Davidenkow Syndrome: A Phenotypic Variant of HNPP Ericka Wong, M.D. Vincent S. DeOrchis, M.D., M.S. Beth Stein, M.D. Steven Herskovitz, M.D.
All authors affiliated with: Albert Einstein College of Medicine/Montefiore Medical Center Department of Neurology. Word Count: 678 Contact Author: Steven Herskovitz, M.D. Montefiore Medical Center EMG Lab 111 E 210th Street Yellow Zone- First Floor Bronx, NY 10467 (718) 920-4930 [email protected] We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines None of the authors has any conflict of interest to disclose.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.25985 This article is protected by copyright. All rights reserved.
Muscle & Nerve
Page 2 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP Key Words: Davidenkow Syndrome Scapuloperoneal Syndrome Charcot-Marie-Tooth Disease Hereditary neuropathy with liability to pressure palsies Peripheral myelin protein 22
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Page 3 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP
In 1939 Davidenkow described a hereditary disorder of autosomal dominant inheritance characterized by slowly progressive scapuloperoneal atrophy, distal sensory loss and pes cavus. 1 We report a case, further establishing the association of Davidenkow syndrome with the PMP-22 deletion and hereditary neuropathy with liability to pressure palsies (HNPP). A 38 year-old man was evaluated for distal leg numbness, severe ankle weakness, and non-radicular low back pain, following a motor vehicle accident. He reported no pre-morbid leg symptoms other than a lifelong history of thin legs. His father, age 69, had a 6 month episode of unexplained foot drop in his youth. No other family members were known to be affected. Examination revealed mild upper thoracic kyphosis, left scapular winging, left ulnar intrinsic hand muscle atrophy, and atrophy of the legs and thighs with pes cavus and hammer toes. There was asymmetric, left greater than right, ulnar intrinsic hand muscle weakness, and severe, slightly asymmetric weakness of fibular greater than tibial-innervated leg muscles. A symmetric stocking-pattern sensory loss up to the knees was present for all modalities. Deep tendon reflexes were reduced in the arms and normal in the knees and ankles. The patient’s father was also examined and had normal feet, no scapular winging, reduced lower extremity reflexes, stocking-glove sensory loss, right ulnar distribution sensory loss, and mild right extensor hallucis longus muscle weakness. Electrodiagnostic testing of the patient revealed a severe sensorimotor polyneuropathy with demyelinating and axonal features, including prolonged distal
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Muscle & Nerve
Page 4 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP motor latencies and late responses, non-uniform slowing of sensory and motor conduction velocities, and median nerve entrapment at the wrist (Table 1). Needle electromyography (EMG) of bilateral tibialis anterior and left gastrocnemius muscles showed mild to moderate amounts of fibrillations potentials and positive sharp waves. Motor unit action potentials were of increased size and decreased recruitment. The left vastus lateralis muscle was normal. The patient was studied again approximately one year later, four weeks after he developed a left wrist drop. There was focal motor slowing and partial conduction block of the radial nerve across the mid-arm, and bilateral median nerve entrapments at the wrists (Table 1). EMG revealed moderate to significant amounts of fibrillation potentials and positive sharp waves in the left extensor digitorum muscle. Motor unit action potentials were of normal size but polyphasic, and demonstrated severely decreased recruitment. The left triceps muscle was normal. Over the next 3 years the patient developed, in a step-wise fashion, right wrist drop, worsening of bilateral foot drop and right facial palsy, all with limited recovery. Direct molecular genetic testing for duplications/deletions in the PMP-22 gene, performed by quantitative dosage analysis of genomic DNA (Athena Diagnostics), revealed a heterozygous deletion of the entire PMP-22 gene on one allele in both the patient and the father. Charcot-Marie-Tooth1A is associated with a 1.4-Mb duplication of the PMP22 gene on chromosome 17p11.2. PMP22 is an integral membrane glycoprotein found in compact myelin. The duplication results in an overexpression of PMP22, causing the characteristic CMT phenotype. HNPP is allelic to CMT1A, with the majority of
