Pathologal nerve process
Additional neurological features
CMT (AD, AR. X-l)
1st–2nd decade (birth-adult)
Chronic motor-sensory polyneuropathy
De-remyelinating or axonal or intermediate
DNA: >30 genes known
± foot surgery
Variable spectrum of severity even within specific subtypes
Typical: usually poorly and slowly progressive without relevant functional impairment
Early onset: usually slowly progressive, with relevant functional impairment
dHMN (AD, AR. X-l)
1st–2nd decade (birth-adult)
Chronic distal motor neuropathy
(± Pyramidal syndrome)
DNA: >10 genes known
± foot surgery
Variable spectrum of severity even within specific subtypes
Typical: usually poorly and slowly progressive without relevant functional impairment
Early onset: usually slowly progressive, with relevant functional impairment
HSAN (AD, AR)
1st–2nd decade (birth-adult)
Chronic sensory (autonomic) neuropathy
DNA: >10 genes known
HSAN1 (SPTLC1 mutations): oral L-serine
Usually progressive, morbidity and mortality variable within different subtypes
1st–3rd decade (all decades)
Acute recurrent multifocal neuropathies
Demyelinating + tomacula
DNA (17p12 deletion or PMP22 mutations)
Rehabilitation ± othosis
Palsies may recur lasting for days to weeks (rarely months) usually without significant residual impairment
Carriers may be asymptomatic
2nd–3rd decade (all decades)
Acute recurrent brachial (rarely lumbar) plexopathies
Intense pain lasts for up two weeks and may result in chronic aching pain
Long-term prognosis is favorable with functional recovery in more than 90 % patients after 4 years
1st decade (typical: early childhood)
Axonal, giant axons
Optic atrophy, nystagmus, cerebellar ataxia, pyramidal syndrome
Curled hair and eyelashes
DNA: GAN ± sural nerve biopsy
Rehabilitation ± othosis
Typical: slowly progressive with death by late adolescence
Adult, (from 3rd–4th to 7th decade)
Axonal, focal amyloid deposits
(± Leptomeningeal amyloidosis)
Weight loss, cardiomyopathy, vitreus opacity, nephropathy
DNA: TTR ± fat periumbilical and/or sural nerve biopsy
First-line: orthotopic liver transplantation
Second-line: tafamidis, diflunisal, si-RNA, doxycycline + TUDCA
Relentless progression if untreated with death 10–15 years after onset
1st–5th decade (usually 1st–2nd)
Relapsing/remitting (or progressive) generalized polyneuropathy ± increased CSF proteins
Pigmentary retinopathy, pupillary abnormalities, hearing loss, anosmia, cerebellar ataxia
Heart, skeletal deformities, ichthyosis, cataract
Blood: phytanic acid
DNA: PHYH, PEX7
Dietary restriction (avoid phytol-containing fish oils, dairy products, ruminant fats)
Plasma exchange for exacerbations
Early diagnosis and continuative treatment lead to significant restoration of neurological function but cranial nerve dysfunction does not regress
Demyelinating, metachromatic inclusions
Progressive psychomotor regression, dysarthria, aphasia, blindness, nistagmus, ataxia, spasticity
Blood: ARSA activity
DNA: ARSA gene
Usually fatal with variations depending on presentation’s age (late-infantile, juvenile, adult)
Demyelinating, globoid macrophages
Progressive psychomotor regression, blindness, ataxia, spasticity
Blood: GALC activity
DNA: GALC gene
± sural nerve biopsy
Late-onset slower progression with peripheral neuropathy and spasticity as the only manifestations
Axonal (± demyelination)
CS lamellar inclusions
DNA: ABCD1 gene
Dietary restriction of VLCFA; “Lorenzo’s oil.” Corticosteroid replacement
Generalized acute polyneuropathy
Psychosis, convulsions, coma, SIADH
Urine: ALA, PGB and stool: copro-/uroporphyrins
Blood: PBG activity
DNA: PBG deaminase
Prevention of acute attacks (be aware of precipitating drugs)
For attacks: i.v. Glucose (10–20 g/h)
or i.v. hematin 1–5 mg/kg/d for 3–5 days
Neuropathy improves with treatment
Avoid precipitants factors
Axonal, small fibers
Lamellated ultrastructural inclusions in perineurial, endothelial, perithelial cells
Angiokeratoma, heart, kidney, corneal opacities, cataract
Blood: α-GLA activity
ERT therapy is beneficial for nephropathy and pain control
Course is slowly progressive
Death may occur by the 5th decade due to strokes or systemic complications
Pseudo-syringomyelic syndrome (or multifocal mononeuropathies)
Axonal, small fibers (demyelination)
CS lipid vacuoles
Large orange tonsils, ischemic cardiomyopathy, corneal opacity, hepatosplenomegaly, decreased cholesterol and HDL levels
Blood: cholesterol, VLDL
Specific treatment unavailable
Progressive course influenced by systemic complications (premature myocardial infarction (30 % of cases), stroke, thrombocytopenia
