The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. These proteins include: transthyretin (ATTR, the most commonly implicated protein), apolipoprotein A1, and gelsolin.

Due to the rareness of the other types of familial neuropathies, transthyretin amyloidogenesis-associated polyneuropathy should probably be considered first.

"FAP-I" and "FAP-II" are associated with transthyretin. (Senile systemic amyloidosis [abbreviated "SSA"] is also associated with transthyretin aggregation.)

"FAP-III" is also known as "Iowa-type", and involves apolipoprotein A1.

"FAP-IV" is also known as "Finnish-type", and involves gelsolin.

Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis.

The familial amyloid neuropathies (or familial amyloidotic neuropathies, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy) are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.

Neuritis is a general term for inflammation of a nerve or the general inflammation of the peripheral nervous system. Symptoms depend on the nerves involved, but may include pain, paresthesia (pins-and-needles), paresis (weakness), hypoesthesia (numbness), anesthesia, paralysis, wasting, and disappearance of the reflexes.

Causes of neuritis include:

Polyneuropathy ( + + ) is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may progress to the arms and legs; and sometimes to other parts of the body where it may affect the autonomic nervous system. It may be acute or chronic. A number of different disorders may cause polyneuropathy, including diabetes and some types of Guillain–Barré syndrome.

Onset occurs in infancy or early childhood, usually before 3 years of age. Progression is slow until the teenage years at which point it may accelerate, resulting in severe disability.

Symptoms are usually more severe and rapidly progressive than in the other more common Charcot–Marie–Tooth diseases. Some patients may never walk and solely use wheelchairs by the end of their first decade, while others may need only a cane (walking stick) or similar support through life.

Dejerine–Sottas disease is characterized by moderate to severe lower and upper extremity weakness and loss of sensation, which occur mainly in the lower legs, forearms, feet and hands. Loss of muscle mass and reduced muscle tone can occur as the disease progresses. Other symptoms may include pain in the extremities, curvature of the spine, clawed hands, foot deformities, ataxia, peripheral areflexia, and slow acquisition of motor skills in childhood. Symptoms that are less common can include limitation of eye movements, other eye problems such as nystagmus or anisocoria, or mild hearing loss.

Mononeuritis multiplex, occasionally termed polyneuritis multiplex, is simultaneous or sequential involvement of individual noncontiguous nerve trunks, either partially or completely, evolving over days to years and typically presenting with acute or subacute loss of sensory and motor function of individual nerves. The pattern of involvement is asymmetric, however, as the disease progresses, deficit(s) becomes more confluent and symmetrical, making it difficult to differentiate from polyneuropathy. Therefore, attention to the pattern of early symptoms is important.

Mononeuritis multiplex also may cause pain, which is characterized as deep, aching pain that is worse at night and frequently in the lower back, hip, or leg. In people with diabetes mellitus, mononeuritis multiplex typically is encountered as acute, unilateral, and severe thigh pain followed by anterior muscle weakness and loss of knee reflex.

Electrodiagnostic medicine studies will show multifocal sensory motor axonal neuropathy.

It is caused by, or associated with, several medical conditions:

Among the signs/symptoms of polyneuropathy, which can be divided (into sensory and hereditary) and are consistent with the following:

- "Sensory polyneuropathy" - ataxia, numbness, muscle wasting and paraesthesiae.

- "Hereditary polyneuropathy" - scoliosis and hammer toes

Signs and symptoms of proximal diabetic neuropathy depend on the region of the plexus which is affected. The first symptom is usually pain in the buttocks, hips, thighs or legs. This pain most commonly affects one side of the body and can either start gradually or come on suddenly. This is often followed by variable weakness in the proximal muscles of the lower limbs. These symptoms, although often beginning on one side, can also spread . Weakness in proximal diabetic neuropathy is caused by denervation of the specific muscles innervated by regions of the plexus affected and can thus these muscles may start exhibiting fasciculations.

Note that diabetic amyotrophy is a condition caused by diabetes mellitus, but separate from the more common condition of polyneuropathy.

Dejerine–Sottas disease, also known as Dejerine–Sottas syndrome, Dejerine–Sottas neuropathy, progressive hypertrophic interstitial polyneuropathy of childhood and onion bulb neuropathy (and, "hereditary motor and sensory polyneuropathy type III" and "Charcot–Marie–Tooth disease type 3"), is a hereditary neurological disorder characterised by damage to the peripheral nerves and resulting progressive muscle wasting. The condition is caused by mutations in a various genes and currently has no known cure.

