Patients with Unverricht–Lundborg disease exhibit myoclonic jerks and tonic-clonic seizures at a young age, between ages 6–16. The myoclonic jerks occur in the muscles of the arms and legs closest to the torso, and are triggered due to a variety of common external stimuli. Seizures begin at an average age of 10.8 years, with myoclonus beginning around 12.1 years. It is not currently possible to diagnose without a genetic test, and since early symptoms are general, it is often mistaken for another more common epilepsy, in many cases juvenile myoclonic epilepsy (JME).

Seizures are purely occipital and primarily manifest with elementary visual hallucinations, blindness or both.

They are usually frequent and diurnal, develop rapidly within seconds and are brief, lasting from a few seconds to 1–3 min, and, rarely, longer.

Elementary visual hallucinations are the most common and characteristic ictal symptoms, and are most likely to be the first and often the only clinical manifestation. They consist mainly of small multicoloured circular patterns that often appear in the periphery of a visual field, becoming larger and multiplying during the course of the seizure, frequently moving horizontally towards the other side.

Other occipital symptoms, such as sensory illusions of ocular movements and ocular pain, tonic deviation of the eyes, eyelid fluttering or repetitive eye closures, may occur at the onset of the seizures or appear after the elementary visual hallucinations. "Deviation of the eyes", often associated with ipsilateral turning of the head, is the most common (in about 70% of cases) nonvisual ictal symptom. It is often associated with ipsilateral turning of the head and usually starts after visual hallucinations, although it may also occur while the hallucinations still persist. It may be mild, but more often it is severe and progresses to hemiconvulsions and secondarily generalised tonic clonic seizures (GTCS). Some children may have seizures of eye deviation from the start without visual hallucinations.

"Forced eyelid closure and eyelid blinking" occur in about 10% of patients, usually at a stage at which consciousness is impaired. They signal an impending secondarily GTCS.

"Ictal blindness", appearing from the start or, less commonly, after other manifestations of occipital seizures, usually lasts for 3–5 min. It can occur alone and be the only ictal event in patients who could, at other times, have visual hallucinations without blindness.

Complex visual hallucinations, visual illusions and other symptoms resulting from more anterior ictal spreading rarely occur from the start. They may terminate in hemiconvulsions or generalised convulsions.

Ictal headache, or mainly orbital pain, may occur and often precedes visual or other ictal occipital symptoms in a small number of patients.

Consciousness is not impaired during the visual symptoms (simple focal seizures), but may be disturbed or lost in the course of the seizure, usually before eye deviation or convulsions.

Occipital seizures of ICOE-G may rarely progress to extra-occipital manifestations, such as hemiparaesthesia. Spread to produce symptoms of temporal lobe involvement is exceptional and may indicate a symptomatic cause.

Post-ictal headache, mainly diffuse, but also severe, unilateral and pulsating, or indistinguishable from migraine headache, occurs in half the patients, in 10% of whom it may be associated with nausea and vomiting.

Circadian distribution: Visual seizures are predominantly diurnal and can occur at any time of the day. Longer seizures, with or without hemi or generalised convulsions, tend to occur either during sleep, causing the patient to wake up, or after awakening. Thus, some children may have numerous diurnal visual seizures and only a few seizures that are exclusively nocturnal or occur on awakening.

Frequency of seizures: If untreated, patients experience frequent and brief visual seizures (often several every day or weekly). However, propagation to other seizure manifestations, such as focal or generalised convulsions, is much less frequent.

Unverricht–Lundborg disease (abbreviated ULD or EPM1) is the most common form of an uncommon group of genetic epilepsy disorders called the progressive myoclonus epilepsies. It is caused due to a mutation in the cystatin B gene (CSTB). The disease is named after Heinrich Unverricht, who first described it in 1891, and Herman Bernhard Lundborg, who researched it in greater detail in 1901 and 1903. ULD onsets in children between the ages of 6 and 16; there are no known cases in which the person was older than 18. Most cases originate from the Baltic region of Europe, though many have been reported from countries in the Mediterranean.

Onset of the disease is characterized by myoclonic jerks and tonic-clonic seizures. Early cases often resulted in the need of a wheelchair and death before the age of 24, but new treatments and medications have increased the life expectancy of individuals with ULD, in some cases even to near that of an unaffected individual.

