Familial dysautonomia is inherited in an autosomal recessive pattern, which means 2 copies of the gene in each cell are altered. If both parents are shown to be carriers by genetic testing, there is a 25% chance that the child will produce FD. Prenatal diagnosis for pregnancies at increased risk for FD by amniocentesis (for 14–17 weeks) or chorionic villus sampling (for 10–11 weeks) is possible.

Genetic testing is performed on a small sample of blood from the tested individual. The DNA is examined with a designed probe specific to the known mutations. The accuracy of the test is above 99%. Dr. Anat Blumenfeld of the Hadasah Medical center in Jerusalem identified chromosome number 9 as the responsible chromosome.

Patients with hereditary motor and sensory neuropathies are diagnosed through a physical evaluation that looks for muscle atrophy, weakness, and sensory responses. In addition to this, EMG (electromyography) and motor nerve conduction tests can help clinicians decide what type of motor and sensory neuropathy it is and how severe the disease is. Final confirmation can come through genetic testing.

Diagnosis is clinical and initially consists of ruling out more common conditions, disorders, and diseases, and usually begins at the general practitioner level. A doctor may conduct a basic neurological exam, including coordination, strength, reflexes, sensation, etc. A doctor may also run a series of tests that include blood work and MRIs.

From there, a patient is likely to be referred to a neurologist or a neuromuscular specialist. The neurologist or specialist may run a series of more specialized tests, including needle electromyography EMG/ and nerve conduction studies (NCS) (these are the most important tests), chest CT (to rule out paraneoplastic) and specific blood work looking for voltage-gated potassium channel antibodies, acetylcholine receptor antibody, and serum immunofixation, TSH, ANA ESR, EEG etc. Neuromyotonia is characterized electromyographically by doublet, triplet or multiplet single unit discharges that have a high, irregular intraburst frequency. Fibrillation potentials and fasciculations are often also present with electromyography.

Because the condition is so rare, it can often be years before a correct diagnosis is made.

NMT is not fatal and many of the symptoms can be controlled. However, because NMT mimics some symptoms of motor neuron disease (ALS) and other more severe diseases, which may be fatal, there can often be significant anxiety until a diagnosis is made. In some rare cases, acquired neuromyotonia has been misdiagnosed as amyotrophic lateral sclerosis (ALS) particularly if fasciculations may be evident in the absence of other clinical features of ALS. However, fasciculations are rarely the first sign of ALS as the hallmark sign is weakness. Similarly, multiple sclerosis has been the initial misdiagnosis in some NMT patients. In order to get an accurate diagnosis see a trained neuromuscular specialist.

A thorough history is essential and should cover family history, diet; drug/toxin exposure social history, including tobacco and alcohol use; and occupational background, with details on whether similar cases exist among coworkers. Treatment of any chronic disease such as pernicious anemia should always be elucidated.

In most cases of nutritional/toxic optic neuropathy, the diagnosis may be obtained via detailed medical history and eye examination. Additionally, supplementary neurological imaging studies, such as MRI or enhanced CT, may be performed if the cause remains unclear.

When the details of the examination and history indicate a familial history of similar ocular or systemic disease, whether or not there is evidence of toxic or nutritional causes for disease, certain genetic tests may be required. Because there are several congenital causes of mitochondrial dysfunction, the patients history, examination, and radiological studies must be examined in order to determine the specific genetic tests required. For example, 90% of cases of Leber’s Hereditary Optic Neuropathy (LHON) are associated with three common mtDNA point mutations (m.3460G>A/MT-ND1, m.11778G>A/MT-ND4, m.14484T>C/MT-ND6) while a wider range of mtDNA mutations (MT-ND1, MT-ND5, MT-ND6; http://www.mitomap.org/) have been associated with overlapping phenotypes of LHON, MELAS, and Leigh syndrome.

Charcot–Marie–Tooth disease was first described in 1886 by Jean-Martin Charcot, Pierre Marie, and independently Howard Henry Tooth. In the 1950s, further classification occurred and separated patients into two distinct groups. Group one was characterized by slow nerve conduction velocities and demyelinating neuropathy. Group two was characterized by mostly normal nerve conduction velocities and degeneration of axons. In 1968, HMSN were classified again into seven groups:

Neuromyotonia is a type of peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability is an umbrella diagnosis that includes (in order of severity of symptoms from least severe to most severe) benign fasciculation syndrome, cramp fasciculation syndrome, and neuromyotonia. Some doctors will only give the diagnosis of peripheral nerve hyperexcitability as the differences between the three are largely a matter of the severity of the symptoms and can be subjective. However, some objective EMG criteria have been established to help distinguish between the three.