The disorder is named for Joseph Jules Dejerine and Jules Sottas, French neurologists who first described it.

The signs and symptoms of autonomic neuropathy include the following:

- Urinary bladder conditions: bladder incontinence or urinary retention

- Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, malabsorption, fecal incontinence, gastroparesis, diarrhoea, constipation

- Cardiovascular system: disturbances of heart rate (tachycardia, bradycardia), orthostatic hypotension, inadequate increase of heart rate on exertion

- Respiratory system: impairments in the signals associated with regulation of breathing and gas exchange (central sleep apnea, hypopnea, bradypnea).

- Nervous system: pupillary defect, exaggerated hippus, dizziness or lightheadedness.

- Other areas: hypoglycemia unawareness, genital impotence, sweat disturbances, sicca (dryness).

Raynaud's phenomenon is frequently the first manifestation of CREST/lcSSc, preceding other symptoms by years. Stress and cold temperature induce an exaggerated vasoconstriction of the small arteries, arterioles, and thermoregulatory vessels of the skin of the digits. Clinically this manifests as a white-blue-red transitions in skin color. Underlying this transition is pallor and cyanosis of the digits, followed by a reactive hyperemia as they rewarm. When extreme and frequent, this phenomenon can lead to digital ulcerations, gangrene, or amputation.

Ulceration can predispose to chronic infections of the involved site.

Presents as a sensation of food getting stuck (dysphagia) in the mid- or lower esophagus, atypical chest pain, or cough. Patients often state they must drink liquids to swallow solid food. This motility problem results from atrophy of the gastrointestinal tract wall smooth muscle. This change may occur with or without pathologic evidence of significant tissue fibrosis.

Proximal diabetic neuropathy, more commonly known as diabetic amyotrophy, is a nerve disorder that results as a complication of diabetes mellitus. It can affect the thighs, hips, buttocks or lower legs. Proximal diabetic neuropathy is a peripheral nerve disease (diabetic neuropathy) characterized by muscle wasting or weakness, pain, or changes in sensation/numbness of the leg. Diabetic neuropathy is an uncommon complication of diabetes. It is a type of lumbosacral plexopathy, or adverse condition affecting the lumbosacral plexus.

There are a number of ways that diabetes damages the nerves, all of which seem to be related to increased blood sugar levels over a long period of time. Proximal diabetic neuropathy is one of four types of diabetic neuropathy.

Proximal diabetic neuropathy can occur in type 2 and type 1 diabetes mellitus patients however, it is most commonly found in type 2 diabetics. Proximal neuropathy is the second most common type of diabetic neuropathy and can be resolved with time and treatment.

The American College of Rheumatology has outlined 19 syndromes that are seen in NPSLE. These syndromes encompass disorders of the central and peripheral nervous systems:

- Aseptic meningitis

- Cerebrovascular disease

- Demyelinating syndrome

- Headache

- Movement disorder

- Myelopathy

- Seizure disorders

- Acute confusional state

- Anxiety disorder

- Cognitive dysfunction

- Mood disorder

- Psychosis

- Acute inflammatory demyelinating polyradiculoneuropathy

- Autonomic disorder

- Mononeuropathy (single/multiplex)

- Myasthenia gravis

- Cranial neuropathy

- Plexopathy

- Polyneuropathy

Each of the 19 syndromes are also stand-alone diagnoses, which can occur with or without lupus.

The majority of cases involve the central nervous system (CNS), which consists of the brain and spinal cord. The CNS syndromes can be subcategorized as either focal or diffuse. The focal syndromes are neurological, while the diffuse syndromes are psychiatric in nature. The most common CNS syndromes are headache and mood disorder.

Though neuropsychiatric lupus is sometimes referred to as "CNS lupus", it can also affect the peripheral nervous system (PNS). Between 10-15% of people with NPSLE have PNS involvement. Mononeuropathy and polyneuropathy are the most common PNS syndromes.

