An average clinical profile from published studies shows that the median onset age for HDLS patients is 44.3 years with a mean disease duration of 5.8 years and mean age of death at 53.2 years. As of 2012, there have been around 15 cases identified with at least 11 sporadic cases of HDLS. HDLS cases have been located in Germany, Norway, Sweden, and the United States, showing an international distribution focusing between Northern Europe and the United States.

Through the study of numerous kindred, it was found that the disease did not occur among just males or females, but rather was evenly distributed indicative of an autosomal rather than a sex-linked genetic disorder. It was also observed that the HDLS cases did not skip generations as it would occur with a recessive inheritance, and as such has been labeled autosomal dominant.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare adult onset autosomal dominant disorder characterized by cerebral white matter degeneration with demyelination and axonal spheroids leading to progressive cognitive and motor dysfunction. Spheroids are axonal swellings with discontinuous or absence of myelin sheaths. It is believed that the disease arises from primary microglial dysfunction that leads to secondary disruption of axonal integrity, neuroaxonal damage, and focal axonal spheroids leading to demyelination. Spheroids in HDLS resemble to some extent those produced by shear stress in a closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport. In addition to trauma, axonal spheroids can be found in aged brain, stroke, and in other degenerative diseases. In HDLS, it is uncertain whether demyelination occurs prior to the axonal spheroids or what triggers neurodegeneration after apparently normal brain and white matter development, although genetic deficits suggest that demyelination and axonal pathology may be secondary to microglial dysfunction. The clinical syndrome in patients with HDLS is not specific and it can be mistaken for Alzheimer's disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.

People with MMND become progressively more weak with time. Generally, affected individuals survive up to 30 years after they are diagnosed.

While moderate to severe traumatic brain injury is a risk for ALS, it is unclear if mild traumatic brain injury increases rates.

In 1994 the National Institute for Occupational Safety and Health (NIOSH) reported a nonsignificant increase in nervous system disorders due to four cases of ALS among National Football League (NFL) players. It was unclear if this was due to chance or not. Another study from 2012 also found a possible increase in ALS in NFL football players. An older study did not find an increased risk among high school football players. A 2007 review found an increased risk among soccer players. ALS may also occur more often among the US military veterans however the reason is unknown. This may be due to head injury.

After the 2012 report was released, some NFL players involved in the legal settlement with the NFL complained that the NFL, which initially agreed to pay $765 million, was not doing enough to help players. The judge in the case concurred, and the NFL then agreed to pay an unlimited amount of damages for players found to have ALS, Parkinson's disease, Alzheimer's disease and dementia.

Juvenile Primary Lateral Sclerosis is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, parents of affected individuals each carry one copy of the altered gene, but do not show any signs or symptoms.

Mutations in the ALS2 gene, found on Chromosome 2, are responsible for causing Juvenile Primary Lateral Sclerosis. The ALS2 gene provides instructions for making a protein called alsin. Alsin is abundant in motor neurons, but its function is not fully understood. Mutations in the ALS2 gene in this disorder disrupt the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is currently unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of juvenile primary lateral sclerosis.

The cause of MMND has not yet been determined. There are cases where MMND appears to be inherited. However, no relevant genes have been identified.

MMND affects many cranial nerves, particularly involving the 7th (facial nerve) and 9th to the 12th cranial nerves (in order: glossopharyngeal nerve, vagus nerve, accessory nerve, spinal accessory nerve).

About 5–10% of cases are directly inherited from a person's parents. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS.

A defect on chromosome 21, which codes for superoxide dismutase, is associated with about 20% of familial cases of ALS, or about 2% of ALS cases overall. This mutation is believed to be transmitted in an autosomal dominant manner, and has over a hundred different forms of mutation. The most common ALS-causing mutation is a mutant "SOD1" gene, seen in North America; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS, and people with this form of the disorder survive for an average of 11 years.

In 2011, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9orf72, which is associated with ALS combined with frontotemporal dementia ALS-FTD, and accounts for some 6% of cases of ALS among white Europeans.

Juvenile primary lateral sclerosis (JPLS) ", also known as primary lateral sclerois (PLSJ)," is a rare genetic disorder, with a small number of reported cases, characterized by progressive weakness and stiffness of muscles in the arms, legs, and face. The disorder damages motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement.

Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases – including amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's – occur as a result of neurodegenerative processes. Such diseases are incurable, resulting in progressive degeneration and/or death of neuron cells. As research progresses, many similarities appear that relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic.