Eyelid myoclonia, not the absences, is the hallmark of Jeavons syndrome.

Eyelid myoclonia consists of marked jerking of the eyelids often associated with jerky upwards deviation of the eyeballs and retropulsion of the head (eyelid myoclonia without absences). This may be associated with or followed by mild impairment of consciousness (eyelid myoclonia with absences). The seizures are brief (3–6 s), and occur mainly and immediately after closing of the eyes (eye closure) and consistently many times a day. All patients are photosensitive.

Generalised tonic-clonic seizures, either induced by lights or spontaneous, are probably inevitable in the long term and are provoked particularly by precipitating factors (sleep deprivation, alcohol) and inappropriate AED modifications.

Myoclonic jerks of the limbs may occur, but are infrequent and random.

Eyelid myoclonic status epilepticus, either spontaneous (mainly on awakening) or photically induced, occurs in a fifth of patients. It consists of repetitive and discontinuous episodes of eyelid myoclonia with mild absence, rather than continuous non- convulsive absence status epilepticus.

Onset is typically in childhood with a peak at age 6–8 years (range 2–14 years). There is a twofold preponderance of girls. Prevalence and incidence is probably low.

Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a pure but rare form of idiopathic occipital epilepsy that affects otherwise normal children and adolescents. It is classified amongst benign idiopathic childhood focal epilepsies such as rolandic epilepsy and Panayiotopoulos syndrome.

Jeavons syndrome is a type of epilepsy. It is one of the most distinctive reflex syndromes of idiopathic generalized epilepsy characterized by the triad of eyelid myoclonia with and without absences, eye-closure-induced seizures, EEG paroxysms, or both, and photosensitivity. Eyelid myoclonia with or without absences is a form of epileptic seizure manifesting with myoclonic jerks of the eyelids with or without a brief absence. These are mainly precipitated by closing of the eyes and lights. Eyelid myoclonia is the defining seizure type of Jeavons syndrome.

Symptoms include:

- intellectual disability (more than half of the patients have an IQ below 50)

- microcephaly

- sometimes pancytopenia (low blood counts)

- cryptorchidism

- low birth weight

- dislocations of pelvis and elbow

- unusually large eyes

- low ears

- small chin

People with PSE experience epileptiform seizures upon exposure to certain visual stimuli. The exact nature of the stimulus or stimuli that triggers the seizures varies from one patient to another, as does the nature and severity of the resulting seizures (ranging from brief absence seizures to full tonic–clonic seizures). Many PSE patients experience an “aura” or feel odd sensations before the seizure occurs, and this can serve as a warning to a patient to move away from the trigger stimulus.

The visual trigger for a seizure is generally cyclic, forming a regular pattern in time or space. Flashing lights or rapidly changing or alternating images (as in clubs, around emergency vehicles, in action movies or television programs, etc.) are examples of patterns in time that can trigger seizures, and these are the most common triggers. Static spatial patterns such as stripes and squares may trigger seizures as well, even if they do not move. In some cases, the trigger must be both spatially and temporally cyclic, such as a certain moving pattern of bars.

Also note: Some people may also find overhead fans spinning to be of the same nature.

Several characteristics are common in the trigger stimuli of many PSE patients. The patterns are usually high in luminance contrast (bright flashes of light alternating with darkness, or white bars against a black background). Contrasts in colour alone (without changes in luminance) are rarely triggers for PSE. Some patients are more affected by patterns of certain colours than by patterns of other colours. The exact spacing of a pattern in time or space is important and varies from one individual to another: a patient may readily experience seizures when exposed to lights that flash seven times per second, but may be unaffected by lights that flash twice per second or twenty times per second. Stimuli that fill the entire visual field are more likely to cause seizures than those that appear in only a portion of the visual field. Stimuli perceived with both eyes are usually much more likely to cause seizures than stimuli seen with one eye only (which is why covering one eye may allow patients to avoid seizures when presented with visual challenges). Some patients are more sensitive with their eyes closed; others are more sensitive with their eyes open.

Sensitivity is increased by alcohol consumption, sleep deprivation, illness, and other forms of stress.

Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response to sound, and problems with gait.

About half of affected patients develop cherry-red spots in the eye.

Children may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia.

- Autosomal recessive disorder; beta-galactosidase deficiency; neuronal storage of GM1 ganglioside and visceral storage of galactosyl oligosaccharides and keratan sulfate.

