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.

Giant axonal neuropathy usually appears in infancy or early childhood, and is progressive. Early signs of the disorder often present in the peripheral nervous system, causing individuals with this disorder to have problems walking. Later, normal sensation, coordination, strength, and reflexes become affected. Hearing or vision problems may also occur. Abnormally kinky hair is characteristic of giant axonal neuropathy, appearing in almost all cases. As the disorder progresses, central nervous system becomes involved, which may cause a gradual decline in mental function, loss of control of body movement, and seizures.

Onset : Early childhood

Progression: Chronic progressive

Clinical: Cerebellar ataxia plus syndrome / Optic Atrophy Plus Syndrome

Ocular: Optic atrophy, nystagmus, scotoma, and bilateral retrobulbar neuritis.

Other: Mental retardation, myoclonic epilepsy, spasticity, and posterior column sensory loss. Tremor in some cases.

Musculoskeletal

Contractures, lower limbs, Achilles tendon contractures, Hamstring contractures, Adductor longus contractures

Systemic

Hypogonadotrophic hypogonadism.

Like other mitochrondrial diseases, "MNGIE is a multisystem disorder". MNGIE primarily affects the gastrointestinal and neurological systems. Gastrointestinal symptoms may include gastrointestinal dysmotility, due to inefficient peristalsis, which may result in pseudo-obstruction and cause malabsorption of nutrients. Additionally, gastrointestinal symptoms such as borborygmi, early satiety, diarrhea, constipation, gastroparesis, nausea, vomiting, weight loss, and diverticulitis may be present in MNGIE patients. Neurological symptoms may include diffuse leukoencephalopathy, peripheral neuropathy, and myopathy. Ocular symptoms may include retinal degeneration, ophthalmoplegia, and ptosis. Those with MNGIE are often thin and experience continuous weight loss. The characteristic thinness of MNGIE patients is caused by multiple factors including inadequate caloric intake due to gastrointestinal symptoms and discomfort, malabsorption of food from bacterial overgrowth due to decreased motility, as well as an increased metabolic demand due to inefficient production of ATP by the mitochondria.

Neuropathy disorders usually have onset in childhood or young adulthood. Motor symptoms seem to be more predominant that sensory symptoms. Symptoms of these disorders include: fatigue, pain, lack of balance, lack of feeling, lack of reflexes, and lack of sight and hearing, which result from muscle atrophy. Patients can also suffer from high arched feet, hammer toes, foot drop, foot deformities, and scoliosis. These symptoms are a result of severe muscular weakness and atrophy. In patients suffering from demyelinating neuropathy, symptoms are due to slow nerve conduction velocities, however people with axonal degradation have average to normal nerve conduction velocities.

Behr syndrome is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay.

Although it is an autosomal recessive disorder, heterozygotes may still manifest much attenuated symptoms. Autosomal dominant inheritance also being reported in a family. Recently a variant of OPA1 mutation with phenotypic presentation like Behr syndrome is also described. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder.

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.

Giant axonal neuropathy is a rare, autosomal recessive neurological disorder that causes disorganization of neurofilaments. Neurofilaments form a structural framework that helps to define the shape and size of neurons and are essential for normal nerve function.

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.

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and POLIP syndrome. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. "A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene".

Familial amyloid polyneuropathy (FAP), also called transthyretin-related hereditary amyloidosis, transthyretin amyloidosis abbreviated also as ATTR (hereditary form), or Corino de Andrade's disease, is an autosomal dominant neurodegenerative disease. It is a form of amyloidosis, and was first identified and described by Portuguese neurologist Mário Corino da Costa Andrade, in 1952. FAP is distinct from senile systemic amyloidosis (SSA), which is not inherited, and which was determined to be the primary cause of death for 70% of supercentenarians who have been autopsied.

FAP can be ameliorated by liver transplantation.

All hereditary motor and sensory neuropathies are inherited. Chromosomes 17 and 1 seem to be the most common chromosomes with mutations. The disease can be inherited in an autosomal dominant, autosomal recessive or X-linked manner.

Centronuclear myopathies (CNM) are a group of congenital myopathies where cell nuclei are abnormally located in skeletal muscle cells. In CNM the nuclei are located at a position in the center of the cell, instead of their normal location at the periphery.

Symptoms of CNM include severe hypotonia, hypoxia-requiring breathing assistance, and scaphocephaly. Among centronuclear myopathies, the X-linked myotubular myopathy form typically presents at birth, and is thus considered a congenital myopathy. However, some centronuclear myopathies may present later in life.

Persons with HDLS can suffer from tremors, decreased body movement, unsteadiness (Parkinsonism, muscles on one side of the body in constant contraction (spastic hemiparesis), impairment in motor and sensory function in the lower extremities (paraparesis), paralysis resulting in partial or total loss of all extremities and torso (tetraparesis), and the lack of voluntary coordination of muscle movements (ataxia).

With symptoms of personality changes, behavioral changes, dementia, depression, and epilepsy, HDLS has been commonly misdiagnosed for a number of other diseases. Dementia or frontotemporal behavioral changes, for example, have commonly steered some clinicians to mistakenly consider diagnoses such as Alzheimer’s disease, frontotemporal dementia or atypical Parkinsonism. The presence of white matter changes has led to misdiagnosis of multiple sclerosis. HDLS commonly manifests with neuropsychiatric symptoms, progressing to dementia, and after a few years shows motor dysfunction. Eventually patients become wheelchair-bound or bedridden.

