Krabbe disease

Krabbe disease belongs to a group of disorders called leukodystrophies, rare genetic disorders that affect the white matter of the brain. Krabbe disease is characterized by a deficiency in the enzyme galactocerebrosidase (GALC) which is an enzyme that uses water molecules to break down certain fats (lipids). Failure to break down these lipids results in deterioration of the protective covering (myelin sheath) surrounding nerves in the brain (demyelination). Characteristic globoid (sphere shaped) cells appear in affected areas of the brain. These enlarged fatty cells accumulate in affected areas and cause a variety of progressive neurological symptoms. Depending on the age that symptoms begin, individuals may present with intellectual and behavioral delays, blindness, deafness, paralysis of facial muscles (pseudobulbar palsy), muscle spasms and seizures. Most patients are diagnosed by measuring GALC enzyme activity in leukocytes taken from a blood sample. Very low activity could indicate a diagnosis of Krabbe disease. In some states, diagnosis may occur through newborn screening. If newborns are diagnosed before 14 days old, they are candidates for early treatment with hematopoietic stem cell transplantation (HSCT). Krabbe disease is inherited in an autosomal recessive pattern.

Krabbe disease has four subtypes based on age of onset: early infantile-onset (<13 months); late-infantile onset (13-36 months), adolescent onset and adult onset. Eighty-five percent (85%) of all patients with Krabbe disease have the early infantile onset type. Early infantile-onset Krabbe disease is marked by initial normal development followed by rapid and severe deterioration. The average age of death after symptoms begin is two years, but it can range between eight months and nine years. Later onset Krabbe disease results in a slower decline in neurologic function and an increased life expectancy averaging eight years after symptoms begin. Adults diagnosed with Krabbe disease can have significant neurologic impairment but can live 30-50 years after diagnosis.

Krabbe disease is an autosomal recessive genetic disorder caused by changes called pathogenic variants in the GALC gene. The gene variants lead to a deficiency in the enzyme galactosylceramidase. This enzyme metabolizes galactosylceramide, a component of the fatty covering (sheath) around the nerves (myelin). Galactosylceramide metabolism is vital to the destruction of old membranes and the creation of new, healthy myelin membranes, so the buildup of certain galactolipids is toxic to myelin-forming cells.

An estimated 1 in 100,000 newborn babies have Krabbe disease. The more severe infantile-onset disease occurs in 85-90% of patients. The other 10-15% of patients are diagnosed with late-onset disease, though this number may now be higher based on data from state newborn screening programs.

Symptoms of the following disorders can be similar to those of Krabbe’s Leukodystrophy. Comparisons may be useful for a differential diagnosis:

X-linked adrenoleukodystrophy (X-ALD) is one of many different leukodystrophies. The childhood cerebral (brain) form resembles Krabbe disease, which involves demyelination of white matter and complications of the adrenal cortex. X-ALD manifests most commonly between age four and eight (well after Krabbe disease symptoms typically appear). X-ALD initially resembles ADHD, and progressive impairment of cognition, behavior, vision, hearing and motor function, often leading to total disability within two years. (For more information on this disorder, choose X-Linked Adrenoleukodystrophy as your search term in the Rare Disease Database).

Hematopoietic stem cell transplantation (HSCT) is the current standard treatment for Krabbe disease. This is stem-cell transplant typically from bone marrow or the umbilical cord. Asymptomatic individuals benefit most from this treatment, initially showing near-normal development with some motor delays. The outcomes of this treatment for symptomatic patients are variable and based on age and progression of disease and symptoms. HSCT is usually not recommended for symptomatic individuals. HSCT effectiveness can be monitored with psychosine concentration, which is a biomarker for treatment with HSCT and should decrease with successful therapy. HSCT slows but does not reverse the progression of Krabbe disease, even when started in presymptomatic children.


Kufor Rakeb Syndrome

For most individuals, symptoms will begin to appear between 10 and 20 years of age. KRS is a neurodegenerative disorder, so the severity of symptoms tends to progress with time. Symptoms varies depending on the individual and can be divided in two major categories: symptoms that affect movement (motor symptoms) and those that do not (non-motor symptoms).

Kufor Rakeb syndrome is an autosomal recessive disorder caused by changes (mutations) in the ATP13A2 gene. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

Kufor Rakeb syndrome is considered an ultra-rare disorder. Fewer than 50 individuals have been reported in the literature. Because KRS is a rare and complex disease, it is possibly underdiagnosed and the real prevalence of the disease is therefore hard to estimate. As it is the case for all autosomal recessive disorders, children of parents who are blood relatives are at an increased risk of developing the disease, as they are more likely to receive the same copy of a disease-causing (pathogenic) mutation from each parent.

As Kufor Rakeb syndrome is a complex progressive neurological disease with varied symptoms, it shares features with many other disorders. The appearance of characteristic symptoms of Parkinson’s disease (parkinsonism) in individuals under age 21 is known as juvenile parkinsonism. The causes of juvenile parkinsonism are multiple, including genetic juvenile onset Parkinson’s disease (KRS being in this category), other neurological or systemic disorders, infections, toxins, and drugs side effects. The following disorders are examples of conditions that can have symptoms similar to Kufor Rakeb syndrome.

A diagnosis of Kufor Rakeb syndrome requires an extensive patient history, as well as a complete physical and neurological examination. KRS can be suspected in individuals that start to develop atypical parkinsonism (typical symptoms of Parkinson’s disease in addition to other features such as dystonia, muscle stiffness, and rapid progression) between 10 and 20 years of age. MRI imaging will also show brain atrophy (cerebral atrophy) and possibly accumulation of iron in a brain structure called the basal ganglia (in the caudate and putamen, specifically). Genetic screening allows the identification of disease-causing (pathogenic) changes (mutations) in the ATP13A2 gene and can lead to a definitive diagnosis.

As there is no cure for Kufor Rakeb syndrome, therapy is focused on the management of symptoms and improvement of quality of life of affected individuals. As it is the case for typical (idiopathic) Parkinson’s disease, a combination of levodopa and carbidopa is usually prescribed. The goal of this medication is to alleviate motor symptoms by increasing the concentration of dopamine in the nervous system. Dopamine receptor agonists can also be used. Trihexylphenidyl and amantadine might also be prescribed, especially in cases where dopaminergic medication is not effective or tolerated. Botulinum toxin (Botox) can be used to treat dystonia. Physical, occupational and/or speech therapy can also be useful interventions. Treatment options for non-motor symptoms are more limited.


L1 syndrome

The variable types of L1 syndrome were once thought to be different diseases, but all of the following conditions are now known to be caused by mutations in the L1CAM gene:

L1 syndrome is an X-linked genetic disorder that occurs primarily in males. L1 syndrome is caused by mutations in the L1CAM gene located on the X chromosome.

L1 syndrome is a genetic condition that occurs almost exclusively in males. The birth prevalence of the HSAS type of L1 syndrome is approximately 1 in 30,000 births. The frequency of all types of L1 syndrome is not known. Approximately 5% of female carriers of an L1CAM gene mutation have some symptoms that are usually mild.

In male patients with spastic paraplegia and developmental delay/intellectual disability, the L1CAM syndrome should be considered.

Neuropathology and neuroimaging are used to reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius, corpus callosum agenesis/hypogenesis, cerebellar hypoplasia, small brain stem, and agenesis of the pyramids.


Zimmermann-Laband syndrome

Gingival Fibromatosis, Abnormal Fingers, Nails, Nose, Ear, Splenomegaly

Laband syndrome, also known as Zimmerman-Laband syndrome, is an extremely rare genetic disorder characterized by abnormalities of the head and facial (craniofacial) area and the hands and feet. Most children with this disorder have abnormally large gums (gingival fibromatosis). Overgrown gums may affect the ability to chew, swallow, and/or speak. In addition, affected infants may exhibit abnormally long, thin fingers and toes and/or deformed (dysplastic) or absent nails at birth. In some cases, mental retardation may also be present. In most cases, Laband syndrome is believed to be inherited as an autosomal dominant trait. However, evidence of autosomal recessive inheritance has also been reported.

Laband syndrome is an extremely rare genetic disorder characterized by abnormalities of the head and face (craniofacial) area and the fingers and toes, particularly the thumbs and great toes. Abnormalities affecting the fingers and toes may be apparent at birth (congenital); other symptoms may not become apparent until later during childhood. The range and severity of symptoms vary from case to case.

Early reports suggest that Laband syndrome is inherited as an autosomal dominant trait. However, evidence for autosomal recessive inheritance exists as well. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Laband syndrome is an extremely rare genetic disorder that affects males and females in equal numbers. It appears that the disease most frequently affects individuals who are of Eastern Indian ancestry from India and the West Indies. However, the disorder has also been reported in individuals of European descent. More than 30 cases have been reported in the medical literature since the disorder’s original description in 1928.

Symptoms of the following disorder can be similar to those of Laband syndrome. Comparisons may be useful for a differential diagnosis:

In most cases, Laband syndrome may be diagnosed during early childhood. The diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. X-ray studies of the fingers and/or toes (digits) and clinical examination of the nose, ears, lips, and tongue may be helpful in identifying the disorder. Malformation or absence of the nails may be apparent at birth (congenital). Confirmation of Laband syndrome may not be made until gingival fibromatosis is observed when the primary teeth appear.


