CLINICAL OVERVIEW

NEUROMUSCULAR DISEASE: A CLINICAL OVERVIEW

This section provides the reader with a brief clinical overview of the most common major NMDs. Any medical practice is likely to encounter these disorders.

MOTOR NEURON DISEASES

AMYOTROPHIC LATERAL SCLEROSIS

ALS is perhaps the most severe of all the major NMDs. ALS is a rapidly progressive NMD that destroys upper and lower motor neurons. This results in diffuse muscular weakness and atrophy. Unlike most primary nerve disorders, ALS also produces spasticity because of the loss of upper motor neurons. This creates unique clinical management issues.

An estimated 10% of all ALS cases are familial, usually inherited as an autosomal dominant trait. About 15% of these cases result from a gene defect on chromosome band 21q12.1, which leads to a mutation in the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1).

Approximately 100 SOD1 mutations have been identified and nearly all are single missense dominant mutations causing toxic gain of function. Over 50 unique superoxide dismutase mutations have been identified. Emerging evidence suggests that these mutations result in increased oxidative stress for the motor neurons, leading to cell death, which is presumably related to free radical toxicity.

However, most ALS cases occur sporadically, with unknown etiology. Studies suggest that excessive glutamate, an excitatory neurotransmitter, in the CNS is involved in the disease process. Serum, spinal fluid, and brain tissue of patients with ALS contain excessive levels of glutamate, which is apparently due to reduced clearance of glutamate from the motor cortex and decreased activity of glutamate transport proteins.

Population studies indicate that the prevalence of ALS is increasing, although this may be because of better recognition of the condition and increased longevity of people with ALS.The worldwide

prevalence rate is 5-7 cases per 100,000 population, making ALS one of the more common NMDs. ALS seems to affect men more commonly than it affects women, with a male-to-female ratio of approximately 1.5:1. ALS primarily affects adults aged 40-60 years, with a mean onset age of 58 years.

A higher prevalence of ALS exists in urban areas, possibly due to environmental factors. Considerable geographic clustering has been seen in association with ALS, most notably in the Western Pacific region of the world, but also in Gulf War veterans. Despite clustering, environmental or causal factors remain to be determined.

A population-based case-control study conducted in 3 counties of western Washington State showed that a history of smoking cigarettes was associated with a twofold increase in risk, while a 3-fold increase was seen in current smokers. The duration and amount of smoking (packs per year, years having smoked) correlated with risk for ALS. Dietary fat increased the risk for ALS, although alcohol consumption did not.

Dietary fiber intake decreased risk, although consumption of antioxidant vitamins from diet or supplement sources did not alter the risk. Interestingly, glutamate consumption did correlate with an increased risk for ALS. The fact that smoking and glutamate consumption are risk factors for ALS supports the current theory that implicates oxidative stress and excitotoxicity in the pathogenesis of ALS.

The major neuropathologic finding in ALS is degeneration and subsequent loss of motor neurons due to apoptosis, or programmed cell death. Apoptosis is characterized by neuronal contraction (to approximately one fifth its normal size) with an extremely condensed nucleus and cytoplasm. Apoptotic bodies can usually be seen in macrophages.

Other neuropathologic findings in ALS include axonal loss in the descending motor tracts, anterior roots, and nerves. There also appears to be subtle involvement of the frontal lobes, hippocampal area, substantia nigra, and dorsal columns.

Motor neuron degeneration begins focally and spreads to contiguous regions in the neuraxis until the neurons controlling respiration are affected, which ultimately leads to death from respiratory failure. The number of motor neurons involved and the spectrum of motor neuron degeneration varies for any individual patient, which accounts for the clinical variability in disease progression.

A number of prognostic predictors exist for determining the severity of a person's ALS course. Presentation with bulbar or pulmonary dysfunction (or both), short time period from symptom onset to diagnosis, findings primarily involving lower motor neuron on electrodiagnostic testing, and advanced age all potentially indicate a poor prognosis.