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Page 5 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP patients harboring a 1.4Mb deletion at 17p11.2 including the PMP22 gene. In contrast to the PMP22 duplication, the PMP22 deletion results in a broad clinical spectrum, including acute mononeuropathies, subacute multiple mononeuropathies, brachial plexus neuropathies, and as further supported in this paper, Davidenkow syndrome. Although the scapuloperoneal syndrome (SPS) contains overlapping features with Charcot-Marie-Tooth (CMT) disease, Davidenkow believed that the disorders were clinically and genetically distinct. 1 Subsequent reports debated this association. Harding and Thomas described a family in which the proband exhibited features of neuropathic SPS, while other family members had findings more consistent with classic CMT. 2 Following electrodiagnostic testing, they hypothesized that Davidenkow syndrome may be a phenotypic manifestation of CMT1. Ricker, et al. dismissed any association between these two diseases after reviewing a large series of families with CMT without a single case of SPS. 3 Schwartz and Swash, who first coined the term Davidenkow syndrome, shared this opinion. 4 Ronen et al. described “onion-bulb” formation seen on a 14 year old boy’s sural nerve biopsy, suggesting that Davidenkow syndrome may be a variant of CMT. 5 Most recently, Verma described a family containing members with both Davidenkow syndrome and CMT1 phenotypes with a deletion at the chromosome 17p11.2 locus, supporting Davidenkow syndrome as part of the phenotypic spectrum associated with PMP-22 deletions. 6
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Muscle & Nerve
Page 6 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP The case described here lends further support to the concept of a broad phenotypic spectrum of HNPP, which includes Davidenkow syndrome of scapuloperoneal weakness.
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Page 7 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP
Table 1: Nerve conduction studies Motor NCS
Initial Left
Follow up (1 year later) Right
Normal Values
Left
Right
6.65
7.25
7.00
≤4.5
Wrist
4.6
6.1
4.6
≥4.5
Elbow
5.2
6.4
4.0
CV (ms)
43
43.6
43.7
F wave (ms)
39.0
DML (ms)
3.70
--
--
≤4
Wrist
5.7
--
--
≥5
B. Elbow
4.3
--
--
CV (ms)
50.5
--
--
F wave (ms)
34.80
DML (ms)
--
--
5.10
5.00
Forearm
--
--
1.6
2.8
Elbow
--
--
1.0
2.6
A.H. Groove
--
--
0.2
2.9
CV (elbow/humeral groove) (ms)
--
--
11.4
42.9
≥49
DML (ms)
7.80
8.95
--
--
≤6.4
Ankle
0.5
0.6
--
--
≥2.5
B.Fib Head
0.4
0.3
--
--
CV (ms)
31.9
27.5
--
--
F wave (ms)
NR
NR
Median-APB DML (ms) Amplitude (mV)
≥49 ≤30
Ulnar-ADM
Amplitude (mV)
≥47 ≤30
Radial-EI
Amplitude (mV)
≥2
Fibular-EDB
Amplitude (mV)
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≥39 ≤53
7
Muscle & Nerve
Page 8 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP Tibial-FDB DML (ms)
8.80
Amplitude (mV)
--
--
≤7 ≥2.5
Ankle
2.2
--
--
--
Pop Fossa
1.3
--
--
--
CV (ms)
36.4
--
--
--
F wave (ms)
70.35
Sensory NCS
≥37 ≤55
Initial
Follow up
Normal Values
Left
Right
Left
Right
Median
NR
--
--
--
Radial
NR
--
NR
NR
Amplitude (µV)
--
6.7
--
--
≥6
CV (ms)
--
32.1
--
--
≥39
Sural
Sup. Fibular
NR
APB: Abductor Pollicis Brevis; DML: Distal Motor Latency; CV: Conduction Velocity; ms: milliseconds; mV: millivolts; µV: microvolts; ADM: Abductor Digiti Minimi; EI: Extensor Indicis; EDB: Extensor Digitorum Brevis; FDB: Flexor Digitorum Brevis; Sup. Fibular: Superficial Fibular; B. Elbow: Below Elbow; B. Fib Head: Below Fibular Head; Pop Fossa: Popliteal Fossa; A.H. Groove: Above Humeral Groove; NR: No Response
Median SNAPs were performed orthodromically. Radial SNAP was performed both anti- and orthodromically. Sural and superficial fibular SNAPs were performed antidromically. F waves recorded are minimal latency.
