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).

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).

Onset usually occurs in childhood, however some adult cases have been found. Generally, physicians look for the symptoms in children. Symptoms include cerebellar ataxia, spasticity, optic atrophy, epilepsy, loss of motor functions, irritability, vomiting, coma, and even fever has been tied to VWM. The neurological disorders and symptoms which occur with VWM are not specific to countries; they are the same all over the world. Neurological abnormalities may not always be present in those who experience onset as adults. Symptoms generally appear in young children or infants who were previously developing fairly normally.

Delays in development of some physical, psychological and behavioral skills; progressive enlargement of the head (macrocephaly), seizures, spasticity, and in some cases also hydrocephalus, idiopathic intracranial hypertension, and dementia.

Patients that present with CARASIL usually experience neurological abnormalities by their 20s or 30s and strokes upon reaching their 40s. About 50% of affected patients present with stroke, and most strokes experienced by patients are lacunar infarcts. Many patients experience some form of mood changes, personality disorders, and or dementia. Alopecia, also known as hair loss, usually presents beginning in adolescence. The presence of spondylosis deformans and the onset of low back pain via the breakdown of intervertebral discs is also usually present. CARASIL is a degenerative disease, and most patients live only 10 years past symptom onset.

Alexander disease, also known as fibrinoid leukodystrophy, is a progressive and fatal neurodegenerative disease. It is a rare genetic disorder and mostly affects infants and children, causing developmental delay and changes in physical characteristics.

Symptoms categorized as medically tested and diagnosed include iron accumulation in the brain, basal ganglia cavitation, and neurodegeneration. Patients who are diagnosed with neuroferritinopathy have abnormal iron accumulation in the brain within the neurons and glia of the striatum and cerebellar cortices. Along with the accumulation of iron in the brain, neuroferritinopathy typically causes severe neuronal loss as well.

Secondary symptoms may also arise. It is possible that the initial iron accumulation will cause additional neuronal damage and neuronal death. The damaged neurons may be replaced by other cells in an effort to reverse the neurodegeneration. These cells often have a higher iron content. The breakdown of the blood brain barrier may also occur due to the loss of neurons and will subsequently allow more iron to access the brain and accumulate over time.

Neuroferritinopathy is mainly seen in those who have reached late adulthood and is generally seen to slowly progress throughout many decades in a lifetime with the mean age of onset being 39 years old. A loss of cognition is generally only seen with late stages of the disease. Diagnosed patients are seen to retain most of their cognitive functioning until the most progressive stages of the illness sets in.

Leukoencephalopathy with vanishing white matter (VWM disease) is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor EIF-2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. The disease belongs to a family of conditions called the Leukodystrophies.

Symptoms categorized as physically visible symptoms include chorea, dystonia, spasticity, and rigidity, all physical symptoms of the body associated with movement disorders. The symptoms accompanying neuroferritinopathy affecting movement are also progressive, becoming more generalized with time. Usually during the first ten years of onset of the disease only one or two limbs are directly affected.

Distinctive symptoms of neuroferritinopathy are chorea, found in 50% of diagnosed patients, dystonia, found in 43% of patients, and parkinsonism, found in 7.5% of patients. Full control of upper limbs on the body generally remains until late onset of the disease. Over time, symptoms seen in a patient can change from one side of the body to the opposite side of the body, jumping from left to right or vice versa. Another route that the physically visible symptoms have been observed to take is the appearance, disappearance, and then reappearance once more of specific symptoms.

While these symptoms are the classic indicators of neuroferritinopathy, symptoms will vary from patient to patient.

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.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), is an inherited disease with symptoms of stroke, hair loss, and low back pain. The disease is rare and has only been diagnosed in about 50 patients, mostly of Japanese descent but few of Chinese and Spanish descent. There is currently no cure for CARASIL.