Women present with bulbar symptoms more frequently than men do. Bulbar palsy appears to progress more rapidly in women; this indicates a poor prognosis. Young males with ALS have the best prognosis and may have a longer life expectancy. Overall, the median 50% survival rate is 2.5 years after diagnosis.

In patients who present with bulbar symptoms, the 50% survival rate drops to 1 year. Survival rates vary depending on the patient's decision to use a feeding tube and assisted ventilation. Nonetheless, by 5 years postdiagnosis, the overall survival rate is only 28%.

SPINAL MUSCULAR ATROPHY

All forms of SMA involve selective destruction of anterior horn cells. The distinct types of SMA clinically differ. Some rare forms affect only distal or bulbar muscles. SMA is usually classified as types I, II, and III. Most forms of SMA are autosomal recessive traits.

SMA I, also known as Werdnig-Hoffmann disease or acute infantile-onset SMA, is a severe disorder that causes death before age 2 years.

SMA II, also known as chronic Werdnig-Hoffmann disease or early-onset intermediate SMA, is less severe. SMA II may not become apparent until age 6-18 months.

SMA III, also known as Kugelberg-Welander disease, has a much later onset, typically age 5-15 years, and is associated with much less morbidity.

Mutations in exons 7 and 8 of the telomeric survival motor neuron gene are present in more than 98% of patients with SMA types I-III. Deletions in the neuronal apoptosis inhibitory protein gene are found in approximately 67% of patients with SMA I; 42% of patients with SMA II and III; and in some patients with adult-onset SMA, although the percentage is not known.

Commercial blood tests (DNA analyses) are now available for use in diagnosing SMA. Prevalence rates for SMA types II and III have been estimated to be as high as 40 cases per million in the general population, although considerable variations exist in demographic studies.

Two forms of later adult-onset SMA exist. The first type is spinobulbar muscular atrophy (SBMA), or Kennedy disease. This disorder, which was first described as recently as 1968, is a sex-linked recessive NMD characterized by progressive spinal and bulbar muscular atrophy, gynecomastia, and reduced fertility.

SBMA has been mapped to the androgen receptor on the X chromosome. The mutation, which consists of an expansion of cytosine, adenine, and guanine (CAG) trinucleotide repeats, occurs in the first exon of the gene, producing decreased sensitivity of androgen receptors on motor neurons. The disease has some clinical variability; however, phenotypic expression does not correlate with the length of CAG repeats.

This phenomenon is in contrast to myotonic muscular dystrophy and fragile X syndrome, in which an increased number of tandem triplet repeats correlate directly with disease severity. SBMA can occur without any family history or gynecomastia, and all males with atypical ALS should undergo DNA testing for SBMA (the DNA test is commercially available).

The other form has onset age of 17-55 years, with either recessive or dominant types of inheritance. This form of SMA clinically resembles SMA III yet may be more progressive. This form of SMA has been mapped to chromosome band 5q11.2-13.3, although commercial testing is not yet available because adult-onset SMA and SBMA are far less common forms of SMA.

PERIPHERAL NEUROPATHIES

CHARCOT-MARIE-TOOTH DISEASE

CMT can be divided into 2 basic types: primarily demyelinating (with secondary axonal loss) and primarily axonal. The remainder of the subclassification of CMT is based on genetic analysis.

In CMT type 1 (CMT1), which is primarily a demyelinating neuropathy, anatomic changes directly affect the myelin sheath, with secondary axonal changes. In areas of focal demyelination, impulse conduction from one node of

Ranvier to the next is slowed as current leakage occurs and the time for impulses to reach threshold at successive nodes of Ranvier is prolonged, producing slowing of conduction velocity along the nerve segment.

CMT type 2 (CMT2) is a primary axonal neuropathy producing changes in the axon and the nerve cell body. CMT2 tends to affect the lower extremities more than the upper extremities. CMT2 is often a clinically less severe disease than CMT1.

Patients with CMT2 may have more lower extremity involvement, although clinically they are not easily distinguished from patients with CMT1. Previous studies have shown that no significant side-to-side difference exists in nerve conduction abnormalities or strength, and, like CMT1, the sensory deficit is usually less severe than the motor deficit. Most of the phenotypic descriptive studies in CMT were done before the advent of DNA testing.