Lacrimoauriculodentodigital syndrome

Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the lacrimal and salivary glands and ducts, ears, teeth and fingers and toes. The most common findings involve malformations in the network of structures of the eye that secrete tears and drain them from the eyes (lacrimal apparatus) and abnormalities of the forearms and fingers. Specific symptoms may vary greatly from person to person. LADD syndrome may occur sporadically or be inherited in an autosomal dominant pattern.

The symptoms of LADD syndrome may greatly vary from person to person. Abnormalities may potentially affect multiple organ systems of the body including the eyes, ears, teeth, and limbs.

LADD syndrome may occur randomly as the result of a spontaneous genetic change (i.e., new mutation). The mutation is inherited in an autosomal dominant fashion. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

LADD syndrome affects males and females in equal numbers. More than 50 cases have been reported in the medical literature since the disorders first description in 1967.

Symptoms of the following disorders can be similar to those of LADD syndrome. Comparisons may be useful for a differential diagnosis.

Molecular genetic testing of the FGF10 gene and selected regions of the FGRF2/3 genes is available to confirm the diagnosis. For information contact:


Lafora disease

Lafora disease is characterized by an onset of symptoms between 8-19 years of age, with the peak symptom onset being between 14-16 years. There are also extremely rare cases of early onset Lafora disease in patients as young as 5 years. Most affected individuals do not have symptoms until adolescence and then may start to have headaches, trouble learning in school and, most characteristically, seizures. The most common type of seizure in Lafora disease is myoclonic seizures, which look like jerking or brief shaking movements. Other seizure types include tonic-clonic seizures (stiffening of muscles followed by jerking or shaking), absence seizures (staring spells), atonic seizures (the body becomes limp), and complex partial seizures (staring spells with jerking or repetitive movements in one part of the body). Focal occipital seizures that present as blindness or hallucinations are possible. Over time, seizures typically increase in severity and become more difficult to control. Status epilepticus (prolonged or back-to-back seizures) may occur.

Lafora disease is caused by changes (pathogenic variants or mutations) in the EPM2A or EPM2B (also called NHLRC1) genes. EPM2A encodes the protein laforin, which is a phosphatase that forms a complex with the ubiquitin ligase, malin, encoded by EPM2B. The malin-laforin complex aids in monitoring and preventing excessive elongation of glycogen branch chains. When elongation is uncontrolled, glycogen branch chains cause glycogen molecules to precipitate into Lafora bodies, or abnormal glycogen particles which cannot be broken down and instead form accumulations that damage cells. These Lafora bodies build up throughout the nervous system as well as in tissues such as muscle, liver and skin.

Lafora disease typically affects adolescent females and males equally and has been reported at higher frequencies in populations from the Mediterranean (Spain, France, Italy), Northern Africa, India and Pakistan. The disease prevalence from reported cases is around 4 per 1,000,000 people; however, this number may be an underestimate due to unreported or undiagnosed cases.

There are many conditions with symptoms that are similar to Lafora disease. They include, but are not limited to:

The diagnostic process for individuals with Lafora disease can occur in multiple ways. The first symptoms that bring a patient to a physician are usually focal or myoclonic seizures. Neurological findings typically start at 8-19 years of age. Lafora disease can be diagnosed with a skin biopsy that shows Lafora bodies in the cells of a patient’s sweat ducts. Molecular genetic testing for pathogenic variants in the EPM2A or EPM2B genes confirms the diagnosis.


Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. It is a miscommunication between the nerve cell and the muscles that lead to the gradual onset of muscle weakness. It starts in the proximal muscles of the legs or arms. LEMS can be categorized into two different classes: LEMS associated with small cell lung cancer (SCLC) and LEMS without cancer association. Approximately 60 percent of patients with LEMS have SCLC, and the onset of LEMS symptoms often precedes the detection of the cancer. LEMS patients with cancer tend to be older, mostly male, and nearly always have a long history of smoking. In patients in which there is no associated cancer, disease onset can be at any age and in males and females. LEMS may impact quality of life depending on the severity of symptoms.

LEMS is characterized by weakness and fatigue especially of the muscles in the legs and arms. The disease may affect the patient’s ability to engage in strenuous exercise and may make such activities as climbing stairs or walking up a steep walkway difficult. Onset is gradual, typically taking place over several weeks to many months. There is often a progression of symptoms whereby the shoulder muscles, muscles of the feet and hands, speech and swallowing muscles and eye muscles are affected in a stepwise fashion. The symptoms progress more quickly when LEMS is associated with cancer. Most LEMS patients also exhibit the following symptoms (sometimes called autonomic symptoms): dry mouth, dry eyes, constipation, impotence and decreased sweating. LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. In summary, LEMS is often described as a clinical triad of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes.

LEMS is an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. LEMS occurs because autoantibodies damage the voltage-gated calcium channels (VGCC) on the motor nerve membrane at the neuromuscular junction. These channels normally conduct calcium into the nerve resulting in the release of a chemical known as acetylcholine. Acetylcholine helps in the communication between nerve cells and muscles and is one of a group of chemicals known as neurotransmitters, which help to transmit nerve impulses. The autoantibodies attack the VGCC resulting in less acetylcholine release.

The estimated worldwide prevalence of LEMS is about 2.8 per million, making it a rare disease. There are approximately 400 known cases of LEMS in the United States. When LEMS is associated with SCLC, the patients tend to be older and are more likely to be male. The average age of onset of SCLC is around 60 years of age. Approximately 3% of SCLC patients develop LEMS, but clinical symptoms of LEMS usually precede the SCLC diagnosis (sometimes by many years). When LEMS is not related to cancer, the syndrome may occur at any age, and the typical onset is about 35 years of age. LEMS is extremely rare in the pediatric population, and there have only been 11 affected children reported in literature.

Symptoms of the following disorders can be similar to those of Lambert-Eaton myasthenic syndrome. Comparisons may be useful for a differential diagnosis:

Myasthenia gravis (MG) is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. Often, LEMS is misdiagnosed as MG because of the similarity in symptoms but there are key differences. In LEMS, eye muscle weakness, when present, tends to be mild and, unlike with MG, is almost never the only symptom of the disease. Severe respiratory muscle weakness, which can be fatal in MG, is rare in LEMS. The autonomic symptoms which affect most LEMS patients are not present in MG. For more information on this disorder, choose myasthenia as your search term in the Rare Disease Database.)


Lamellar ichthyosis

Babies born with LI are sometimes called collodion babies. They are covered in a clear membrane (collodion) so it looks like they are covered with plastic wrap. Their skin can look red or dark, tight, and split. These newborns can have skin that is so tight that it forces their lips to turn outward. Also, the skin on their hands may be tight, preventing them from extending their fingers. Newborns can have problems regulating their body temperature and preventing water loss. They may also be more likely to develop skin infections. The collodion membrane is usually shed a few days to a few weeks after birth. Once this happens, the newborn is covered with broad, dark scales. The space in between the scales may be shallow or deep.

LI can be caused by harmful changes in several genes. The most common gene related to this condition is TGM1. Other genes include NIPAL4, ALOX12B, and CYP4F22. These genes provide the instructions to make enzymes and proteins. These enzymes and proteins are important for normal development, function, and shedding of skin cells. There is also evidence that more genes are related to LI. The severity of the condition cannot always be determined based on genetic testing results.

LI occurs in about one in 200,000 people. The condition can affect people of all genders, races, and ethnicities.

Signs and symptoms of the following disorders may be like those of LI.


Landau-Kleffner syndrome

acquired aphasia with convulsive disorder

Landau Kleffner syndrome (LKS) is a rare childhood disorder characterized by the loss of language comprehension (auditory verbal agnosia) and verbal expression (aphasia) in association with severely abnormal electroencephalographic (EEG) findings during sleep and clinical seizures in most patients.

The symptoms typically begin between the ages of three and seven years although the condition may rarely occur in children as young as 18 months of age. Affected children often appear to have acquired deafness since they fail to respond to verbal language and in some cases to nonverbal sounds. A significant minority of children with LKS also develops serious behavioral dysfunction, including hyperactivity, temper outbursts, or withdrawn behaviors but rarely the severe social impairments seen in autism spectrum disorders.

The cause of Landau-Kleffner syndrome is unknown although a spectrum of epileptic conditions including LKS has been described in individuals with GRIN2A gene mutations and other candidate genes including RELN, BSN, EPHB2 and NID2 have been suggested. The response in some patients to immunosuppression has raised the question of autoimmune and other inflammatory mechanisms as potential contributors.

Landau-Kleffner syndrome is a rare disorder that affects twice as many males as females. Affected siblings and discordant monozygotic twins have been reported rarely.

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental condition typically appearing before the age of thirty months. They are characterized by impairments in social communication and severely restricted interests or repetitive patterns of behavior.  A significant minority of affected children have a history of developmental regression affecting language, social and behavioral functioning, which usually occurs between 18 and 30 months of age. Between 30-40 percent of children with ASDs have low scores on standardized intelligence tests. The clinical expression and severity of ASDs vary widely. The functional outcomes of those with ASDs   are improved with intensive behavioral and developmental interventions beginning in early life.