Moreover, the generic use of the term "peripheral nerve hyperexcitability syndromes" to describe the aforementioned conditions is recommended and endorsed by several prominent researchers and practitioners in the field.

EMG test is often performed together with another test called nerve conduction study, which measures the conducting function of nerves. NCV study shows loss of nerve conduction in the distal segment (3 to 4 days after injury). According to NCV study, in axonotmesis there is an absence of distal sensory-motor responses.

In terms of the differential diagnosis for polyneuropathy one must look at the following:

In 1993, Peter James Dyck divided HSAN I further into five subtypes HSAN IA-E based on the presence of additional features. These features were thought to result from the genetic diversity of HSAN I (i.e. the expression of different genes, different alleles of a single gene, or modifying genes) or environmental factors. Molecular genetic studies later confirmed the genetic diversity of the disease.

The diagnosis of HSAN I is based on the observation of symptoms described above and is supported by a family history suggesting autosomal dominant inheritance. The diagnosis is also supported by additional tests, such as nerve conduction studies in the lower limbs to confirm a sensory and motor neuropathy. In sporadic cases, acquired neuropathies, such as the diabetic foot syndrome and alcoholic neuropathy, can be excluded by the use of magnetic resonance imaging and by interdisciplinary discussion between neurologists, dermatologists, and orthopedics.

The diagnosis of the disease has been revolutionized by the identification of the causative genes. The diagnosis is now based on the detection of the mutations by direct sequencing of the genes. Nevertheless, the accurate phenotyping of patients remains crucial in the diagnosis. For pregnant patients, termination of pregnancy is not recommended.

HSAN I must be distinguished from hereditary motor and sensory neuropathy (HMSN) and other types of hereditary sensory and autonomic neuropathies (HSAN II-V). The prominent sensory abnormalities and foot ulcerations are the only signs to separate HSAN I from HMSN. HSAN II can be differentiated from HSAN I as it is inherited as an autosomal recessive trait, it has earlier disease onset, the sensory loss is diffused to the whole body, and it has less or no motor symptoms. HSAN III-V can be easily distinguished from HSAN I because of congenital disease onset. Moreover, these types exhibit typical features, such as the predominant autonomic disturbances in HSAN III or congenital loss of pain and anhidrosis in HSAN IV.

The diagnosis of polyneuropathies begins with a history and physical examination to ascertain the pattern of the disease process (such as-arms, legs, distal, proximal) if they fluctuate, and what deficits and pain are involved. If pain is a factor, determining where and how long the pain has been present is important, one also needs to know what disorders are present within the family and what diseases the person may have. Although diseases often are suggested by the physical examination and history alone, tests that may be employed include: electrodiagnostic testing, serum protein electrophoresis, nerve conduction studies, urinalysis, serum creatine kinase (CK) and antibody testing (nerve biopsy is sometimes done).

Other tests may be used, especially tests for specific disorders associated with polyneuropathies, quality measures have been developed to diagnose patients with distal symmetrical polyneuropathy (DSP).

Electromyography (EMG) is a medical test performed to evaluate and record the electrical activity (electromyogram) produced by skeletal muscles using an instrument called electromyograph. In axonotmesis, EMG changes (2 to 3 weeks after injury) in the denervated muscles include:

1. Fibrillation potentials (FP)

2. Positive sharp waves

Peripheral neuropathy may first be considered when an individual reports symptoms of numbness, tingling, and pain in feet. After ruling out a lesion in the central nervous system as a cause, diagnosis may be made on the basis of symptoms, laboratory and additional testing, clinical history, and a detailed examination.

During physical examination, specifically a neurological examination, those with generalized peripheral neuropathies most commonly have distal sensory or motor and sensory loss, although those with a pathology (problem) of the nerves may be perfectly normal; may show proximal weakness, as in some inflammatory neuropathies, such as Guillain–Barré syndrome; or may show focal sensory disturbance or weakness, such as in mononeuropathies. Classically, ankle jerk reflex is absent in peripheral neuropathy.

A physical examination will involve testing the deep ankle reflex as well as examining the feet for any ulceration. For large fiber neuropathy, an exam will usually show an abnormally decreased sensation to vibration, which is tested with a 128-Hz tuning fork, and decreased sensation of light touch when touched by a nylon monofilament.