Axonal, no clusters of regenerating fibers
Pyramidalism, dysarthria, nistagmus
Cardiomyopathy, diabetes (consider diabetes neuropathy)
No proven effective disease modifying therapies. Idebenone is given to slow progression of cardiomyopathy
Cardiomyopathy is a frequent cause of premature mortality
Several therapeutic strategies under investigation
Blood: vitamin E
DNA: TTPA gene
Treatment with vitamin E slow progression
Onset (childhood or adult) and natural history influenced by residual TTP activity
Retinitis pigmentosa, acanthocytosis, malabsorption, hypocholesterolemia deficits, liposoluble vitamins
Blood: vitamin E, cholesterol, acanthocytosis
CIDP or CMT1-like evolution and features
± ptosis, ophthalmoparesis, leukoencephalopathy
Myopathy with RRF, mtDNA deletion and/or depletion
Severe gastrointestinal dysmotility (pseudo-obstruction), cachexia
Blood: reduced TYMP activity; increased urinary and plasma dThd, dUrd
DNA: TYMP mutations. Muscle: RRF and COX-fibers, mtDNA deletions
Continuous peritoneal dialysis. HSCT
Erythrocyte-entrapped enzymatic therapy
Caution with liver primary metabolizing drugs
Variable from rapid, often lethal course between 20–40 years to late-onset and slower forms 
Axonopathy or axonal-demyelinating
± dysarthria, ophthalmoparesis
Hearing loss, migraine, myopathy with RRF and mtDNA depletion
C10ORF72: mild or subclinical, rarely severe
NARP (matrilinear mtDNA)
Axonopathy (may be the unique feature)
Moderate to severe
(1) Chronic length–dependent polyneuropathies: hereditary motor-sensory neuropathies (alias CMT); distal hereditary motor neuropathies [(dHMN), alias spinal CMT or distal spinal muscular atrophy (dSMA)]; hereditary sensory and autonomic neuropathies (HSAN). (2) Relapsing/progressive motor–sensory polyneuropathies (Refsum disease). (3) Chronic, progressive, motor–sensory polyneuropathies with early small-fiber involvement (e.g., familial amyloid polyneuropathies). (4) Painful neuropathies (Fabry disease). (5) Acute generalized polyneuropathies (porphyrias). (6) Chronic sensory neuronopathies associated with hereditary ataxias. (7) Chronic sensory (and motor) neuropathies due to mitochondrial disorders . Recurrent focal neuropathies/plexopathies: hereditary neuropathy with liability to pressure palsies (HNPP); hereditary neuralgic amyotrophy (HNA).
Clinical picture; neurophysiology; DNA testing; other laboratory tests in selected disorders: blood biochemical tests; MRI and or ultrasonography (US); CSF analysis; nerve biopsy.
Top differential diagnosis
Phenotypically convergent acquired neuropathies.
Principles of treatment – Rehabilitation; symptomatic treatments (e.g., pain). Disease-modifying therapies available for selected forms, e.g., FAP (liver transplantation; pharmacotherapy; gene therapy); Fabry disease [Enzyme replacement therapy (ERT)]; acute intermittent porphyria [(AIP): hematine, glucose]; Refsum disease [diet; plasma exchange (PE); mitochondrial neurogastrointestinal encephalopathy [MNGIE: ERT, allogenic hematopoietic stem cell transplantation (HSCT)]. Disease-modifying therapies under investigation for many forms, e.g., CMT.
Outcome and disability – Variable, from minor disability throughout life (e.g., CMT) to relentless fatal course over years if untreated (e.g., FAP).
35.1.1 Charcot-Marie-Tooth Disease (CMT)
Alias: Hereditary Motor and Sensory Neuropathy (HMSN) or peroneal muscular atrophy.
The most frequent hereditary neuromuscular disorder with a general prevalence of about 1:2500. All modes of Mendelian inheritance are possible. In most European and US populations, 90 % of cases are autosomal dominant or X-dominant (CMTX), while 10 % are autosomal recessive. Autosomal dominant CMT: demyelinating subtypes (CMT1) more common (60 %) than the axonal subtypes (CMT2) (40 %), but the true prevalence of CMT2 is unknown and approximately 70 % of the CMT2 genes remain unidentified .
126.96.36.199 Clinical Features
associated to CMT1, CMTX, and CMT2: onset in infancy or childhood, difficulty in running, twisting of ankles, pes cavus (planus at onset) and hammertoes, progressive peroneal atrophy with steppage gait, foot drop, mild sensory ataxia, weakness/wasting of hand intrinsic muscles, stocking-glove multimodal sensory loss.
Clinical clues: positive family history, presentation in the first-second decade, long and slow progression, foot deformities, paucity of positive sensory symptoms, degree of functional impairment milder than neurophysiological involvement. Postural tremor may be prominent independently of genetic subtypes (Roussy-Lévy syndrome).