- Early psychomotor deterioration: decreased activity and lethargy in the first weeks; never sit; feeding problems - failure to thrive; visual failure (nystagmus noted) by 6 months; initial hypotonia; later spasticity with pyramidal signs; secondary microcephaly develops; decerebrate rigidity by 1 year and death by age 1–2 years (due to pneumonia and respiratory failure); some have hyperacusis.

- Macular cherry-red spots in 50% by 6–10 months; corneal opacities in some

- Facial dysmorphology: frontal bossing, wide nasal bridge, facial edema (puffy eyelids); peripheral edema, epicanthus, long upper lip, microretrognathia, gingival hypertrophy (thick alveolar ridges), macroglossia

- Hepatomegaly by 6 months and splenomegaly later; some have cardiac failure

- Skeletal deformities: flexion contractures noted by 3 months; early subperiosteal bone formation (may be present at birth); diaphyseal widening later; demineralization; thoracolumbar vertebral hypoplasia and beaking at age 3–6 months; kyphoscoliosis. *Dysostosis multiplex (as in the mucopolysaccharidoses)

- 10–80% of peripheral lymphocytes are vacuolated; foamy histiocytes in bone marrow; visceral mucopolysaccharide storage similar to that in Hurler disease; GM1 storage in cerebral gray matter is 10-fold elevated (20–50-fold increased in viscera)

- Galactose-containing oligosacchariduria and moderate keratan sulfaturia

- Morquio disease Type B: Mutations with higher residual beta-galactosidase activity for the GM1 substrate than for keratan sulfate and other galactose-containing oligosaccharides have minimal neurologic involvement but severe dysostosis resembling Morquio disease type A (Mucopolysaccharidosis type 4).

Onset of late infantile GM1 is typically between ages 1 and 3 years.

Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.

The onset of symptoms tends to be fairly gradual and to occur over 1–7 days.

Symptoms of Hashimoto's encephalopathy may include:

- personality changes

- aggression

- delusional behavior

- concentration and memory problems

- coma

- disorientation

- headaches

- jerks in the muscles (myoclonus – 65% cases)

- lack of coordination (ataxia – 65% cases)

- partial paralysis on the right side

- psychosis

- seizures (60% cases)

- sleep abnormalities (55% cases)

- speech problems (transient aphasia – 80% cases)

- status epilepticus (20% cases)

- tremors (80% cases)

Diagnosis may be made by noting the correlation between exposure to specific visual stimuli and seizure activity. More precise investigation can be carried out by combining an EEG with a device producing "Intermittent Photic Stimulation" (IPS). The IPS device produces specific types of stimuli that can be controlled and adjusted with precision. The testing physician adjusts the IPS device and looks for characteristic anomalies in the EEG, such as photoparoxysmal response (PPR), that are consistent with PSE and/or may herald the onset of seizure activity. The testing is halted before a seizure actually occurs.

Sometimes diagnostic indicators consistent with PSE can be found through provocative testing with IPS, and yet no seizures may ever occur in real-life situations. Many people will show PSE-like abnormalities in brain activity with sufficiently aggressive stimulation, but they never experience seizures and are not considered to have PSE.

Nuclear factor-kappa B Essential Modulator (NEMO) deficiency syndrome is a rare type of primary immunodeficiency disease that has a highly variable set of symptoms and prognoses. It mainly affects the skin and immune system but has the potential to affect all parts of the body, including the lungs, urinary tract and gastrointestinal tract. It is a monogenetic disease caused by mutation in the IKBKG gene (IKKγ, also known as the NF-κB essential modulator, or NEMO). NEMO is the modulator protein in the IKK inhibitor complex that, when activated, phosphorylates the inhibitor of the NF-κB transcription factors allowing for the translocation of transcription factors into the nucleus.

The link between IKBKG mutations and NEMO deficiency was identified in 1999. IKBKG is located on the X chromosome and is X-linked therefore this disease predominantly affects males, However females may be genetic carriers of certain types of mutations. Other forms of the syndrome involving NEMO-related pathways can be passed on from parent to child in an autosomal dominant manner – this means that a child only has to inherit the faulty gene from one parent to develop the condition. This autosomal dominant type of NEMO deficiency syndrome can affect both boys and girls.

A relapsing encephalopathy occurring in association with Hashimoto's thyroiditis, with high titers of anti-thyroid antibodies. Clinically, the condition may present one or more symptoms.

