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.

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.

Some of the most prevalent symptom types in people exhibiting CBD pertain to identifiable movement disorders and problems with cortical processing. These symptoms are initial indicators of the presence of the disease. Each of the associated movement complications typically appear asymmetrically and the symptoms are not observed uniformly throughout the body. For example, a person exhibiting an alien hand syndrome (explained later) in one hand, will not correspondingly display the same symptom in the contralateral limb. Predominant movement disorders and cortical dysfunctions associated with CBD include:

- Parkinsonism

- Alien hand syndrome

- Apraxia (ideomotor apraxia and limb-kinetic apraxia)

- Aphasia

Alien hand syndrome has been shown to be prevalent in roughly 60% of those people diagnosed with CBD. This disorder involves the failure of an individual to control the movements of his or her hand, which results from the sensation that the limb is “foreign.” The movements of the alien limb are a reaction to external stimuli and do not occur sporadically or without stimulation. The presence of an alien limb has a distinct appearance in CBD, in which the diagnosed individual may have a “tactile mitgehen.” This mitgehen (German, meaning “to go with”) is relatively specific to CBD, and involves the active following of an experimenter’s hand by the subject’s hand when both hands are in direct contact. Another, rarer form of alien hand syndrome has been noted in CBD, in which an individual’s hand displays an avoidance response to external stimuli. Additionally, sensory impairment, revealed through limb numbness or the sensation of prickling, may also concurrently arise with alien hand syndrome, as both symptoms are indicative of cortical dysfunction. Like most of the movement disorders, alien hand syndrome also presents asymmetrically in those diagnosed with CBD.

Sydenham's chorea is characterized by the abrupt onset (sometimes within a few hours) of neurologic symptoms, classically chorea, usually affecting all four limbs. Other neurologic symptoms include behavior change, dysarthria, gait disturbance, loss of fine and gross motor control with resultant deterioration of handwriting, headache, slowed cognition, facial grimacing, fidgetiness and hypotonia. Also, there may be tongue fasciculations ("bag of worms") and a "milk sign", which is a relapsing grip demonstrated by alternate increases and decreases in tension, as if hand milking.

Non-neurologic manifestations of acute rheumatic fever are carditis, arthritis, erythema marginatum, and subcutaneous nodules.

The PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) syndrome is similar, but is not characterized by Sydenham's motor dysfunction. PANDAS presents with tics and/or a psychological component (e.g., OCD) and occurs much earlier, days to weeks after GABHS infection rather than 6–9 months later. It may be confused with other conditions such as lupus and Tourette syndrome.

Movements cease during sleep, and the disease usually resolves after several months. Unlike in Huntington's disease, which is generally of adult onset and associated with an unremitting autosomal dominant movement disorder and dementia, neuroimaging in Sydenham's chorea is normal and other family members are unaffected. Other disorders that may be accompanied by chorea include abetalipoproteinemia, ataxia-telangiectasia, biotin-thiamine-responsive basal ganglia disease, Fahr disease, familial dyskinesia-facial myokymia (Bird-Raskind syndrome) due to an ADCY5 gene mutation, glutaric aciduria, Lesch-Nyhan syndrome, mitochondrial disorders, Wilson disease, hyperthyroidism, lupus erythematosus, pregnancy (chorea gravidarum), and side effects of certain anticonvulsants or psychotropic agents.

Autonomic dysreflexia can become chronic and recurrent, often in response to longstanding medical problems like soft tissue ulcers or hemorrhoids. Long term therapy may include alpha blockers or calcium channel blockers.

Complications of severe acute hypertension can include seizures, pulmonary edema, myocardial infarction or cerebral hemorrhage. Additional organs that may be affected include the kidneys and retinas of the eyes.

This condition is distinct and usually episodic, with the people experiencing remarkably high blood pressure (often with systolic readings over 200 mm. Hg), intense headaches, profuse sweating, facial erythema, goosebumps, nasal stuffiness, a "feeling of doom" or apprehension, and blurred vision. An elevation of 40 mm Hg over baseline systolic should be suspicious for dysreflexia.