Caveats: truly isolated cases may occur, caused by de novo dominant mutations. Dominant forms may be associated to age-independent intrafamilial phenotypical variability, from asymptomatic to severe disease. CMTX may be suggested by pedigree analysis (no male-to-male transmission; males affected, females asymptomatic or mildly affected) but a few CMTX females may be severely affected.
with perinatal onset, hypotonia, and breathing difficulties, or with delay of motor milestones. Severe weakness and wasting of distal and proximal muscles, sensory ataxia, foot and spine deformities, possible cranial involvement (mild ophthalmoparesis, facial weakness, neurosensorial hearing loss, vocal cord paralysis). Inheritance may be autosomal dominant with most cases isolated due to de novo mutations (demyelinating CMT3 alias Dejerine-Sottas disease), or autosomal recessive (demyelinating CMT4, or axonal AR-CMT2).
Adult Onset Phenotype
Associated to CMT1B, CMTX women, CMT2. Symptoms develop after 40–50 years.
CMTX may be suggested by marked involvement of abductor pollicis brevis; exceptional CMTX cases may present acute transitory leukoencephalopathies. Adult onset CMT2 may be associated with pupillary abnormalities, hearing loss and/or paresthesias/pain (CMT2I/J). CMT2 may be associated with optic neuritis/optic atrophy (CMT2-VI) or with brisk reflexes in the upper and proximal lower limbs (CMT2-V). Some genetic subtypes of CMT2 have a prevalent motor (CMT2F) or sensory involvement (CMT2B) that may affect prevalently the arms (CMT2D), or cause vocal cord paralysis (CMT2C).
188.8.131.52 Diagnostic Markers
No biochemical markers available.
Causal genes have been increasingly identified (more than 50 genes known, updated database at www.molgen.ua.ac.be/CMTMutations/). Many genes are tested currently by Sanger sequencing using a single-gene approach based on mutational frequencies; high throughput mutational analysis done by next-generation-sequencing techniques is becoming available for diagnostic purposes. Approximately 80–90 % of CMT1 have the duplication of chromosome 17p12 (PMP22 gene), the remaining have mutations (mostly point mutations) in GJB1/Cx32 (CMT1X, 6–20 %), MPZ/P0 (CMT1B, 5 %), EGR2, PMP22, LITAF/SIMPLE. Only 25–30 % of CMT2 receive a molecular diagnosis having mutations of MFN2 (CMT2A, 10–20 % of all cases), GJB1/Cx32 (CMTX), MPZ/P0 (CMT2J), NEFL (CMT2E), GDAP1 (CMT2K), HSPB1 (CMT2F), TRPV4 (CMT2C), GARS (CMT2D), or even other rarer genes. Dominant intermediate CMT is most frequently reported to be associated with GJB1 (CMTX), NEFL (CMT2E), and DNM2 (CMT2M). Autosomal recessive CMT is most frequently associated with mutation of SH3TC2 (CMT4C, early, prominent kyphoscoliosis), GDAP1 (CMT4A, AR-CMT2, AR- CMT intermediate), HINT1 (predominant motor ± neuromyotonia).
Is not analyzed with exception of the differential diagnosis with acquired neuropathies, when molecular investigations are negative, or for the diagnosis of an acquired disorder superimposed onto a known genetic neuropathy. Mildly increased protein content is occasionally found in CMT1 and CMT3, without any clear-cut boundary levels with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
In CMT1-CMT3 inversion recovery (STIR)-MRI neurography may disclose hypertrophy ± MRI contrast enhancement of spinal roots, cauda equina, plexuses and/of median and ulnar nerves; ultrasound (US) discloses marked and diffuse increase of the cross-sectional area (CSA).
Autosomal dominant CMT1 and CMT3, and autosomal recessive CMT4: uniformly slow nerve conduction velocities (NCV) with median and ulnar motor NCV (MNCV) < 38 m/s (below 12 m/s in CMT3) and proportionate delay in distal motor latencies and F-wave latencies. There is a relative preservation of CMAP while SAP decreases or is absent. In CMT1, NCV changes are fully penetrant independently of the clinical status. Autosomal dominant CMT2 and autosomal recessive AR-CMT2: NCV is preserved or mildly decreased (usually median or ulnar MNCV > 38 m/s), while CMAP and SAP are reduced. In CMT2, the electrodiagnostic changes may have incomplete penetrance. CMT1X male and rare autosomal dominant intermediate DI-CMT: median or ulnar MNCV between 25 and 45 m/s; MNCV is normal or slightly reduced in CMT1X women. In CMT1X, nerve conduction abnormalities may be non-uniform between and within nerve trunks with excessive temporal dispersion and conduction blocks.
A sural nerve biopsy is no longer indicated unless for a differential diagnosis with other inherited neuropathies or with various, eventually superimposed, acquired neuropathies.
Besides demonstrating hypertrophic de-remyelination (CMT1, CMT4), hypo-amyelination (CMT3), or a chronic axonal neuropathy (CMT2), nerve biopsy may disclose additional pathological abnormalities of peculiar genetic forms: outfoldings and myelin uncompaction in CMT1B; prominent myelin outfoldings and/or basal-lamina SC onion bulbs in some CMT4 subtypes; giant axons in CMT2E.
