This page copies a pamphlet produced by Athena Diagnostics. Last updated: 4/21/1995.
Athena Diagnostics
Pressure Palsy Neuropathy Test
Athena Diagnostics, formerly Genica Pharmaceuticals Corporation, is located at Four Biotech Park, 377 Plantation Street, Worchester, MA 01605. They can be reached by calling 1-800-394-4493.
Table of Contents
Pressure Palsy Neuropathy Test
Hereditary Neuropathy with liability to Pressure Palsies (HNPP; also called Tomaculous neuropathy or familial recurrent polyneuropathy) is an autosomal dominant disorder which presents as recurrent mononeuropathy simplex or multiplex that may be related to a trauma that normally would not cause damage. Peripheral palsy neuropathy (PPN), carpal tunnel syndrome (CTS) and other entrapment neuropathies may be manifestations of HNPP.[7] Patients may have slightly reduced nerve conduction velocities in both affected and unaffected nerves. Sural nerve biopsies show sausage-like ("tomaculous") swellings of myelin, transnodal myelination, and segmental demyelination.[3]
Athena Diagnostics is pleased to offer the Pressure Palsy Neuropathy Test for the detection of Hereditary Neuropathy with liability to Pressure Palsies (HNPP). The test utilizes a highly informative DNA detection technique, pulsed-field gel electrophoresis (PFGE), to detect the chromosome 17 DNA deletion. This test was developed at the University of Utah Medical Center by Dr. Phillip F. Chance and his colleagues, and offers the highest level of accuracy available.[4]
Detection of the HNPP deletion has important implications for diagnosing patients with inherited as well as sporadic peripheral neuropathies. In addition to its identification in patients with familial HNPP, spontaneous HNPP mutations have also been found and may account for spontaneous HNPP. The Pressure Palsy Neuropathy test is thus a highly specific diagnostic marker of disease which can supplement or, in some circumstances, replace electrophysiologic tests currently in use. This test has further clinical applications in genetic counselling of patients and at-risk family members, as well as in prenatal diagnosis.
Any patient who has recurrent episodic peripheral neuropathy, regardless of family history, is a candidate for the Pressure Palsy Neuropathy test.
Figure 1 HNPP Deletion.
Figure 1. Shows a representative autoradiograph from a patient with the HNPP deletion specific junction fragments compared with a normal individual.
Peripheral Palsy Neuropathies (PPN) is a diagnostic term that covers many paralytic disorders of the peripheral nervous system involving entrapment neuropathy or compressive neuropathy. These disorders may present with highly variable symptoms that depend on the nature of the entrapment or compression, its location, and its severity. Clinical indications may include paralysis, pain, numbness, muscle atrophy, and tenderness.[1]
Compressive neuropathies are defined as pressures exerted upon a nerve through overlying tissues that may be externally or internally applied. Entrapment neuropathies are specifically constrictions of the nerve within a fibrous or fibro-osseous tunnel or band.[2]
The typical age-of-onset for HNPP is adolescence, however it may present in early childhood.
Indications for testing include:
- Patients with idiopathic entrapment or compressive neuropathies.
- Patients with acute unexplained partial paralysis of limbs or face, with or without sensory disturbances.
- Symptoms suggestive of Charcot-Marie-Tooth (CMT) neuropathy with acute presentation.
- Individuals with a history of recurring, unexplained, episodic palsies, followed by periods of recovery.
- Individuals with relatives diagnosed with CMT with acutely occurring symptoms.
- Patients being evaluated for Carpal Tunnel Syndrome (CTS).
- Patients being evaluated for brachial plexopathy.
Charcot-Marie-Tooth (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP) are two distinct clinical entities, however, they are related in a genetic sense. CMT1A is the result of a 1.5 Mb duplication in the PMP-22 gene that codes for a peripheral myelin protein.[6,8,9,10] HNPP is the result of a deletion of the same 1.5 Mb fragment.[4] Leading researchers in the field believe that CMT1A and HNPP are the result of a reciprocal crossover mutation, meaning that for every spontaneously occurring gamete bearing a CMT1A duplication, there should also be a gamete with an HNPP mutation.