Sydenham's chorea (SC) or chorea minor (historically referred to as St Vitus's dance) is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. Sydenham's chorea results from childhood infection with Group A beta-haemolytic "Streptococcus" and is reported to occur in 20–30% of patients with acute rheumatic fever (ARF). The disease is usually latent, occurring up to 6 months after the acute infection, but may occasionally be the presenting symptom of rheumatic fever. Sydenham's chorea is more common in females than males and most patients are children, below 18 years of age. Adult onset of Sydenham's chorea is comparatively rare and the majority of the adult cases are associated with exacerbation of chorea following childhood Sydenham's chorea.

Four cardinal symptoms have sometimes been used as diagnostic criteria:

1. painful, fatty lipomas (benign fatty tumors) across anatomy

2. obesity, frequently in menopausal age

3. weakness and fatigue

4. emotional instability, depression, epilepsy, confusion, and dementia.

There are also potential signs of the disease which are identified as the following:

However, as it is unclear which symptoms are cardinal and which symptoms are minor signs in Dercum's disease, it is unclear which should be used as diagnostic criteria. Researchers have proposed a 'minimal definition' based on symptoms most often part of Dercum's disease: 1) Generalized overweight or obesity. 2) Chronic pain in the adipose tissue. The associated symptoms in Dercum's disease include obesity, fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, bloating, constipation, fatigue, weakness and joint and muscle aches. Regarding the associated symptoms in Dercum's disease, only case reports have been published. No study involving medical examinations has been performed in a large group of patients.

Autosomal Dominant Retinal Vasculopathy with Cerebral Leukodystrophy (AD-RVCL) (previously known also as Cerebroretinal Vasculopathy, CRV, or Hereditary Vascular Retinopathy, HVR or Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke, HERNS) is an inherited condition resulting from a frameshift mutation to the TREX1 gene. This genetically inherited condition affects the retina and the white matter of the central nervous system, resulting in vision loss, lacunar strokes and ultimately dementia. Symptoms commonly begin in the early to mid-forties, and treatments currently aim to manage or alleviate the symptoms rather than treating the underlying cause. The overall prognosis is poor, and death can sometimes occur within 10 years of the first symptoms appearing.

AD-RVCL (CRV) Acronym

Autosomal Dominance (genetics) means only one copy of the gene is necessary for the symptoms to manifest themselves.

Retinal Vasculopathy means a disorder that is associated with a disease of the blood vessels in the retina.

Cerebral means having to do with the brain.

Leukodystrophy means a degeneration of the white matter of the brain.

Pathogenesis

The main pathologic process centers on small blood vessels that prematurely “drop out” and disappear. The retina of the eye and white matter of the brain are the most sensitive to this pathologic process. Over a five to ten-year period, this vasculopathy (blood vessel pathology) results in vision loss and destructive brain lesions with neurologic deficits and death.

Most recently, AD-RVCL (CRV) has been renamed. The new name is CHARIOT which stands for Cerebral Hereditary Angiopathy with vascular Retinopathy and Impaired Organ function caused by TREX1 mutations.

Treatment

Currently, there is no therapy to prevent the blood vessel deterioration.

About TREX1

The official name of the TREX1 gene is “three prime repair exonuclease 1.” The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes.

Changes (mutations) to the TREX1 gene can result in a range of conditions one of which is AD-RVCL. The mutations to the TREX1 gene are believed to prevent the production of the 3-prime repair exonuclease 1 enzyme. Researchers suggest that the absence of this enzyme may result in an accumulation of unneeded DNA and RNA in cells. These DNA and RNA molecules may be mistaken by cells for those of viral invaders, triggering immune system reactions that result in the symptoms of AD-RVCL.

Mutations in the TREX1 gene have also been identified in people with other disorders involving the immune system. These disorders include a chronic inflammatory disease called systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin.

The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644

The immune system.

- The immune system is composed of white blood cells or leukocytes.