Epilepsy is a collective term given to a group of disorders of the central nervous system characterized by repeated seizures which are manifest by observable changes in consciousness, muscle activity or other neurological functions caused by electrochemical disturbances in the brain. The major symptoms include loss of consciousness, convulsions, body-jerking, sensory loss, confusion, and disturbances of involuntary body functions (autonomic nervous system). EEGs often show characteristic patterns of electrical discharge even in-between the clinical episodes. There are many different forms of epilepsy including primary generalized which can manifest by convulsive motor movements or staring unresponsiveness and focal  seizures which may be preceded by an aura, sometimes  described as a feeling of vague discomfort or change in sensation followed by  varying combinations of motor and sensory alterations. (For more information on this disorder, choose Epilepsy as your search term in the Rare Disease Database.)


无脑回畸形伴小脑发育不全

Lissencephaly with cerebellar hypoplasia

LCH is a disorder presenting in either single or multiple locations and thus causing a variety of signs and symptoms from mild to life-threatening. Single system presentations may be exclusively in the skin, bone, pituitary, or lungs. Patients affected in multiple systems most often have skin and bone involvement with any combination of other sites. When the liver, spleen, and bone marrow are involved, these patients are given the designation high risk which means the chance of death is approximately 15%. All patients with LCH in sites other than the bone marrow, spleen, and liver can be cured. (Gadner, Allen 2015)

LCH is caused by mutations in a cell signaling pathway known as the MAPKinase pathway. Key genes mutated in this pathway include BRAF (65-70%), MAP2K (20%), and other rarer genes, all of which lead to abnormal activation of a gene known as ERK. (Durham) These mutations are genetic accidents which occur during DNA copying in dendritic cells and are not inherited. The maturation stage of the dendritic cell will determine what type of disease a patient will develop. If the mutation occurs when the dendritic cell is still in stem cell stage, this early precursor may go to any organ in the body-especially liver, spleen and bone marrow. Mutation in a more mature dendritic cell will lead to LCH in a variety of organs, but not the high risk ones mentioned before. An even more mature dendritic cell carrying this mutation may go to only skin and bone.

Hispanics have a higher incidence of diffuse LCH involvement and Blacks are less affected than Whites. (Riberio) The overall incidence of LCH is between 4 and 9 cases per million with males slightly more affected than females (1.2:1) and the highest number of cases presenting in the first four years of life. The incidence is adults is not known, but may be 1-2 per million.

Symptoms of the following disorders can be similar to those of Langerhans cell histiocytosis. Comparisons may be useful for a differential diagnosis:

Rosai-Dorfman disease (RDD) is a rare disorder characterized by overproduction) and accumulation of a specific type of white blood cell (macrophage/histiocyte) in the lymph nodes of the body (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). In some patients, abnormal accumulation of histiocytes (macrophages) may occur in other areas of the body besides the lymph nodes (extranodal). These areas include the skin, central nervous system, kidney, and digestive tract. The symptoms and physical findings associated with RDD vary depending upon the specific areas of the body that are affected. The disorder predominantly affects children, adolescents or young adults. Some RDD patients have KRAS and MAP2K mutations, but many have none. The diagnosis of RDD is made by finding excessive numbers of histiocytes that often have lymphocytes passing through their cytoplasm. (For more information on this disorder, choose Rosai-Dorfman as your search term in the Rare Disease Database.)


Large Granular Lymphocyte Leukemia

T细胞大颗粒淋巴细胞性白血病

The symptoms that patients with LGL leukemia most commonly experience are related to the changes in neutrophils, red blood cells and platelets. Changes in neutrophils are the most common, followed by changes in red blood cells, with changes in platelets being the least common. Patients can also have a combination of these changes. Many patients with LGL leukemia report fatigue and flu-like symptoms or other symptoms that are commonly associated with having an active infection, even when they do not have an infection (Lamy & Loughran, 2003). As discussed above, the LGL cells that do not die off continue to make the same inflammatory signals that they would during an active infection, so these additional symptoms are likely due to the body continuing to respond to those signals.

The exact cause of LGL leukemia is not known. Ongoing research in the Loughran Lab at the University of Virginia has led researchers to theorize that patients develop LGLL following exposure to foreign antigens, potentially due to a viral infection. It is proposed that cells that are fighting off that virus are transformed by gene changes (mutations) and cannot die off as they typically would after they have fought off the virus (Kanchan & Loughran, 2003). These mutations develop in a group of mature cells after birth, so they are not passed down to a patient’s children. Recent research studies have catalogued the most frequently mutated genes in LGL leukemia (Olson et al., 2021; Cheon et al., 2022).

The incidence of LGL leukemia increases with age. It is usually diagnosed in older people and rarely occurs in individuals under 30 years old. LGLL almost never affects children and is very rare in patients under the age of twenty. In the United States, the incidence of LGLL is thought to be 0.2 to 0.72 cases out of every 1,000,000 people, but this may be an underestimate. Patients in an early stage of the disease or people without symptoms may go undiagnosed.

LGL leukemia cells can develop from two different types of large granular lymphocytes, cytotoxic T-cells and natural killer (NK) cells. The type associated with NK cells is very rare, and accounts for only 10-15% of cases. LGL leukemia of either type typically exhibits a slow-moving, chronic disease course. However there is an aggressive form of NK type of LGL leukemia that is primarily seen in Asian populations and is distinctly different than the chronic type of NK-LGL leukemia. Therefore, it is important to have an accurate and thorough workup focused on the known markers for LGL leukemia to correctly categorize the type of LGL leukemia.


Larsen Syndrome

The symptoms and severity of Larsen syndrome vary greatly, including between individuals belonging to the same family. In one large family whose members had Larsen syndrome caused by one of the recurring mutations, some affected individuals have cleft palate and multiple large joint dislocations, but others have no major anomalies and manifested only short stature and mild features, such as short distal phalanges (toe and fingertip bones) and extra bones in the wrist and ankle Mild short stature is common with height below the tenth percentile in 70% of the cases.

The classic form of Larsen syndrome follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Larsen syndrome affects males and females in equal numbers. It is estimated to occur in 1 in 100,000 individuals in the general population. Because of the difficulty in diagnosing Larsen syndrome, determining its true frequency in the general population is difficult. Larsen syndrome was first described in the medical literature as a distinct disease entity by Dr. Loren Larsen in 1950.

Symptoms of the following disorders can be similar to those of Larsen syndrome. Comparisons may be useful for a differential diagnosis. For more information on these disorders, use the specific disorder name as a search term in the Rare Disease Database.

The diagnosis of Larsen syndrome is made based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic clinical and radiological findings. Radiographic examination can detect the presence and severity of associated skeletal findings. Molecular genetic testing can confirm the presence of the FLNB gene mutation.


Laryngeal Dystonia

The severity of LD can fluctuate from symptom-free periods with normal voice to severely disabling periods where an affected individual will experience significant difficulty speaking clearly or be barely able to speak. Symptom fluctuation can occur during the same day or from day to day or longer. LD tends to affect normal conversational speech. Several studies have shown that singing, laughing, and yelling, are often unaffected.

Most cases of LD are idiopathic, which means a cause is not identifiable. Several different factors may be involved in the development of the disorder (multifactorial). Several theories exist that attempt to explain the underlying mechanisms of LD including abnormal functioning of portions of the brain involved in muscle control, or imbalances in neurotransmitters. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one brain cell (neuron) to another, enabling nerve cells to communicate. Although the underlying mechanisms and causes of LD are not well understood, research is ongoing to determine the specific roles that genetic, environmental, and other factors ultimately play in the development of the disorder.

LD occurs more often in females than males and can affect individuals of all ethnic backgrounds. Onset can occur at any age, but usually occurs between 30 and 60 years of age. The exact incidence or prevalence of the disorder is unknown. LD is estimated to affect approximately 50,000 people in North America. However, determining the true frequency of LD in the general population is difficult because many cases are misdiagnosed or go undiagnosed.

Symptoms of the following disorders can be similar to those of LD. Comparisons may be useful for a differential diagnosis:

The diagnosis of LD usually involves careful assessment of the voice and speaking under different conditions by a speech pathologist, otolaryngologist, or neurologist. It also includes inspection of the voice box (laryngoscopy) to rule out structural abnormalities of the vocal cords such as nodules, polyps, or tumors.


Laryngotracheoesophageal cleft

When there is a connection between an infant’s airway and esophagus, food and liquid can pass into the lungs. This can lead to a variety of problems, including chronic cough, frequent lung infections, a high-pitched gasping sound usually heard during breathing in (stridor), a high-pitched musical sound usually heard when breathing out (wheezing), skin turning blue (cyanosis), pauses in breathing (apnea) and respiratory distress. Affected children often have feeding difficulties such as gagging, choking or coughing during eating, which can lead to failure to gain weight. Signs and symptoms of LTEC often begin in the first few days of life if the cleft is severe enough to affect feeding and breathing. Milder LTEC may not be diagnosed until years later.