184.108.40.206 Top Differential Diagnoses
CMT1: CIDP, anti-MAG neuropathy, familial amyloid polyneuropathies (FAP).
CMT3: metachromatic leukodystrophy, hereditary ataxias, Refsum disease, mitochondrial encephalomyopathies (MNGIE).
CMT2: acquired axonal neuropathies, FAP, distal myopathy, dHMN, HSAN, spinal dysraphism, mitochondrial encephalomyopathies (MNGIE, POLG1 mutations), GAN.
CMT5: hereditary spastic paraplegias (HSP).
There are no specific medical therapies for any of the genetic subtypes. Treatment is supportive with rehabilitation and orthotics. Mild-to-moderate exercise is safe and likely effective. Effects of high-resistance training are controversial because it could result in overwork-weakness. Passive stretching is advised to prevent and counteract tendon retractions. Plantar and/or custom-fitted ankle-foot orthoses are prescribed to correct foot position and to overcome foot drop.
Different surgical interventions for foot deformities.
Symptomatic therapy of neuropathic pain, joint/bone pain, paresthesias, cramps, fatigue, and restless leg syndrome is done as for other neuropathies.
Genetic counseling of probands and families is mandatory for diagnostic, predictive, prenatal, and pre-implantation testing.
Independently of the primary demyelinating or axonal process, evolution is associated with axonal loss. CMT-neuropathy score (CMT-NS), a composite clinical and neurophysiological score, is a validated tool for natural-history studies; patients are classified as mild (≤10), moderate (11–20), or severe (>20); in CMT1A the mean annual progression is 0.69 points/year. Most patients with CMT1A and CMT1X do not require ambulation aids beyond ankle-foot orthoses. CMT3 patients may require above-the-knee bracing, walkers, or wheelchairs by 20 years of age.
Periods of self-limiting worsenings may be related to growth in childhood and adolescence. Acute or subacute worsenings should prompt to exclude a superimposed, treatable, acquired neuropathy (e.g., GBS, CIDP, diabetic neuropathy).
Guillain-Barré syndrome or GBS-like syndromes have been reported after chemotherapy; cancer in CMT should be treated with less neurotoxic chemotherapeutic agents.
Some patients report faster deterioration during pregnancy, usually but not always, with recovery.
Anesthetics are well tolerated but regional anesthesias are considered somewhat contraindicated.
35.1.2 Hereditary Neuropathy with Liability to Pressure Palsy (HNPP)
220.127.116.11 Terminology and Definitions
HNPP (alias tomaculous neuropathy) is an autosomal dominant demyelinating polyneuropathy manifesting most frequently with acute/subacute painless palsies at common entrapment sites, caused by haploinsufficiency of PMP22 (commonly associated to the 1.4 Mb deletion of chromosome 17p12).
Prevalence is theoretically similar to CMT1A. Up to 25 % of the carriers of the 17p12 deletion may be asymptomatic, having a subclinical polyneuropathy. All ages are involved; the first episode is usually in the second-third decade, occasionally in childhood.
18.104.22.168 Clinical Features
Typical Presentation (Approximately Two-Thirds of Patients)
episodic, painless, recurrent focal, and motor palsies affecting variably the median, ulnar, peroneal nerves or brachial plexus often preceded by minor compression or trauma at vulnerable sites (wrist, elbow, knee, shoulder). Palsies may be debilitating and last for days or weeks (or rarely months). Besides episodes, patients often complain of positional acroparesthesias and disclose reduced or absent deep tendon reflexes and mild pes cavus.
may occur in up 30 % of patients and include: chronic sensory polyneuropathies, CMT1-like polyneuropathies, chronic ulnar neuropathies, acute syndromes with multiple limbs involved, carpal tunnel syndromes.
Haploinsufficiency associated to the common deletion of PMP22 (90–95 % of cases) or to rare micromutations cause a mild chronic demyelinating polyneuropathy marked by sausage-like “tomaculous” focal thickenings of the myelin sheath. Focal constrictions of axons segments enclosed by tomacula may predispose to mechanically induced CB and acute clinical deficits.
22.214.171.124 Diagnostic Markers
The most common molecular lesion is the 1.4 Mb 17p12 (PMP22) deletion. A minority of cases (approximately 5 %) have micromutations of PMP22 (nonsense or frameshifting mutations).
US may disclose nerve enlargements at multiple sites of entrapment but its sensitivity and specificity is still limited.
Neurophysiological testing provides a reliable picture even in asymptomatic cases. Distal motor latencies (DML) are prolonged in median, ulnar nerves, and peroneal nerves with only mild slowing in the distal segments (median MNCV usually above 38 m/s); SAPs are diffusely reduced; coNduction blocks CB over entrapment sites are characteristic in symptomatic nerves.
