Case 12: My Doctor Says That I Have ALS!

Presenting Complaint

A 47-year-old, white man is referred to the neuromuscular clinic with the diagnosis of amyotrophic lateral sclerosis (ALS).

History

The patient complained to his primary doctor about a “funny feeling” in his right lower extremity, of which he first noticed 1 year ago. Sometimes his leg feels numb and sometimes he experiences mild tingling. He occasionally walks with a slight limp.

He denies muscle twitching or atrophy. He can climb up and down stairs normally and has no complaints in regard to his upper extremities. He works full-time and is independent in activities of daily living. He denies fever, weight loss, shortness of breath, chest pain, nausea, or vomiting. He has experienced no bowel, bladder, swallowing, or sexual dysfunction.

Although he has experienced no noticeable functional limitations as an adult, as a child he was never very good at sports and was the slowest runner in his class.

Past medical history

Hypercholesterolemia.

Allergies

None.

Social history

Businessman, lives with his wife, no smoking or illicit drug use, drinks 1 glass of wine per day.

Family history

His sister carries the diagnosis of multiple sclerosis. His mother is alive at 80 and his father died at 72 of Alzheimer's disease. He has 2 healthy children.

Medications

Atorvastatin for 3 years without change in dosage.

Physical exam

Pleasant man in no distress, with normal general examination.

Neurologic Exam

Mental status, affect, and language are normal. Cranial nerves are normal except for mild bilateral facial weakness involving upper and lower facial muscles. Benign fundus examination.

Strength is 5 of 5 in the deltoids, biceps, triceps, wrist extensors, small muscles of the hand, iliopsoas, quadriceps, hamstrings, tibialis anterior, gastrocnemius, toe flexors, and toe extensors.

Sensory exam shows normal responses to fine touch, pinprick, vibration, and proprioception. The sensory exam is likewise normal along the distribution of abnormal feeling in the right leg.

Deep tendon reflexes are 2+ and symmetric throughout, with downgoing toes.

His gait is normal and he can toe, heel, and tandem walk; negative Romberg's sign.

The patient has difficulty quickly releasing his grip after making a tight fist. When his abductor pollicis brevis muscle is struck with a reflex hammer, the muscle remains contracted for several seconds.

Previous ALS Diagnosis

The referring diagnosis of ALS was based on an electromyogram (EMG) that was interpreted to show abnormal spontaneous activity and neurogenic changes in all muscles tested in the left lower limb, right lower limb, right hand, left upper limb, and bilateral cervical and thoracic paraspinal muscles. The patient's neurologist thought that this was consistent with “definite amyotrophic lateral sclerosis by the World Federation of Neurology and the Lambert criteria,” although clinical evidence was actually insufficient to make this diagnosis by the revised criteria.[1,2] The patient underwent repeat neurometric testing (Figure 1).

1. This patient does not have ALS. What did carefully performed repeat neurometric testing most likely demonstrate?

   1. Completely normal study
   2. Myokymia
   3. Myotonic discharge
   4. Conduction block
   5. Slow conduction velocities with fasciculation potentials

Figure 1.

Repeat electromyographic (EMG) findings are not consistent with a diagnosis of amyotrophic lateral sclerosis.

Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed, for the editor's eye only or for possible publication via email: glundberg@medscape.net

Corrected Diagnosis

EMG demonstrated profuse true myotonic discharges in every muscle that was tested, with normal motor unit potential morphology and normal conduction velocity. The initial misdiagnosis of ALS resulted from an incorrectly interpreted EMG.

Myotonia

“Clinical myotonia” refers to impaired relaxation of skeletal muscle after voluntary contraction.[3] The exam in this case demonstrated 2 abnormalities suggesting clinical myotonia: difficulty relaxing grip after strong fist closure and “percussion myotonia” revealed by prolonged contraction of the abductor pollicis brevis muscles following a brisk strike with a reflex hammer.

Abnormal muscle fiber membrane activity can cause EMG myotonia, seen on EMG as repetitive discharges that wax and wane in frequency and amplitude, and producing a sound that is similar to a revving engine.[3] EMG myotonia may occur without clinical correlate, but often patients will notice difficulty relaxing their grip or trouble with repeated movements, such as chewing.

Nerve conduction velocities are not affected by the muscle fiber membrane abnormalities that cause myotonia.

The combination of poor athletic prowess during childhood, myotonia, bilateral facial weakness, unusual limb sensations, and intermittent weakness suggested a diagnosis of myotonic dystrophy (DM).

Myotonia is also associated with other genetic disorders, such as myotonia congenita, paramyotonia congenita, hyperkalemic periodic paralysis, and hypokalemic periodic paralysis.[4] On rare occasions, myotonia has been attributed to medications, including colchicine, oxaliplatin, and statins.[5–10]

A preliminary protocol for clinical quantification of myotonia has been proposed,[11] but because symptoms typically wax and wane, a patient's description of how his or her myotonia interferes with daily activities and social interactions is more useful for planning treatment approaches.[3]

• 2.
  Which types of myotonia are associated with a genetic abnormality in the skeletal muscle chloride channel?