Approximately 2 million people in the world suffer from multiple sclerosis Tumefactive multiple sclerosis cases make up 1 to 2 of every 1000 multiple sclerosis cases. This means that only around 2000 people in the world suffer of tumefactive MS. Of those cases, there is a higher percentage of females affected than males. The median age of onset is 37 years.

As in general MS, there are differences for gender, ethnicity and geographic location. Based on epidemiological studies, there are about 3 times more female MS patients than male patients, indicating a possibility of an increased risk due to hormones. Among different ethnic groups, MS is the most common among Caucasians and seems to have a greater incidence at latitudes above 40° as compared to at the equator. While these associations have been made, it is still unclear how they result in an increased risk of MS onset.

Diffuse myelinoclastic sclerosis, sometimes referred to as Schilder's disease, is a very infrequent neurodegenerative disease that presents clinically as pseudotumoural demyelinating lesions, that make its diagnosis difficult. It usually begins in childhood, affecting children between 5 and 14 years old, but cases in adults are possible.

This disease is considered one of the borderline forms of multiple sclerosis because some authors consider them different diseases and others MS variants. Other diseases in this group are neuromyelitis optica (NMO), Balo concentric sclerosis and Marburg multiple sclerosis.

Keutel syndrome (KS) is a rare autosomal recessive genetic disorder characterized by abnormal diffuse cartilage calcification, hypoplasia of the mid-face, peripheral pulmonary stenosis, hearing loss, short distal phalanges (tips) of the fingers and mild mental retardation. Individuals with KS often present with peripheral pulmonary stenosis, brachytelephalangism, sloping forehead, midface hypoplasia, and receding chin. It is associated with abnormalities in the gene coding for matrix gla protein (MGP). Being an autosomal recessive disorder, it may be inherited from two unaffected, abnormal MGP-carrying parents. Thus, people who inherit two affected MGP genes will likely inherit KS.

It was first identified in 1972 as a novel rare genetic disorder sharing similar symptoms with chondrodysplasia punctata. Multiple forms of chondrodysplasia punctata share symptoms consistent with KS including abnormal cartilage calcification, forceful respiration, brachytelephalangism, hypotonia, psychomotor delay, and conductive deafness, yet peripheral pulmonary stenosis remains unique to KS.

No chromosomal abnormalities are reported in affected individuals, suggesting that familial consanguinity relates to the autosomal recessive mode of inheritance. Also, despite largely abnormal calcification of regions including the larynx, tracheobronchial tree, nose, pinna (anatomy), and epiglottis, patients exhibit normal serum calcium and phosphate levels.

The prognosis of this disease is very variable and can take three different courses: a monophasic, not remitting;

remitting;

and finally, progressive, with increase in deficits.

Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

Common proteinopathies that are found in FTLD include the accumulation of Tau proteins and TARDBPs. Mutations in the C9orf72 gene have been established as a major genetic contribution of FTLD, although defects in the GRN and MAPT genes are also associated with it.

Treatment is symptomatic, often addressing indicators associated with peripheral pulmonary artery stenosis. Laryngotracheal calcification resulting in dyspnea and forceful breathing can be treated with bronchodilators including the short and long-acting β2-agonists, and various anticholinergics. Prognosis is good, yet life expectancy depends on the severity and extent of diffuse pulmonary and arterial calcification.

MS is more common in people who live farther from the equator, although exceptions exist. These exceptions include ethnic groups that are at low risk far from the equator such as the Samis, Amerindians, Canadian Hutterites, New Zealand Māori, and Canada's Inuit, as well as groups that have a relatively high risk close to the equator such as Sardinians, inland Sicilians, Palestinians and Parsis. The cause of this geographical pattern is not clear. While the north-south gradient of incidence is decreasing, as of 2010 it is still present.

MS is more common in regions with northern European populations and the geographic variation may simply reflect the global distribution of these high-risk populations. Decreased sunlight exposure resulting in decreased vitamin D production has also been put forward as an explanation. A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November as compared to May being affected later in life. Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk to MS. If migration takes place after age 15, however, the person retains the risk of their home country. There is some evidence that the effect of moving may still apply to people older than 15.

The expected future course of the disease depends on the subtype of the disease; the individual's sex, age, and initial symptoms; and the degree of disability the person has. Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.

The average life expectancy is 30 years from the start of the disease, which is 5 to 10 years less than that of unaffected people. Almost 40% of people with MS reach the seventh decade of life. Nevertheless, two-thirds of the deaths are directly related to the consequences of the disease. Suicide is more common, while infections and other complications are especially dangerous for the more disabled. Although most people lose the ability to walk before death, 90% are capable of independent walking at 10 years from onset, and 75% at 15 years.

Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) because the unknown etiology of some of them, and sometimes known as borderline forms of multiple sclerosis, is a collection of multiple sclerosis variants, sometimes considered different diseases, but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.

Multiple Sclerosis for some people is a syndrome more than a single disease. It can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour. Multiple sclerosis also has a prodromal stage in which an unknown underlying condition, able to damage the brain, is present, but no lesion has still developed.

Genetic testing is available for symptomatic individuals and asymptomatic relatives.

Some hypotheses as to the cause of the disease include genetics, cycad seeds, and ingested beta-Methylamino-L-alanine (BMAA) from the consumption of fruit bats.

Susac's syndrome is named for Dr. John Susac (1940–2012), of Winter Haven, Florida, who first described it in 1979. Susac's syndrome is a very rare disease, of unknown cause, and many persons who experience it do not display the bizarre symptoms named here. Their speech can be affected, such as the case of a female of late teens who suffered speech issues and hearing problems, and many experience unrelenting and intense headaches and migraines, some form of hearing loss, and impaired vision. The problem usually corrects itself, but this can take up to five years. In some cases, subjects can become confused. The syndrome usually affects women around the age of 18 years, with female to male ratio of cases of 2:1.

William F. Hoyt was the first to call the syndrome "Susac syndrome" and later Robert Daroff asked Dr. Susac to write an editorial in Neurology about the disorder and to use the eponym of Susac syndrome in the title, forever linking this disease with him.

Lytico-bodig disease, sometimes spelled Lytigo-bodig, is the name of a disease in the language of Chamorro. It is referred to by neuroscientists as amyotrophic lateral sclerosis-parkinsonism-dementia (ALS-PDC), a term coined by Asao Hirano and colleagues in 1961. It is a neurodegenerative disease of uncertain etiology that exists in the United States territory of Guam.

The disease resembles Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, and Alzheimer's. First reports of the disease surfaced in three death certificates on Guam in 1904. These death certificates made some mention of paralysis. The frequency of cases grew amongst the Chamorro people on Guam until it was the leading cause of adult death between 1945 and 1956. The incidence rate was 200 per 100,000 per year and it was 100 times more prevalent than in the rest of the world.

Neurologist Oliver Sacks detailed this disease in his book "The Island of the Colorblind"

. Sacks and Paul Alan Cox subsequently wrote that a local species of flying fox, which is now extinct due to overhunting, had been feeding on cycads and concentrating β-methylamino--alanine (BMAA), a known neurotoxin, in its body fat. The hypothesis suggests that consumption of the fruit bat by the Chamorro exposed them to BMAA, contributing to or causing their condition. Decline in consumption of the bats has been linked to a decline in the incidence of the disease.

There are 3 main histological subtypes found at post-mortem:

- FTLD-tau is characterised by tau positive inclusions often referred to as Pick-bodies. Examples of FTLD-tau include; Pick's disease, corticobasal degeneration, progressive supranuclear palsy.

- FTLD-TDP (or FTLD-U ) is characterised by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusions. The pathological histology of this subtype is so diverse it is subdivided into four subtypes based on the detailed histological findings:

Two physicians independently categorized the various forms of TDP-43 associated disorders. Both classifications were considered equally valid by the medical community, but the physicians in question have jointly proposed a compromise classification to avoid confusion.

- FTLD-FUS; which is characterised by FUS positive cytoplasmic inclusions, intra nuclear inclusions, and neuritic threads. All of which are present in the cortex, medulla, hippocampus, and motor cells of the spinal cord and XIIth cranial nerve.

Dementia lacking distinctive histology (DLDH) is a rare and controversial entity. New analyses have allowed many cases previously described as DLDH to be reclassified into one of the positively defined subgroups.

Incidence of demyelinating diseases vary from disorder to disorder. Some conditions, such as Tabes dorsalis appear predominantly in males and begins in mid-life. Optic neuritis on the other hand, occurs preferentially in females typically between the ages of 30 and 35. Other conditions such as multiple sclerosis vary in prevalence depending on the country and population. This condition can appear in children as well as adults.

Though for the most of the cases these diseases are still idiopathic, recent researchs have found the causes for some of them, making them not idiopathic anymore. There are currently two identified auto-antibodies and a genetic variant. The autoantibodies are anti-AQP4 and anti-MOG so far and the genetic variant is a mutation in the gene NR1H3.