Previous studies have shown that, overall, CMT is a slowly progressive disorder characterized by diffuse muscle weakness and prominent distal atrophy, predominantly involving the intrinsic muscles of the feet and the peroneal muscles. Subjects with CMT produce 20-40% less force than normal controls using quantitative isometric and isokinetic strength measures, even though manual muscle test scores may be normal. No significant side-to-side difference exists concerning strength.

From a functional standpoint, the sensory deficit is usually less severe than the motor deficit. Prior studies have also documented that subjects with CMT have a marked reduction in functional aerobic capacity during exercise testing despite having normal or relatively normal preexercise pulmonary function, exercise heart rate, and blood pressure and maximum ventilation.

The number of molecular forms of CMT and related neuropathies is always growing. However, CMT1 is the most common type overall. CMT1A is the most common subtype of CMT1 and results from a duplication of chromosome segment 17p11.2, which contains the gene for peripheral myelin protein 22 (PMP22).

Interestingly, patients with a related disorder, hereditary neuropathy with liability to pressure palsies (HNPP), show a large deletion, rather than a duplication, in the PMP22 gene.HNPP is an autosomal

dominant disorder that produces episodic recurrent nerve compression with focal demyelination at common sites of compression or entrapment (wrist, elbow, fibular head). Nerve compression can occur in the absence of true entrapment.

CMT X is an X-linked dominant, primarily demyelinating neuropathy with a mutation in the connexin 32 gene (CX32) that codes for a membrane protein (gap junction protein, beta 1) involved in the formation of gap junctions. CMT X1 is clearly a distinct entity. Some varieties of CMT X1 may exhibit abnormal temporal dispersion and heterogeneous conduction velocities that are very atypical of other hereditary neuropathies.

Mutations in the CX32 gene can produce a neuropathy with either demyelinating or axonal electrodiagnostic features. Some clinical and electrodiagnostic data in males with different missense mutations in the CX32 gene appear to differ significantly. Furthermore, males with a non-sense mutation have an earlier onset and a more severe phenotype than males with missense mutations.

Point mutations in the PMP22 or the myelin protein zero gene (MPZ) may cause Dejerine-Sottas disease. Thus, many cases of Dejerine-

Sottas disease are now considered severe phenotypes within the genotypic spectrum of CMT1. Congenital hypomyelinating neuropathy is a severe and often fatal newborn disorder that presents with respiratory distress at birth and has been linked to the early growth response gene 2 (EGR2) in some families.

MUSCULAR DYSTROPHY

DUCHENNE AND BECKER MUSCULAR DYSTROPHIES

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders that primarily affect skeletal and cardiac muscle.

Dystrophin, a large cell wall (sarcolemma) structural protein, is absent in DMD and of abnormal molecular weight or of reduced amounts in BMD. Dystrophin stabilizes the sarcolemma during muscle contractions. Without dystrophin, the sarcolemma is unstable, cell homeostasis is impaired, and, ultimately, the myofiber deteriorates. Despite some regeneration, the repair capacity is rendered insufficient, and the muscle is replaced by fat and connective tissue.

DMD is the most common childhood NMD with an estimated overall prevalence of 63 cases per million population. This is an ultimately

fatal progressive myopathy, with death usually occurring in people younger than 30 years. Life expectancy has risen considerably over the past decade because of better management of respiratory or cardiac complications. Only a few decades ago, boys with DMD rarely lived to be older than 20 years.  

BMD is less common, with an estimated prevalence rate of 24 cases per million population. BMD is associated with the same muscle

weakness that DMD is but with a much later onset age and slower rate of progression. The abnormal gene for DMD and BMD is on the short arm of the X chromosome at position Xp21.

MYOTONIC MUSCULAR DYSTROPHY

Myotonic muscular dystrophy (MMD) is clinically characterized by progressive, primarily distal muscle weakness and myotonia (delayed muscle relaxation). Patients with MMD typically have characteristic facies, including frontal baldness and temporal wasting. Other problems include gonadal atrophy, cataracts, cardiac dysrhythmias, and an increased risk for diabetes. MMD is an autosomal dominant trait with a prevalence of 1 case per 8000 population.