- There are 5 different types of leukocytes.

- Combined, the 5 different leukocytes represent the 2 types of immune systems (The general or innate immune system and the adaptive or acquired immune system).

- The adaptive immune system is composed of two types of cells (B-cells which release antibodies and T-cells which destroy abnormal and cancerous cells).

How the immune system becomes part of the condition.

During mitosis, tiny fragments of “scrap” single strand DNA naturally occur inside the cell. Enzymes find and destroy the “scrap” DNA. The TREX1 gene provides the information necessary to create the enzyme that destroys this single strand “scrap” DNA. A mutation in the TREX1 gene causes the enzyme that would destroy the single strand DNA to be less than completely effective. The less than completely effective nature of the enzyme allows “scrap” single strand DNA to build up in the cell. The buildup of “scrap” single strand DNA alerts the immune system that the cell is abnormal.

The abnormality of the cells with the high concentration of “scrap” DNA triggers a T-cell response and the abnormal cells are destroyed. Because the TREX1 gene is identical in all of the cells in the body the ineffective enzyme allows the accumulation of “scrap” single strand DNA in all of the cells in the body. Eventually, the immune system has destroyed enough of the cells in the walls of the blood vessels that the capillaries burst open. The capillary bursting happens throughout the body but is most recognizable when it happens in the eyes and brain because these are the two places where capillary bursting has the most pronounced effect.

Characteristics of AD-RVCL

- No recognizable symptoms until after age 40.

- No environmental toxins have been found to be attributable to the condition.

- The condition is primarily localized to the brain and eyes.

- Optically correctable, but continuous, deterioration of visual acuity due to extensive multifocal microvascular abnormalities and retinal neovascularization leading, ultimately, to a loss of vision.

- Elevated levels of alkaline phosphatase.

- Subtle vascular changes in the retina resembling telangiectasia (spider veins) in the parafovea circulation.

- Bilateral capillary occlusions involving the perifovea vessels as well as other isolated foci of occlusion in the posterior pole of the retina.

- Headaches due to papilledema.

- Mental confusion, loss of cognitive function, loss of memory, slowing of speech and hemiparesis due to “firm masses” and white, granular, firm lesions in the brain.

- Jacksonian seizures and grand mal seizure disorder.

- Progressive neurologic deterioration unresponsive to systemic corticosteroid therapy.

- Discrete, often confluent, foci of coagulation necrosis in the cerebral white matter with intermittent findings of fine calcium deposition within the necrotic foci.

- Vasculopathic changes involving both arteries and veins of medium and small caliber present in the cerebral white matter.

- Fibroid necrosis of vessel walls with extravasation of fibrinoid material into adjacent parenchyma present in both necrotic and non-necrotic tissue.

- Obliterative fibrosis in all the layers of many vessel walls.

- Parivascular, adventitial fibrosis with limited intimal thickening.

Conditions with similar symptoms that AD-RVCL can be misdiagnosed as:

- Brain tumors

- Diabetes

- Macular degeneration

- Telangiectasia (Spider veins)

- Hemiparesis (Stroke)

- Glaucoma

- Hypertension (high blood pressure)

- Systemic Lupus Erythematosus (SLE (same original pathogenic gene, but definitely a different disease because of a different mutation in TREX1))

- Polyarteritis nodosa

- Granulomatosis with polyangiitis

- Behçet's disease

- Lymphomatoid granulomatosis

- Vasculitis

Clinical Associations

- Raynaud's phenomenon

- Anemia

- Hypertension

- Normocytic anemia

- Normochromic anemia

- Gastrointestinal bleeding or telangiectasias

- Elevated alkaline phosphatase

Definitions

- Coagulation necrosis

- Endothelium

- Fibrinoid

- Fibrinoid necrosis

- Frameshift mutation

- Hemiparesis

- Jacksonian seizure

- Necrotic

- Necrosis

- Papilledema

- Perivascular

- Retinopathy

- Telangiectasia

- Vasculopathy

- Vascular

What AD-RVCL is not:

