| Motor neuron diseases (MND) are disorders in which specialized nerve cells (motor neurons) that control voluntary muscle movement gradually stop working and eventually die. There are two types of motor neurons, upper and lower. Normally, upper motor neurons carry electrical impulses from the brain down to the brainstem or spinal cord, where they meet with lower motor neurons that carry impulses onward to muscles. Muscles then respond to these impulses by contracting or relaxing, depending on the desired voluntary movement. This figure shows the location of motor neurons. The solid green lines represent upper motor neurons, while the broken blue lines are the lower motor neurons. Disorders may affect one or both types of neurons. For instance, degeneration of upper motor neurons may cause primary lateral sclerosis or spastic paraparesis, while degeneration of lower motors neurons may cause progressive muscular atrophy, and degeneration of both upper and lower motor neurons causes ALS |  |
| Amyotrophic lateral sclerosis, called ALS, Lou Gehrig disease, Charcot disease and, in Europe, motor neuron disease or MND, occurs because of degeneration of the nerve tracts that control voluntary muscles. There are two components to these tracts: upper and lower motor neurons. Both types of neurons are affected in multiple regions of the body in ALS.
In the diagram the solid lines extending down from the brain represent the upper motor neurons, while the dotted lines that meet them in either the brain stem or spinal cord and extend out to the muscles are the lower motor neurons. And again, according to the Escorial criteria for diagnosing ALS, both types of neurons must be affected in several regions of the body for a person to be diagnosed with ALS.
Muscle tissue deteriorates because it is not being stimulated by one or both of these types of neurons. This results in progressive weakness, atrophy (muscle wasting) and often spasticity (excess muscle tone). The sensory neurons that bring in information regarding hearing, taste, vision, touch and so on, usually remain healthy.
Cognitive impairment may occur in along with ALS. The impairment may range from mild difficulties with decision making, judgment and mood to seriously disabling frontotemporal dementia (FTD). FTD occurs because the frontal and temporal lobes of the brain degenerate. Estimates of the number of ALS patients affected by cognitive impairment and FTD vary widely, ranging from less than 10% to as much as 45%. Since the impairment may be very mild it may difficult to recognize.
The area of the brain called the motor strip, located at the back of the frontal lobe where it abuts the temporal lobe, is where the top part of upper motor neurons are located. So the areas of the brain that are affected in FTD are next to the upper motor neurons. Frequency
There are two to three new ALS cases per 100,000 people diagnosed each year worldwide. In the US approximately 15 new cases are diagnosed each day and roughly 30,000 people are living with ALS at any given time. While most patients are between 50 and 60 years old, ALS can occur at any age. Men are affected slightly more frequently than women. Types / Causes
Some studies have identified geographical areas that at certain times have had greater than the expected numbers of cases, a phenomenon sometimes called a cluster. This was documented in the past in the western Pacific islands (Guam) and parts of Japan and Australia. Clusters have been reported within the US as well, but further careful investigations have not supported the reports. A recent example is the reported excess at Kelly Air Force Base in Texas.
Inherited or familial ALS (FALS) accounts for about 10 percent of all ALS cases. FALS usually is inherited in a dominant manner, with multiple cases appearing in multiple generations. In 1993, our division director, Dr. Siddique, led an international team that discovered the first gene that causes about 20% of dominantly inherited cases, superxoide dismutase or SOD1. He also led a consortium that recently identified mutations in the fused-in-sarcoma gene (FUS) in about 3% of remaining FALS families. Mutations in gene coding for the TAR binding protein (TDP 43 or TAR 43) are now implicated in a very small portion of FALS cases as well. Very rarely, ALS occurs as a recessive disorder, generally with its onset in childhood. Our team identifed the ALSIN gene as the cause of a portion of these cases. (Mutations in ALSIN may also cause PLS.)
About 90% of the time ALS occurs as single case within a family, when it is called sporadic ALS (SALS). The causes of SALS are still unknown. Our hypothesis is that a group of genetic changes, either mutations or single nucleotide polymorphisms (SNPs) may be inherited together as predisposing factors, or factors which increase a person’s risk for developing ALS. Their presence forms a threshold, and when certain, so far largely unidentified environmental factors are present, a person may be "pushed" over, developing the symptoms of ALS. While both the predisposing genes and environmental factors are largely unknown at this time, our research team and others have associated changes in the paraoxanase cluster of genes (PON) with SALS. This may be the first step in understanding how SALS can develop.