There are several types of immune-mediated neuropathies recognised. These include

- Chronic inflammatory demyelinating polyneuropathy (CIPD) with subtypes:

- Classical CIDP

- CIDP with diabetes

- CIDP/monoclonal gammopathy of undetermined significance

- Sensory CIDP

- Multifocal motor neuropathy

- Multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome)

- Multifocal acquired sensory and motor neuropathy

- Distal acquired demyelinating sensory neuropathy

- Guillain-Barre syndrome with subtypes:

- Acute inflammatory demyelinating polyradiculoneuropathy

- Acute motor axonal neuropathy

- Acute motor and sensory axonal neuropathy

- Acute pandysautonomia

- Miller Fisher syndrome

- IgM monoclonal gammopathies with subtypes:

- Waldenstrom's macroglobulinemia

- Mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome

- Myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS)

For this reason a diagnosis of chronic inflammatory demyelinating polyneuropathy needs further investigations.

The diagnosis is usually provisionally made through a clinical neurological examination. Patients usually present with a history of weakness, numbness, tingling, pain and difficulty in walking. They may additionally present with fainting spells while standing up or burning pain in extremities. Some patients may have sudden onset of back pain or neck pain radiating down the extremities, usually diagnosed as radicular pain. These symptoms are usually progressive and may be intermittent.

Autonomic system dysfunction can occur; in such a case, the patient would complain of orthostatic dizziness, problems breathing, eye, bowel, bladder and cardiac problems. The patient may also present with a single cranial nerve or peripheral nerve dysfunction.

On examination the patients may have weakness, and loss of deep tendon reflexes (rarely increased or normal). There may be atrophy (shrinkage) of muscles, fasciculations (twitching) and loss of sensation. Patients may have multi-focal motor neuropathy, as they have no sensory loss.

Most experts consider the necessary duration of symptoms to be greater than 8 weeks for the diagnosis of CIDP to be made.

Typical diagnostic tests include:

- Electrodiagnostics – electromyography (EMG) and nerve conduction study (NCS). In usual CIDP, the nerve conduction studies show demyelination. These findings include:

1. a reduction in nerve conduction velocities;

2. the presence of conduction block or abnormal temporal dispersion in at least one motor nerve;

3. prolonged distal latencies in at least two nerves;

4. absent F waves or prolonged minimum F wave latencies in at least two motor nerves. (In some case EMG/NCV can be normal).

- Serum test to exclude other autoimmune diseases.

- Lumbar puncture and serum test for anti-ganglioside antibodies. These antibodies are present in the branch of CIDP diseases comprised by anti-GM1, anti-GD1a, and anti-GQ1b.

- Sural nerve biopsy; biopsy is considered for those patients in whom the diagnosis is not completely clear, when other causes of neuropathy (e.g., hereditary, vasculitic) cannot be excluded, or when profound axonal involvement is observed on EMG.

- Ultrasound of the periferal nerves may show swelling of the affected nerves

- MRI can also be used in the diagnosic workup

In some cases electrophysiological studies fail to show any evidence of demyelination. Though conventional electrophysiological diagnostic criteria are not met, the patient may still respond to immunomodulatory treatments. In such cases, presence of clinical characteristics suggestive of CIDP are critical, justifying full investigations, including sural nerve biopsy.

Usually manifesting itself between 20 and 40 years of age, it is characterized by pain, paresthesia, muscular weakness and autonomic dysfunction. In its terminal state, the kidneys and the heart are affected. FAP is characterized by the systemic deposition of amyloidogenic variants of the transthyretin protein, especially in the peripheral nervous system, causing a progressive sensory and motor polyneuropathy.

Diabetic neuropathy affects all peripheral nerves including sensory neurons, motor neurons, but rarely affects the autonomic nervous system. Therefore, diabetic neuropathy can affect all organs and systems, as all are innervated. There are several distinct syndromes based on the organ systems and members affected, but these are by no means exclusive. A patient can have sensorimotor and autonomic neuropathy or any other combination. Signs and symptoms vary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years.

Symptoms may include the following:

- Trouble with balance

- Numbness and tingling of extremities

- Dysesthesia (abnormal sensation to a body part)

- Diarrhea

- Erectile dysfunction

- Urinary incontinence (loss of bladder control)

- Facial, mouth and eyelid drooping

- Vision changes

- Dizziness

- Muscle weakness

- Difficulty swallowing

- Speech impairment

- Fasciculation (muscle contractions)

- Anorgasmia

- Retrograde ejaculation (in males)

- Burning or electric pain

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy (because it involves the nerve roots). CIDP is closely related to Guillain–Barré syndrome and it is considered the chronic counterpart of that acute disease. Its symptoms are also similar to progressive inflammatory neuropathy. An asymmetrical variant of CIDP is known as Lewis-Sumner Syndrome.