White matter degeneration is associated with and makes differential diagnoses out of other adult onset leukodystrophies such as metachromatic leukodystrophy (MLD), Krabbe disease (globoid cell leukodystrophy), and X-linked adrenoleukodystrophy (X-ADL).

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.

As with other myopathies, the clinical manifestations of MTM/CNM are most notably muscle weakness and associated disabilities. Congenital forms often present with neonatal low muscle tone, severe weakness, delayed developmental milestones (particularly gross motor milestones such as head control, crawling, and walking) and pulmonary complications (presumably due to weakness of the muscles responsible for respiration). While some patients with centronuclear myopathies remain ambulatory throughout their adult life, others may never crawl or walk and may require wheelchair use for mobility. There is substantial variability in the degree of functional impairment among the various centronuclear myopathies. Although this condition only affects the voluntary muscles, several children have suffered from cardiac arrest, possibly due to the additional stress placed on the heart.

Other observed features have been high arched palate, long digits, bell shaped chest and long face.

Myotubular myopathy only affects muscles and does not impact intelligence in any shape or form.

X-linked myotubular myopathy was traditionally a fatal condition of infancy, with life expectancy of usually less than two years. There appears to be substantial variability in the clinical severity for different genetic abnormalities at that same MTM1 gene. Further, published cases show significant differences in clinical severity among relatives with the same genetic abnormality at the MTM1 gene. Most truncating mutations of MTM1 cause a severe and early lethal phenotype, while some missense mutations are associated with milder forms and prolonged survival (up to 54 years).

Centronuclear myopathies typically have a milder presentation and a better prognosis. Recently, researchers discovered mutations at the gene dynamin 2 (DNM2 on chromosome 19, at site 19p13.2), responsible for the autosomal dominant form of centronuclear myopathy. This condition is now known as dynamin 2 centronuclear myopathy (abbreviated DNM2-CNM). Research has indicated that patients with DNM2-CNM have a slowly progressive muscular weakness usually beginning in adolescence or early adulthood, with an age range of 12 to 74 years.

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.

Peripheral neuropathy may be classified according to the number and distribution of nerves affected (mononeuropathy, mononeuritis multiplex, or polyneuropathy), the type of nerve fiber predominantly affected (motor, sensory, autonomic), or the process affecting the nerves; e.g., inflammation (neuritis), compression (compression neuropathy), chemotherapy (chemotherapy-induced peripheral neuropathy).

Infantile Refsum disease is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD). Although they share a similar molecular basis for disease, Infantile Refsum disease is less severe than Zellweger syndrome.

Infantile Refsum disease is a developmental brain disorder. In addition, patients can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as (hypomyelination). Myelin is critical for normal CNS functions. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.

Infantile Refsum disease can also affect the function of many other organ systems. Patients can show craniofacial abnormalities, hepatomegaly (enlarged liver), and progressive adrenal dysfunction. Newborns may present with profound hypotonia (low muscle tone), and a poor ability to feed. In some patients, a progressive leukodystrophy has been observed that has a variable age of onset.

Common manifestations of sensory issues include numbness or painful sensations in the arms and legs, abnormal sensations like “pins and needles,” and heat intolerance. Pain experienced by individuals depends on the severity of the polyneuropathy. It may be dull and constant in some individuals while being sharp and lancinating in others. In many subjects, tenderness is seen upon the palpitation of muscles in the feet and legs. Certain people may also feel cramping sensations in the muscles affected and others say there is a burning sensation in their feet and calves.

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:

Sensory symptoms are gradually followed by motor symptoms. Motor symptoms may include muscle cramps and weakness, erectile dysfunction in men, problems urinating, constipation, and diarrhea. Individuals also may experience muscle wasting and decreased or absent deep tendon reflexes. Some people may experience frequent falls and gait unsteadiness due to ataxia. This ataxia may be caused by cerebellar degeneration, sensory ataxia, or distal muscle weakness. Over time, alcoholic polyneuropathy may also cause difficulty swallowing (dysphagia), speech impairment (disarthria), muscle spasms, and muscle atrophy.

In addition to alcoholic polyneuropathy, the individual may also show other related disorders such as Wernicke-Korsakoff syndrome and cerebellar degeneration that result from alcoholism-related nutritional disorders.

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.

Quite often, the presenting symptom of ornithine aminotransferase (OAT) deficiency is myopia which progresses to night blindness. The onset of myopia is often in early childhood. Ophthalmological findings in affected individuals include constricted visual fields, posterior subcapsular cataracts (can begin in late teens), elevated dark adaptation thresholds and decreased or absent electroretinographic responses. Symptoms of OAT deficiency are progressive, and between the ages of 45 and 65, most affected individuals are almost completely blind.

In some cases, affected individuals will present in the neonatal period with disease that closely mimics a classic urea cycle defect, such as ornithine transcarbamylase deficiency, as the block in ornithine metabolism leads to secondary dysfunction of the urea cycle. These individuals present with hyperammonemia, poor feeding, failure to thrive and increased excretion of orotic acid.