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Page 9 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP Abbreviations: HNPP: Hereditary neuropathy with liability to pressure palsies SPS: Scapuloperoneal Syndrome CMT: Charcot-Marie-Tooth Disease PMP-22: Peripheral myelin protein 22
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Muscle & Nerve
Page 10 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP References: 1. Davidenkow S. Scapulo-peroneal amyotrophy. Archives of Neurology & Psychiatry (Chic) 1939;41:694-701. 2. Harding AE, Thomas PK. Distal and scapuloperoneal distributions of muscle involvement occurring within a family with type I hereditary motor and sensory neuropathy. J Neurol 1980;224:17-23. 3. Ricker K, Mertens HG, Schimrigk K. The neurogenic scapulo-peroneal syndrome. European Neurology 1968;1:257-74. 4. Schwartz MS, Swash M. Scapuloperoneal atrophy with sensory involvement: Davidenkow’s syndrome. J Neurol Neurosurg Psychiatr 1975;38:1063-7. 5. Ronen GM, Lowry N, Wedge JH, Sarnat HB, Hill A. Hereditary motor sensory neuropathy type I presenting as scapuloperoneal atrophy (Davidenkow syndrome) electrophysiological and pathological studies. Can J Neurol Sci. 1986 Aug;13(3):264-6 6. Verma A. Neuropathic scapuloperoneal syndrome (Davidenkow’s syndrome) with chromosome 17p11.2 deletion. Muscle Nerve 2005;32:667-71.
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All authors affiliated with: Albert Einstein College of Medicine/Montefiore Medical Center Department of Neurology. Word Count: 678 Contact Author: Steven Herskovitz, M.D. Montefiore Medical Center EMG Lab 111 E 210th Street Yellow Zone- First Floor Bronx, NY 10467 (718) 920-4930 [email protected] We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines None of the authors has any conflict of interest to disclose.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.25985 This article is protected by copyright. All rights reserved.
Muscle & Nerve
Page 2 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP Key Words: Davidenkow Syndrome Scapuloperoneal Syndrome Charcot-Marie-Tooth Disease Hereditary neuropathy with liability to pressure palsies Peripheral myelin protein 22
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
2
Page 3 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP
In 1939 Davidenkow described a hereditary disorder of autosomal dominant inheritance characterized by slowly progressive scapuloperoneal atrophy, distal sensory loss and pes cavus. 1 We report a case, further establishing the association of Davidenkow syndrome with the PMP-22 deletion and hereditary neuropathy with liability to pressure palsies (HNPP). A 38 year-old man was evaluated for distal leg numbness, severe ankle weakness, and non-radicular low back pain, following a motor vehicle accident. He reported no pre-morbid leg symptoms other than a lifelong history of thin legs. His father, age 69, had a 6 month episode of unexplained foot drop in his youth. No other family members were known to be affected. Examination revealed mild upper thoracic kyphosis, left scapular winging, left ulnar intrinsic hand muscle atrophy, and atrophy of the legs and thighs with pes cavus and hammer toes. There was asymmetric, left greater than right, ulnar intrinsic hand muscle weakness, and severe, slightly asymmetric weakness of fibular greater than tibial-innervated leg muscles. A symmetric stocking-pattern sensory loss up to the knees was present for all modalities. Deep tendon reflexes were reduced in the arms and normal in the knees and ankles. The patient’s father was also examined and had normal feet, no scapular winging, reduced lower extremity reflexes, stocking-glove sensory loss, right ulnar distribution sensory loss, and mild right extensor hallucis longus muscle weakness. Electrodiagnostic testing of the patient revealed a severe sensorimotor polyneuropathy with demyelinating and axonal features, including prolonged distal
