A novel small deletion in PMP22 causes a mild hereditary neuropathy with liability to pressure palsies phenotype

Introduction: In this study we examined a family with electrophysiological findings of hereditary neuropathy with liability to pressure palsies (HNPP) and a mild clinical presentation.Methods: Four members of a family were referred for diagnosis of HNPP. Electrophysiological studies included motor and sensory nerve conduction studies in the upper and lower extremities. Investigations of microsatellites, using polymorphic repeat markers flanking the gene, and multiplex ligation‐dependent probe amplification (MLPA) were performed for molecular studies. Results: The initial study of microsatellites did not detect any change, but MLPA demonstrated a small deletion of exon 5 in the PMP22 gene. Conclusion: Our findings demonstrate the important role of small deletions in the PMP22 gene in the etiology of HNPP with a normal microsatellite study. Muscle Nerve 45: 135–138, 2012     

Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland

An epidemiological study of hereditary neuropathy with liability to pressure palsies (HNPP) was carried out in south western Finland, with a population of 435 000. The diagnosis was established in 69 patients from 23 unrelated families through family and medical history, clinical neurological and neurophysiological examinations and with documentation of the deletion at gene locus 17p11.2 in at least one member of each family. This gave a prevalence of at least 16/100 000, which is remarkably high. However, due to the insidious nature of HNPP, most probably it is still an underestimation. This is the first population-based prevalence figure reported for HNPP. The prevalence is somewhat lower than that obtained for CMT in the same population, which agrees with the proposal that HNPP and CMT 1A are reciprocal products of the same unequal crossing-over. The clinical pictures of our patients were, in general, similar to those previously described in HNPP.     

DNA analysis as a tool to confirm the diagnosis of asymptomatic hereditary neuropathy with liability to pressure palsies (HNPP) with further evidence for the occurrence of de novo mutations

We performed DNA analysis in four families with hereditary neuropathy with liability to pressure palsy (HNPP). An interstitial deletion of the 17 p11.2 region was found in typically affected patients as well as in as yet asymptomatic patients. The opportunity for an individual genotyping permitted to ascertain a de novo deletion in one clinically affected case with no relevant familial history. DNA analysis thus becomes the most sensitive tool in diagnosing HNPP, since potentially affected patients may lack either informative familial history, or clinical symptoms or even suggestive EMG or histopathological data (tomaculas).     

Hereditary neuropathy with liability to pressure palsies associated with central nervous system myelin lesions

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder most commonly caused by a 1.5-Mb deletion in chromosome 17p11.2 which contains the peripheral myelin protein-22 (PMP22) gene. Mutations resulting in functional loss of one PMP22 gene copy are less frequent. We present a 51-year-old patient with a l.5-Mb deletion in chromosome 17p11.2 who exhibited signs of peripheral as well as central nervous system lesions. He gave a history of recurrent episodes of limb numbness and weakness with spontaneous but incomplete recovery since age 20. His father and two brothers had similar symptoms. Neurological examination revealed signs of multiple mononeuropathy associated with frontal lobe, corticospinal tract and cerebellar dysfunction, as well as signs of initial cognitive impairment. Electrophysiological investigations showed a demyelinating peripheral nerve disease with multiple conduction blocks and conduction disturbances in both optic nerves. Magnetic resonance imaging of the brain revealed multiple subcortical and periventricular foci of myelin lesions. The association of central and peripheral nervous system lesions in this patient indicates a possible role of PMP22 not only in peripheral but also in central nervous system myelin structure.     

Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) provides a human model to investigate the role of PMP22 in myelinated peripheral nerve, since the disease is caused by a deletion of one of the two PMP22 alleles. To systematically characterize the phenotype of HNPP, we prospectively evaluated the clinical features and electrophysiological findings in 17 genetically confirmed patients, 7 men and 10 women, ranging in age from 9 to 66 years (mean, 41 +/- 13). Fifteen symptomatic patients presented with episodes of transient focal weakness or sensory loss that were usually related to particular activities causing nerve compression, including stretching or minor repetitive focal trauma. No patient sought medical attention for symptoms of a symmetric polyneuropathy. Neurological examinations were either normal or mildly abnormal. Neither focal slowing of nerve conduction studies, nor reduction in compound muscle action potential (CMAP) or sensory nerve action potential (SNAP) amplitudes consistently predicted the site of symptoms. We conclude that the majority of patients with HNPP present with transient, recurrent, focal symptoms of weakness or sensory loss in the distribution of individual nerves or plexus, and that a diffuse symmetric sensorimotor polyneuropathy is an unusual presentation of HNPP. These studies suggest that the function of PMP22, at least in part, is to stabilize myelin so that it will be protected from injuries resulting from repetitive, minor trauma.     

经基因确诊的遗传性压力易感性周围神经病的临床与神经电生理分析

目的:探讨遗传性压力易感性周围神经病(HNPP)的临床、神经电生理及基因特点,为该病的诊断提供依据.方法:对3例患者进行临床特点总结、行电生理检查和基因检测.结果:3例患者均表现为无痛性下肢远端无力.电生理检查示四肢广泛神经传导速度减慢.基因检测示3例患者均存在周围髓鞘蛋白22(PMP22)基因缺失突变.结论:HNPP多以神经易卡压部位发病,表现为受累神经支配区的运动感觉异常,神经电生理表现为广泛神经脱髓鞘损伤,基因检测能确诊.     

