HMSN Type Research Articles

New allelic variant of autosomal recessive hereditary motor and sensory neuropathy type 2S resulted from mutations in gene IGHMBP2

Hereditary motor and sensory neuropathy (HMSN, Charcot–Marie–Tooth disease) is a group of genetically heterogeneous disorders with more than 80 genes linked to different phenotypes, including IGHMBP2 gene responsible for HMSN type 2S (OMIM 616155). Until recently, mutations in IGHMBP2 were exclusively associated with neonatal distal spinal muscular atrophy with respiratory distress (SMARD1, OMIM 604320). A case report presents a boy with infant onset decreased distal muscle tone and weakness, distal wasting and deformation in legs and hands, areflexia and decreased sensation without respiratory involvement; at age seven he had severe fixed kypho-scoliosis. EMG revealed signs distal axonal neuropathy. The exsome sequencing confirmed the allelic variant of two compound heterozygous mutations in gene IGHMBP2: known missens mutation с.1616С>Т (р.Ser539Leu) in exone 11 and a novel deletion с.2601_2602delGA in exone 13. The diagnosis of infant HMSN type 2S was confirmed. The phenotype of HMSN type 2S and its diagnostics differences between SMARD1 are discussed.

HSMNR belongs to the most frequent types of hereditary neuropathy in the Czech Republic and is twice more frequent than HMSNL.

Hereditary motor and sensory neuropathy type Russe (HMSNR), also called CMT4G, is an autosomal recessive inherited peripheral neuropathy (IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin, we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and appears to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of disease duration. The group of 20 patients with HMSNR presented here is the first report about the prevalence of HMSNR from central Europe.

Clinical-sonographic and neurophysiological comparisons in hereditary motor and sensory neuropathy

The article presents the results of ultrasound studies in patients with hereditary motor and sensory neuropathy, or Charcot-Marie-Tooth disease (CMT). Based on standard electroneuromiography, the patients were divided into two groups with demyelinating (n=25) or axonal (n=31) process, CMT1 and CMT2 respectively. Demyelinating forms were characterized by specific prolonged sonographic changes with uniform thickening of all studied nerves and abnormalities of their cable structure. In axonal forms the character of structural changes was not as severe and specific as in CMT1, but symmetrical prolongation of the nerve structure was seen in this type of CMT as well. The description of genetically confirmed familial cases of HMSN type 1X in male relatives is presented, which demonstrates modern potential of unltrasound studies in diagnosing the involvement of peripheral nerves in patients from a heterogeneous group of hereditary neuropahies.

Severe generalized neuropathy in an 18-year-old patient with hereditary sensory-motor polyneurpathy (HMSN) type 1 treated with vincristine due to acute leukemia

We report about the 18-year-old male patient with hereditary sensory-motor polyneuropathy (HMSN) type 1. Despite a positive family history, the patient had no complaints. He was able to walk, to run and even to jump. He was diagnosed with HMSN type 1 when he went through chemotherapy due to an acute leukemia in November 2007. After the third dose of vincristine it came to a rapid neurological deterioration with the loss of the ability to walk and to stand, the bimanual function and a general weakness due to a particular sensitivity to vincristine, which was abandoned straight afterwards. In the end, the patient was only lying in bed. Then a genetic analysis was done due to the high frequency of HSMN type 1 in the family and a duplication on chromosome 17p11.2-p12 was found in the patient, which confirmed the diagnosis. During the rehabilitation therapy which was started parallel to the chemotherapy, the patient was not only enabled to walk a distance of 1500m without any devices, but also his bimanual skills and his ability to write were acquired. At discharge, the patient was again fully independent in his activities of daily life. Although he underwent a new chemotherapy treatment and suffered from pneumonia and aspergillosis of the lung, which led to a lobectomy of the right side, it did not come to a deterioration or even loss of the motoric skills.

Different types of fatigue in patients with facioscapulohumeral dystrophy, myotonic dystrophy and HMSN-I. Experienced fatigue and physiological fatigue

Although fatigue is a common symptom in neuromuscular disorders, little is known about different types of fatigue. Sixty-five FSHD, 79 adult-onset MD and 73 HMSN type I patients were studied. Experienced fatigue was assessed with the CIS-fatigue subscale. Physiological fatigue was measured during a 2-min sustained maximal voluntary contraction of the biceps brachii muscle using the twitch interpolation technique to assess central activation failure (CAF) and peripheral fatigue. Experienced fatigue, CAF and peripheral fatigue appeared to be predominantly separate types of fatigue.