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
3
Muscle & Nerve
Page 4 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP motor latencies and late responses, non-uniform slowing of sensory and motor conduction velocities, and median nerve entrapment at the wrist (Table 1). Needle electromyography (EMG) of bilateral tibialis anterior and left gastrocnemius muscles showed mild to moderate amounts of fibrillations potentials and positive sharp waves. Motor unit action potentials were of increased size and decreased recruitment. The left vastus lateralis muscle was normal. The patient was studied again approximately one year later, four weeks after he developed a left wrist drop. There was focal motor slowing and partial conduction block of the radial nerve across the mid-arm, and bilateral median nerve entrapments at the wrists (Table 1). EMG revealed moderate to significant amounts of fibrillation potentials and positive sharp waves in the left extensor digitorum muscle. Motor unit action potentials were of normal size but polyphasic, and demonstrated severely decreased recruitment. The left triceps muscle was normal. Over the next 3 years the patient developed, in a step-wise fashion, right wrist drop, worsening of bilateral foot drop and right facial palsy, all with limited recovery. Direct molecular genetic testing for duplications/deletions in the PMP-22 gene, performed by quantitative dosage analysis of genomic DNA (Athena Diagnostics), revealed a heterozygous deletion of the entire PMP-22 gene on one allele in both the patient and the father. Charcot-Marie-Tooth1A is associated with a 1.4-Mb duplication of the PMP22 gene on chromosome 17p11.2. PMP22 is an integral membrane glycoprotein found in compact myelin. The duplication results in an overexpression of PMP22, causing the characteristic CMT phenotype. HNPP is allelic to CMT1A, with the majority of
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
4
Page 5 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP patients harboring a 1.4Mb deletion at 17p11.2 including the PMP22 gene. In contrast to the PMP22 duplication, the PMP22 deletion results in a broad clinical spectrum, including acute mononeuropathies, subacute multiple mononeuropathies, brachial plexus neuropathies, and as further supported in this paper, Davidenkow syndrome. Although the scapuloperoneal syndrome (SPS) contains overlapping features with Charcot-Marie-Tooth (CMT) disease, Davidenkow believed that the disorders were clinically and genetically distinct. 1 Subsequent reports debated this association. Harding and Thomas described a family in which the proband exhibited features of neuropathic SPS, while other family members had findings more consistent with classic CMT. 2 Following electrodiagnostic testing, they hypothesized that Davidenkow syndrome may be a phenotypic manifestation of CMT1. Ricker, et al. dismissed any association between these two diseases after reviewing a large series of families with CMT without a single case of SPS. 3 Schwartz and Swash, who first coined the term Davidenkow syndrome, shared this opinion. 4 Ronen et al. described “onion-bulb” formation seen on a 14 year old boy’s sural nerve biopsy, suggesting that Davidenkow syndrome may be a variant of CMT. 5 Most recently, Verma described a family containing members with both Davidenkow syndrome and CMT1 phenotypes with a deletion at the chromosome 17p11.2 locus, supporting Davidenkow syndrome as part of the phenotypic spectrum associated with PMP-22 deletions. 6
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5
Muscle & Nerve
Page 6 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP The case described here lends further support to the concept of a broad phenotypic spectrum of HNPP, which includes Davidenkow syndrome of scapuloperoneal weakness.
John Wiley & Sons, Inc. This article is protected by copyright. All rights reserved.