Sural nerve biopsy has full specificity and almost complete sensitivity but is no longer indicated. It discloses a chronic demyelinating polyneuropathy with a variable number of tomacula (sausage-like myelin thickenings) in semithin and ultrathin sections and in teased fibers.
126.96.36.199 Top Differential Diagnoses
Entrapment neuropathies. Vasculitic neuropathies. Familial carpal tunnel syndrome (CTS). Idiopathic and hereditary neuralgic amyotrophy (HNA).
HNA is an autosomal dominant disorder caused by mutations or intragenic duplications of the septin 9 (SEPT9) gene that manifests with recurrent attacks of pain, weakness, and sensory disturbance with predilection for the brachial plexus. It progresses 2–3 weeks after the onset of pain and involves, in some cases, the phrenic nerves and/or cranial nerves VII and X. Associated features include: short stature, hypotelorism, long nasal bridge, cleft palate, epicanthal folds, facial asymmetry, and partial syndactyly. HNA may develop in all ages (most commonly in the second-third decade), possibly triggered by periods of physical (partum), immunological, or emotional stress.
188.8.131.52 Prognosis and Therapy
Management is mainly preventive: employment or recreational activities which increase the risk of nerve compression should be avoided. Obstetricians and surgeons should be informed of the diagnosis, to avoid prolonged positioning of the body and limbs. Peripheral regional anesthesia is somewhat contraindicated. Surgery is sometimes offered for nerve entrapment release but any benefit tends to be short-lived.
Life expectancy is normal and most patients have a good quality of life. About 10 % of patients make an incomplete recovery from episodes of nerve palsy due to persistent CBs. Age-related irreversible motor axonal damage may ensue at entrapment sites .
Management is mainly preventive: employments or recreational activities with increased risk of nerve compression should be avoided. Obstetricians and surgeons should be informed of the diagnosis to avoid prolonged positioning of the body and limbs.
35.1.3 Familial Amyloid Polyneuropathies (FAP)
184.108.40.206 Terminology and Definitions
Autosomal dominant disorders associated with the extracellular deposition of amyloid fibrils made of the mutated proteins: transthyretin (TTR), apolipoprotein A1 (APOA1), or gelsolin (GSN). TTR is a plasma transporter for thyroxine and vitamin A produced predominantly by liver.
TTR-FAP variants are world widely distributed: incidence in the USA is 1:100,000 individuals; the Val30Met variant is endemic in some areas of northern Portugal (incidence 1 in 538 individuals), northern Sweden, Japan, and Brazil. GSN-FAP has some clusters in southeastern Finland and it is very rare in other European countries, USA, and Japan. APOA1-FAP, described in an Iowa kindred with British extraction, was also reported in rare families with different ancestries .
220.127.116.11 Clinical Features
Val30Met in endemic areas: onset in third-fourth decade, relentless sensory-motor-autonomic polyneuropathy with superimposed CTS, cardiac and kidney dysfunction.
Clues to diagnosis: stabbing lancinating pain, gastrointestinal motility disturbances, erectile dysfunction, orthostatic hypotension, neurogenic bladder, bulbar involvement, cardiomyopathy with thickened ventricular walls, advanced atrio-ventricular block, cotton-wool inclusions of vitreous body, glaucoma, albuminuria, hyperazotemia.
Val30Met in non-endemic areas and other molecular variants: reduced penetrance (less than 50 %), later adult onset (up to seventh decade, mean age 55–60 years), lack of familiarity, CIDP or Amyotrophic Lateral Sclerosis (ALS)-like evolution with fasciculations, lack of pain or dysautonomia, much later multi-system involvement, isolated CTS preceding polyneuropathy of several years. A minority of TTR mutations may lead to selective oculo-leptomeningeal amyloidosis (stroke, seizures, hydrocephalus, spinal cord infarction, vitreous opacities) or cardiac amyloidosis (restrictive cardiomyopathy).
Onset in third-fourth decades. Corneal lattice dystrophy, multiple cranial neuropathies (facial and bulbar weakness), cutis laxa. Late generalized polyneuropathy. Symptoms generally worsen with age.
Onset in the third-fourth decades. Painful, autonomic, sensorimotor polyneuropathy. Early renal involvement, peptic ulcer disease.
In non-endemic areas the mean interval from onset to diagnosis of TTR-FAP is 3–4 years.
Mutational analysis of involved genes.
Analysis is not indicated; when done may be misleading revealing an increased protein content.
Some serum variants of TTR may be detected by mass spectrometry (not routinely); plasma NT-proBNP, high sensitivity troponin, creatinine clearance and albuminuria (for evaluating cardiac and renal progression).
TTR–FAP: NCV studies consistent with an axonal polyneuropathy ± CTS, sometimes with a demyelinating polyneuropathy . EMG: denervation. Autonomic tests: sympathetic skin reflex, quantitative sensory testing (QST), beat-to-beat heart rate variability (HRV: ECG rate monitoring while breathing in-and-out at six breaths per minute).
ECG and Two-Dimensional Echocardiography
TTR–FAP: cardiac assessment and non-invasive diagnosis of amyloidotic cardiomyopathy.