  1. Myotonia congenita and Thomsen's disease
  2. Hyperkalemic periodic paralysis and paramyotonia congenita
  3. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2)
  4. All of these
• 3.
  Which types of myotonia are associated with a genetic abnormality in the skeletal muscle sodium channel?

  1. Myotonia congenita and Thomsen's disease
  2. Hyperkalemic periodic paralysis and paramyotonia congenita
  3. DM1 and DM2
  4. None of these

Myotonia congenita can be caused by at least 80 different mutations in the CLCN1 gene encoding a skeletal muscle chloride channel.[12] Dominant and recessive forms demonstrate wide variation in symptom severity and penetrance. Thomsen first described an autosomal dominant form of this disease in 1876.

Hyperkalemic periodic paralysis and paramyotonia result from mutations in the SCN4A gene encoding a skeletal muscle sodium channel.[13]

Several distinct mutations in the genes encoding skeletal muscle calcium channels, sodium channels, and potassium channels can lead to hypokalemic periodic paralysis.[4]

• What would be the next step for establishing a diagnosis of DM?

  1. Demonstrate percussion myotonia in a parent and one other relative
  2. Genetic testing
  3. Check for elevated creatine kinase (CK) level
  4. Muscle biopsy
  5. Tensilon testing

Searching for percussion myotonia in relatives might be fun, but many individuals with DM2 do not have clinically apparent myotonia and, thus, would not be revealed by a search.[3] Even the presence of EMG myotonia is highly variable in DM2 and frequently difficult to detect.

Elevated CK is common in the DMs but not specific. The patient presented here had a CK of 497 (normal, 24-195) at initial examination.[3]

Muscle biopsy is not a part of the diagnostic work-up.[3] Both types of DMs show nonspecific myopathic changes often with central nucleation. Type 1 fiber atrophy is more common in DM1, and type 2 fiber atrophy with pyknotic nuclear clumps is more common in DM2.[14]

Genetic testing reveals that this patient possesses the repeat expansion mutation that causes DM2.

• 5.
  Which type of inheritance pattern do the DMs demonstrate?

  1. Autosomal dominant
  2. Autosomal recessive
  3. X-linked dominant
  4. X-linked recessive
  5. Mitochondrial
• 6.
  Which phenomenon is associated with DM1?

  1. Diet alters symptoms
  2. Absence of variable penetrance
  3. All affected individuals are herpes simplex virus-positive by polymerase chain reaction (PCR)
  4. Anticipation
  5. Higher incidence in families with lupus
• 7.
  What is the molecular basis of the mutation in the DMs?

  1. Substitutions or deletions in a coding region
  2. Deletion in a noncoding region
  3. Translocation
  4. Repeat expansion in a coding region
  5. Repeat expansion in a noncoding region

A typical DM1 family pedigree may include a grandparent with mild symptoms, a mother with adult-onset disabling facial and limb weakness, and a congenitally affected child.[3]

Both DM1 and DM2 are caused by pathogenic RNA resulting from repeat expansions in noncoding regions.[15]

Whole blood from the described patient revealed an abnormal allele for DM2 with greater than 15,000 tetranucleotide repeats and a normal allele with 128 repeats. Both DM1 alleles were normal.

Discussion

DM

DM is one of the most common forms of muscular dystrophy presenting in adulthood. Scientists have identified 2 distinct genes that are capable of producing this phenotype: DMPK on chromosome 19 (DM1) and ZNF9 on chromosome 3 (DM2).[16] DM1 is estimated to have a prevalence of 1:8000 in most populations, but the prevalence of DM2 has not been determined.[3]

Both forms of DM are clinically heterogeneous multisystem diseases characterized by myotonia, diffuse weakness, muscle wasting, iridescent cataracts, cardiac arrhythmia, cardiomyopathy, insulin insensitivity, and endocrine abnormalities, including hypotestosteronism and oligospermia.[3]

DM2 is usually a milder disease than DM1, with some patients complaining only of fluctuating weakness, stiffness, and peculiar myalgias, as did our patient.[3,17] DM1 is more likely to cause distinctive facies myopathica with baldness. DM2 is not associated with congenital abnormalities and mental retardation as is DM1.

Before the mutation causing DM2 was isolated, this form of muscular dystrophy was thought to preferentially affect the proximal muscles and was referred to as proximal myotonic myopathy or proximal DM. Gene identification allowed better characterization of the clinical features of DM2, revealing variable involvement of both the proximal and distal muscle groups.[3,15]

The phenotypes associated with DM1 and DM2 result from unstable repeat expansions in the noncoding regions of 2 unrelated genes.[18] DM1 is caused by a CTG triplet repeat expansion in the 3' portion of a kinase gene; DM2 is caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 gene. These expanded noncoding transcripts become pathogenic RNA sequences by interfering with the expression of at least 13 other proteins. Both DM1 and DM2 expansions can disrupt the accurate splicing of unrelated gene products, including cardiac troponin T, insulin receptors, a chloride channel, and 3 forms of the RNA-binding protein muscleblind. By this mechanism, the DMs are multiorgan diseases, notably involving muscle, the heart, the eyes, the endocrine glands, and the brain.