Onset is often gradual and may go unnoticed by the patient and close associates to the patients.

Symptoms sometimes resolve themselves within days to weeks, leaving a patient undiagnosed. For many other patients, the condition may result in ongoing problems with a variety of manifestations, often confusing clinicians due to the diffuse nature of symptoms.

For people with this disorder, cognition and sensation are otherwise normal; for instance, patients can still feel discriminative touch (though not always temperature), and there are no detectable physical abnormalities.

Because children with the disorder cannot feel pain, they may not respond to problems, thus being at a higher risk of more severe diseases. Children with this condition often suffer oral cavity damage both in and around the oral cavity (such as having bitten off the tip of their tongue) or fractures to bones. Unnoticed infections and corneal damage due to foreign objects in the eye are also seen.

There are generally two types of non-response exhibited:

- Insensitivity to pain means that the painful stimulus is not even perceived: a patient cannot describe the intensity or type of pain.

- Indifference to pain means that the patient can perceive the stimulus, but lacks an appropriate response: they do not flinch or withdraw when exposed to pain.

In addition to persistent daily headache of HC, which is usually mild to moderate (and frequently severe), HC can present other symptoms. These additional symptoms of HC can be divided into three main categories:

1. Autonomic symptoms:

- conjunctival injection

- tearing

- rhinorrhea

- nasal stuffiness

- eyelid edema

- forehead sweating

2. Stabbing headaches:

- Short, "jabbing" headaches superimposed over the persistent daily headache.

- Usually lasting less than one minute.

3. Migrainous features:

- throbbing pain

- nausea and/or vomiting

- phonophobia

- photophobia

Cholinergic urticaria (CU) is a type of physical urticaria (or "hives") that appears when a person is sweating.

The Seckel syndrome or microcephalic primordial dwarfism (also known as bird-headed dwarfism, Harper's syndrome, Virchow-Seckel dwarfism, and Bird-headed dwarf of Seckel) is an extremely rare congenital nanosomic disorder.

Inheritance is autosomal recessive.

It is characterized by intrauterine growth retardation and postnatal dwarfism with a small head, narrow bird-like face with a beak-like nose, large eyes with down-slanting palpebral fissures , receding mandible and intellectual disability.

A mouse model has been developed. This mouse model is characterized by a severe deficiency of ATR protein. These mice suffer high levels of replicative stress and DNA damage. Adult Seckel mice display accelerated aging. These findings are consistent with the DNA damage theory of aging.

Congenital insensitivity to pain (CIP), also known as congenital analgesia, is one or more rare conditions in which a person cannot feel (and has never felt) physical pain. The conditions described here are separate from the HSAN group of disorders, which have more specific signs and cause. Because feeling physical pain is vital for survival, CIP is an extremely dangerous condition. It is common for people with the condition to die in childhood due to injuries or illnesses going unnoticed. Burn injuries are one of the more common injuries.

Diagnosis

Originally NEMO deficiency syndrome was thought to be a combination of Ectodermal Dysplasia (ED) and a lack of immune function, but is now understood to be more complex disease. NEMO Deficiency Syndrome may manifest itself in the form of several different diseases dependent upon mutations of the IKBKG gene such as Incontinentia pigmenti or Ectodermal dysplasia.

The clinical presentation of NEMO deficiency is determined by three main symptoms:

1. Susceptibility to pyogenic infections in the form of severe local inflammation

2. Susceptibility to mycobacterial infection

3. Symptoms of Ectodermal Dysplasia

To determine whether or not patient has NEMO deficiency, an immunologic screen to test immune system response to antigen may be used although a genetic test is the only way to be certain as many individuals respond differently to the immunological tests.

Commonly Associated Diseases

NEMO deficiency syndrome may present itself as Incontinentia pigmenti or Ectodermal dysplasia depending on the type of genetic mutation present, such as if the mutation results in the complete loss of gene function or a point mutation.

Amorphic genetic mutations in the IKBKG gene, which result in the loss of gene function, typically present themselves as Incontinetia Pigmenti (IP). Because loss of NEMO function is lethal, only heterozygous females or males with XXY karyotype or mosaicism for this gene survive and exhibit symptoms of Incontinetia Pigmenti, such as skin lesions and abnormalities in hair, teeth, and nails. There are a variety of mutations that may cause the symptoms of IP, however, they all involve the deletion of exons on the IKBKG gene.