For some time scientists have investigated whether naturally-occurring toxic chemicals could cause ALS. For example, glutamate is a chemical that occurs naturally in the brain where it helps carry messages from one cell to another. Normally, once that task is done, the glutamate is removed by another chemical called a transporter. Higher than normal amounts of glutamate have been observed in ALS patients. One hypothesis is that in ALS the transporter does not properly remove excess glutamate, leaving it to over-stimulate motor neurons until they die. This is the proposed mechanism of action of riluzole therapy. Riluzole is a chemical that suppresses release of glutamate into the nervous system, so theoretically it helps control the amount available for stimulation of neurons. Currently, the only FDA approved drug for the treatment for ALS is Rilutek, which is the brand name for riluzole. |
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| The spastic parapareses (SP) are a broad group of clinically and genetically diverse disorders characterized by insidiously progressive lower extremity weakness and spasticity. SP may occur as a single case within a family or as one of multiple cases within a family, in which case it is called hereditary spastic paraparesis or HSP. HSP is the more common form. Symptoms occur because of degeneration of the distal (further down) portion of upper motor neurons that meet with lower motor neurons serving the distal portion of the trunk and legs. The lower motor neurons remain healthy. |  |
Symptoms are generalized muscle weakness, flaccid neck muscles and sometimes an inability to walk. Brain involvement may cause seizures, deafness, loss of balance, and mental retardation. Onset varies from early infancy to adulthood with variable progression. Inheritance is maternal mitochondrial, autosomal dominant, or autosomal recessive. (Read more about Mitochondrial Myopathy)
Symptoms are variable weakness of shoulders, hips, face, and neck muscles. Onset ranges from early infancy to adulthood with variable progression; carnitine supplementation is often effective. Inheritance is autosomal recessive. ( Read more about Carnitine Deficiency)
Symptoms are the inability to sustain moderate prolonged exercise or fasting due to the chance of causing severe muscle destruction, urine discoloration, and kidney damage. Onset is young adulthood with variable severity. Inheritance is autosomal recessive. (Read more about Carnitine Palmityl Deficiency)
Symptoms are muscle pain and weakness, with muscle damage and urine discoloration possible during intense exercise of brief duration. Onset ranges from childhood to adolescence. Progression is variable, and avoidance of extreme exercise is recommended. Inheritance is X-linked recessive or autosomal recessive. (Read more about Phosphoglycerate Kinase Deficiency)
Symptoms are variable weakness of shoulders, hips, face, and neck muscles. Onset ranges from early infancy to adulthood with variable progression; carnitine supplementation is often effective. Inheritance is autosomal recessive. (Read more about Carnitine Deficiency)
Symptoms are variable weakness of shoulders, hips, face, and neck muscles. Onset ranges from early infancy to adulthood with variable progression; carnitine supplementation is often effective. Inheritance is autosomal recessive. (Read more about Carnitine Deficiency)
Symptoms are weakness and atrophy of the muscles of the hands and lower legs, with foot deformities and some loss of sensation in the feet. Onset occurs in childhood to early adulthood with progression being slow but variable and not affecting life expectancy. Inheritance is autosomal dominant, autosomal recessive, and X-linked recessive. (Read more about CMT)
Symptoms are similar to CMT, however more severe with delayed motor development in childhood, weakness and muscle wasting of the hands and lower legs, and some loss of sensation in the feet. Onset ranges from early childhood with progression being variable. Inheritance is believed to be autosomal dominant (Read more about Dejerine Sottas Disease)
Symptoms are impairment of limb coordination with weakness, muscle wasting, and sometimes diabetes and heart disease. Onset ranges from childhood to adolescence with progression and severity varying. Inheritance is autosomal recessive. (Read more about Freidreich's Ataxia)
Symptoms of generalized muscle weakness and muscle wasting affecting limb and trunk muscles first with enlarged calves. The disease progresses slowly, with an onset about 2-6 years. Survival is rarely beyond late twenties. Inheritance is X-linked recessive. (Read more about DMD)
Symptoms are almost identical to Duchenne muscular dystrophy with regards to the muscle weakness and wasting, but is often much less severe. There can be significant heart involvement. The disease progresses slowly, with an onset in adolescence or adulthood, with survival well into mid to late adulthood. Inheritance is X-linked recessive. (Read more about BMD)
Symptoms are weakness and wasting of the shoulder, upper arms, and shin muscles with possible joint deformities. Cardiac involvement is common. The disease progresses slowly, with an onset in childhood to early teens. Inheritance is X-linked recessive the majority of the time. (Read more about EDMD)
Symptoms are weakness and wasting affecting shoulder and pelvic girdle muscles. Cardiopulmonary complications occur in later stages of the disease. The disease progresses slowly with onset in childhood to middle age. Inheritance is autosomal recessive or X-linked. (Read more about LGMD)
Symptoms are facial muscle weakness and wasting of the shoulders and upper arms. The disease progresses slowly with some periods of rapid deterioration with onset in childhood to early adulthood. The disease may span many decades. Inheritance is autosomal dominant. (Read more about FSHD)
Symptoms are generalized weakness and muscle wasting affecting the face, hands, feet and neck. People experience delayed relaxation of muscles after contraction. Progression is slow with onset in childhood to middle age, however there are some forms of congenital myotonic dystrophy that can be more severe. Inheritance is autosomal dominant. (Read more about DM)