- Infection

- Cancer

- Diabetes

- Glaucoma

- Hypertension

- A neurological disorder

- Muscular dystrophy

- Systemic Lupus Erythematosis (SLE)

- Vasculitis

Things that have been tried but turned out to be ineffective or even make things worse:

- Antibiotics

- Steroids

- X-Ray therapy

- Immunosuppression

History of AD-RVCL (CRV)

- 1985 – 1988: CRV (Cerebral Retinal Vasculopathy) was discovered by John P. Atkinson, MD at Washington University School of Medicine in St. Louis, MO

- 1988: 10 families worldwide were identified as having CRV

- 1991: Related disease reported, HERNS (Hereditary Endiotheliopathy with Retinopathy, Nephropathy and Stroke – UCLA

- 1998: Related disease reported, HRV (Hereditary Retinal Vasculopathy) – Leiden University, Netherlands

- 2001: Localized to Chromosome 3.

- 2007: The specific genetic defect in all of these families was discovered in a single gene called TREX1

- 2008: Name changed to AD-RVCL Autosomal Dominant-Retinal Vasculopathy with Cerebral Leukodystrophy

- 2009: Testing for the disease available to persons 21 and older

- 2011: 20 families worldwide were identified as having CRV

- 2012: Obtained mouse models for further research and to test therapeutic agents

Posterior cortical atrophy (PCA), also called Benson's syndrome, is a form of dementia which is usually considered an atypical variant of Alzheimer's disease (AD). The disease causes atrophy of the posterior part of the cerebral cortex, resulting in the progressive disruption of complex visual processing. PCA was first described by D. Frank Benson in 1988.

In rare cases, PCA can be caused by dementia with Lewy bodies and Creutzfeldt–Jakob disease.

PCA usually affects people at an earlier age than typical cases of Alzheimer's disease, with initial symptoms often experienced in people in their mid-fifties or early sixties. This was the case with writer Terry Pratchett (1948-2015), who went public in 2007 about being diagnosed with PCA. In "The Mind's Eye", neurologist Oliver Sacks examines the case of concert pianist Lilian Kallir (1931–2004), who suffered from PCA.

The main symptom resulting from PCA is a decrease in visuospatial and visuoperceptual capabilities. Because the posterior region of the brain is home to the occipital lobe, which is responsible for visual processing, visual functions are impaired in PCA patients. The atrophy is progressive; early symptoms include difficulty reading, blurred vision, light sensitivity, issues with depth perception, and trouble navigating through space. Additional symptoms include apraxia, a disorder of movement planning, alexia, an impaired ability to read, and visual agnosia, an object recognition disorder. Damage to the ventral, or “what” stream, of the visual system, located in the temporal lobe, leads to the symptoms related to general vision and object recognition deficits; damage to the dorsal, or “where/how” stream, located in the parietal lobe, leads to PCA symptoms related to impaired movements in response to visual stimuli, such as navigation and apraxia.

As neurodegeneration spreads, more severe symptoms emerge, including the inability to recognize familiar people and objects, trouble navigating familiar places, and sometimes visual hallucinations. In addition, patients may experience difficulty making guiding movements towards objects, and may experience a decline in literacy skills including reading, writing, and spelling. Furthermore, if neural death spreads into other anterior cortical regions, symptoms similar to Alzheimer's disease, such as memory loss, may result. PCA patients with significant atrophy in one hemisphere of the brain may experience hemispatial neglect, the inability to see stimuli on one half of the visual field. Anxiety and depression are also common in PCA patients.

Hippocampal sclerosis (HS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus, specifically in the CA-1 (Cornu Ammonis area 1) and subiculum of the hippocampus. It was first described in 1880 by Wilhelm Sommer. Hippocampal sclerosis is a frequent pathologic finding in community-based dementia. Hippocampal sclerosis can be detected with autopsy or MRI. Individuals with hippocampal sclerosis have similar initial symptoms and rates of dementia progression to those with Alzheimer's disease (AD) and therefore are frequently misclassified as having Alzheimer's Disease. But clinical and pathologic findings suggest that hippocampal sclerosis has characteristics of a progressive disorder although the underlying cause remains elusive.