Although the genes associated with DM1 and DM2 code for unrelated proteins, it is believed that the similar phenotypes stem from pathogenic RNA sequences that are capable of interfering with the same set of diverse proteins.[19] Phenotypic differences between DM1 and DM2 could result from the slightly different affinities of the CTG and CCTG expansion repeats. The wide range of signs and symptoms manifested by patients with identical DM alleles may result from dissimilar genetic environments, because even related individuals can possess different forms of the genes that are potentially vulnerable to interference by pathogenic RNA transcripts.

Unstable forms of the DM1 gene have 50-1000 copies of the triplet repeat (normal, 5-37).[3] Mild symptoms are associated with a smaller number of repeats. Anticipation, the phenomenon of more severely affected patients presenting in subsequent generations, is associated with expansion of the unstable region during germline transmission.

Abnormal forms of the DM2 gene have 177-11,000 copies of the quartet repeat in germline cells (normal, 104-176).[3] The presence of anticipation has not been well documented for this form of DM, but DM2 is associated with an unprecedented level of repeat instability and expansion in somatic cells. Somatic instability may contribute to the varied organ involvement and disease severity because there can be significant variation in quartet repeat numbers within different tissues of a single individual.[3]

Treatment

There is no specific treatment for DM2. Given the range of presentations, the approach should be individualized.[3,20,21]

All patients should undergo cardiac evaluation following diagnosis to rule out conduction abnormalities or cardiomyopathy. Severe cardiac involvement is more common in DM1, but sudden cardiac death has been described in patients with DM2.[22] Ophthalmic evaluation should be performed with cataract extraction if necessary. Patients should be screened regularly for hypothyroidism because untreated thyroid disorders can exacerbate myotonia. Some patients will develop insulin resistance and should be managed with standard diabetic medications.

Many patients with DM2 do not require treatment for their mild myotonia and muscle weakness. Antiarrhythmic drugs, including mexiletine and procainamide, have been used to reduce myotonia, but given the risk for cardiac involvement, these drugs should be avoided.[23] Myotonia and cramps sometimes improve with phenytoin, carbamazepine, dehydroepiandrosterone sulfate (DHEAS), or quinine, but there is no standardized regimen.[20,21,23] Preliminary open trials of creatine and DHEAS for muscle weakness in DM1 demonstrated some improvement, but subsequent trials have been less promising.[24]

Genetic counseling is complicated by the unstable repeat expansion and the unpredictable genotype-phenotype correlation. Without severe cardiac involvement, most patients with DM2 have a normal life expectancy and many have mild symptoms.[3]

A higher incidence of complications during surgical anesthesia has been described in patients with skeletal muscle channelopathies, the most significant being the susceptibility to malignant hyperthermia associated with a calcium channel mutation.[4,25] Cases of patients with DM1 and DM2 experiencing complications from anesthesia have been reported, but the degree of risk has not been defined.[26,27] In addition, no one has established whether patients with DM1 or DM2 have increased susceptibility to malignant hyperthermia. Patients with DM1 or DM2 should be advised to inform their surgeons and anesthesiologists about the need for vigilance during procedures.

Case Revisited

After establishing the diagnosis of DM2, the patient's family history was reviewed.

The patient's 52-year-old sister had been diagnosed with an atypical form of multiple sclerosis on the basis of a gradually progressive dementia with confluent white matter lesions. She had required cataract extraction during early adulthood and first complained of muscle pain and weakness during her late 30s. Genetic testing revealed DM2. Her 25-year-old daughter has also been diagnosed with cataracts.

The patient's father had experienced symptoms that were suggestive of DM and had died at 72 not of Alzheimer's disease but of a rapidly progressive dementia with frontotemporal features. The patient's mother has no symptoms of DM at age 82.

DM1 has been associated with degenerative white matter changes, memory deficits, personality abnormalities, and progressive dementia.[28–30] White matter changes have also been found in patients with DM2, although only a few patients with DM2-associated dementia have been reported.[31,32] Pathologic studies of the central nervous system in patients with DM1 and DM2 sometimes demonstrate altered expression of tau proteins with neurofibrillary tangles, similar to the tau abnormalities that are seen in frontotemporal dementia.[32,33] The pathologic repeat expansions present in DM1 and possibly DM2 are believed to directly alter tau expression.[3] In addition, one large family has demonstrated evidence of a third gene on chromosome 15 that can cause a multisystem myotonic disorder associated with severe frontotemporal dementia.[34]

Possibly the progressive dementing illness affecting our patient's sister and father was related to altered tau expression and resulting neurofibrillary tangles induced by the pathogenic RNA transcribed from the DM2 allele.

Treatment Plan

Our patient underwent cardiac evaluation, ophthalmic evaluation, and brain magnetic resonance imaging (MRI), all of which were normal. As soon as he learned that he did not have ALS, he decided that his symptoms could safely be ignored and he did not start any symptomatic treatment.