Diagnostic tests include electromyography (EMG) and nerve conduction studies (NCSs), which assess large myelinated nerve fibers. Testing for small-fiber peripheral neuropathies often relates to the autonomic nervous system function of small thinly- and unmyelinated fibers. These tests include a sweat test and a tilt table test. Diagnosis of small fiber involvement in peripheral neuropathy may also involve a skin biopsy in which a 3 mm-thick section of skin is removed from the calf by a punch biopsy, and is used to measure the skin intraepidermal nerve fiber density (IENFD), the density of nerves in the outer layer of the skin. Reduced density of the small nerves in the epidermis supports a diagnosis of small-fiber peripheral neuropathy.

Laboratory tests include blood tests for vitamin B-12 levels, a complete blood count, measurement of thyroid stimulating hormone levels, a comprehensive metabolic panel screening for diabetes and pre-diabetes, and a serum immunofixation test, which tests for antibodies in the blood.

Traditional autonomic testing is used to aid in the diagnosis of AAG. These tests can include a Tilt Table Test (TTT), thermoregulatory sweat test (TST), quantitative sudomotor autonomic reflex testing (QSART) and various blood panels. Additionally, a blood test showing high levels of the antibody ganglionic nicotenic acetylcholine receptor (gAChr) occur in about 50% of patients with AAG (seropositive AAG). The seronegative patients (those without detectable gAChR levels) are theorized to have one or more different antibodies responsible for the autonomic dysfunction. However, both seropositive and seronegative patients have been seen to respond to the same treatments. A paraneoplastic panel may also be ordered to rule out paraneoplastic syndrome.

Those diseases understood as congenital in origin could either be specific to the ocular organ system (LHON, DOA) or syndromic (MELAS, Multiple Sclerosis). It is estimated that these inherited optic neuropathies in the aggregate affect 1 in 10,000

Of the acquired category, disease falls into further etiological distinction as arising from toxic (drugs or chemicals) or nutritional/metabolic (vitamin deficiency/diabetes) insult. It is worth mentioning that under-nutrition and toxic insult can occur simultaneously, so a third category may be understood as having a combined or mixed etiology. We will refer to this as Toxic/Nutritional Optic Neuropathy, whereby nutritional deficiencies and toxic/metabolic insults are the simultaneous culprits of visual loss associated with damage and disruption of the RGC and optic nerve mitochondria.

While the presence of several symptoms may point towards a particular genetic disorder of the spinal muscular atrophy group, the actual disease can be established with full certainty only by genetic testing which detects the underlying genetic mutation.

Detection of this type of neuropathy has concentrated mostly on detecting presence of antibodies because the antibodies are the main cause for the disease. Anti-MAG antibodies can be readily detected in a patient’s sera using various types of assays, but mainly an ELISA has been shown to be most effective. There are also various biological indicators, such as elevated cerebral spinal fluid proteins and elevated IgM monoclonal levels. These can also be tested either by drawing serum from a patient or by drawing spinal fluid from a spinal tap and testing using an assay or blot.

As in multiple sclerosis, another demyelinating condition, it is not possible to predict with certainty how CIDP will affect patients over time. The pattern of relapses and remissions varies greatly with each patient. A period of relapse can be very disturbing, but many patients make significant recoveries.

If diagnosed early, initiation of early treatment to prevent loss of nerve axons is recommended. However, many individuals are left with residual numbness, weakness, tremors, fatigue and other symptoms which can lead to long-term morbidity and diminished quality of life.

It is important to build a good relationship with doctors, both primary care and specialist. Because of the rarity of the illness, many doctors will not have encountered it before. Each case of CIDP is different, and relapses, if they occur, may bring new symptoms and problems. Because of the variability in severity and progression of the disease, doctors will not be able to give a definite prognosis. A period of experimentation with different treatment regimens is likely to be necessary in order to discover the most appropriate treatment regimen for a given patient.

Among the methods of diagnosing tropical spastic paraparesis are MRI (magnetic resonance imaging) and lumbar puncture (which may show lymphocytosis).

Diagnosis consists of a variety of tests, including but not limited to:

- Measurement of orthostatic blood pressure

- Coordination

- rapid, alternating movements

- stroking of heel from along the opposite shin from knee to ankle

- finger-to-nose testing.

- Primary sensory modalities are examined with the following methods, searching for focal sensory loss, graded distal sensory loss, or levels of decreased sensation, hyperesthesia or dysesthesia.

- light touch

- pin-prick

- temperature

- position

- vibration

- Focused gait examination, which examines stationary position and walking abnormalities. Walking generally exposes any faults within the complex neurological communication between systems as weight is shifted from one foot to the other.