TTR–FAP: cardiac magnetic resonance (delayed gadolinium enhancement to detect amyloid in the myocardial interstitium).
Scintigraphy with 99mTc-DPD to image amyloid in the myocardium. Scintigraphy with 123I-MIBG to reveal loss of sympathetic nerve endings in heart. Scintigraphy with 123I-SAP to evaluate extent and distribution of amyloid deposits in soft tissues and visceral organs except heart.
TTR–FAP: demonstration of amyloid deposits by Congo red staining (green birefringence under polarized light) and electron microscopy is essential for eligibility for liver transplantation. Sensitivity is as follows: subcutaneous fat approximately 60 % (repeatable); sural nerve or gastrointestinal mucosa approximately 80 %. Immunohistochemistry with anti-TTR antibodies is mandatory to characterize the biochemical nature of the amyloid fibrils. Liquid chromatography-tandem mass spectrometry may also identify precursor proteins of amyloid fibrils, including variant TTR.
18.104.22.168 Top Differential Diagnoses
AL (amyloid light chain)-amyloidosis. Diabetic, alcoholic neuropathies. CIDP. Paraneoplastic neuropathies. CMT2. Fabry disease. ALS.
Orthotopic liver transplantation (OLT) is the first line therapy, removing approximately 95 % of mutant blood TTR. OLT is indicated in early stages with bioptically proven amyloidosis ; [see also Familial Amyloidotic Polyneuropathy world Transplant Registry and Domino Liver Transplant Registry (www.fapwtr.org)].
Life expectancy is better in Val30Met patients (10-year survival approximately 74 % compared with 44 % in non-Val30Met patients), in patients transplanted earlier in the disease, in patients <50 years. Low modified body mass index (<600) is a negative predictor. Besides life expectancy, some Val30Met patients reported improvement of gastrointestinal, autonomic, peripheral-nerve symptoms, but recovery of nerve function does not occur. Patients in later stages and some non-Val30Met patients disclose progression after transplantation due to continued deposition of wild type TTR and/or of the mutant TTR in heart (progressive restrictive cardiomyopathy, cardiac autonomic denervation) and PNS.
OLT is not indicated in predominantly leptomeningeal amyloidosis.
Combined heart and liver transplant is indicated in severe heart failure due to amyloidotic cardiomyopathy in patients without advanced neurologic involvement. Liver transplant is also an option for non-Val30Met candidates with echocardiographic evidence of cardiomyopathy.
Domino liver transplant of FAP-livers in patients with liver failure is an accepted procedure but it may lead to TTR-FAP in the recipients after 8–10 years.
The following pharmacotherapies are a second line option for patients not eligible for OLT or waiting for OLT in early stages of disease : kinetic stabilizers (tafamidis, authorized for marketing in Europe for early stages of disease; diflunisal); fibril disruptors (oxycycline/tauroursodeoxycholic acid). Gene-therapy approaches are becoming available including antisense oligonucleotides (ASO) and RNA interference-based molecules vehicled by lipid nanoparticles.
TTR–FAP is relentlessly progressive. Untreated patients with the classical Portuguese phenotype die 10–15 years after onset because of malnutrition, cardiac or renal failure, or cardiac arrhythmias (Transthyretin Amyloidosis Outcomes Survey –THAOS – www.thaos.net).
Follow-up should be done every 6 months including neurological disability scores, full neurophysiological and cardiological laboratory tests, and evaluation of the modified body mass index (BMI) (BMI multiplied by serum albumin level). Degrees of clinical involvement: 0 = no symptoms, variant TTR form, evidence of amyloid deposits; I = unimpaired ambulation; mostly mild sensory, motor, and autonomic neuropathy in the lower limbs; III = assistance with ambulation required; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk; III = wheelchair-bound or bedridden; severe sensory, motor, and autonomic involvement of all limbs.
35.1.4 Porphiric Neuropathy
22.214.171.124 Terminology and Definitions
Acute neuropathy resembling Guillain-Barré syndrome (GBS), associated to dysfunction of the autonomic and central nervous systems. Neuropathic porphyrias are caused by the following autosomal dominant enzymatic defects in the hepatic biosynthesis of heme: porphobilinogen (PBG) deaminase (acute intermittent porphyria – AIP); copro oxidase (hereditary coproporphyria – HCP); proto oxidase (variegate porphyria – VP).
Carriers of the genetic defect are estimated to be 1/80.000 people; prevalence was 20-times higher in the psychiatric hospital populations in the USA. Ten to forty percent of carriers may develop neuropathy. Attacks are five times more frequent in women and manifest usually in the third and fourth decades.
Predominantly proximal motor axonal damage with Wallerian degeneration and secondary demyelination. Peripheral and central neuronal involvement might result from impaired energy metabolism due to heme deficiency and/or toxicity by the common precursor δ-aminolevulinic acid (ALA).