Table 1 summarizes the clinical findings associated with CMT1A and HNPP.
Table 1 Clinical findings in CMT1A and HNPP.
HNPP is associated with a submicroscopic 1.5 million base pair DNA deletion on the short arm of chromosome 17.[4,11,12] The HNPP deletion has been identified in multiple HNPP families of varied ethnic origins, in multiple unrelated HNPP patients and in sporadic (de novo) patients. It is therefore a valuable biological marker for HNPP in many pedigrees and is useful in the clinical evaluation of patients with a history of recurrent episodic neuropathies .
The PMP-22 gene, which encodes a peripheral nerve myelin protein, has been mapped within the HNPP deletion and has been proposed as the candidate gene. This was recently confirmed by the identification of a PMP-22 point mutation in a rare non-deletion patient with clinical HNPP.[13] The majority of HNPP patients, however, have the HNPP deletion.
Interestingly, the genetic mechanism which appears to generate the HNPP deletion on chromosome 17 has also been able to account for the duplication on chromosome 17 associated with Charcot-Marie-Tooth type 1A (CMT1A). Frequently HNPP and CMT1A may be distinguished on clinical and pathological grounds, however, there appears to be occasional overlap of symptoms in patients with long-standing or recurrent bouts of HNPP.
Athena Diagnostic's test for HNPP is a molecular test which identifies the chromosome 17 deletion using the most informative DNA detection method currently available.
The test was developed at the University of Utah Medical Center by Dr. Phillip F. Chance and colleagues, who first reported the association of HNPP with a chromosome 17 deletion .
Patients' white blood cells are separated and carefully embedded in agarose plugs prior to processing the DNA, thus minimizing the shear stress of DNA extraction techniques. Restriction endonucleases are diffused into the agarose-embedded patient DNA and pulsedfield gel electrophoresis then is utilized to separate large segments of DNA containing HNPP deletion-specific junction fragments. These junction fragments are then detected by hybridization with a junction fragment specific probe (CMT1A-rep).[5] This probe identifies the homologous regions that flank the HNPP deletion.
Athena Diagnostic's test for 770/820 Kb HNPP deletion specific junction fragments indicates a positive result and is diagnostic for hereditary neuropathy with liability to pressure palsies (figure 1). These patients should be referred for genetic counselling.
A negative result is indicated by the absence of the 770/820 Kb deletion junction fragments (figure 1).
The HNPP deletion has been identified in the majority of patients with clinical HNPP. Rare point mutations in the peripheral nerve myelin protein gene, PMP-22, have recently been identified in some HNPP patients who did not exhibit the deletion.[13] A negative result therefore does NOT completely rule out a diagnosis of HNPP.
History
A 9 year old female presented with an acute onset of a left foot drop. Five years previously she had experienced right foot drop. She had made minimal recovery of her peroneal palsy when seen again six weeks later. Neither parent had signs of weakness, atrophy or sensory disturbances, nor did they have a history of pressure palsies. A maternal grandfather had experienced an episode of bilateral foot drop in his 20's and presently carries a diagnosis of Charcot-Marie-Tooth neuropathy.
Examination
Neurologic examination revealed weakness of dorsiflexion of the left foot and decreased motor nerve conduction velocity in the left peroneal nerve. Her neurological examination was otherwise normal.
Differential diagnosis
Isolated peroneal palsy and Charcot-Marie-Tooth.
Key laboratory tests
Nerve conduction velocities were measured, DNA analysis for HNPP was done with positive results for the child, her mother, and her maternal grandfather.
Diagnosis
Hereditary Neuropathy with liability to Pressure Palsy.
