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Test Code NMPAN Neuromuscular Genetic Panels by Next-Generation Sequencing (NGS)


Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.


Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. Molecular Genetics: Neurology Patient Information in Special Instructions

3. If not ordering electronically, complete, print, and send a Neurology Specialty Testing Client Test Request (T732) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)

Secondary ID

65434

Useful For

Establishing a diagnosis of a neuromuscular disorder associated with known causal genes

 

Serving as a second-tier test for patients in whom previous targeted gene mutation analyses for specific inherited neuromuscular disorder-related genes were negative

 

Identifying mutations within genes known to be associated with inherited neuromuscular disorders, allowing for predictive testing of at-risk family members

Method Name

Custom Sequence Capture and Targeted Next-Generation Sequencing (NGS), Polymerase Chain Reaction (PCR), qPCR, Sanger Sequencing, and/or Gene Dosage Analysis by Multiplex Ligation-Dependent Probe Amplification (MLPA)

Reporting Name

Neuromuscular Genetic Panels

Specimen Type

Varies

Specimen Minimum Volume

3 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Reject Due To

No specimen should be rejected.

Clinical Information

Inherited neuromuscular disorders are a diverse group of diseases with heterogeneous genetic causes that affect the peripheral nervous system. The age of onset for these disorders ranges from in utero to old age. Based on the pattern of inheritance; clinical presentation; nerve conductions including, electromyography (EMG) pattern, and muscle and nerve biopsy findings; inherited neuromuscular disorders can be divided into major categories. These categories include muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, ion channel hyperexcitable muscle diseases, metabolic myopathies, congenital myasthenic syndromes, hereditary motor and sensory neuropathies, hereditary motor neuropathies, motor neuron disorders, hereditary spastic paraplegias, and hereditary sensory neuropathies. Due to the considerable overlap in the clinical phenotypes of various neuromuscular disorders, it is often difficult to distinguish these specific inherited disorders from acquired forms without genetic testing. Additionally, even though most myopathies present with proximal shoulder and girdle weaknesses, some forms may present with distal weakness and, thereby, mimic neuropathies. Therefore, genetic testing can be extremely helpful in making the diagnosis. This is especially true for some genetic forms where neurophysiology may be ambiguous, as both neuropathy and myopathy exist simultaneously.

 

Motor Neuron Disease (MND):

MND selectively affect the motor neurons with degeneration. MND include 1) primary lateral sclerosis (PLS), 2) primary muscular atrophy (PMA), and 3) amyotrophic lateral sclerosis (ALS). In PLS and PMA, the motor neuron degeneration is limited to the upper motor neuron and lower motor neuron, respectively. The clinical phenotype of PLS can include gradual progressive leg weakness and spasticity and spastic bulbar weakness. In ALS, the most frequent form of MND, degeneration involves both upper and lower motor neurons and results in progressive muscle weakness, paralysis, and death from respiratory failure, usually within 3 to 5 years of disease onset.

 

Muscular Dystrophy:

Muscular dystrophies are characterized by skeletal muscle wasting. The muscular dystrophies can be subdivided into the dystrophinopathies, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophies, distal myopathies, and congenital muscular dystrophies. A clinical diagnosis is typically based on distribution and severity of muscular involvement, mode of inheritance, and other associated symptoms.

 

The dystrophinopathies include Duchenne muscular dystrophy and Becker muscular dystrophy. These 2 forms are inherited in an X-linked manner and typically present with variable degrees of a limb-girdle pattern of weakness and can develop dilated cardiomyopathy. Limb-girdle muscular dystrophy is characterized by weakness and wasting predominately of the hips, shoulders, and proximal extremity muscles. Congenital muscular dystrophies are progressive early-onset muscle disorders that often have brain and other organ involvement. They are characterized by hypotonia, delayed motor development, and progressive weakness.

 

Emery-Dreifuss Muscular Dystrophy:

Emery-Dreifuss muscular dystrophy is characterized by the triad of joint contractures, slowly progressive muscle weakness and wasting, and cardiac involvement. Joint contractures usually being in early childhood and predominate in the elbows, ankles, and postcervical muscles. Age of onset, progression, and severity of disease demonstrate inter- and intrafamilial variability.