126.96.36.199 Clinical Features
Acute attacks are often triggered by fasting, porphyrinogenic treatments (estrogen/progesterone contraceptives, barbiturates, sulfonamides, antiepileptics, any drug that is metabolized by the P450 system), sepsis or alcohol (possibly misinterpreted as acute intoxication). Attacks feature the classic triad of abdominal pain, psychosis, and neuropathy. They manifest as an autonomic neuropathy (resting tachycardia, papillary abnormalities, abdominal pain, nausea, vomiting, and severe constipation mimicking a surgical abdomen) and neuropsychiatric changes (anxiety, insomnia, seizures, hallucinations, sudden changes in behavior; the recurrence during the luteal phase may be misdiagnosed as a bipolar disorder). Motor neuropathy manifests subacutely 3–75 after onset (within 1 month in 80 % of cases) and progresses symmetrically for over 1 month; at nadir total quadriplegia and respiratory insufficiency may ensue requiring ventilatory support; facial and bulbar weakness are common. Evolution may be descendent from arms to legs with rapid muscle wasting. Sensory symptoms may be associated or not to distal sensory loss; tendon reflexes are diminished or absent, rarely retained. Atypical presentations include progressive motor neuropathies, mostly affecting the upper limbs, without abdominal pain.
Patients with HCP and VP may develop cutaneous photosensitivity in adult life.
188.8.131.52 Top Differential Diagnosis
GBS, vasculitis, heavy metal intoxication, poliomyelitis.
184.108.40.206 Diagnostic Markers
Proteins can be normal or mildly elevated.
Blood and Urine
The diagnosis of porphiric attack is made revealing a marked elevation of PBG and ALA in blood, urine, and stool. During an attack, urine may be brown reflecting high concentration of porphyrin metabolites. Enzymatic assays may identify and distinguish among hepatic porphyrias, but the results may be misleading.
NCV studies show an axonal neuropathy with decreased amplitudes of motor responses and possible slowing of conduction velocities secondary to large-fiber loss, without CB or abnormal temporal dispersion; sensory function is relatively or completely spared. EMG demonstrates prominent fibrillation potentials within weeks of onset, most prominent in proximal muscles.
220.127.116.11 Prognosis and Therapies
Once aborted, the prognosis of a single attack is generally good with rapid resolution of the autonomic and psychiatric symptoms. Recovery of neuropathy is slower, often occurring over many months (approximately 10 months for proximal muscles and 20 for distal muscles), usually with incomplete recovery. Sixty-eighty percent of patients have a single acute attack of porphyria. Since cumulative fixed deficits may ensue after repeated attacks, the long-term prognosis depends on successful prevention of attacks.
The prognosis of AIP is good even in severe, acute attacks. Anyway, AIP carries a potentiality fatal outcome due to motor and autonomic involvement with respiratory and bulbar paralysis and/or cardiac arrhythmias.
Prevention is based by awareness and avoidance of precipitating drugs and situations. During an attack abortive therapies include IV glucose (10–20 g/h) followed, if there is no improvement, by IV hematin (1–5 mg/kg/day infused over 30–60 min); supportive therapies are discussed in the following section of GBS. **
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35.2 Title: Immunomediated Neuropathies
Terminology and definitions
Acute forms – GBS: acute inflammatory polyradiculoneuropathies reaching their maximal severity within 4 weeks. Variants AIDP, AMAN, acute motor-conduction-block neuropathy, AMSAN, acute sensory neuronopathy, MFS, GBS-MFS overlaps, acute panautonomic neuropathy. MFS: acute ataxia, with ophthalmoplegia and areflexia.
Chronic forms CIDP = Acquired demyelinating neuropathy reaching maximal severity in at least 8 weeks.:
MMN = Peripheral neuropathy with slowly progressive or remitting asymmetric distal weakness and persistent motor conduction blocks, without significant sensory loss.
Acute forms – Incidence: 1.8/100,000 for GBS; 0.1/100,000 for MFS. Gastrointestinal or respiratory upper-tract infection before onset in 66 % of patients. Progressive weakness of both legs and arms with areflexia characterize AIDP, AMSANm AMAN.
In MFS ophthalmoparesis may develop asymmetrically but often becomes complete; pupillary involvement is uncommon.
Chronic forms – CIDP prevalence: 1.97–4.77/100,000. Typical forms (80 % of cases) are characterized by symmetrical distal and proximal weakness, sensory loss and paresthesias, absent deep tendon reflexes with progressive or relapsing/remitting course.
MMN prevalence: 1–2/100,000. MMN show weakness developing over months or years with a multifocal asymmetric distribution in individual nerves and usually prominent in the distal arms.
Blood – Ig auto-Ab anti-GM1 in: AMAN, AMSAN, and acute motor-conduction-block neuropathy. MFS: Ab anti-GQ1b in 95 % of patients.
MMN – IgM auto-Ab anti-GM1 in 40–50 % of patients.
CSF – Albumin-cytologic dissociation. Normal in MMN.
MRI – Possible enhancement and/or hypertrophy of the cauda equina, lumbosacral nerve roots, brachial and lumbosacral plexuses.
