Spinal Muscular Atrophies and other Motor Neuron Diseases involving nerve cells in the spinal cord

Spinal Muscular Atrophies (SMA) comprise a group of autosomal recessive diseases characterized by a gradual weakening of the lower motor neurons, affecting the communication between the brain’s messages and the muscles coordinating voluntary movements, such as: walking, crawling, breathing, swallowing, and head and neck control. ‘Autosomal recessive’ translates to these disorders being genetically inherited and that two copies of an abnormal gene must be present in order for the disorder to develop. There are several classifications of spinal muscular atrophies, but the most widely accepted and used is the International SMA Consortium System, according to which there are four types of spinal muscular atrophies: acute infantile (SMA type I, or Werdnig-Hoffman disease, chronic infantile (SMA type II), chronic juvenile (SMA type III, or Kugelberg-Welander disease), and adult onset (SMA type IV). Rarer types of spinal muscular atrophies include: spinal muscular atrophy with respiratory distress (SMARD), spinobulbar muscular atrophy (SBMA, or Kennedy’s syndrome) is a rarer form of adult SMA, distal SMA, congenital SMA with arthrogryposis.

Kennedy’s syndrome or spinobulbar muscular atrophy is a rare form of adult SMA. It only affects men, it usually develops between the ages of 20 and 40. Rarely, the syndrome can affect teenage boys, and similarly uncommon is for symptomatology to become more visible after the age of 40.

Spinal muscular atrophy with respiratory distress (SMARD) is a very rare form of SMA. It is a condition similar to SMA types I-IV.

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. The term ‘amyotrophic’ refers to the atrophy of the muscle fibers, while ‘lateral sclerosis’ refers to the changes observed in the lateral columns of the spinal cord (one of the three segments comprising the ‘butterfly-shaped’ form of a cross-section of the spinal cord) due to a degeneration of the upper motor neurons. ALS is a fatal disease with a median survival period of 3 years from onset of muscle weakness.

Primary lateral sclerosis (PLS) is a progressive, degenerative disease of the upper motor neurons causing progressive muscle weakness. What differentiates PLS from ALS is that the first usually affects adults and is sporadic in nature. PLS also progresses more slowly than ALS and is usually not fatal. There is a subtype of PLS called juvenile primary lateral sclerosis that begins in childhood and is passed down hereditarily through a faulty gene (mutations of ALS2).

Causes

Spinal Muscular Atrophies

SMA is caused by defects in the gene SMN1, which regulates the production of a protein (SMN protein) ensuring the survival of motor neurons

Insufficient levels of SMN produce a degeneration of the lower motor neurons, this in turn leading to a weakening and wasting of the skeletal muscles (the muscles that are attached to the bones through collagen fibers known as tendons)

The weakness tends to usually be more severe in the trunk and upper leg and arm muscles, than in muscles of the hands and feet due to the fact that the muscles closer to the center of the body (the proximal muscles) are usually affected first and more severe than distal muscles

 

Kennedy’s syndrome or spinobulbar muscular atrophy

The condition is a rare form of adult SMA

 

Spinal muscular atrophy with respiratory distress

The condition is a very rare form of SMA

 

Amyotrophic lateral sclerosis

A clear cause determining the onset of the illness has yet to be established

In some cases ALS is inherited, but in the majority of cases it seems to occur randomly

Potential causes under research:

Gene mutation

Chemical imbalance: people with ALS have unusually high levels of glutamate, a chemical messenger (nearly all excitatory neurons in the central nervous system are glutamate regulated)

Auto-immune disorder

 

Primary lateral sclerosis

In the case of adult primary lateral sclerosis the cause is unknown

In the case of juvenile primary lateral sclerosis the onset is determined by mutations in the ALS2 gene

Symptoms and signs

Spinal Muscular Atrophies

SMA type I – Acute infantile or Werdnig-Hoffman disease

The condition is usually evident by the time the infant reaches 6 months of age

Diffuse muscle weakness and hypotonia (severely reduced muscle tone), causing difficulties when moving, breathing, eating and swallowing

Difficulties in raising the head in an upward position, or in sitting without support

Muscles are thin and weak, limbs appearing limp and floppy

Breathing problems caused by weakness in the baby’s chest

Some children also develop scoliosis (exaggerated curvature of the spine)

Most affected children die before reaching 2 years of age, mostly due to respiratory difficulties

SMA type II – Chronic infantile form

It is believed to be the most common form of SMA

Symptoms usually appear when an infant is 7 to 18 months old and are less severe than type I, but are more noticeable