Several forms of MMD exist, primarily because of the unusual genetic basis of the disease. MMD is caused by a DNA sequence within the gene on chromosome band 19q13.3 that is repeated to varying degrees, producing an expanded, unstable area of the chromosome. This abnormal gene, referred to as a triplet repeat mutation, may grow as it is passed from generation to generation. This can cause the disease to present earlier and more severely in passing generations in a family line.

The most severe form of MMD is known as congenital MMD. Patients with congenital MMD have been shown to have substantially more repeats than those found in patients with typical MMD. The repeated DNA sequences known as CTG (trinucleotide cytosine, thymine guanidine) are linked to the production of the protein myotonin-protein kinase, which has important functions in smooth and skeletal muscle, eye, hair, and brain, and decreased levels of the mRNA and protein expression.

A new form of MMD has been discovered that is known as type 2 MMD (MMD2 or DM2). It has also been referred to as proximal myotonic myopathy. A mutation on chromosome 3 causes MMD2, which is thought to be clinically less severe than typical MMD and congenital MMD. MMD2 may be associated with insulin insensitivity, diabetes, and low testosterone levels in males.

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

Facioscapulohumeral dystrophy (FSHD) is a slowly progressive myopathy with prominent involvement of shoulder, pelvic, and facial musculature. FSHD is an autosomal dominant trait with an estimated prevalence of 10-20 cases per million population or possibly higher if accounting for undiagnosed, mild cases.

The abnormal gene is on the end of chromosome 4, and DNA testing for diagnostic purposes is now commercially available. FSHD can be quite heterogeneous in its clinical presentation and course; this raises questions regarding genetic homogeneity.

LIMB-GIRDLE MUSCULAR DYSTROPHY

Limb-girdle muscular dystrophies (LGMDs) are a very heterogeneous group of myopathies that share many clinical features. This family of dystrophic myopathies usually has an onset age ranging from 3-12 years with equal male and female prevalence.

The distribution and pattern of weakness are similar to those of DMD but with a much slower rate of progression. These diseases have been linked to abnormalities of the dystrophin-associated glycoproteins (DAGs), alpha-sarcoglycan (adhalin) in particular, a 50-kd DAG, and gamma-sarcoglycan. The 50-kd DAG protein has been linked to the 17q12-q21.33 locus.

Other forms of LGMD have been linked to chromosome band 13q12. Individuals with these forms may show a primary deficiency of gamma-sarcoglycan and a secondary deficiency of alpha-sarcoglycan. Patients with LGMD with a deletion on chromosome band 4q12 have a primary deficiency in beta-sarcoglycan, and patients with LGMD with a chromosome band 5q33-q34 deletion have a primary deficiency of delta-sarcoglycan.

Most of the primary sarcoglycan abnormalities lead to secondary deficiencies of alpha-sarcoglycan. People with LGMD generally have normal results on tests for dystrophin. All the DAGs are reduced in patients with DMD because the C-terminal portion of dystrophin binds to the dystrophin-associated proteins and maintains their integrity. A less severe autosomal recessive form of LGMD has been linked to chromosome band 15q1-q21.1, the gene for the protein calpain 3. Diagnosis of all forms of LGMD subtypes is best confirmed based on muscle biopsy.

Of the 7 recessive loci identified to date, 4 are sarcoglycan genes. These 4 proteins make up the sarcoglycan complex, which may interact directly with the 43-kd DAG and with dystrophin. Dystrophin-associated glycoproteins probably provide connections between the extracellular matrix (the protein merosin) and the intracellular membrane cytoskeleton (attached to dystrophin).

An abnormality of the dystrophin-glycoprotein complex, resulting from primary deficiencies of 1 or more of the dystrophin-associated glycoproteins, results in a disruption in the linkage between the intracellular sarcolemmal cytoskeleton and the extracellular matrix. Disruption of the membrane cytoskeleton is common to the pathophysiology of most muscular dystrophies, the dystrophinopathies.