Autonomic neuropathy (also AN or AAN) is a form of polyneuropathy that affects the non-voluntary, non-sensory nervous system (i.e., the autonomic nervous system), affecting mostly the internal organs such as the bladder muscles, the cardiovascular system, the digestive tract, and the genital organs. These nerves are not under a person's conscious control and function automatically. Autonomic nerve fibers form large collections in the thorax, abdomen, and pelvis outside the spinal cord. They have connections with the spinal cord and ultimately the brain, however. Most commonly autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and 2. In most—but not all—cases, autonomic neuropathy occurs alongside other forms of neuropathy, such as sensory neuropathy.

Autonomic neuropathy is one cause of malfunction of the autonomic nervous system (referred to as dysautonomia), but not the only one; some conditions affecting the brain or spinal cord also may cause autonomic dysfunction, such as multiple system atrophy, and therefore, may cause similar symptoms to autonomic neuropathy.

A number of terms are used to describe critical illness polyneuropathy, partially because there is often neuropathy and myopathy in the same person, and nerve and muscle degeneration are difficult to distinguish from each other in this condition. Terms used for the condition include: critical illness polyneuromyopathy, critical illness neuromyopathy, and critical illness myopathy and neuropathy (CRIMYNE). Bolton's neuropathy is an older term, which is no longer used.

People with CIP/CIM have diffuse, symmetric, flaccid muscle weakness. CIP/CIM typically develops in the setting of a critical illness and immobilization, so patients with CIP/CIM are often receiving treatment in the intensive care unit (ICU).

Weakness (motor deficits) occurs in generalized fashion, rather than beginning in one region of the body and spreading. Limb and respiratory (diaphragm) muscles are especially affected. The muscles of the face are usually spared, but in rare cases, the eye muscles may be weakened, leading to ophthalmoplegia.

Respiratory difficulties can be caused by atrophy of the muscles between the ribs (intercostals), atrophy of the diaphragm muscle, and degeneration of the nerve that stimulates the diaphragm (phrenic nerve). This can prolong the time the wean a person off of a breathing machine (mechanical ventilation) by as much as 7 – 13 days.

Deep tendon reflexes may be lost or diminished, and there may be bilateral symmetric flaccid paralysis of the arms and legs. The nervous system manifestations are typically limited to peripheral nerves, as the central nervous system is usually unaffected.

Diffuse scleroderma can cause musculoskeletal, pulmonary, gastrointestinal, renal and other complications. Patients with greater cutaneous involvement are more likely to have involvement of the internal tissues and organs. Most patients (over 80%) have vascular symptoms and Raynaud's phenomenon, which leads to attacks of discoloration of the hands and feet in response to cold. Raynaud's normally affects the fingers and toes. Systemic scleroderma and Raynaud's can cause painful ulcers on the fingers or toes which are known as digital ulcers. Calcinosis (deposition of calcium in lumps under the skin) is also common in systemic scleroderma, and is often seen near the elbows, knees or other joints.

- Musculoskeletal

The first joint symptoms that patients with scleroderma have are typically non specific joint pains, which can lead to arthritis, or cause discomfort in tendons or muscles. Joint mobility, especially of the small joints of the hand, may be restricted by calcinosis or skin thickening. Patients may develop muscle weakness, or myopathy, either from the disease or its treatments.

- Lungs

Some impairment in lung function is almost universally seen in patients with diffuse scleroderma on pulmonary function testing; however, it does not necessarily cause symptoms, such as shortness of breath. Some patients can develop pulmonary hypertension, or elevation in the pressures of the pulmonary arteries. This can be progressive, and can lead to right-sided heart failure. The earliest manifestation of this may be a decreased diffusion capacity on pulmonary function testing.

Other pulmonary complications in more advanced disease include aspiration pneumonia, pulmonary hemorrhage and pneumothorax.

- Digestive tract

Diffuse scleroderma can affect any part of the gastrointestinal tract. The most common manifestation in the esophagus is reflux esophagitis, which may be complicated by peptic stricturing, or benign narrowing of the esophagus. This is best initially treated with proton pump inhibitors for acid suppression, but may require bougie dilatation in the case of stricture.