Neurophysiology – Demyelination and CBs in AIDP and CIDP; axonopathy in AMAN.
Top Differential Diagnoses
Acute forms – Polymyositis, myasthenia gravis, CIDP. MFS: Brainstem ischemia, Wernicke’s encephalopathy.
Chronic forms – CIDP: Polyneuropathies of different cause; Myopathies.
MMN: Motor neuron disorders. CIDP. Myopathies.
Prognosis and Principles of treatment
Acute forms – PE or IVIg within the first 2–4 weeks from onset.
Chronic forms – CIDP: Steroids, PE and IVIg. MMN: IgIV are effective in 79–86 % of patients. Steroids are contraindicated in MMN.
Acute forms – GBS: 5 % of patients die, 5–10 % remain disabled or severely fatigued, 15 % are asymptomatic 1–2 years after onset. MFS: mostly benign. Recovery takes a median of 1–3 months. By 6 months, most patients are free from ataxia and ophthalmoparesis.
Chronic forms – CIDP: age <45 years predicts a better outcome; axonal loss is associated with poorer prognosis. In the long term, mortality ranges from 1.3 to 9 %; 40 % of patients have no or non-disabling symptoms, 75 % are able to work, 24 % carry severe handicap.
MMN: very uncommon spontaneous remissions. In the long term, 1/3 of patients improves, 1/3 is IgG dependent, and 1/3 continues to be non-responsive.
35.2.1 Guillain-Barré Syndrome (GBS)
18.104.22.168 Definition and Terminology
GBS is an acute, inflammatory, areflexic paralysis with variable degree of weakness that reaches maximal severity within 4 weeks, usually with an ascending progression from lower to upper limbs and cranial nerves, and albuminocytologic dissociation .
Clinical and/or electrophysiological variants:
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
Acute motor axonal neuropathy (AMAN)
Acute motor-conduction-block neuropathy
Acute motor-sensory axonal neuropathy (AMSAN)
Acute sensory neuronopathy
Miller-Fisher syndrome (MFS)
Acute panautonomic neuropathy
Worldwide mean annual incidence is 1.8 per 100,000 for GBS (ranging from 0.8 for age <18 years to 3.2 for age >60 years) and 0.1 per 100,000 for MFS. Males are affected more frequently than females (1.5:1). AIDP accounts for 90 % of cases in North America and Europe; AMAN accounts for 30–47 % of cases in Asia and Central and South America and 5 % of cases in Western countries. AIDP is non-seasonal; AMAN may occur in summer epidemics in northern China affecting children and young adults and is likely associated with Campylobacter (C.) jejuni infections.
Two-thirds of patients report an event 1–4 weeks before onset, most frequently symptoms or signs of gastrointestinal or respiratory upper-tract infection: C. jejuni (30 %), cytomegalovirus (CMV) (10 %), Epstein-Barr virus, Varicella-zoster virus, HIV, Mycoplasma pneumoniae, Haemophilus influenzae.
Incidence of GBS is 0.25–0.65 per 1000 cases of C. jejuni infection and 0.6–2.2 per 1000 cases of primary CMV infection. Less frequent antecedents: vaccinations (only brain-derived rabies vaccines have been associated with elevated risk above the background incidence), drugs (heroin, streptokinase, suramin, gangliosides), or surgical procedures.
Immune-mediated disorders resulting from generation of autoimmune antibodies and/or inflammatory cells which cross-react with epitopes on peripheral nerves and roots, leading to demyelination or axonal damage or both. Molecular mimicry may involve ganglioside epitopes of myelin (AIDP) or axonal membranes (AMAN) and lipopolysaccharide epitopes of infectious agents. Antiganglioside antibodies that cross-react with C. jejuni are common in AMAN and AMSAN (anti-GM1 in 65 % of patients); MFS (anti-GQ1b in more than 90 % of patients) and acute sensory neuronopathy (anti-GD1B).
In AIDP anti-myelin antibodies directed against epitopes on the abaxonal SC membrane may lead to demyelination with activation of complement and recruitment of macrophages, followed by secondary axonal degeneration. In AMAN anti-GM1 antibodies react against epitopes at nodes of Ranvier and along the axolemma of motor fibers; activation of complement and recruited macrophages lead to Wallerian degeneration.
Diagnosis is based on clinical characteristics and ancillary laboratory investigations . New criteria to better identify patients for vaccine safety studies are under validation .
Required features: progressive weakness of both legs and arms; areflexia. Supportive features: progression over days to 4 weeks (more often with ascending evolution); relative symmetry of symptoms and signs; mild sensory symptoms or signs (distally decreased vibration sense); moderate-severe pain in extremities, interscapular area or back (in up 89 % of patients in the acute phase); bifacial palsies (45–75 % of patients, whereas involvement of extraocular muscles and lower cranial nerve is less common); autonomic instability (in up to 65 % of patients); monophasic evolution pattern with recovery beginning 2–4 weeks after progression ceases.
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