A diagnosis of hippocampal sclerosis has a significant effect on the life of patients because of the notable mortality, morbidity and social impact related to epilepsy, as well as side effects associated with antiepileptic treatments.

Auditory neuropathy spectrum disorder (ANSD) is a specific form of hearing loss defined by the presence of normal or near-normal otoacoustic emissions (OAEs) but the absence of normal middle ear reflexes and severely abnormal or completely absent auditory brainstem response (ABRs).

Individuals presenting with this recently recognised hearing loss appear to display sporadic windows of hearing and not. Very few (1 in 14) will go on to develop normal speech and language but with poor speech perception in background noise and in others, no speech perception and therefore language development is possible.

The condition was originally termed auditory neuropathy (AN) and in 2001 as Auditory Neuropathy / Auditory Dys-synchrony (AN/AD) (to include those cases where no true neuropathy was apparent). In 2008 at a meeting convened at Lake Como in Italy (Guidelines Development

Conference on the Identification and Management

of Infants with Auditory Neuropathy, International

Newborn Hearing Screening Conference, Como, Italy,

June 19–21, 2008), a group of leading authorities on the condition reached a consensus and renamed it as auditory neuropathy spectrum disorder.

Frontotemporal dementia (FTD) is the clinical presentation of frontotemporal lobar degeneration, which is characterized by progressive neuronal loss predominantly involving the frontal or temporal lobes, and typical loss of over 70% of spindle neurons, while other neuron types remain intact.

It was first described by Arnold Pick in 1892 and was originally called "Pick's disease", a term now reserved for Pick disease, one specific type of frontotemporal dementia. Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for 20% of young-onset dementia cases. Signs and symptoms typically manifest in late adulthood, more commonly between the ages of 55 and 65, approximately equally affecting men and women.

Common signs and symptoms include significant changes in social and personal behavior, apathy, blunting of emotions, and deficits in both expressive and receptive language. Currently, there is no cure for FTD, but there are treatments that help alleviate symptoms.

Ammon's horn (or hippocampal) sclerosis (AHS) is the most common type of neuropathological damage seen in individuals with temporal lobe epilepsy. This type of neuron cell loss, primarily in the hippocampus, can be observed in approximately 65% of people suffering from this form of epilepsy. Sclerotic hippocampus is pointed to as the most likely origin of chronic seizures in temporal lobe epilepsy patients, rather than the amygdala or other temporal lobe regions. Although hippocampal sclerosis has been identified as a distinctive feature of the pathology associated with temporal lobe epilepsy, this disorder is not merely a consequence of prolonged seizures as argued. A long and ongoing debate addresses the issue of whether hippocampal sclerosis is the cause or the consequence of chronic and pharmaceutically resistant seizure activity. Temporal lobectomy is a common treatment for TLE, surgically removing the seizure focal area, though complications can be severe.

Other variants of temporal lobe epilepsy include mesial temporal lobe epilepsy (MTLE), MTLE due to hippocampal sclerosis, thalamic changes in temporal lobe epilepsy with and without hippocampal sclerosis, and hippocampal sclerosis with and without mesial temporal lobe epilepsy.

The clinical presentation of hydrocephalus varies with chronicity. Acute dilatation of the ventricular system is more likely to manifest with the nonspecific signs and symptoms of increased intracranial pressure. By contrast chronic dilatation (especially in the elderly population) may have a more insidious onset presenting, for instance, with Hakim's triad (Adams triad).

Symptoms of increased intracranial pressure may include headaches, vomiting, nausea, papilledema, sleepiness or coma. Elevated intracranial pressure may result in uncal or tonsillar herniation, with resulting life-threatening brain stem compression.