Infants are usually able to sit unattended, but cannot stand or walk without assistance

Weak respiratory muscles, which can inhibit coughing

Breathing problems

Weakness in the muscles of the arms and especially of the legs

Swallowing and feeding problems

Slight tremor of the fingers

Some children develop scoliosis

Some develop deformities of the hands, feet, chest and joints as muscles shrink

SMA type II may shorten life expectancy, but the majority of children are expected to live into adulthood

SMA type III – Chronic juvenile or Kugelberg-Welander syndrome

It is the mildest form of childhood SMA

Symptoms of muscle weakness usually appear after 18 months of age, though sometimes they may appear during late childhood

Most children are able to stand and walk unaided, though many find it difficult to walk or get up from a sitting position

Balance problems

Difficulty walking

Breathing and swallowing difficulties are very rare and the condition does not usually affect life expectancy

Over time, muscles become weaker resulting in children potentially losing their ability to walk when older

SMA type IV – adult onset

It is a less common form of SMA that begins in adulthood

Symptoms are usually mild to moderate

Muscle weakness in the hands and feet

Muscle tremor and twitching

The condition does not affect life expectancy

 

Kennedy’s syndrome or spinobulbar muscular atrophy

Initial symptoms may include:

Tremor of the hands

Muscle cramps when performing physical activities

Muscle twitches and weakness of limb muscles

As the condition progresses:

Weakness of the face and tongue muscles which may cause difficulties when swallowing and speaking

Recurring pneumonia

Some patients also develop enlarged male breasts (gynaecomastia), diabetes and a low sperm count or infertility

The syndrome does not usually affect life expectancy

 

Spinal muscular atrophy with respiratory distress

Age of onset between 1 to 6 months of age

A predominant symptom is severe respiratory distress due to the involvement of diaphragm muscles

Distal muscle weakness

Sensory and autonomic nervous system may also be involved

 

Amyotrophic lateral sclerosis

The upper motor neuron controlling muscle movement gradually degenerate, muscles becoming gradually weaker and begin to waste away

In 75-80% of patients symptoms are first observed at limb level:

Tripping, stumbling, awkward running

Weakness in the legs, feet or ankles

Hand weakness or clumsiness: reduced fingers dexterity, cramping, stiffness

Muscle cramps and twitching in arms, shoulders and tongue

Difficulty keeping posture

Slurred speech

Hoarseness or decreased volume when speaking

Aspiration or choking when eating

Emotional and cognitive symptoms specific to ALS onset:

Involuntary laughing or crying

Depressive episodes

Troubled social behavior

Difficulties related to working memory, reasoning, problem solving and execution of tasks

Features of more advanced ALS:

Muscle atrophy becomes more prominent

Spasticity frequently impairs gait and manual dexterity

Common muscle cramps

Voice changes: hypernasality, development of a strained vocal quality, eventually speech may be lost

Swallowing difficulties

Drooling

 

Primary lateral sclerosis

PLS usually presents with gradual progression:

Stiffness, weakness and spasticity of legs

Tripping, difficulty in maintaining balance

Weakness and stiffness that progresses towards the trunk and subsequently to the arms, hands, jaw, and tongue

Hoarseness

Difficulties speaking, slurred speech

Drooling

Difficulty swallowing and breathing in more advanced stages

Less commonly, symptoms firstly appear in the tongue or hands and progresses downwards to the spinal cord and legs

Advice

Spinal Muscular Atrophies

Currently, there is no treatment of the genetic fault causing SMA, but therapy aims at ameliorating symptoms and varies according to the type and severity of the condition

Exercise (physiotherapy) for maintaining circulation, preventing joint stiffness, improving flexibility and range of movement

Assistive equipment in the form of walking chairs and powered wheelchairs

Nutrition and feeding may need monitoring and/or the aid of feeding tubes if feeding and swallowing problems are severe

Breathing support

Treatment for scoliosis

Speech and language therapy

Occupational therapy

Kennedy’s syndrome or spinobulbar muscular atrophy

There is no known cure, therapy aiming at ameliorating symptomatology

Physical therapy and rehabilitation to reduce muscle weakness and atrophy

Spinal muscular atrophy with respiratory distress

There is no cure for SMARD, therapy aiming at ameliorating symptomatology

Amyotrophic lateral sclerosis

Since reversing the disease’s progression cannot be achieved, treatment focuses on slowing the progression down, preventing unnecessary complications and assuring a level of independence as high as possible

Therapy:

