrellectual impairment
- Prognosis poor
Krabbes Disease
- deficiency of galactosylceramide beta
galactosidase
- accumulation of galactocerebroside in brain
and PN
- Fatal w/in 1-2 years of onset
BASSEN-KORNZWEIG Rare autosomal recessive - DTR absence/dimished- earliest LABORATORY: extremely
SYNDROME (A- Accumulation of triglycerides in neurological finding low serum cholesterol and
BETALIPOPROTEINAEMIA) intestinal mucosa & impaired - Vibratory and position sense loss LDL (defect in triglyceride
absorption of fat soluble vitamins - Developmental delay transfer protein), dec. Vit E
- Cerebellar signs (progressive ataxia of
Steatorrhea often precedes weak and gait, trunk and extremities, titubation of (d/t malabsoption),
unsteady gait head, dysarthtria acanthocytosis (RBCs)-
ONSET: 2 y/o areflexia - Peripheral neuropathy (impaired posture identifying feature
sense, loss of pain and temperature
sense) COMPLICATIONS: cardiac
- Ophthalmoparesis enlargement and
- Retinitis pigmentosa
congestive failure
- Muscle weakness
- Babinski sign
- Skeletal abnormalities- pes cavus and NEUROPATHOLOGIC
kyphoscoliosis FINDINGS: demyelination
of peripheral nerves and
Constriction of visual fields and ring scotomata- degeneration of nerve cells
macular degeneration and retinitis pigmentosa in spinal gray matter and
cerebellar cortex

MANAGEMENT: high
doses of fat-soluble
vitamins & dietary fat
restrictions

PROGNOSIS: may live to


middle age
TANGIER DISEASE (HIGH- Rare, familial, small-fiber - Cholesterol deposition in tonsils LABORATORY: absent
DENSITY LIPOPROTEIN neuropathy - Swollen yellow-orange tonsils producing serum high-density
DEFICIENCY) Autosomal recessive difficulty of breathing and swallowing lipoproteins & extremely
GENE MUTATION INHIBITS - Impaired pain and temperature sense low cholesterol and high
FUNCTION OF ATP CASSETTE sometimes limited to face and upper triglyceride serum levels
TRANSPORTER PROTEIN extremities (pseudosyringomyelia) Fat-laden
- Tactile and proprioceptive sensations
macrophages in bone
preserved
marrow
Neuropathy progresses
slowly
TREATMENT: dietary
restrictions of fats
(Patients die due to
respiratory arrest)
REFSUMS DISEASE Autosomal recessive - Retinitis pigmentosa, night blindness, DIAGNOSIS: increased
(HEREDITARY ATAXIC NEURO., DEFICIENCY OF PHYTANOYL- pupillary abnormalities, cataracts, constricted phytanic acid in blood
PHYTANIC ACID STORAGE COENZYME A (COA) visual fields (normal 0.3) of patients
DISEASE) HMSN IV INABILITY TO BREAK DOWN - Ataxia with chronic peripheral
PHYTANIC ACIDS - Chronic polyneuropathy neuropathy
- Inc. blood phytanic acid
ONSET: late childhood,
- Neurogenic deafness
adolescence, early adult life - Progressive peripheral neuropathy, all TREATMENT: Low phytol
Slowly progressive diet
sensations are reduced
- Ichthyosis
CAUSE OF DEATH
cardiac involvement

FABRYS DISEASE (ANDERSON- -GALACTOSIDASE A Lipid deposition in all tissues and body fluids TREATMENT:
FABRY DSE., ANGIOKERATOMA DEFICIENCY Deposition of glycolipid (ceramide anticonvulsants
CORPORIS DIFFUSUM) X-linked recessive trihexodase) in nerves and cells of spinal (phenytion,
ganglia and anterior and intermediolateral carbamazepine,
horns of spinal cord gabapentine, amitriptline)
Heterozygous women (10%) have later onset for pain, enzyme
and milder neuropathic symptoms than men replacement therapy

INITIAL SYMPTOM: Pain (burning/stab quality- CAUSE OF DEATH renal


initial symptom in childhood and adolescence), failure
followed by paresthesias of palms and soles

Telangiectasia of lower trunk and upper legs

Impairment of renal function and cerebral and


cardiac infarction

Dark red macules and


papules(angiokeratomas),about 2mm diameter,
over trunk and limbs, some cluster around thigh
and lower limbs and around umbilicus-
angiokeratoma corporis diffusum
ACUTE INTERMITTENT DEFECT IN UROPORHYRINOGEN-1 severe colicky abdominal pain w/ vomiting, DIAGNOSIS:
PORPHYRIA SYNTHETASE abnormal behavior, severe ascending determination of
Autosomal dominant neuropathy, rapidly ascending flaccid paralysis, erythrocyte urobilinogen-
INCIDENCE: 1.5/100,000 cranial nerve palsies, autonomic involvement, 1 synthetase
deep red color of urine
TREATMENT: IV glucose
Other metabolic dysfunctions @ 10 20 g/h, haematin 4
mg/kg/12 h,
Evidence of SIADH, salt-losing nephropathy Chlorpromazines

Liver damage PROGNOSIS: Poor; 25-


50% mortality; Recovery
at 6-8 wks; slow &
incomplete

DIAGNOSIS OF EARLY CHRONIC POLYNEUROPATHY DIAGNOSIS OF LATE CHRONIC DIAGNOSIS OF LATE CHRONIC
POLYNEUROPATHY POLYNEUROPATHY
SENSORIMOTOR PARALYSIS Diabetes Usually heredofamilial or CIDP
(LEGS>arms, DISTAL > Occult neoplasia sporadic mutations of Refsum disease
proximal) HIV infection genes Tangier disease
Paraproteinemia DNA testing is very Porphyria
Connective tissue helpful GBS
diseases Slowly progressive
CIDP Alcoholic-nutritional
polyneuropathy with CNS
Toxic neuropathies Toxic neuropathies
degeneration particularly
Vit. B deficiency / cerebellar ataxia is most
malnutrition
often hereditary

PURELY SENSORY Carcinoma


POLYNEUROPATHY NOT Paraprotinemia
CAUSED BY DIABETES Sjorgen syndrome
Primary and Familial
Amylodosis