Laryngotracheoesophageal clefts are congenital, meaning they are present at birth. The cause is unknown.

Laryngeal clefts are estimated to occur in 1 out of every 10,000-20,000 births. Laryngotracheoesophageal clefts are a subtype of laryngeal cleft, and the incidence of LTECs is even lower, estimated around 1/600,000 births.

LTECs can occur alone or in association with other health problems as a part of a syndrome. Some of the syndromes associated with LTEC include Opitz syndrome, DiGeorge syndrome, VACTERL association, CHARGE syndrome and Pallister-Hall syndrome. More information is available about these conditions in the Rare Disease Database.

The diagnosis of LTEC may be suspected based on clinical signs and symptoms. A doctor may perform a modified barium swallow study to further investigate symptoms. A swallow study involves having the infant or child drink a liquid that has been dyed with a white powder called barium. X-rays are taken of the child while swallowing to visualize any leakage of dye from the esophagus into the airway, which would indicate possible laryngeal cleft. Barium is not harmful to the child’s health. A swallow study can be supportive in diagnosing LTEC, but the preferred method of diagnosis is with a rigid laryngoscopy and bronchoscopy. This procedure involves using a camera with a light to look inside the larynx and trachea. This is typically performed under general anesthesia in the operating room. During this procedure, doctors measure the size of the connection between the airway and esophagus to understand the type and severity of LTEC.

The primary treatment for a laryngeal cleft is surgery to close the connection between the airway and esophagus. This surgery can be done either endoscopically by entering through a child’s mouth or an open approach by going through their neck. During this procedure, a surgeon will close the cleft with stiches. Endoscopic repair is preferable for mild laryngeal clefts, while open repair is often necessary for more severe LTECs (types III & IV) which is often the case for young infants with small airways. Both procedures are done when the child is asleep under general anesthesia in the operating room. Further management may include tracheostomy and/or gastrostomy tube for breathing and feeding assistance, among other supportive measures.


Laurence-Moon syndrome

The major signs that people present with which raise the suspicion that they may have LNMS are summarized below. The individual components of this condition can notably vary greatly in severity however.

LNMS is most commonly attributed to changes (mutations) in the PNPLA6 gene. Genes are specific sequences in DNA that provide instructions for the production of proteins. Proteins serve as the body’s cellular machinery and building blocks. The PNPLA6 gene is responsible for the production of proteins that drive the breakdown of cell membranes. The PNPLA6 protein is an enzyme that is thought to drive the growth of nerve and non-nerve cells as they grow and mature. This gene is notably associated not only with LNMS but also Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, and spastic paraplegia type 39. These conditions are described in brief under the Related Disorders section.

Males and females are affected equally. In North America, it is estimated that 1 in 100,000 people is affected by LNMS. Kuwait and Newfoundland are two places where the number of people affects with LNMS are comparatively high.

The following conditions have notably been considered in the differential diagnosis for patients with LNMS given the similar presentation of symptoms. They are only briefly summarized here. Without genetic testing, it can be very difficult to clinically differentiate these conditions.

Due to its highly variable clinical presentation of the condition, no formal diagnostic criteria have been established for LMS or, for that matter, any PNPLA6-related disorders. LMS is definitively diagnosed with molecular testing for mutations in the PNPLA6 gene.


Littoral cell hemangioma of the spleen

Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or a cone shape to the front of the eye (keratoconus). LCA is usually inherited as an autosomal recessive genetic condition.

Children born with LCA have light-gathering cells (rods and cones) of the retina that do not function properly. Absence or reduction of the electrical activity of the retina is always observed and is necessary for the diagnosis of LCA.

LCA is a monogenic disease and at least 27 genes are implicated. Changes (mutations) in these genes can account for about 80-90% of diagnosed cases of LCA. The genes responsible for the remaining 10-20% of diagnoses are not known. LCA is usually inherited as an autosomal recessive genetic condition. Twenty-four of the genes associated with LCA cause only recessive disease. Two genes (IMPDH1 and OTX2) are known to cause dominant disease. One gene (CRX) is known to cause either dominant or recessive disease, depending on the specific mutation.

The prevalence of LCA has been estimated to be 1-2/100,000 births. This disorder affects males and females in equal numbers.

Symptoms of the following disorders can be similar to those of Leber congenital amaurosis. Comparisons may be useful for a differential diagnosis:

Loken-Senior syndrome is a rare autosomal recessive genetic disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. (For more information on this disorder, choose Loken-Senior as your search term in the Rare Disease Database.)


Leber hereditary optic neuropathy

Leber遗传性视神经病

Leber hereditary optic neuropathy (LHON) is often characterized by bilateral, painless subacute loss of central vision most commonly during young adult life. In most cases, symptoms begin with one eye first, followed a few weeks later by visual failure in the other eye. Extremely rarely there may be neurologic abnormalities, such as peripheral neuropathy, postural tremor, nonspecific myopathy, and movement disorders. LHON is caused by changes (called variants or mutations) in mitochondrial DNA and it is strictly transmitted by maternal inheritance. The prevalence of LHON in carriers and affected is approximately 1:50,000 people. Many carriers never suffer significant visual loss; males are about four to five times more likely than females to lose vision and be affected.  The incidence of visual loss, therefore, is much less and about 1:10 million/year

Individuals with LHON typically display symptoms while young adult. If vision is lost, then it usually occurs before 40 years of age.

LHON is caused by genetic mutations in the mitochondrial DNA (mtDNA). Mothers with a LHON gene mutation may not show symptoms, but family history often reveals maternal relatives with visual loss at an early age.

The prevalence of visual loss from LHON is approximately 1:50,000 people. Most carriers never suffer significant visual loss; males are about four to five times more likely than females to lose vision and be affected.

Symptoms of the following disorders are similar to LHON. Comparisons may be useful for a differential diagnosis:

Autosomal dominant optic atrophy (DOA) is related to the OPA1 family of genes that influences mitochondrial biogenesis and function. The family pedigree is autosomal dominant. The symptoms tend to come on at an earlier age (6-9) than in LHON and to do so in a more insidious and milder way. Generally, before puberty the child develops slowly progressive loss of vision and central scotomas a mild optic atrophy that progresses until about 20 years of age to a moderate loss of vision and optic atrophy. This difference in tempo and symmetry as well as the different genetics allows for the distinction with LHON.


Legg Calvé Perthes Disease

Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The osteochondroses typically are characterized by degeneration and subsequent regeneration of the growing end of a bone (epiphyses). In LCPD, the growing end of the upper portion of the thigh bone (femur) is affected. The upper section of the thigh bone is known as the head or the ball and connects to the hip in a depression or socket. This is the hip joint, which is a ball and socket joint. The disorder results from an unexplained interruption of the blood supply (ischemia) to the head of the femur, which causes degeneration (avascular necrosis) and deformity of the femoral head. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; and/or limited or restricted movement of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (re-ossifies) in the affected area. The exact cause for the temporary interruption of blood flow to the femoral epiphysis is not fully understood. Most cases appear to occur randomly for no apparent reason (sporadically).

The age of onset, severity, duration, and associated complications of Legg-Calvé-Perthes disease vary greatly from one person to another. Generally, the onset is slow and the progression is gradual. The disorder usually affects children between the ages of eight and ten years, with some instances occurring as early as age two or as late as age 12. The disease typically affects one leg (unilateral); however, in approximately 10% of cases, the condition may subsequently develop in the other leg (bilateral).

The symptoms of Legg-Calvé-Perthes disease develop due to damage to the growing portion (epiphysis) of the upper end of the thigh bone. This damage results from interruption of the blood supply (ischemia) to this region. This damages the bone-forming cells (osteoblasts) and resident bone cells (osteocytes) and results in degeneration (necrosis) and softening of the bone in this area. The upper end of thigh bone becomes fragile as bone mass is lost. It is possible that this fragile area may fracture internally, causing deformity. A thin line of decreased density (Caffey sign) may be apparent on the epiphysis, which may represent such a fracture within the bone (subchondral). Damaged bone may fragment and cause irregularities when blood flow to the affected area eventually resumes (revascularization). As the bone regrows and rehardens (re-ossifies), it may deform, resulting in permanent malformation of the upper thigh bone (e.g., abnormally flattened or unusually enlarged epiphysis).

Legg-Calvé-Perthes disease affects males approximately four to five times as often as females (4-5:1). According to reports in the medical literature, when the disorder occurs sporadically, males are predominantly affected. However, in families with more than one affected member (kindreds), the disorder appears to occur relatively equally among males and females. Reported cases of LCPD include several individuals within multiple, multigenerational families.

Symptoms of the following disorder can be similar to those of Legg-Calvé-Perthes disease. Comparisons may be useful for a differential diagnosis:

Multiple epiphyseal dysplasia (MED) is a rare inherited spectrum of disorders characterized by malformation (dysplasia) of the growing portion or head of the long bones (epiphyses). Affected individuals may have an abnormally short thighbone (femur), unusually short hands and fingers, mild short stature, a waddling gait, and/or pain in the hips and knees. In some cases, painful swelling and inflammation of certain joints (arthritis) may be present as early as five years of age. Most cases of multiple epiphyseal dysplasia are inherited as autosomal dominant traits; rare cases are inherited as autosomal recessive traits. (For more information on these disorders, choose multiple epiphyseal dysplasia as your search term in the Rare Disease Database.)