History
During weight training, a previously healthy 19 year old male experienced a "crunch" and a brief sharp pain in his left shoulder. Over a two week period he developed weakness and numbness of the fourth and fifth digits and ulnar aspect of the left hand. There was no prior history of brachial plexopathy or other peripheral neuropathy in the patient or his family.
Examination
Neurologic exam confirmed sensory loss in the left hand and diffuse weakness in the left upper arm, consistent with a brachial plexopathy. Passive movement of the left arm produced pain in the shoulder. Neurologic examination was normal with the exception of diminished sensation in the ventral aspect of the left fifth finger.
Differential diagnosis
HNPP and brachial plexopathy.
Key laboratory tests
Nerve conduction studies disclosed prolonged distal latencies in the affected arm. The patient had partial recovery from his brachial plexopathy over a three month period, and underwent a re-evaluation one year later because of persistent numbness of the left fifth digit. Repeated electrophysiological studies found prolonged distal latencies of most sensory action potentials with normal amplitudes and conduction velocities.
DNA analysis on the patient and his father detected a deletion on chromosome 17p11.2-12, confirming the clinical diagnosis of HNPP.
Diagnosis
Hereditary Neuropathy with liability to Pressure Palsies.
History
A 20 year old male presented with a two year history of transient weakness of the left hand and acute onset of bilateral foot drop.
Examination
Diffuse nerve conduction abnormalities were obtained and a diagnosis of isolated bilateral peroneal palsies was made. Subsequent clinical evaluation revealed normal strength. hypoactive deep tendon reflexes, pes cavus, enlarged ulnar nerves and mild ichthyosis. Both parents were normal with the exception of pes cavus in the patient's mother.
Differential diagnosis
A diagnosis of X-linked Charcot-Marie-Tooth neuropathy with ichthyosis was suspected.
Key laboratory tests
Motor nerve conduction velocities were mildly prolonged in multiple nerves. DNA analysis on the patient and his parents detected a de novo deletion on chromosome 17p11.2-12, associated with the spontaneous occurrence of HNPP in this family.
Diagnosis
Hereditary Neuropathy with Liability to Pressure Palsies.
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- Entrapment Neuropathies. in "Neurology in Clinical Practice", Bradley, Walter G., et al, eds, Butterworth-Heinemann, Boston, 1991.
- Johnson, Richard T.: Current Therapy in Neurologic Disease-3. B C Decker, Inc., Philadelphia, 1990.
- Meier, Claus, and Moll, Carl.: Hereditary neuropathy with liability to pressure palsies. Neurology 228: 73-95, 1982.
- Chance, Phillip F., et al.: DNA deletion associated with Hereditary Neuropathy with Liability to Pressure Palsies. Cell 72: 143-151, 1993.
- Pentao, L., et al.: Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the t 5 Mb monomer unit. Nature Genetics 2: 292-300, 1992.
- Patel, P.I., et al.: The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature Genetics 1: 159-165, 1992.
- Windebank, A.J.: Inherited recurrent focal neuropathies. In Peripheral Neuropathy, 3rd ed Dyck, P J, et al., eds. Philadelphia: W B Saunders, pp 1137-1148, 1993.
- Matsunami, N., et al.: Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nature Genetics 1: 176-179, 1992.
- Valentijn, L.J., et al.: The peripheral myelin gene PMP22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. Nature Genetics 1: 166-170, 1992.
- Timmerman, V., et al.: The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nature Genetics 1: 171-175.
- Lupski, J.R., et al.: Inherited Peripheral Neuropathies: Molecular Genetics and Clinical Application. JAMA 270: 2326-2330, 1993.
- Chance, P.F., et al.: Two autosomal dominant neuropathies result from reciprocal duplication/deletion of a region of chromosome 17. Human Molecular Genetics 3: 223-228, 1994.
- Nicholson, G.A., et al.: A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies. Nature Genetics 6: 263-266, 1994.