Treatment consists of physical rehabilitation programs designed to improve overall function, increase strength and improve balance. The ultimate goal is to increase the patient's degree of independence, thus improving the patient's quality of life. Exercise typically begins with simple movements, gradually transitioning into more complex actions. Various aspects of treatment are assessed based on the individual patient's condition, utilizing many assessment tools:

- Functional Reach Test

- External Perturbation Test – Push, Release

- External Perturbation Test – Pull

- Clinical Sensory Integration Test

- Single Leg Stance Test

- Five Times Sit to Stand Test

Various scales are also utilized

- Brief Ataxia Rating Scale

- Friedreich's Ataxia Impact Scale

- Scale For Assessment and Rating of Ataxia

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.

Hereditary sensory neuropathy type IV (HSN4) is a rare genetic disorder characterized by the loss of sensation (sensory loss), especially in the feet and legs and, less severely, in the hands and forearms. The sensory loss is due to abnormal functioning of small, unmyelinated nerve fibers and portions of the spinal cord that control responses to pain and temperature as well as other involuntary or automatic body processes. Sweating is almost completely absent with this disorder. Intellectual disability is usually present.

Type 4, congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive condition and affected infants present with episodes of hyperthermia unrelated to environmental temperature, anhidrosis and insensitivity to pain. Palmar skin is thickened and charcot joints are commonly present. NCV shows motor and sensory nerve action potentials to be normal. The histopathology of peripheral nerve biopsy reveals absent small unmyelinated fibers and mitochondria are abnormally enlarged.

Management of Hereditary sensory and autonomic neuropathy Type 4:

Treatment of manifestations: Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology. For anhidrosis: Monitoring body temperature helps to institute timely measures to prevent/manage hyperthermia or hypothermia. For insensitivity to pain: Modify as much as reasonable a child’s activities to prevent injuries. Inability to provide proper immobilization as a treatment for orthopedic injuries often delays healing; additionally, bracing and invasive orthopedic procedures increase the risk for infection. Methods used to prevent injuries to the lips, buccal mucosa, tongue, and teeth include tooth extraction, and/or filing (smoothing) of the sharp incisal edges of teeth, and/or use of a mouth guard. Skin care with moisturizers can help prevent palmar and plantar hyperkeratosis and cracking and secondary risk of infection; neurotrophic keratitis is best treated with routine care for dry eyes, prevention of corneal infection, and daily observation of the ocular surface. Interventions for behavioral, developmental, and motor delays as well as educational and social support for school-age children and adolescents are recommended.

Prevention of secondary complications: Regular dental examinations and restriction of sweets to prevent dental caries; early treatment of dental caries and periodontal disease to prevent osteomyelitis of the mandible. During and following surgical procedures, potential complications to identify and manage promptly include hyper- or hypothermia and inadequate sedation, which may trigger unexpected movement and result in secondary injuries.

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.

Dissociated sensory loss is a pattern of neurological damage caused by a lesion to a single tract in the spinal cord which involves "selective" loss of fine touch and proprioception "without" loss of pain and temperature, or vice versa.

Understanding the mechanisms behind these selective lesions requires a brief discussion of the anatomy involved.

Loss of pain and temperature are due to damage to the lateral spinothalamic tracts, which cross the central part of the cord close to the level where they enter it and travel up the spinal column on the opposite side to the one they innervate (i.e. they "ascend contralaterally"). Note that a lesion of the lateral spinothalamic tract at a given level will not result in sensory loss for the dermatome of the same level; this is due to the fibers of the tract of Lissauer which transmit the neuron one or two levels above the affected segment (thus bypassing the segmental lesion on the contralateral side).

Loss of fine touch and proprioception are due to damage to the dorsal columns, which do not cross the cord until the brainstem, and so travel up the column on the same side to the one they innervate (i.e. they "ascend ipsilaterally").

This means that a lesion of the dorsal columns will cause loss of touch and proprioception below the lesion and on the same side as it, while a lesion of the spinothalamic tracts will cause loss of pain and temperature below the lesion and on the opposite side to it.

Dissociated sensory loss always suggests a focal lesion within the spinal cord or brainstem.

The location of cord lesions affects presentation—for instance, a central lesion (such as that of syringomyelia) will knock out second order neurons of the spinothalamic tract as they cross the centre of the cord, and will cause loss of pain and temperature without loss of fine touch or proprioception.

Other causes of dissociated sensory loss include:

- Diabetes mellitus

- Syringomyelia

- Brown-Séquard syndrome

- Lateral medullary syndrome aka Wallenberg's syndrome

- Anterior spinal artery thrombosis

- Tangier disease

- Subacute combined degeneration

- Multiple sclerosis

- Tabes dorsalis

- Friedreich's ataxia (or other spinocerebellar degeneration)