Legionella infection

Legionnaires’ disease, caused by the aerobic gram-negative coccobacillus Legionella, mostly L. pneumophila, is an important cause of community-acquired pneumonia (CAP), accounting for approximatively 10% of cases. The exact incidence of Legionnaires’ disease is unknown due to different awareness levels in different countries, diagnostic methods and reporting, but the US Centers for Disease control (CDC) reported nearly 10,000 cases in the USA in 2018. Infection with Legionella occurs through the inhalation of an aerosol containing bacteria generated by water droplets, usually coming from a contaminated water system. It does not spread from person-to-person. Legionnaires’ disease often affects individuals over the age of 50, people who are heavy smokers and immunocompromised individuals.

Legionnaires’ disease is a respiratory disease, which means it affects the lungs. The lungs are composed of lobes, two for the left and three for the right lung. The air travels in the lungs through the bronchi, then bronchioles and then into alveoli, which are little sacs forming lung tissue. Pneumonia is an inflammation of the lungs caused by an infection, where the alveoli fill with pus and can eventually become solid (consolidation).

Legionellosis refers to disease caused by an infection with bacteria of the Legionella family, which includes 59 known species, from which 26 are known to cause disease in humans. These bacteria are gram-negative coccobacilli. The most common agent reported to cause Legionnaires’ disease is Legionella pneumophila serogroup 1.

The incidence of Legionnaires’ disease in the USA was estimated to be 10,000 cases in 2018. There is seasonal variation as most patients are diagnosed in the summer and early autumn. Studies show that most cases were community-acquired pneumonia (CAP) while about a quarter of the cases were travelled-related and less than 10% were health-care-related. However, it is hard to get an accurate estimate of the incidence of this disease since it is underdiagnosed, underreported and it has been shown that some people will develop only mild illness or show no symptoms at all.

Like Legionnaires’ disease, Pontiac fever is also caused by exposure to bacteria from the Legionella family. Its symptoms usually include malaise, fever, headache, chills, muscle pain (myalgia), nausea, vomiting and diarrhea. The characteristic symptoms of pneumonia from Legionnaires’ disease are absent in Pontiac fever. The incubation period for Pontiac fever is one to two days, compared to two to 10 days in Legionnaires’ disease. Individuals affected by Pontiac fever usually do not require any treatment, as the illness is self-limited. Patients usually recover in one to eight days (median of four days) with no residual ill effects. Diagnostic tests are not usually performed on patients with Pontiac fever as there is no agreed-upon definition, specific findings or specific laboratory test to diagnose it. Therefore, clinical suspicion should be based on possible exposures, however, individuals with Pontiac fever can test positive with a urinary antigen test, which is discussed in the ‘’Diagnosis’’ section below. Pontiac fever does not affect specific groups more or less than others, unlike Legionnaires’ disease.

As mentioned above, a failure to respond to beta-lactam antibiotics or the appearance of gastrointestinal and neurological symptoms in pneumonia patients should raise suspicions about an infection with Legionella.  Legionnaires’ disease can be diagnosed with different laboratory tests such as PCR, cultures and a urinary antigen test. Legionella bacteria are very hard to detect on gram-stain so this is not the diagnostic method of choice in the case of Legionella pneumophila pneumonia. Blood tests can also be done to detect the presence of specific antibodies in the serum, but they are not a reliable diagnostic method as it takes several weeks for antibodies to appear in the blood and a positive result could be from a previous Legionella subclinical infection.


Leigh syndrome

Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years, but some patients do not exhibit signs and symptoms until several years later. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. Several different genetically determined enzyme defects can cause the syndrome, initially described over 60 years ago. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and maternal inheritance, due to a mitochondrial DNA mutation, are additional modes of transmission.

The symptoms of classical Leigh syndrome (infantile necrotizing encephalopathy), a rapidly progressive neurological disorder, usually begin between the ages of 3 months and 2 years. In most children, the first noticeable sign is the loss of previously acquired motor skills. When there is early onset (i.e., 3 months), loss of head control and poor sucking ability may be the first noticeable symptoms. This may be accompanied by a profound loss of appetite, recurrent vomiting, irritability, continuous crying and possible seizure activity. Delays in reaching developmental milestones may also occur. Affected infants may fail to grow and gain weight at the expected rate (failure to thrive).

Several different types of genetically determined metabolic defects can lead to Leigh syndrome. The condition may be caused by a deficiency of one or a number of different enzymes (e.g., mitochondrial respiratory chain enzymes or enzyme components of the pyruvate dehydrogenase complex). These enzyme deficiencies are caused by changes (mutations) in one of several different disease genes (genetic heterogeneity). These mutations may be inherited as an autosomal recessive trait, an X-linked recessive trait, or as a mutation found within the DNA of mitochondria. In some cases of Leigh syndrome, no genetic cause can be identified.

The classical form of Leigh syndrome develops during infancy (infantile necrotizing encephalopathy) and usually begins between the ages of 3 months and 2 years. This form of the disease affects males and females in equal numbers.

Symptoms of the following disorders can be similar to those of Leigh syndrome. Comparisons may be useful for a differential diagnosis:

Wernicke syndrome and Korsakoff syndrome are related disorders that often occur due to a deficiency of thiamine (vitamin B1). Wernicke’s syndrome, also known as Wernicke encephalopathy, is a neurological disease characterized by the clinical triad of confusion, the inability to coordinate voluntary movement (ataxia), and eye (ocular) abnormalities. Korsakoff’s syndrome is a neurological disorder characterized by disproportionate memory loss in relation to other mental aspects. When these two disorders occur together, the term Wernicke-Korsakoff syndrome is used. In the United States, most cases occur in alcoholics. Some researchers believe Wernicke and Korsakoff syndromes are separate yet related disorders; others believe them to be different stages of the same disorder or disease spectrum. Wernicke syndrome is considered the acute phase with a shorter duration and more serious symptoms. Korsakoff syndrome is considered the chronic phase and is a long-lasting condition. (For more information on this disorder, choose Wernicke as your search term in the Rare Disease Database.)


Leiomyosarcoma

Leiomyosarcoma is a malignant (cancerous) tumor that arises from smooth muscle cells. There are essentially two types of muscles in the body – voluntary and involuntary. Smooth muscles are involuntary muscles – the brain has no conscious control over them. Smooth muscles react involuntarily in response to various stimuli. For example, smooth muscle that lines the walls of the digestive tract causes wave-like contractions (peristalsis) that aid in the digestion and transport of food. Smooth muscles in the salivary glands cause the glands to squirt saliva into the mouth in response to taking a bite of food. Smooth muscle in the skin causes goose bumps to form in response to cold.

The symptoms of a leiomyosarcoma vary depending upon the exact location, size, and spread of the tumor. A leiomyosarcoma, especially in the early stages, may not be associated with any obvious symptoms (asymptomatic). General symptoms associated with cancer may occur including fatigue, fever, weight loss, a general feeling of ill health (malaise), and nausea and vomiting.

The exact cause of leiomyosarcoma is unknown. Researchers speculate that genetic factors may play a contributing role in causing LMS.

Leiomyosarcomas affect both males and females. Leiomyosarcoma is a form of soft tissue sarcoma. According to the American Cancer Society, at least 15,000 new cases of soft tissue sarcoma occur each year in the U.S. Soft tissue sarcomas affect men and women equally and occur more often in adults than children or adolescents. Soft tissue sarcomas account for 1 percent of all adult cancers in the U.S. According to one estimate, leiomyosarcomas account for 7-11 percent of all cases of soft tissue sarcomas.

Symptoms of the following disorders can be similar to those of a leiomyosarcoma. Comparisons may be useful for a differential diagnosis.

A diagnosis of a leiomyosarcoma may be made based upon a detailed patient history, a thorough clinical evaluation and a variety of tests including blood tests, surgical removal and microscopic examination of tissue (biopsies) and various imaging techniques. In some cases, individuals may notice a painful lump or mass in the affected area. A key diagnostic aspect is distinguishing malignant leiomyosarcoma from its benign counterpart, the leiomyoma.


Leishmaniasis

Leishmaniasis can affect people in different ways. Some have truly silent infection, and do not develop any signs or symptoms. Other people develop mild to moderate disease, but some develop severe infection which can lead to permanent damage and potentially life-threatening complications.

Leishmanial infections are caused by > 20 different species of Leishmania parasites. Parasites are microscopic organisms that live in another organism (called the host, e.g., man) and survive by taking nutrients at the host’s expense. Leishmania are transmitted to humans or animals through the bite of an infected sand fly. Sand flies become infected by biting and sucking the blood of infected people or animals, especially dogs. Sand flies are very small and do not make any noise. Sometimes, their bites can be painful; most often, the bites are painless and go unnoticed. Sand flies are most active from dusk to dawn.