 

Distal Myopathy:

Distal myopathies are characterized by distal weakness and atrophy that starts in the muscles of the hands or feet and lack of cranial involvement or sensory loss. Distal myopathies are classified based on clinical features, inheritance pattern, and histopathological findings, such as the presence of rimmed vacuoles. Categories of distal myopathies include late adult-onset autosomal dominant forms, adult-onset autosomal dominant forms, early-onset autosomal dominant forms, early-onset autosomal recessive forms, and early adult-onset autosomal recessive forms. Additionally, inclusion body myositis presents with distal muscle weakness and may be in the differential with the distal myopathies.

 

Myofibrillar Myopathy:

Myofibrillar myopathies are characterized by slowly progressive weakness involving the proximal and distal muscles. The clinical phenotype can include peripheral neuropathy, cardiomyopathy, muscle stiffness, aching and cramps. While myofibrillar myopathies are typically adult onset disorders, individuals can present anywhere from early childhood through adulthood.

 

Congenital Myopathy:

Congenital myopathies are characterized by early-onset and specific histopathologic abnormalities on muscle biopsy. The clinical phenotype can include congenital hypotonia, generalized muscle weakness, delayed motor milestones, feeding difficulties, and facial muscle involvement. While congenital myopathies typically occur in childhood, individuals do occasionally present in adulthood. Also, individuals typically have slow progressive weakness, but in some cases the course may be severe.

 

Congenital Myasthenic Syndrome:

Congenital myasthenic syndromes are characterized by fatigable weakness involving ocular, bulbar, and limb muscles. The severity and disease course is highly variable, but individuals usually present in infancy or early childhood. The clinical phenotype associated with a neonatal onset can include feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and muscle weakness. The clinical phenotype associated with a later childhood onset can include abnormal muscle fatigue, delayed motor milestones, ptosis, and extraocular muscle weakness.

 

Metabolic Myopathy:

Metabolic myopathies are a diverse group of inherited biochemical diseases involving limitation of the use of fuels by skeletal muscle to generate energy. These diseases can be categorized as disorders of lipid metabolism, glycogen and glucose metabolism, or mitochondrial myopathies that impair both lipid and glucose metabolism. Biochemical testing in multiple tissue types including blood, urine, and muscle, can help to determine which category of muscle disease is most likely.

 

Disorders of fatty acid oxidation (FAO) are one category of metabolic myopathies characterized by hypoketotic hypoglycemia, hepatic dysfunction, skeletal myopathy, dilated and hypertrophic cardiomyopathy, and sudden or unexpected death. Mitochondrial fatty acid beta-oxidation plays an important role in energy production, particularly in skeletal and heart muscle, and in hepatic ketone body formation during periods of fasting. Biochemical testing such as urine organic acids, plasma acylcarnitines, and fatty acids can aid in diagnosis. These test results are influenced by dietary factors and the clinical status of the patient, however, which often leads to incomplete diagnostic information or even false-negative results.

 

Disorders of glycogen and glucose metabolism are another category of metabolic myopathies primarily affecting muscle and resulting in exercise intolerance, recurrent rhabdomyolysis, and myoglobinuria. Creatine kinase level is typically elevated during a major event. Muscle biopsy is often performed to verify absence of enzyme activity for the specific type of glycogenosis disease.

 

Polyglucosan body disease involves progressive neurogenic bladder, spasticity and weakness causing gait difficulties from either primary muscle or nerve involvements, sensory loss mainly in the distal lower extremities, and mild cognitive difficulties such as executive dysfunction. Mitochondrial myopathy due to coenzyme Q10 (CoQ10) deficiency is a group of heterogenous diseases. These mitochondrial diseases are characterized by muscle weakness, exercise intolerance, elevated creatine kinase, and abnormal muscle biopsy findings.

 

Skeletal Muscle Channelopathy:

Nondystrophic myotonias are characterized by muscle stiffness generated by voluntary movement. Other features included transient or prolonged weakness, pain associated with myotonia, and fatigue. The nondystrophic myotonias include myotonia congenita, paramyotonia congenital, and sodium channel myotonia. The periodic paralyses are characterized by episodic attacks of weakness often triggered by diet or rest after exercise. They include hyperkalemic periodic paralysis, hypokalemic periodic paralysis, and Andersen-Tawil syndrome.