Symptoms of standard MS consist of both sensory and motor symptoms. The more common symptoms include spasticity, visual loss, difficulty in walking and paresthesia which is a feeling of tickling or numbness of the skin. but symptoms of tumefactive MS are not so clear. They often mimic a variety of other diseases including ischemic stroke, peroneal nerve palsy and intracranial neurologic disease.

Subjects have been reported to suffer from a decreased motor control resulting in a ‘foot drop’, or significantly reduced leg movement. In other cases closer mimicking strokes, subjects may suffer from confusion, dizziness, and weakness in one side of the face. Symptoms also can mimic a neoplasm with symptoms such as headaches, aphasia, and/ or seizures.[13]

There are some differences with normal MS symptoms.

Spasticity is not as in tumefactive cases, because it standard MS it is caused by demyelination or inflammation in the motor areas of the brain or the spinal cord. This upper motor neuron syndrome appears when motor control of skeletal muscles is affected due to damage to the efferent motor pathways. Spasticity is an involuntary muscle movement like an exaggerated stretch reflex, which is when a muscle overcompensates and contracts too much in response to the muscle being stretched. It is believed that spasticity is the result of the lack of inhibitory control on the muscles, an effect of neuronal damage.

Visual loss or disturbances are also different. In standard MS are a result of inflammation of the optic nerve, known as optic neuritis. The effects of optic neuritis can be loss of color perception and worsening vision. Vision loss usually starts off centrally in one eye and may lead to complete loss of vision after a period of time.

The possible cognitive dysfunction is also rare in tumefactive cases. MS patients may show signs of cognitive impairment where there is a reduction in the speed of information processing, a weaker short-term memory and a difficulty in learning new concepts. This cognitive impairment is associated with the loss of brain tissue, known as brain atrophy which is a result of the demyelination process in MS.

About fatigue, most MS patients experience fatigue and this could be a direct result of the disease, depression or sleep disturbances due to MS. It is not clearly understood how MS results in physical fatigue but it is known that the repetitive usage of the same neural pathways results in nerve fiber fatigue that could cause neurological symptoms. Such repeated usage of neural pathways include continuous reading which may result in temporary vision failure.

Some specific symptoms vary from one type of leukodystrophy to the next but the vast majority of symptoms are shared as the causes for the disease generally have the same effects. Symptoms are dependent on the age of onset, which is predominantly in infancy and early childhood, although the exact time of onset may be difficult to determine. Hyperirritability and hypersensitivity to the environment are common, as well as some tell-tale physical signs including muscle rigidity and a backwards-bent head. Botox therapy is often used to treat patients with spasticity. Juvenile and adult onsets display similar symptoms including a decrease or loss in hearing and vision. While children do experience optic and auditory degeneration, the course of the disease is usually too rapid, causing death relatively quickly, whereas adults may live with these conditions for many years. In children, spastic activity often precedes progressive ataxia and rapid cognitive deterioration which has been described as mental retardation. Epilepsy is commonplace for patients of all ages. More progressed patients show weakness in deglutition, leading to spastic coughing fits due to inhaled saliva. Classic symptomatic progression of juvenile x-linked adrenoleukodystrophy is shown in the 1992 film, "Lorenzo's Oil".