Hakim's triad of gait instability, urinary incontinence and dementia is a relatively typical manifestation of the distinct entity normal pressure hydrocephalus (NPH). Focal neurological deficits may also occur, such as abducens nerve palsy and vertical gaze palsy (Parinaud syndrome due to compression of the quadrigeminal plate, where the neural centers coordinating the conjugated vertical eye movement are located). The symptoms depend on the cause of the blockage, the person's age, and how much brain tissue has been damaged by the swelling.

In infants with hydrocephalus, CSF builds up in the central nervous system, causing the fontanelle (soft spot) to bulge and the head to be larger than expected. Early symptoms may also include:

- Eyes that appear to gaze downward;

- Irritability;

- Seizures;

- Separated sutures;

- Sleepiness;

- Vomiting.

Symptoms that may occur in older children can include:

- Brief, shrill, high-pitched cry;

- Changes in personality, memory, or the ability to reason or think;

- Changes in facial appearance and eye spacing;

- Crossed eyes or uncontrolled eye movements;

- Difficulty feeding;

- Excessive sleepiness;

- Headache;

- Irritability, poor temper control;

- Loss of bladder control (urinary incontinence);

- Loss of coordination and trouble walking;

- Muscle spasticity (spasm);

- Slow growth (child 0–5 years);

- Slow or restricted movement;

- Vomiting.

Because hydrocephalus can injure the brain, thought and behavior may be adversely affected. Learning disabilities including short-term memory loss are common among those with hydrocephalus, who tend to score better on verbal IQ than on performance IQ, which is thought to reflect the distribution of nerve damage to the brain. However, the severity of hydrocephalus can differ considerably between individuals and some are of average or above-average intelligence. Someone with hydrocephalus may have coordination and visual problems, problems with coordination, or may be clumsy. They may reach puberty earlier than the average child (see precocious puberty). About one in four develops epilepsy.

Adiposis dolorosa, also known as Dercum's disease or Anders disease, is a rare condition characterized by generalized obesity and fatty tumors in the adipose tissue. The tumors are normally painful and found in multiples on the extremities. The cause and mechanism of Dercum's disease remains unknown. Possible causes include nervous system dysfunction, mechanical pressure on nerves, adipose tissue dysfunction, and trauma.

Dercum's disease was first described at Jefferson Medical College by neurologist Francis Xavier Dercum in 1892.

FTD is traditionally difficult to diagnose due to the heterogeneity of the associated symptoms. Signs and symptoms are classified into three groups based on the functions of the frontal and temporal lobes:

- Behavioural variant frontotemporal dementia (BvFTD) is characterized by changes in social behavior and conduct, with loss of social awareness and poor impulse control.

- Semantic dementia (SD) is characterized by the loss of semantic understanding, resulting in impaired word comprehension, although speech remains fluent and grammatically faultless.

- Progressive nonfluent aphasia (PNFA) is characterized by progressive difficulties in speech production.

However, the following abilities in the person with FTD are preserved:

- Perception

- Spatial Skills

- Memory

- Praxis

In later stages of FTD, the clinical phenotypes may overlap. FTD patients tend to struggle with binge eating and compulsive behaviors. These binge eating habits are often associated with abnormal eating behavior including overeating, stuffing oneself with food, changes in food preferences (cravings for more sweets, carbohydrates), eating inedible objects and snatching food from others. Recent findings from structural MRI research have indicated that eating changes in FTD are associated with atrophy (wasting) in the right ventral insula, striatum, and orbitofrontal cortex.

Patients with FTD show marked deficiencies in executive functioning and working memory. Most FTD patients become unable to perform skills that require complex planning or sequencing. In addition to the characteristic cognitive dysfunction, a number of primitive reflexes known as frontal release signs are often able to be elicited. Usually the first of these frontal release signs to appear is the palmomental reflex which appears relatively early in the disease course whereas the palmar grasp reflex and rooting reflex appear late in the disease course.

In rare cases, FTD can occur in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis). The prognosis for people with MND is worse when combined with FTD, shortening survival by about a year.