Leishmaniasis seldom occurs in the U.S. Most people from the U.S. who become infected do so from travel to or living in regions where the disease is common. Cutaneous infection is periodically reported, however, in Texas and Oklahoma and one case was recently reported further north in North Dakota.

There are numerous different infectious diseases, inflammatory conditions, malignant neoplasms and skin conditions that can resemble the signs and symptoms of leishmaniasis.

The diagnosis of leishmaniasis is based upon characteristic symptoms and signs, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A detailed patient history includes whether a person has lived in or traveled to areas where the disease is common. For example, cutaneous leishmaniasis should always be considered with a non-healing or progressive skin lesion in a person who has traveled to or lived in a region where leishmaniasis is found.


Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Affected children experience several different types of seizures, most commonly atonic, tonic and atypical absence seizures. Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems. Lennox-Gastaut syndrome can be caused by a variety of underlying conditions, but in some cases no cause can be identified. Lennox-Gastaut syndrome can be difficult to treat because it is resistant (refractory) to many kinds of antiseizure medications. Research is ongoing to identify and assess new therapies for Lennox-Gastaut syndrome.

The symptoms of Lennox-Gastaut syndrome usually begin during infancy or childhood, most often between 3 to 5 years of age. Multiple types of seizures, which are basically electrical disturbances in the brain, affect children with Lennox-Gastaut syndrome. Most affected individuals experience multiple types of seizures, multiple times throughout the day. As affected individuals grow older, the types and frequency of seizure activity may change.

In approximately 70-80 percent of patients, Lennox-Gastaut syndrome has an identifiable cause. These cases may be referred to as symptomatic Lennox-Gastaut syndrome. Examples of conditions that can cause Lennox-Gastaut syndrome include abnormal development of the brain cortex (cortical dysplasia or other malformations), congenital infections, stroke, trauma, reduced oxygen supply that occurs before birth (perinatal hypoxia), infections of the central nervous system such as encephalitis or meningitis and a rare, genetic disorder called tuberous sclerosis. Approximately 17-30 percent of individuals with Lennox-Gastaut syndrome have a previous history of West syndrome. In general, these cases tend to be more severe.

Lennox-Gastaut syndrome affects males slightly more often than females. Lennox-Gastaut syndrome is estimated to occur in .1-.28 people per 100,000 and is thought to account for 1-4 percent of all cases of childhood epilepsy. The annual incidence in children is estimated to be 2 per 100,000 children. Onset of Lennox-Gastaut syndrome is usually between 2-7 years with a peak onset between 3 to 5 years.

Symptoms of the following disorders can be similar to those of Lennox-Gastaut syndrome. Comparisons may be useful for a differential diagnosis.

Lennox-Gastaut syndrome is defined as having three specific findings that must be identified for a diagnosis. This consists of multiple seizures of different types, a distinctive EEG brain wave pattern (slow [1.5- to 2.5-Hz] spike-and-wave pattern) (Note this pattern may not be present on every EEG.) and some degree of cognitive impairment and behavioral abnormalities. However, these symptoms may not all be present at the onset of the disorder, making an accurate diagnosis of Lennox-Gastaut syndrome difficult. The wide variety of potential causes of Lennox-Gastaut syndrome also complicates the diagnosis.


Lenz Microphthalmia Syndrome

Lenz microphthalmia syndrome is an extremely rare inherited disorder characterized by small eyes (microphthalmos or microphthalmia) and/or droopy eyelids (blepharoptosis), resulting in visual impairment. Rarely, affected infants may exhibit complete absence of the eyes (anophthalmos or anophthalmia). Additional physical anomalies are often associated, including a small head (microcephaly) and/or anomalies of the teeth, ears and/or fingers and/or toes (digits). The range and severity of findings may vary from person to person. Most affected children also exhibit developmental delays and intellectual disability.

In affected males, the primary physical characteristic associated with Lenz microphthalmia syndrome is small eyes (one eye or both). In most cases, both eyes are affected and the eyes maybe of different size (bilateral, asymmetrical microphthalmos/microphthalmia). The front (anterior), clear portion of the eye through which light passes (cornea) may be small (microcornea). In addition, the colored portion of the eye (iris) may be differently formed with absent tissue (coloboma), giving the iris a keyhole appearance. Colobomas may also affect other parts of the eye, including the ciliary body, choroid and/or optic disc. In many patients, the upper eyelids may droop (blepharoptosis) due to paralysis of muscles that control the eyelids. In rare cases, affected infants may exhibit absence or only rudimentary (vestigial) portions of the eyes (anophthalmos/anophthalmia). Such eye findings may result in varying degrees of visual impairment or, in some people, blindness. The degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.

Lenz microphthalmia syndrome is caused by changes or pathogenic variants in the BCOR gene and is inherited in an X-linked pattern. Some researchers speculate that severe cases of Lenz microphthalmia syndrome may result from deletions of genetic material from two or more adjacent genes (contiguous gene syndrome) located on the X chromosome.

Approximately 12 affected males with fully expressed Lenz microphthalmia syndrome have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of Lenz microphthalmia syndrome. For more information on each of these disorders, enter the disease name as your search term in the Rare Disease Database.

The diagnosis of Lenz microphthalmia syndrome may be confirmed at birth, based upon a thorough clinical evaluation, characteristic physical findings and imaging techniques. Ultrasonography studies of the internal structure of the eye may demonstrate that the length from the front to the back of the eye (anteroposterior axis) is smaller than normal, confirming a diagnosis of microphthalmia. In some people, however, it may be difficult to distinguish severe microphthalmia from anophthalmia. Therefore, ultrasound imaging or magnetic resonance imaging (MRI) may sometimes be used to help confirm which condition is present. When MRI scanning is unable to clarify which malformation is present, other diagnostic steps may sometimes be taken to determine whether rudimentary (vestigial) portions of the eyes are present or absent.


LEPR Deficiency

瘦素受体基因缺陷所致肥胖

obesity, morbid, due to leptin receptor deficiency

The symptoms of LEPR deficiency are different from person to person, with the most common symptom being early onset obesity. At birth, babies with LEPR deficiency have a normal weight. The earliest symptoms are constant hunger and excessive eating (hyperphagia) leading to rapid weight gain and obesity before one year of age. People with LEPR deficiency always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms may include low thyroid hormone and insulin resistance, which can lead to type 2 diabetes. Some children with LEPR deficiency get frequent infections because their immune system doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking.

LEPR deficiency is caused by pathogenic variants (mutations) in the LEPR gene. The LEPR gene is responsible for making the leptin receptor, which works together with the protein, leptin. Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin receptors, leptin can’t do its job and the body doesn’t recognize when the body has enough energy and it’s time to stop eating.

LEPR deficiency is a very rare disorder. In 2021, approximately 88 patients had been reported worldwide. It has been estimated that 1.34 per 1 million people may have this condition.

LEPR deficiency is one of several rare inherited conditions that include early-onset obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.

LEPR deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.

Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to LEPR deficiency which has been diagnosed by genetic testing. This drug is given by daily injection. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss. People with LEPR deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.


Leprechaunism

Leprechaunism is an extremely rare disorder characterized by abnormal resistance to insulin that results in a variety of distinguishing characteristics, including growth delays and abnormalities affecting the endocrine system (i.e., the system of glands that secrete hormones into the blood system). Affected infants may also have distinctive characteristics of the head and face (craniofacial region), low birth weight, skin abnormalities, and enlargement of the breast and clitoris in females and the penis in males. Leprechaunism is inherited in an autosomal recessive pattern.

Leprechaunism is characterized by growth delays, as well as abnormalities of the head and face (craniofacial region) and of the endocrine system. Many of the symptoms associated with leprechaunism are present at birth (congenital). The range and severity of symptoms and physical characteristics may vary from person to person.

Leprechaunism may be caused by disruption or changes (mutations) of the insulin receptor gene. Due to the mutation in the insulin receptor gene, individuals with leprechaunism are unable to use insulin effectively. Insulin is a hormone produced by the pancreas that plays an important role in the absorption of sugar (glucose) into muscle cells. Glucose is the body’s main source of energy. Some symptoms associated with leprechaunism, including growth deficiencies and hyperglycemia, develop as a result of severe insulin resistance of affected individuals.

In reported cases, leprechaunism has occurred twice as often in females as in males More than 50 cases have been reported in the medical literature. Leprechaunism was first identified in the 1948 by Dr. W.L. Donohue.

Symptoms of the following disorders can be similar to those of leprechaunism. Comparisons may be useful for a differential diagnosis:

Patterson pseudoleprechaunism syndrome is an extremely rare genetic disorder characterized by a normal birth weight, bronze discoloration of the skin (hyperpigmentation), loose skin on the hands and feet (cutis gyrata), and malformation (dysplasia) of the skeleton. Abnormalities affecting the endocrine system include enlargement of the adrenal glands and the adrenal cortex (hyperadrenocorticism) and diabetes mellitus. The exact cause of Patterson pseudoleprechaunism syndrome is not known.


Leprosy

Leprosy is a chronic infectious disease of humans caused by the bacteria Mycobacterium leprae. For many years, it was considered a mysterious disorder associated with some type of curse, and persons with the disease were isolated and ostracized. Today, there is effective treatment and the disease can be cured. There is no longer any justification for isolating persons with leprosy.