Course and timetable are dependent on the age of onset with infants showing a lifespan of 2–8 years, juveniles 2–10 years and adults typically 10+ years. Adults typically see an extended period of stability followed by a decline to a vegetative state and death. While treatments do exist, most are in the experimental phase and can only promise a halt in the progression of symptoms, although some gene therapies have shown some symptomatic improvement. The debilitating course of the disease has led to numerous philosophical and ethical arguments over experimental clinical trials, patients’ rights and physician-assisted suicide.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurological disorders in which iron accumulates in the basal ganglia, resulting in progressive dystonia, Parkinsonism, spasticity, optic atrophy or retinal degeneration and neuropsychiatric abnormalities. NBIA disorders have been associated with genes in synapse and lipid metabolism related pathways. Describes a group of disorders characterized by an accumulation of brain iron and the presence of axonal spheroids in the central nervous system. Iron accumulation can occur any where in the brain, with accumulation typically occurring in globus pallidus, substantia nigra, pars reticula, striatum and cerebellar dentate nuclei. Symptoms can include various movement disorders, seizures, visual disturbances, and cognitive decline, usually in combination. The known causes of NBIA disorders are mutations in genes directly involved in iron metabolism, impaired phospholipid and ceramide metabolism, lysosomal disorders, as well as mutations in genes with unknown functions. Onset can occur at different ages, from early childhood to late adulthood. Magnetic resonance imaging (MRI) is used to distinguish between the different forms of NBIA due to the accumulation of iron in different areas of the brain. Patients typically fall into two different categories: (1) early onset, rapid progression or (2) late onset, slow progression. The first type is considered to be the classic presentation, while the second type is the atypical presentation. Phenotypes of the different disorders appear to be dependent on age, i.e. amount of iron accumulation and cognitive ability.

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.

Symptoms of MMND begin appearing when people are young, often before the age of 15. An affected individual is generally thin with weak arms and legs. They may lose control of the muscles that control their face, mouth, nose, and throat. This in turn, will cause difficulties speaking and swallowing. Further complications from the loss of facial motor control include drooling, as well facial droop. People with MMND may also suffer from a loss of hearing and sight.

Superficial siderosis is characterized by many symptoms resulting from brain damage:

- Sensorineural hearing loss- This is the most common symptom associated with superficial siderosis and its absence is rare. The highest pitches are often lost first, and over a period of one to twelve years hearing loss progresses to total deafness or loss of all hearing but low pitches.

- Ataxia- The impairment of gait, which is the second most common symptom.

- Pyramidal signs- Various signs that indicate a condition of the pyramidal tracts.

- Dementia- Occurs in approximately one-quarter of those affected by superficial siderosis.

- Disturbances of the bladder

- Anosmia- Loss of sense of smell.

- Anisocoria- Unequal size of pupils.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC, or Van der Knaap disease) is a form of hereditary CNS demyelinating disease. It belongs to a group of disorders called leukodystrophies.

It is associated with MLC1. Van der Knaap disease is named after Dutch neurologist Marjo van der Knaap.

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.

Leukodystrophy is one of a group of disorders characterized by degeneration of the white matter in the brain. The word "leukodystrophy" comes from the Greek roots "leuko", "white", "dys", "abnormal", and "troph", "growth". The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers.

When damage occurs to white matter, immune responses can lead to inflammation in the CNS, along with loss of myelin. The degeneration of white matter can be seen in a MRI and used to diagnose leukodystrophy. Leukodystrophy is characterized by specific symptoms including decreased motor function, muscle rigidity, and eventually degeneration of sight and hearing. While the disease is fatal, the age of onset is a key factor as infants are given a lifespan of 2–8 years (sometimes longer), while adults typically live more than a decade after onset. There is a great lack of treatment, although cord blood and hematopoietic stem cell transplantation (bone marrow transplant) seem to help in certain types while further research is being done.

The combined incidence of the leukodystrophies is estimated at 1:7,600. The majority of types involve the inheritance of a recessive, dominant, or X-linked trait, while others, although involving a defective gene, are the result of spontaneous mutation rather than genetic inheritance.

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.

Madras motor neuron disease (MMND) is a motor neuron disease affecting primarily lower motor neurons. It is similar to Monomelic amyotrophy and primarily affects young adults in southern India.

Authors of a large case study, published in 2008, proposed that MMND be divided into two categories: spontaneously-arising MMND and Familial Madras Motor Neuron Disease (FMMND). Using this method, cases in which the disease is inherited would be categorized as FMMND, while cases that displayed no genetic linkage would be categorized as spontaneously-arising MMND.

According to the same study, there is a variant form known as MMNDV, which is classified by additional optic atrophy.

Due to the rareness of MMND, it is classified as a orphan disease.

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.