6
Page 7 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP
Table 1: Nerve conduction studies Motor NCS
Initial Left
Follow up (1 year later) Right
Normal Values
Left
Right
6.65
7.25
7.00
≤4.5
Wrist
4.6
6.1
4.6
≥4.5
Elbow
5.2
6.4
4.0
CV (ms)
43
43.6
43.7
F wave (ms)
39.0
DML (ms)
3.70
--
--
≤4
Wrist
5.7
--
--
≥5
B. Elbow
4.3
--
--
CV (ms)
50.5
--
--
F wave (ms)
34.80
DML (ms)
--
--
5.10
5.00
Forearm
--
--
1.6
2.8
Elbow
--
--
1.0
2.6
A.H. Groove
--
--
0.2
2.9
CV (elbow/humeral groove) (ms)
--
--
11.4
42.9
≥49
DML (ms)
7.80
8.95
--
--
≤6.4
Ankle
0.5
0.6
--
--
≥2.5
B.Fib Head
0.4
0.3
--
--
CV (ms)
31.9
27.5
--
--
F wave (ms)
NR
NR
Median-APB DML (ms) Amplitude (mV)
≥49 ≤30
Ulnar-ADM
Amplitude (mV)
≥47 ≤30
Radial-EI
Amplitude (mV)
≥2
Fibular-EDB
Amplitude (mV)
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≥39 ≤53
7
Muscle & Nerve
Page 8 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP Tibial-FDB DML (ms)
8.80
Amplitude (mV)
--
--
≤7 ≥2.5
Ankle
2.2
--
--
--
Pop Fossa
1.3
--
--
--
CV (ms)
36.4
--
--
--
F wave (ms)
70.35
Sensory NCS
≥37 ≤55
Initial
Follow up
Normal Values
Left
Right
Left
Right
Median
NR
--
--
--
Radial
NR
--
NR
NR
Amplitude (µV)
--
6.7
--
--
≥6
CV (ms)
--
32.1
--
--
≥39
Sural
Sup. Fibular
NR
APB: Abductor Pollicis Brevis; DML: Distal Motor Latency; CV: Conduction Velocity; ms: milliseconds; mV: millivolts; µV: microvolts; ADM: Abductor Digiti Minimi; EI: Extensor Indicis; EDB: Extensor Digitorum Brevis; FDB: Flexor Digitorum Brevis; Sup. Fibular: Superficial Fibular; B. Elbow: Below Elbow; B. Fib Head: Below Fibular Head; Pop Fossa: Popliteal Fossa; A.H. Groove: Above Humeral Groove; NR: No Response
Median SNAPs were performed orthodromically. Radial SNAP was performed both anti- and orthodromically. Sural and superficial fibular SNAPs were performed antidromically. F waves recorded are minimal latency.
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Page 9 of 10
Muscle & Nerve
Davidenkow Syndrome: A Phenotypic Variant of HNPP Abbreviations: HNPP: Hereditary neuropathy with liability to pressure palsies SPS: Scapuloperoneal Syndrome CMT: Charcot-Marie-Tooth Disease PMP-22: Peripheral myelin protein 22
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Muscle & Nerve
Page 10 of 10
Davidenkow Syndrome: A Phenotypic Variant of HNPP References: 1. Davidenkow S. Scapulo-peroneal amyotrophy. Archives of Neurology & Psychiatry (Chic) 1939;41:694-701. 2. Harding AE, Thomas PK. Distal and scapuloperoneal distributions of muscle involvement occurring within a family with type I hereditary motor and sensory neuropathy. J Neurol 1980;224:17-23. 3. Ricker K, Mertens HG, Schimrigk K. The neurogenic scapulo-peroneal syndrome. European Neurology 1968;1:257-74. 4. Schwartz MS, Swash M. Scapuloperoneal atrophy with sensory involvement: Davidenkow’s syndrome. J Neurol Neurosurg Psychiatr 1975;38:1063-7. 5. Ronen GM, Lowry N, Wedge JH, Sarnat HB, Hill A. Hereditary motor sensory neuropathy type I presenting as scapuloperoneal atrophy (Davidenkow syndrome) electrophysiological and pathological studies. Can J Neurol Sci. 1986 Aug;13(3):264-6 6. Verma A. Neuropathic scapuloperoneal syndrome (Davidenkow’s syndrome) with chromosome 17p11.2 deletion. Muscle Nerve 2005;32:667-71.
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10