The earliest symptoms are usually skin lesions that are typically flat, pale (hypopigmented) or reddish (erythematous) spots in the skin with slightly decreased sensitivity to touch or pain. These lesions typically do not present with other symptoms, such as burning or pain. There may be some hair loss in the affected area. As the skin lesions progress, they may become raised and, in some cases, nodules may form. The symptoms of nerve involvement include diminished sensation or feeling in the affected areas (anesthesia) and, sometimes, burning and tingling sensations (paresthesias). In more advanced cases, there may be weakness, paralysis, and atrophy of muscle in the hands or feet.

Leprosy is a chronic infectious disease of humans caused by the bacteria Mycobacterium leprae. The disease has been known and described for several thousand years in India and China. Over 100 years ago, Armauer Hansen in Norway identified the bacteria as the cause of leprosy.

Leprosy is relatively rare in the United States but is prevalent in some countries of Asia, Africa, and South America. There are about 7,000 persons in the United States that have been treated for the disease, and from 150-200 new cases are reported annually in the United States. About 85% of the U.S. cases are persons who have immigrated from other countries. North American Indians in the U.S.A. appear to be immune to this disease.

The diagnosis can usually be made by the history and characteristic findings on examination. The important findings are decreased ability to feel light touch in a skin spot, enlarged or tender nerves in the arms or legs, numbness in a hand or foot, and finding the bacteria in the skin. There may also be loss of hair in the affected skin areas. A special type of skin smear is commonly done and will demonstrate the bacteria in the skin in lepromatous and borderline lepromatous cases. The bacteria are too few in tuberculoid cases to be found in a skin smear. A skin biopsy of a lesion can also be helpful to confirm the diagnosis. There are no blood tests or skin tests at the present time that are helpful in the diagnosis.


Leptospirosis

Leptospirosis is an infectious disease that affects humans and animals. It results in a wide range of symptoms, and some people may have no symptoms at all. It is caused by a spiral-shaped bacterium (spirochete). Symptoms include high fever, chills, muscle aches, headache, vomiting, diarrhea, and jaundice (yellow skin and eyes).

The symptoms of leptospirosis vary considerably.  Some people may experience no symptoms at all.  Some may experience moderate or more severe flu-like symptoms.  Some may experience very serious complications if the disease is not treated.

Humans usually become infected through contact with water, food or soil containing urine from infected animals.  The bacterium associated with the disease, Leptospira, can be found in the urine of many different animals, such as dogs, cats, cattle, horses, pigs, and, especially, rodents.  The disease is transmitted to humans when infected urine enters the body when one swallows contaminated food or water or through breaks in the skin or contact with mucosal surfaces such as the eyes or nose.  The disease is not known to be spread from person to person.

While leptospirosis is rare in the United States, it is common through tropical and semitropical regions.  It can affect individuals of all ages.  At least 75 percent of individuals with leptospirosis are male, mainly because workers in jobs that are at risk of the infection are more often held by males.

Many types of bacterial infections may cause fever and other symptoms similar to the symptoms of leptospirosis.

Diagnosis may be made during the early stage of the infection (days 1-7) by culturing the Leptospira bacterium from body fluids. From days 4 through 10, the cerebrospinal fluid is cultured, and after day 10, the patient's urine may be cultured. There are other tests of the blood and immune system that may be performed.


Leri Pleonosteosis

Leri Pleonosteosis is an extremely rare inherited disorder characterized by unusual, flattened facial features, abnormalities of the hands and feet, skeletal malformations, short stature, and/or limitation of joint movements. Characteristic abnormalities of the hands and feet may include unusually broad and/or short thumbs and great toes (brachydactyly) that may be bent outward from the body (valgus position); as a result, the hands may have a spade-shaped appearance. Skeletal malformations may include knees that are bent backward (genu recurvitum) and abnormal enlargement of the cartilaginous structures that surround the upper portion of the spinal cord (posterior neural arches of the cervical vertebrae). In addition, affected individuals may develop thickened tissue on the palms (palmar) and forearms. Symptoms may vary from case to case. Leri pleonosteosis is inherited as an autosomal dominant genetic trait.

Infants with this disorder typically have a flattened facial appearance that may be similar to that of infants with Down syndrome.  In rare cases, affected infants may also have an abnormally narrow distance between the upper and lower eyelids (blepharophimosis) and/or an unusually small part of the eye through which light passes (microcornea).

When it was first identified, researchers believed that the signs of the disorder were due to the premature hardening (pleonosteosis) of the end portions of the long bones (epiphyses).  However, since that time, some researchers have speculated that the basic abnormality may be the pulling away of specialized connective tissue (periosteal traction) from the shafts of the long bones (metaphyses).

Leri pleonosteosis is an extremely rare inherited disorder that affects males and females in equal numbers.  Approximately 20 cases have been reported worldwide, with most of these outside of North America. The symptoms and physical characteristics associated with Leri pleonosteosis usually become apparent during infancy or early childhood.

Symptoms of the following disorders can be similar to those of Leri Pleonosteosis .  Comparisons may be useful for a differential diagnosis:

Acromicric Dysplasia is an extremely rare inherited disorder characterized by unusual facial features, abnormally short hands and feet, and/or severe growth retardation.  Characteristic facial features may include abnormally narrow eyelid folds (palpebral fissures) and/or a short nose with nostrils that flare forward (anteverted nares).  Malformation of the bones of the hands and feet (e.g., metacarpals and phalanges) may also be present.  Acromicric Dysplasia is believed to result from a spontaneous genetic change that occurs for no unknown reasons (sporadic).  In addition, some researchers believe that the disorder may be inherited as an autosomal dominant genetic trait.


Léri-Weill dyschondrosteosis

The specific signs and symptoms associated with LWD can vary greatly from one person to another. Generally, females appear to be affected more severely than males. The classic findings of the disorder are mesomelic shortening of the limbs, short stature, and Madelung deformity. Some individuals do not develop Madelung deformity and/or may obtain normal height.

In most instances, LWD is caused by alterations (mutations) in or loss (deletion) of the short stature homeobox-containing (SHOX) gene or its regulatory regions. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

LWD is a rare disorder that can affect males or females. More cases of the disorder have been reported in the medical literature in females than in males by a 4:1 ratio. The prevalence is unknown, but often given as between 1 in 1000-2000 in the general population. However, many affected individuals may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of LWD in the general population.

Differential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp.

A diagnosis is based upon a thorough clinical examination and identification of characteristic physical findings. A diagnosis can be difficult because certain symptoms may not be apparent until puberty. X-ray studies (radiographs), in particular a wrist X-ray, can reveal characteristic changes to the affected bones.

The treatment of LWD is symptomatic and supportive.


次黄嘌呤鸟嘌呤磷酸核糖转移酶缺乏症

Lesch-Nyhan syndrome is a rare inborn error of purine metabolism characterized by the absence or deficiency of the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Purines are nitrogen-containing compounds found in many foods (e.g., organ meats, poultry, and legumes). In the absence of HPRT, the purines hypoxanthine and guanine are not built into nucleotides. Uric acid levels are abnormally high in people with Lesch-Nyhan syndrome and sodium urate crystals may abnormally accumulate in the joints and kidneys. Lesch-Nyhan syndrome is inherited as an X-linked recessive genetic disorder that, with rare female exceptions, most often affects males. The symptoms of Lesch-Nyhan syndrome include impaired kidney function, acute gouty arthritis, and self-mutilating behaviors such as lip and finger biting and/or head banging. Additional symptoms include involuntary muscle movements, and neurological impairment.

The symptoms of Lesch-Nyhan syndrome may become apparent as early as six months of age. Earlier urate crystal formation, resulting from abnormally increased levels of uric acid in the urine, leads to the presence of orange colored deposits (orange sand) in the diapers of infants with this disorder. This may be the first manifestation of Lesch-Nyhan syndrome, but it is seldom recognized in early infancy.

The only gene known to be associated with Lesch-Nyhan syndrome is located on the X chromosome and called HPRT1. Abnormalities (mutations) in the HPRT1 gene result in the absence or deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) and the abnormal accumulation of uric acid in the blood.

Lesch-Nyhan syndrome is a rare disorder that affects males. Rarely, females may be affected by the disorder. However, in most cases, females may be carriers of the disease gene, but do not exhibit any symptoms. According to one estimate, the disorder occurs at the rate of approximately one in 380,000 births in the United States.

Symptoms of the following disorders can be similar to those of Lesch-Nyhan syndrome in the sense that self-injurious behavior may occur. Comparisons may be useful for a differential diagnosis:

Familial dysautonomia is a rare genetic disorder of the autonomic nervous system that primarily affects people of Eastern European Jewish heritage. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. Symptoms of this disorder are apparent at birth. The autonomic nervous system controls vital involuntary body functions. (For more information on this disorder, choose familial dysautonomia as your search term in the Rare Disease Database.)