Breathing care – i.e. mechanical ventilation

Physical therapy for improving muscle function

Occupational therapy

Speech therapy for learning adaptive techniques, exploring alternative ways of communication

Computer-based equipment to ensure communication can still take place

Nutritional support

Psychological and social support

Medication:

The drug Rilutek is the only drug approved by the FDA for treatment of ALS

Other medications used to relieve:

Muscle cramps and spasms

Spasticity

Constipation

Fatigue

Excessive salivation

Pain

Depression

Sleep disturbances

Uncontrolled outbursts of laughing or crying

Primary lateral sclerosis

The treatments focus on ameliorating symptomatology, and there are no treatments for preventing, stopping or reversing the disease’s progression

Physical therapy for preserving muscle and joint function

Speech therapy

Assistive devices: cane, walker, wheelchair

Medications to relieve muscle spasticity

Antidepressant medications if experiencing depressive episodes

MISCONCEPTIONS
  • Amyotrophic lateral sclerosis

    ALS is caused by Lyme disease or other infections

    ALS affects only motor activity

    ALS is an old people’s disease

    ALS is caused by practicing sports – incomplete researches have possibly suggested a certain correlation between football players and ALS, but mainly due to the repeated injuries to the athletes’ nervous systems, not the sport in itself

     

Statistics

Spinal Muscular Atrophies

Spinal muscular atrophy affects 1 in 6,000 to 1 in 10,000 people

The spinal muscular atrophies are the second most common autosomal-recessive inherited disorders

The acute infantile-onset SMA (type I) affects approximately 1 per 10,000 live births; the chronic forms (types II and III) affect 1 per 24,000 births

There is a 25% risk that each offspring of two carrier parents will be affected with the autosomal recessive inherited forms of SMA

In patients with SMA type I, the median survival is 7 months, with a mortality rate of 95% by age 18 months

Male individuals are most frequently affected, especially with the early-onset forms of spinal muscular atrophy, i.e, types I and II.

In the case of SMA type IV the mean onset is around mid ‘30s

About 95% of those with SMA have the SMN1 gene defect

 

Kennedy’s syndrome or spinobulbar muscular atrophy

The estimated incidence is approximately 1 case in 40,000 men

Affected men cannot pass the genetic trait on to their sons, but their daughters have a 100% risk of being carriers

Carrier females have a 50% risk of having sons with the disease gene and a 50% risk of having daughters who are carriers

 

Amyotrophic lateral sclerosis

The annual incidence of ALS in the U.S. is of approximately 2-3 cases per 100,000 population

Thus, ALS seems to be about equal in numbers to cases of multiple sclerosis and 5 times higher than reported cases of Huntington’s disease

5-10% of people with ALS inherited the disease (familial ALS)

ALS most commonly occurs in people between the ages of 40 and 60

Before the age of 65 slightly more men than women develop ALS, but this difference disappears after age 70

The lifetime risk for developing ALS in individuals aged 18 is estimated to be 1 in 350 for men and 1 in 420 for women (U.S. and European studies)

 

Primary lateral sclerosis

Data on the prevalence of PLS in the U.S. are uncertain

An estimated prevalence of 2 million patients out of approximately 4 million people diagnosed with ALS has been calculated

Men and women seem to be equally affected

A series of 43 patients reported a mean age of onset of 54.62 ±9 years, with a range of 33-74 years

Onset in a patient as young as 20 years of age has been reported by Younger et al. (1988)

 

Did you know?

Spinal Muscular Atrophies

Affected individuals have two copies of the altered gene

Those who carry one copy are usually unaffected carriers. Hence, there is often no family history

Alteration of the healthy SMN1 gene results in loss of function of specific proteins required for RNA processing

This abnormal RNA processing seems to have a toxic effect on the lower motor neurons and results in their progressive degeneration in the spinal cord and also in the brainstem motor nuclei of cranial nerves V, VII, IX and XII

The body has an almost identical copy of the SMN1 gene – the SMN2 gene

 

Kennedy’s syndrome or spinobulbar muscular atrophy

The disorder is a disease of the X chromosome; therefore, only males express the full phenotype (any individual’s observable traits such as blood type, eye and hair color, height, determined by both genetic and environmental factors)

The disease typically lasts at least 2-3 decades

 

Spinal muscular atrophy with respiratory distress

Inheritance is autosomal recessive due to mutations in the IGHMBP2 gene on chromosome 11q13

 

Amyotrophic lateral sclerosis

ALS is also called Lou Gehrig’s disease, after a famous American baseball player

Finland has one of the highest rates of ALS in the world