Brachial plexus involvement as the only expression of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant focal neuropathy characterized by recurrent entrapment neuropathies. Single members of families with HNPP and brachial plexus involvement have been reported previously. We describe a family with three affected members and in which the only symptom of entrapment was recurrent brachial plexopathy. The diagnosis of HNPP in this family was confirmed by both neurophysiological methods and DNA analysis. The distinction between HNPP and hereditary neuralgic amyotrophy is discussed.     

Sonographic features in hereditary neuropathy with liability to pressure palsies

Introduction: Diagnostic nerve ultrasound is becoming more commonly used by both radiologists and clinicians. The features of different neuromuscular conditions must be described to broaden our understanding and ability to interpret findings. Methods: Our study examines the sonographic features of 7 subjects with hereditary neuropathy with liability to pressure palsies (HNPP) in comparison to 32 controls by measuring the nerve cross‐sectional area (CSA) of the median, ulnar and tibial nerves. Results: Significant differences (P < 0.05) in nerve size were found. The HNPP group had a larger CSA for the median nerve at the wrist and ulnar nerve at the elbow (entrapment sites), but not the forearms. The tibial nerve at the ankle was also larger in the HNPP group, suggesting possible concomitant tibial neuropathy at the ankle. Conclusion: These results will help shape imaging protocols to better detect conditions with non‐uniform nerve enlargements. Muscle Nerve 2011     

Hereditary neuropathy with liability to pressure palsies: electrophysiological and genetic study of a family with carpal tunnel syndrome as only clinical manifestation

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease characterized by recurrent sensory or motor manifestations. The molecular basis of HNPP is a deletion on chromosome 17p11.2. We studied a family (father, 61 years; mother, 55 years; 6 children of mean age 25.3 years) showing symptoms of carpal tunnel syndrome in 4 members (the parents and 2 sons). No one of them reported episodes of nerve palsy. In all the patients, except the mother and the younger son, electrophysiologic evaluation showed a sensorimotor polyneuropathy with delayed sensorimotor latencies. Genetic analysis was carried out in the parents and the eldest son. The 17p11.2 deletion was detected in the father and son, indicating paternal transmission of the disease. Clinical manifestations of HNPP may be atypical. Sometimes there is no history of acute nerve palsy, as in this family. For this reason, the frequence of HNPP might be underestimated. Electrophysiological examination is of great importance for the diagnosis of HNPP. Genetic analysis is a rapid and reliable diagnostic tool that can be combined with simplified electrophysiological examination, avoiding the need for nerve biopsy. In conclusion, the diagnosis of HNPP should be invoked in early onset entrapment neuropathies. Received: 8 November 2002 / Accepted in revised form: 28 March 2003 Correspondence to: R. Del Colle     

Clinical,electrophysiological and magnetic resonance findings in a family with hereditary neuropathy with liability to pressure palsies caused by a novel PMP22 mutation

Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder mainly caused by a 1.5-Mb deletion at 17p11.2-12 (and in some rare cases by point mutations) and clinically associated with recurrent painless palsies. Here, we performed electrophysiological (motor, sensory and terminal latency index), MRI and genetic studies in a family referred for ulnar neuropathy with pain.Surprisingly, we found typical neurophysiological features of HNPP (prolongation of distal motor latencies and diffuse SNCV slowing with significant slowing of motor nerve conduction velocities). Besides, the proband presented conduction block in left ulnar, left median and both peroneal nerves. MRI findings were consistent with an underlying neuropathy. Molecular studies identified a novel frameshift mutation in PMP22 confirming the diagnosis of HNPP.Our data suggest that neurophysiological studies are essential to characterize underdiagnosed HNPP patients referred for peripheral neuropathy. Our experience shows that MRI could be a complementary tool for the diagnosis of these patients.     

Hereditary neuropathy with liability to pressure palsies: description of seven patients without known family history

Objectives –  Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited disorder resulting in a polyneuropathy with particular involvement at sites of entrapment, and is often underdiagnosed or misdiagnosed. We report findings on seven patients referred for evaluation of focal mononeuropathies or polyneuropathies of undetermined etiology, in whom we established a diagnosis of HNPP.
Materials and methods –  We retrospectively reviewed clinical, electrophysiological and laboratory data for patients diagnosed with HNPP over a 4-year period at our institution.
Results –  All patients had transient or recurrent neurological symptoms, some with residual deficits. No patients had a family history of any neuropathy. Electrodiagnostic studies revealed abnormal conduction findings at symptomatic and asymptomatic sites. Testing for the Peripheral Myelin Protein ( PMP22 ) deletion was positive in all patients.
Conclusions –  A high index of clinical suspicion and thorough electrodiagnostic evaluation can lead to correct diagnosis of HNPP, despite the absence of a positive family history.     

Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies or brachial plexopathies, commonly associated with a chromosome 17p11.2-12 deletion encompassing the peripheral myelin protein-22 (PMP22) gene. We tried to identify criteria distinguishing HNPP among patients with acute painless mononeuropathy/plexopathy. We investigated by pulsed-field gel electrophoresis the presence of the deletion in 27 patients with isolated or recurrent acute painless mononeuropathy or brachial plexopathy, and no obvious cause of neuropathy. Eight patients carried the deletion, whereas 19 had neither the deletion nor mutations in the PMP22 gene. Age at onset, presenting modality, precipitating events, and rate of recovery did not significantly differ in the two groups. Family history was informative for HNPP diagnosis in 3 cases only. HNPP patients more often showed recurrent episodes, brachial plexopathy, and clinical or electrophysiologic involvement of other nerves. Non-HNPP patients more frequently had peroneal palsy, recent weight loss, and normal electrophysiologic examination in other nerves. Signs of generalized neuropathy and evidence of disease in other family member are often subtle in HNPP and must be thoroughly investigated in patients with acute painless mononeuropathy/plexopathy. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1686–1691, 1998.     

Hereditary neuropathy with liability to pressure palsies (HNPP) in a toddler presenting with toe-walking, pain and stiffness

The typical clinical presentation of hereditary neuropathy with liability to pressure palsies is an adult-onset recurrent, painless monoparesis. Electrophysiological abnormalities - decreased nerve conduction velocities and delayed distal latencies - can be detected even in asymptomatic patients. We describe a toddler, who presented with asymmetric toe walking, painful cramps and stiffness in the legs. He had calf hypertrophy, brisk tendon reflexes and bilateral Babinski signs and the electrophysiological examination was normal. The unlikely diagnosis of hereditary neuropathy with liability to pressure palsies was reached 5 years later, when the boy started to complain of episodic numbness and weakness in the upper extremities. His father, paternal aunt and grandmother had similar symptoms, but they had never been investigated. The typical 1.5 Mb deletion on chromosome 17p11.2–12 was found in our patient and his affected relatives.     

Recurrent brachial plexus palsies as the only clinical expression of hereditary neuropathy with liability to pressure palsies associated with a de novo deletion of the peripheral myelin protein-22 gene

There is phenotypic heterogeneity in patients with hereditary neuropathy with liability to pressure palsies. In rare cases, recurrent brachial plexopathy is the only expression of the disease. We describe a patient with three episodes of plexus brachialis palsy and a de novo deletion of the peripheral myelin protein-22 gene. We conclude that DNA analysis is a key issue not only for the differentiation of peripheral neuropathies but also in the diagnosis of recurrent plexopathies. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1199–1201, 1998.     

Molecular diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) by detection of 17p11.2 deletion in Italian patients

Hereditary neuropathy with a liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent pressure palsies generally precipitated by minor trauma; weakness and paraesthesia usually improve and recover completely in a few months. By Southern blotting and fluorescent in situ hybridization analysis we confirm the presence of a 17p11.2 deletion in familial and in isolated cases of HNPP, suggesting that molecular analysis of the 17p11.2 region could also be a reliable and non-invasive method of diagnosis in sporadic cases, where a correct diagnosis usually requires a nerve biopsy. Although HNPP is a mild disease and not all patients seek medical attention, a presymptomatic diagnosis is useful for assessing the risk during genetic counselling, due to the inheritance of the mutation.     

Hereditary neuropathy with liability to pressure palsies and amyotrophic lateral sclerosis

A 56-year-old male with recurrent painless focal neuropathies and a family history of peripheral neuropathy of unknown etiology presented with progressively worsening of impaired sensations and weakness in his lower extremities. His initial electrodiagnostic evaluation was suggestive of severe sensory and motor peripheral polyneuropathy. The genetic testing was performed for familial causes of peripheral neuropathy as there was a family history of peripheral neuropathy of unknown etiology. The patient was found to have 1.5-Mb deletion in the PMP22 gene which was confirmatory of hereditary neuropathy with liability to pressure palsies (HNPP). He developed progressive upper and lower extremity weakness, bulbar dysfunction and widespread fasciculations during the course of his illness. He was subsequently diagnosed with amyotrophic lateral sclerosis (ALS). This is the second reported case of HNPP associated with ALS. We discuss significant clinical and electrodiagnostic findings of this interesting case.     

儿童遗传性压迫易感性周围神经病的临床、肌电图与基因特征(附1例报告)

目的探讨儿童遗传性压迫易感性周围神经病(HNPP)的临床、EMG与基因特点。方法报道基因诊断明确的1例HNNP,并结合文献分析HNPP的临床、EMG与基因特点。结果患儿,女,11岁8个月,于入院10 d前运动后出现左足麻木,不能背屈,查EMG提示多发性周围神经源性损害。患儿父亲及伯父有类似病史。患儿基因检查示chr17:14095421~15458636杂合缺失,大小1363.2kb,诊断HNPP。结论轻微牵拉或压迫后出现肢体无力患儿,及早进行EMG检查,对于周围神经损害广泛而肢体麻痹局限,且有类似家族史的患儿,应注意HNPP,并进行基因检查。