The presenting symptom of dementia with Lewy bodies is often cognitive dysfunction, though dementia eventually occurs in all individuals with DLB. In contrast to Alzheimer's disease (AD), in which memory loss is the first symptom, those with DLB first experience impaired attention, executive function, and visuospatial function, while memory is affected later. These impairments present as driving difficulty, such as becoming lost, misjudging distances, or as impaired job performance. In terms of cognitive testing, individuals may have problems with figure copying as a result of visuospatial impairment, with clock-drawing due to executive function impairment, and difficulty with serial sevens as a result of impaired attention. Short-term memory and orientation to time and place remain intact in the earlier stages of the disease.

While the specific symptoms in a person with DLB may vary, core features include: fluctuating cognition with great variations in attention and alertness from day to day and hour to hour, recurrent visual hallucinations (observed in 75% of people with DLB), and motor features of Parkinson's disease. Suggestive symptoms are rapid eye movement (REM)-sleep behavior disorder and abnormalities detected in PET or SPECT scans. REM sleep behavior disorder (RBD) often is a symptom first recognized by the patient's caretaker. RBD includes vivid dreaming, with persistent dreams, purposeful or violent movements, and falling out of bed. Benzodiazepines, anticholinergics, surgical anesthetics, some antidepressants, and over-the-counter drug cold remedies may cause acute confusion, delusions, and hallucinations.

Tremors are less common in DLB than in Parkinson's disease. Parkinsonian features may include shuffling gait, reduced arm-swing during walking, blank expression (reduced range of facial expression), stiffness of movements, ratchet-like cogwheeling movements, low speech volume, sialorrhea, and difficulty swallowing. Also, DLB patients often experience problems with orthostatic hypotension, including repeated falls, fainting, and transient loss of consciousness. Sleep-disordered breathing, a problem in multiple system atrophy, also may be a problem.

One of the most critical and distinctive clinical features of the disease is hypersensitivity to neuroleptic and antiemetic medications that affect dopaminergic and cholinergic systems. In the worst cases, a patient treated with these medications could become catatonic, lose cognitive function, or develop life-threatening muscle rigidity. Some commonly used medications that should be used with great caution, if at all, for people with DLB, are chlorpromazine, haloperidol, or thioridazine.

Visual hallucinations in people with DLB most commonly involve perception of people or animals that are not there, and may reflect Lewy bodies or AD pathology in the temporal lobe. Delusions may include reduplicative paramnesia and other elaborate misperceptions or misinterpretations. These hallucinations are not necessarily disturbing, and in some cases, the person with DLB may have insight into the hallucinations and even be amused by them, or be conscious they are not real. People with DLB also may have problems with vision, including double vision, and misinterpretation of what they see, for example, mistaking a pile of socks for snakes or a clothes closet for the bathroom.

Early-onset Alzheimer's disease, also called early-onset Alzheimer's, or early-onset AD, is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5-10% of all Alzheimer's cases. Approximately 13% of the cases of early-onset Alzheimer's are familial Alzheimer's disease, where a genetic predisposition leads to the disease. The other incidences of early onset Alzheimer's, however, share the same traits as the 'late onset' form of Alzheimer's disease, and little is understood about how it starts.

Non-familial early onset Alzheimer's can develop in people who are in their thirties or forties, but that is extremely rare. The majority of people with early-onset Alzheimer's are in their fifties or early sixties.

Tauopathy belongs to a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as paired helical filaments). The precise mechanism of tangle formation is not completely understood, and it is still controversial as to whether tangles are a primary causative factor in the disease or play a more peripheral role. Primary tauopathies, i.e., conditions in which neurofibrillary tangles (NFT) are predominantly observed, include:

- Primary age-related tauopathy (PART)/Neurofibrillary tangle-predominant senile dementia, with NFTs similar to AD, but without plaques.

