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 [3].

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.

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.

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.

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.

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 [4].

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.

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 [5].

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).

In non-endemic areas the mean interval from onset to diagnosis of TTR-FAP is 3–4 years.

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 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.

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).

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.

GBS, vasculitis, heavy metal intoxication, poliomyelitis.

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. **