Scleroderma can decrease motility anywhere in the gastrointestinal tract. The most common source of decreased motility is the esophagus and the lower esophageal sphincter, leading to dysphagia and chest pain. As scleroderma progresses, esophageal involvement from abnormalities in decreased motility may worsen due to progressive fibrosis (scarring). If this is left untreated, acid from the stomach can back up into the esophagus, causing esophagitis and GERD. Further scarring from acid damage to the lower esophagus many times leads to the development of fibrotic narrowing, also known as strictures which can be treated by dilatation, and Barrett's esophagus.

Duodenum: In patients with neuromuscular disorders, particularly progressive systemic sclerosis and visceral myopathy, the duodenum is frequently involved. There may be dilatation, which is often more pronounced in the second, third and fourth parts. The dilated duodenum may be slow to empty and the grossly dilated, atonic organ may produce a sump effect.

The small intestine can also become involved, leading to bacterial overgrowth and malabsorption of bile salts, fats, carbohydrates, proteins, and vitamins. The colon can be involved, and can cause pseudo-obstruction or ischemic colitis.

Rarer complications include pneumatosis cystoides intestinalis, or gas pockets in the bowel wall, wide mouthed diverticula in the colon and esophagus, and liver fibrosis. Patients with severe gastrointestinal involvement can become profoundly malnourished.

Scleroderma may also be associated with gastric antral vascular ectasia (GAVE), also known as "watermelon stomach". This is a condition where atypical blood vessels proliferate usually in a radially symmetric pattern around the pylorus of the stomach. GAVE can be a cause of upper gastrointestinal bleeding or iron deficiency anemia in patients with scleroderma.

- Kidneys

Renal involvement, in scleroderma, is considered a poor prognostic factor and frequently a cause of death.

The most important clinical complication of scleroderma involving the kidney is "scleroderma renal crisis". Symptoms of scleroderma renal crisis are malignant hypertension (high blood pressure with evidence of acute organ damage), hyperreninemia (high renin levels), azotemia (kidney failure with accumulation of waste products in the blood) and microangiopathic hemolytic anemia (destruction of red blood cells). Apart from the high blood pressure, hematuria (blood in the urine) and proteinuria (protein loss in the urine) may be indicative.

In the past scleroderma renal crisis was almost uniformily fatal. While outcomes have improved significantly with the use of ACE inhibitors the prognosis is often guarded, as a significant number of patients are refractory to treatment and develop renal failure. Approximately 5–10% of all diffuse cutaneous scleroderma patients develop renal crisis at some point in the course of their disease. Patients that have rapid skin involvement have the highest risk of renal complications. It is most common in diffuse cutaneous scleroderma, and is often associated with antibodies against RNA polymerase (in 59% of cases). Many proceed to dialysis, although this can be stopped within three years in about a third of cases. Higher age and (paradoxically) a lower blood pressure at presentation make it more likely that dialysis is needed.

Treatments for scleroderma renal crisis include ACE inhibitors. Prophylactic use of ACE inhibitors is currently not recommended, as recent data suggest a poorer prognosis in patient treated with these drugs prior to the development of renal crisis. Transplanted kidneys are known to be affected by scleroderma and patients with early onset renal disease (within one year of the scleroderma diagnosis) are thought to have the highest risk for recurrence.

Neuropsychiatric systemic lupus erythematosus or NPSLE refers to the neurological and psychiatric manifestations of systemic lupus erythematosus. SLE is a disease in which the immune system attacks the body's own cells and tissues. It can affect various organs or systems of the body. It is estimated that over half of people with SLE have neuropsychiatric involvement.

In the skin, systemic sclerosis causes hardening and scarring. The skin may appear tight, reddish, or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage may weaken limbs and affect appearance. Patients report severe and recurrent itching of large skin areas. The severity of these symptoms varies greatly among patients: Some having scleroderma of only a limited area of the skin (such as the fingers) and little involvement of the underlying tissue, while others have progressive skin involvement. Digital ulcers — open wounds on especially on fingertips and less commonly the knuckles — are not uncommon.

Polyradiculoneuropathy describes a condition in which polyneuropathy and polyradiculopathy occur together. An example is Guillain–Barré syndrome.

Treatment with a single course of intravenous immunoglobulin (IVIG) infusions has been demonstrated to be a potentially effective treatment (reported to have caused prolonged remission in a case associated with systemic lupus (Systemic lupus erythematosus) ).