 

Rhabdomyolysis:

Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which lead to leakage of potentially toxic cellular contents into the blood stream. The clinical severity can range from asymptomatic creatine kinase elevation to a life-threatening disease. The clinical features include acute-onset myalgia, transient muscle weakness, and pigmenturia. Genetic causes of rhabdomyolysis include metabolic muscle disorders, mitochondrial disorders, disorders of intramuscular calcium release and excitation-coupling, and muscular dystrophies.

Reference Values

An interpretive report will be provided.

Interpretation

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Reference

1. Richards CS, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424

2. Finsterer J, Burgunder JM: Recent progress in the genetics of motor neuron disease. Eur J Med Genet 2014 Feb;57(2-3):103-112

3. Hermans MC, Pinto YM, Merkies IS, et al: Hereditary muscular dystrophies of the heart. Neuromuscul Disord 2010;20(8):479-492

4. Wicklund MP, Kissel JT: The limb-girdle muscular dystrophies. Neurol Clin 2014;32(3):729-749

5. Flanigan KM: The muscular dystrophies. Semin Neurol 2012;32(3):255-263

6. Iannaccone ST, Castro D: Congenital muscular dystrophies and congenital myopathies. Continuum (Minneap Minn). 2013 Dec;19(6 Muscle Disease):1509-1534

7. Olive M, Kley RA, Goldfarb LG: Myofibrillar myopathies: new developments. Curr Opin Neurol 2013;26(5):527-535

8. D'Amico A, Bertini E: Congenital myopathies. Curr Neurol Neurosci Rep 2008;8(1):73-79

9. Engel AG, Shen XM, Selcen D, et al: Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 2015;14(4):420-434

10. Sharp LJ, Haller RG: Metabolic and Mitochondrial Myopathies. Neurol Clin 2014;32(3):777-799

11. Emery AE: Emery-Dreifuss muscular dystrophy-a 40 year retrospective. Neuromusc Disord 2000;10(4-5):228-232

12. Udd B: Distal myopathies. Curr Neurosci Rep 2014;14(3):434

13. Burge JA, Hanna MG: Novel insights into the pathomechanisms of skeletal muscle channelopathies. Curr Neurol Neurosci Rep 2012;12(1):62-69

14. Scalco RS, Gardiner AR, Pitceathly RD, et al: Rhabdomyolysis: a genetic perspective. Orphanet J Rare Dis 2015;10:51

Day(s) and Time(s) Performed

Performed weekly; Varies

Analytic Time

10 weeks

Performing Laboratory

Mayo Medical Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

LOINC Code Information

Test ID Test Order Name Order LOINC Value
NMPAN Neuromuscular Genetic Panels In Process

 

Result ID Test Result Name Result LOINC Value
37980 Client Provided Sub-Panel 19145-2
37981 Result Summary 50397-9
37982 Result 82939-0
37983 Interpretation 69047-9
37984 Additional Information 48767-8
37989 Method 49549-9
37990 Disclaimer 62364-5
37986 Specimen 31208-2
37987 Source 31208-2
37988 Released By 18771-6

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
_G090 Motor Neuron Disease Panel No, (Bill Only) No
_G091 Muscular Dystrophy Panel No, (Bill Only) No
_G092 Myofibrillar Myopathy Panel No, (Bill Only) No
_G093 Congenital Myopathy Panel No, (Bill Only) No
_G094 Congenital Myasthenic Syndromes No, (Bill Only) No
_G095 Metabolic Myopathy Panel No, (Bill Only) No
_G096 Emery-Dreifuss Panel No, (Bill Only) No
_G097 Distal Myopathy Panel No, (Bill Only) No
_G098 Skeletal Muscle Channelopathy Panel No, (Bill Only) No
_G099 Myopathy Expanded Panel No, (Bill Only) No
_G100 Distal Weakness Expanded Panel No, (Bill Only) No
_G101 Rhabdomyolysis and Myopathy Panel No, (Bill Only) No

CPT Code Information

81243

81260

81325

81401

81403

81404

81405

81406

81407

81408

81479

Testing Algorithm

See Inherited Motor Neuron Disease Testing Algorithm in Special Instructions.