- Chronic traumatic encephalopathy, including dementia pugilistica

- Progressive supranuclear palsy

- Corticobasal degeneration

- Frontotemporal dementia and parkinsonism linked to chromosome 17

- Lytico-Bodig disease (Parkinson-dementia complex of Guam)

- Ganglioglioma and gangliocytoma

- Meningioangiomatosis

- Postencephalitic parkinsonism

- Subacute sclerosing panencephalitis

- As well as lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis

Neurofibrillary tangles were first described by Alois Alzheimer in one of his patients suffering from Alzheimer's disease (AD), which is considered a secondary tauopathy. AD is also classified as an amyloidosis because of the presence of senile plaques.

The degree of NFT involvement in AD is defined by Braak stages. Braak stages I and II are used when NFT involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there's also involvement of limbic regions such as the hippocampus, and V and VI when there's extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.

In both Pick's disease and corticobasal degeneration, tau proteins are deposited as inclusion bodies within swollen or "ballooned" neurons.

Argyrophilic grain disease (AGD), another type of dementia, is marked by an abundance of argyrophilic grains and coiled bodies upon microscopic examination of brain tissue. Some consider it to be a type of Alzheimer's disease. It may co-exist with other tauopathies such as progressive supranuclear palsy and corticobasal degeneration, and also Pick's disease.

Huntington's disease (HD): a neurodegenerative disease caused by a CAG tripled expansion in the Huntington gene is the most recently described tauopathy (Fernandez-Nogales et al. Nat Med 2014). JJ Lucas and co-workers demonstrate that, in brains with HD, tau levels are increased and the 4R/3R balance is altered. In addition, the Lucas study shows intranuclear insoluble deposits of tau; these "Lucas' rods" were also found in brains with Alzheimer's disease.

Tauopathies are often overlapped with synucleinopathies, possibly due to interaction between the synuclein and tau proteins.

The non-Alzheimer's tauopathies are sometimes grouped together as "Pick's complex" due to their association with frontotemporal dementia, or frontotemporal lobar degeneration.

Pick's disease is a term that can be used in two different ways. It has traditionally been used as a term for a group of neurodegenerative diseases with symptoms attributable to frontal and temporal lobe dysfunction. Common symptoms that are noticed early are personality and emotional changes, as well as deterioration of language. This condition is now more commonly called frontotemporal dementia by professionals, and the use of "Pick's disease" as a clinical diagnosis has fallen out of fashion. The second use of the term (and the one now used among professionals) is to mean a specific pathology that is one of the causes of frontotemporal lobar degeneration. These two uses have previously led to confusion among professionals and patients and so its use should be restricted to the specific pathological subtype described below. It is also known as Pick disease and PiD (not to be confused with pelvic inflammatory disease (PID) or Parkinson's disease (PD)). A defining characteristic of the disease is build-up of tau proteins in neurons, accumulating into silver-staining, spherical aggregations known as "Pick bodies".

During the final stages, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.

Dementia with Lewy bodies (DLB) is a type of dementia that worsens over time. Additional symptoms may include fluctuations in alertness, visual hallucinations, slowness of movement, trouble walking, and rigidity. Excessive movement during sleep and mood changes such as depression are also common.

The cause is unknown. Typically, no family history of the disease exists among those affected. The underlying mechanism involves the buildup of Lewy bodies, clumps of alpha-synuclein protein in neurons. It is classified as a neurodegenerative disorder. A diagnosis may be suspected based on symptoms, with blood tests and medical imaging done to rule out other possible causes. The differential diagnosis includes Parkinson's and Alzheimer's.

At present there is no cure. Treatments are supportive and attempt to relieve some of the motor and psychological symptoms associated with the disease. Acetylcholinesterase inhibitors, such as donepezil, may provide some benefit. Some motor problems may improve with levodopa. Antipsychotics, even for hallucinations, should generally be avoided due to side effects.

DLB is the most common cause of dementia after Alzheimer's disease and vascular dementia. It typically begins after the age of 50. About 0.1% of those over 65 are affected. Men appear to be more commonly affected than women. In the late part of the disease, people may depend entirely on others for their care. Life expectancy following diagnosis is about eight years. The abnormal deposits that cause the disease were discovered in 1912 by Frederic Lewy.