Lacrimoauriculodentodigital syndrome

Leukocyte adhesions deficiency (LAD) syndromes are a group of rare disorders affecting the immune system. LAD syndromes are characterized by defects affecting how white blood cells (leukocytes) respond and travel to the site of a wound or infection. Three distinct types of leukocyte adhesion syndrome have been identified. The specific symptoms and the severity of LAD syndromes vary from one person to another. All affected individuals develop an increased susceptibility to developing recurrent bacterial and fungal infections. Additional symptoms may occur depending upon the specific subtype present. LAD syndromes are caused by mutations of specific genes that contain instructions for creating certain proteins that are necessary for white blood cells to travel from the bloodstream to the site of an infection or inflammation. Individuals with severe forms of LAD may have near complete absence of these proteins. Individuals who have milder forms of LAD syndromes have deficient levels of these proteins, but retain some residual protein activity.

The symptoms of LAD syndromes can vary greatly from one person to another based upon the subtype present, the amount of residual protein activity and additional factors. The LAD syndromes are primary immunodeficiency disorders that cause individuals to be abnormally susceptible to developing infections. Affected individuals also have elevated levels of white blood cells (leukocytosis).

Leukocyte adhesion syndromes are rare, genetic disorders. LAD I is caused by mutations of the ITGB2 gene. LAD II is caused by mutations of the SLC35C1 gene. The genetic defect in LAD III is a mutation in the gene for Kindlin 3, a protein essential for all integrins activation. Lack of integrins activation affects the ability of leukocytes and platelets to bind to the endothelium. In some cases, there is also a mutation in the gene for CalDAGGEF1, another protein important in integrins activation.

LAD syndromes affect males and females in equal numbers. The exact incidence of these disorders in the general population is unknown. LAD I is by far the more common one with several hundreds of patients reported in the medical literature from all over the world. LAD II is very rare reported in less than 10 patients and LAD III is also rare with 25 patients mainly from the Middle East region. These disorders often go unrecognized and may be misdiagnosed, making it difficult to determine their true frequency in the general population. LAD I was first described in the medical literature in 1979. LAD II was first reported in 1992. LAD III was first reported in 1997.

Symptoms of the following disorders can be similar to those of LAD syndromes. Comparisons may be useful for a differential diagnosis.

A diagnosis of a LAD syndrome is suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests such as a complete blood count (CBC). A CBC can detect elevated levels of a type of white blood cell known as a neutrophil (neutrophilia) and also lymphocytes. A diagnosis of LAD I should be ruled out in any infant with recurrent soft tissue infections and a very high white blood cell count (leukocytosis).


Leukodystrophy

Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can’t function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.

Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. Some inherited leukoencephalopathies have stable white matter abnormalities.

Leukodystrophies are genetic disorders caused by specific gene abnormalities that lead to abnormal development or destruction of the myelin sheath in the nervous system or white matter in the brain. Each type of leukodystrophy follows a particular pattern of inheritance such as autosomal recessive, X-linked recessive or autosomal dominant. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

The leukodystrophies can affect either adults or children, but are more common in children. Some types of leukodystrophy affect males and females equally but other types predominantly affect males.

Symptoms of the following disorder can be similar to those of leukodystrophy. Comparisons may be useful for a differential diagnosis:

Multiple sclerosis (MS) is a chronic inflammatory disease affecting the myelin sheath of the brain and spinal cord (central nervous system). It may be progressive, relapsing and remitting, or stable. MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. These plaques on the myelin sheath prevent proper transmission of nervous system signals. White matter lesions in leukodystrophies tend to be more symmetric and confluent then in MS which may help distinguish the two conditions. Symptoms may include visual and speech problems, numbness, walking difficulty and loss of bladder or bowel control. MS affects both children and adults, and its cause is unknown.

Treatment of most leukodystrophies is symptomatic and supportive. Medications and physical therapy may be helpful for spasticity and motor difficulties. Anti-epileptic medications should be provided for seizures and burning paresthesia from peripheral neuropathy may respond to medications for neuropathic pain. Please review the NORD report on the specific type of leukodystrophy for information about successful therapies. Genetic counseling is beneficial for affected individuals and their families.


脑干脊髓受累脑白质病-高乳酸综合征

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a rare disorder characterized by a range of neurological issues. Affected individuals have disease of the white matter of the brain (leukoencephalopathy). White matter forms what is known as the myelin sheath, which is the protective covering of the nerve fibers. Without white matter, the signals between nerve cells cannot be transmitted properly. Lactate is a metabolite found in the brain; it’s exact role in the brain is not fully understood but it may help to supply energy to nerve cells. Lactate is elevated in most individuals with LBSL. Affected individuals exhibit a variety of symptoms including spasticity, weakness and progressive cerebellar ataxia. Spasticity is stiffness of the muscles, which leads to progressive difficulty with walking and for some, loss of the ability to walk. Cerebellar ataxia is difficulty with coordinating voluntary movements, which can lead a variety of issues including poor manual coordination, difficulty with fine motor tasks, and unsteadiness when walking. LBSL is caused by an abnormal variant (mutation) in the DARS2 gene. There is no cure and treatment is aimed at the specific symptoms that are present.

Although researchers have been able to establish some characteristic or core symptoms that define LBSL, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the fact that many combinations of mutation types can produce this disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

LBSL is caused by an abnormal variant on in the DARS2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain and spinal cord.

LBSL is an extremely rare disorder that was first reported in the medical literature in 2002. According to the nonprofit organization, A Cure for Ellie, as of April 2018, there are about 100 individuals worldwide who have been identified with the disorder. Because rare diseases like LBSL often go undiagnosed or misdiagnosed, it is difficult to determine the true frequency in the general population.

Symptoms of the following disorders can be similar to those of LBSL. Comparisons may be useful for a differential diagnosis.

A diagnosis of LBSL is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including genetic testing to determine mutations in the DARS2 gene.

There is no cure for LBSL. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists in diagnosing and treating disorder of the brain and central nervous system in children (neurologists), physical therapists, geneticists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.


Li-Fraumeni Syndrome

LFS may be suspected if someone has a personal or family history of cancers featured in LFS. In addition, there are certain rare cancers that are characteristic of the syndrome that should alert clinicians to the potential of a diagnosis of LFS. Patients and families with multiple childhood cancers, or specific rare cancers such as adrenocortical, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, sonic hedgehog medulloblastoma, or hypodiploid acute lymphoblastic leukemia should alert practitioners to the potential of a hereditary cancer syndrome such as LFS. Although increasingly identified as a hereditary cancer syndrome, not all physicians are aware of the diagnosis of LFS.

Li-Fraumeni syndrome is caused by an inherited (germline) pathogenic variant of the TP53 tumor suppressor gene on chromosome 17. LFS was first recognized in 1969, and in 1979, TP53 was identified in the tumor tissue of more than 50% of all cancer patients. However, it wasn’t until 1990 that a TP53 germline variant was discovered to be the cause of LFS.

Though it is challenging to estimate to frequency in the population, there are likely over 1,000 multigenerational families worldwide with LFS. To date, inquiries on the LFS Association website have arrived from 172 countries.

There are several other conditions with an increased cancer risk not related to variants of TP53.

Li-Fraumeni syndrome is diagnosed based on the presence of a so called pathogenic or likely pathogenic variant in the TP53 gene.


Lichen Planus

Lichen planus (LP) is a rare, chronic, inflammatory autoimmune skin and mucous membrane disease. LP most commonly presents as itchy, shiny, reddish-purple spots (lesions) on the skin (cutaneous LP) or as white-gray lesions in the mouth or on the lips (oral LP). Less commonly, LP may also involve the genitals (penile or vulvar LP), scalp (lichen planopilaris), ears (otic LP), nails, eyes, and esophagus. Similar to lichen found growing on trees and rocks in forests, the skin lesions are often flat-topped and can be somewhat scaly, hence the name lichen planus.

weeks or months and intermittent recurrences may occur for years. The appearance of the lesions is dependent on their location. In cutaneous LP, the lesions can present anywhere on the skin, usually on the wrists, legs, palms and soles or torso and are 2 to 4 mm in diameter with angular borders, a violet color and a distinct sheen in cross-lighting. These lesions tend to be symmetrically distributed and may also coalesce into rough scaly patches. Rarely, blisters may develop. Moderate to severe itching is common and frequently fails to respond to treatment.

In most affected individuals, the exact cause of LP is unclear. It is suspected that exposure to infections, drugs, allergens, or injury may sensitize the immune system and cause the immune system to attack skin cells. This initial eruption may persist for weeks to months, and recurrences can continue throughout the individual’s lifetime. There have been reports of LP in family members, indicating that there may be a genetic predisposition, but the genetic factors of LP are still being researched and are uncertain.

There is limited data on how many people are affected by LP, but most studies estimate that LP occurs in less than 1 percent of the world’s population. Cutaneous LP occurs at similar frequencies in men and women, but women are somewhat more likely to develop oral LP or lichen planopilaris. There does not appear to be a racial predisposition for the disease. The majority of LP develops between 30 and 60 years of age but can affect older and younger individuals as well. In rare cases, children may be affected.

There are several diseases that can look very similar to LP and are important to differentiate.

A diagnosis of LP can often be made from an examination of the skin or mucous membranes and identification of the characteristic clinical features.