Symptoms occur as weakness of the in the muscles of the eyelid and throat. Progression is slow and swallowing problems are common as the disease progresses; onset is early adulthood to middle age. Inheritance is autosomal dominant. (Read more about OPMD)
Symptoms are weakness and wasting of muscles of the hands, forearms, and lower legs. Onset is between 40 to 60 years. It progresses slowly and is not life threatening. Inheritance is autosomal dominant. (Read more about DD)
Symptoms are generalized muscle weakness with possible joint deformities. Progression is very slow but onsets at birth. Inheritance is autosomal dominant and autosomal recessive. (Read more about CMD)
Symptoms are weakness of the upper arm and upper leg muscles with some muscle wasting. Onset ranges from childhood to adulthood with progression and symptoms improving with treatment of the underlying thyroid condition. (Read more about Hyperthyroid Myopathy)
Symptoms are weakness of farm and leg muscles with stiffness and muscle cramping. Onset ranges from childhood to adulthood with progression and symptoms improving with treatment of the underlying thyroid condition. (Read more about Hypothyroid Myopathy)
Symptoms are weakness of neck and limb muscles; muscle pain; and sometimes associated with malignancy. Onset ranges from childhood to late adulthood with progression and severity varying as well. This disease can respond to drug therapy. (Read more about Polymyositis)
Symptoms are weakness of the neck and limb muscles, muscle pain, and skin rashes affecting the cheeks, eyelids, neck, chest, and limbs. Onset ranges from childhood to late adulthood with progression and severity varying as well. This disease can respond to drug therapy. (Read more about Dermatomyositis)
Symptoms are weakness of arms, legs, hands, especially the thighs, wrists, and fingers. Onset is typically after 50 years with progression being slow. ( Read more about IBM)
Symptoms are generalized weakness and muscle wasting with muscle twitches. Onset is in adulthood and progression is rapid, with the average survival being 3-5 years. ALS is usually sporadic, with some cases having autosomal dominant or autosomal recessive inheritance. (Read more about ALS)
Symptoms are generalized muscle weakness, weak cry, difficulty swallowing and sucking, and respiratory problems. Onset is between birth and 3 months with rapid progression leading to early childhood death. Inheritance is autosomal recessive. (Read more about SMA)
Symptoms are weakness in arms, legs, and upper and lower torso. Onset is between 6-12 months with progression varying according to the extent of respiratory involvement. Inheritance is autosomal recessive. (Read more about SMA)
Symptoms are weakness in leg, hip, shoulder, arm, and sometimes respiratory muscles. Onset is between 13 months and adolescence with slow progression and no effect on lifespan. Inheritance is autosomal recessive. (Read more about SMA)
Symptoms are generalized weakness and muscle wasting with muscle twitching. Onset is over 18 years into adulthood with variable progression and normal life expectancy. Inheritance is autosomal recessive. (Read more about SMA)>
Symptoms are weakness and muscle wasting of the bulbar muscles (throat and mouth) and skeletal muscles. Facial and muscle jumping is common; breast development, infertility and testicular wasting can occur. It usually affects only men. Females are carriers who are usually asymptomatic or have a mild form. Onset is adulthood with progression being slow and variable with normal lifespan. Inheritance is X-linked recessive. (Read more about SBMA)
Symptoms are muscle stiffness and cramps usually occurring after periods of rest; however muscle function returns to normal with activity. Onset ranges from infancy to childhood with the disease causing discomfort but normal life-expectancy. Inheritance is autosomal dominant and autosomal recessive. (Read more about Mytonia Congenita)
Symptoms are poor or difficult relaxation of muscles which may worsen after repeated use or exercise and is often associated with hyperkalemic periodic paralysis. Onset is childhood to early adulthood with the disease causing discomfort but normal life-expectancy. Inheritance is autosomal dominant. (Read more about Paramyotonia Congenita)
Symptoms are delayed motor development with possible hip dislocation at birth. Onset is early infancy to childhood with progression varying such that it may be disabling. Inheritance is autosomal dominant. (Read more about Central Core Disease)
Symptoms are delayed motor development with weakness of arms, legs, trunk, face, and throat muscles. Onset is in early childhood with progression varying and may be life-threatening. Inheritance is autosomal dominant or autosomal recessive. (Read more about Nemaline Myopathy)
Symptoms are drooping of upper eyelids, facial weakness, blackout spells, weakness of the limbs and trunk muscles, and absent reflexes. Onset is infancy with slow progression. Inheritance is X-linked recessive, autosomal recessive, or autosomal dominant. (Read more about Myotubular Myopathy)
Symptoms are episodes of generalized muscle weakness with periods of paralysis affecting arms, legs, and neck. Onset ranges from childhood to adulthood with varying frequency of the attacks. These diseases may respond to drug therapy. Inheritance is autosomal dominant. (Read more about Periodic Paralysis)
Symptoms are weakness and fatigability of the muscles of the eyes, fact, neck, throat, limbs, and/or trunk. Onset ranges from childhood to adulthood with progression varying. This disease can respond to drug therapy or removal of the thymus gland as an effective treatment. ( Read more about MG)
Symptoms include weakness and fatigue of the hip muscles with aching back and thigh muscles common; sometimes associated with lung tumors. Onset is typically during adulthood with progression varying based on the success of drug therapy and treatment of malignancy. (Read more about Lambert-Eaton Syndrome)
Symptoms are generalized weakness and fatigability of voluntary muscles including those that control mobility, eye movement, swallowing, and breathing. Onset is infancy or childhood, however can be later, with progression varying in severity. ( Read more about CMS)
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