Hypomorphic genetic mutations in the IKBKG gene, resulting in a partial loss of gene function, cause the onset of Anhidrotic ectodermal dysplasia with Immunodeficiency (EDA-IP). The lack of NEMO results in a decreased levels of NF-κB transcription factor translocation and gene transcription, which in turn leads to a low level of immunoglobulin production. Because NF-κB translocation is unable to occur without proper NEMO function, the cell signaling response to immune mediators such as IL-1β, IL-18, and LPS are ineffective thus leading to a compromised immune response to various forms of bacterial infections.

Treatment

The aim of treatment is to prevent infections so children will usually be started on immunoglobulin treatment. Immunoglobulin is also known as IgG or antibody. It is a blood product and is given as replacement for people who are unable to make their own antibodies. It is the mainstay of treatment for patients affected by primary antibody deficiency. In addition to immunoglobulin treatment, children may need to take antibiotics or antifungal medicines to prevent infections or treat them promptly when they occur. Regular monitoring and check-ups will help to catch infections early. If an autoimmune response occurs, this can be treated with steroid and/or biologic medicines to damp down the immune system so relieving the symptoms.

In some severely affected patients, NEMO deficiency syndrome is treated using a bone marrow or blood stem cell transplant. The aim is to replace the faulty immune system with an immune system from a healthy donor.

The following diagnostic criteria are given for hemicrania continua:

1. Headache for more than 3 months fulfilling other 3 criteria:

2. All of the following characteristics:

- Unilateral pain without side-shift

- Daily and continuous, without pain-free periods

- Moderate intensity, but with exacerbations of severe pain

3. At least one of the following autonomic features occurs during exacerbations and ipsilateral to the side of pain:

- Conjunctival injection and/or lacrimation

- Nasal congestion and/or rhinorrhea

- Ptosis and/or miosis

4. Complete response to therapeutic doses of indomethacin, although cases of hemicrania continua that do not resolve with indomethacin treatment have been documented.

A variant on hemicrania continua has also been described, in which the attacks may shift sides, although meeting the above criteria in all other respects.

Main features differentiating CPH from cluster headaches (migrainous neuralgia, above) are the higher frequency and shorter duration of attacks, higher incidence in women, and the response to treatment with indomethacin. CPH is not associated with cranial nerve palsies.

CU typically presents with a number of small, short-lasting hives but may also involve cutaneous inflammation (wheals) and pain which develops usually in response to exercise, bathing, staying in a heated environment, or emotional stress. Although the symptoms subside rapidly, commonly within 1 hour, CU may significantly impair quality of life, especially in relation to sporting activities.

There are seven types of attacks. Ninety percent of all patients have their first attack before they are 18 years old. All develop over 2–4 hours and last anywhere from 6 hours to 4 days. Most attacks involve fever.

1. Abdominal attacks, featuring abdominal pain, affect the whole abdomen with all signs of peritonitis (inflammation of abdominal lining), and acute abdominal pain like appendicitis. They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.

2. Joint attacks mainly occur in large joints, especially in the legs. Usually, only one joint is affected. 75% of all FMF patients experience joint attacks.

3. Chest attacks include pleuritis (inflammation of the pleura) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40% of patients and makes it difficult to breathe or lie flat, but pericarditis is rare.

4. Scrotal attacks due to inflammation of the tunica vaginalis occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion).

5. Myalgia (rare in isolation)

6. Erysipeloid (a skin reaction on the legs, rare in isolation)

7. Fever without any of the other symptoms listed above (25%)

AA-amyloidosis with kidney failure is a complication and may develop without overt crises. AA amyloid protein is produced in very large quantities during attacks, and at a low rate between them, and accumulates mainly in the kidney, as well as the heart, spleen, gastrointestinal tract, and thyroid.

There appears to be an increase in the risk for developing particular vasculitis-related diseases (e.g. Henoch–Schönlein purpura), spondylarthropathy, prolonged arthritis of certain joints and protracted myalgia.

The main symptoms of AIE include:

- Diarrhea (frequent loss of fluids)

- Intestinal inflammation

- Vomiting

- Intestinal bleeding

- Difficulty or inability to gain weight

- Rapid weight loss

- Decreased urine output from dehydration