Charcot-Marie-tooth disease presenting in a young Nigerian male: A case report.

Background: Charcot-Marie-Tooth disease is a heterogeneous group of inherited peripheral neuropathy. It has various genetic and phenotypic characteristics and can be a significant cause of morbidity with severe disabling consequences. Often the diagnosis may be missed. It is not commonly encountered in Nigerian medical clinics and there is no documented prevalence rate for the jcountry. Method: a case report of a 31-year-old man presenting to the medical outpatient clinic of the University of Nigeria Teawching Hospital Enugu with features of Charcot-Marie-Tooth disease is presented. Relevant literature is also reviewed. Result: A thirty three year old Nigerian male presented to the medical clinic with a thirteen-year history of progressive paraesthesiae in the feet, which later involved the hands. This was accompanied seven years later by jgradual onset weakness of the muscles especially the distal group in both upper and lower limbs which led to paralysis. No sphineter involvement. Family history was not contributory. He had typical features of HMSN type I and was a possible proband. Conclusion: Though not common, the inhjerited peripheral neuropathies are a cause of significant morbidity. Whenm recognized there are p[otential issues of genetic counseling that arise kfor which Nigerians are yet to come to terms with. Keywords : Charcot-Marie-tooth;Inherited ZPeripheral Neuropathies; Nigerian Journal of College of Medicine Vol. 12 (1) 2007: pp.35-38

A comparison of methods for gene dosage analysis in HMSN type 1

A number of different approaches are used in diagnostic laboratories to detect the 1.5 Mb duplication at 17p11.2 seen in approximately 70% of patients with hereditary motor and sensory neuropathy...

Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy.

A white British family with the axonal form of hereditary motor and sensory neuropathy (HMSN, type II) contained one member who developed a recurrent laryngeal nerve palsy at the age of 41 years, in addition to 4 years of symptomatic polyneuropathy and an abducens nerve palsy. Neither of the other family members (the mother and sister) with electrophysiologically confirmed polyneuropathy had any neuropathic symptoms in the limbs or laryngeal or respiratory muscle involvement. An autosomal dominant pattern of inheritance is likely. This is a second report of this rare form of HMSN (type IIC) in which there is associated laryngeal or respiratory muscle weakness. This family differs from the two previously reported pedigrees in which laryngeal or diaphragm weakness had commenced within the first two decades. The discovery of asymptomatic family members attests to the diagnostic value of clinical and electrophysiological study of first-degree relatives when laryngeal or bulbar symptoms develop in the context of chronic axonal polyneuropathy. HMSN type IIC should be distinguished from the more common forms of HMSN - type IIA, in which axonal polyneuropathy is restricted to the limbs, and type IIB, which is of early onset and associated with foot ulceration.

Differences between hereditary motor and sensory neuropathy type 2 and chronic idiopathic axonal neuropathy. A clinical and electrophysiological study.

To evaluate whether chronic idiopathic axonal polyneuropathy (CIAP) should be considered as hereditary motor and sensory neuropathy type 2 (HMSN type 2), we compared the clinical features of 48 patients with CIAP with those of 47 patients with HMSN type 2. In addition, we studied electrophysiological data in 20 patients with CIAP and in 20 patients with HMSN type 2. We found, in patients with HMSN type 2, that the initial symptoms were predominantly motor and that weakness and handicap were more severe and skeletal deformities more frequent, compared with those of CIAP patients. Electrophysiologically, the tibialis anterior muscle showed more denervation in patients with HMSN type 2, consistent with the predominance of motor symptoms. There was no important effect of age of onset on clinical features in HMSN type 2 patients. We conclude that in an individual patient with a sensory or sensorimotor idiopathic axonal polyneuropathy and no family history of polyneuropathies, the diagnosis HMSN type 2 is unlikely. However, if motor symptoms predominate, the diagnosis of HMSN type 2 should be considered.

Perineurium talin immunoreactivity decreases in diabetic neuropathy

We studied the immunolocalization of Dp116 (a 116 kDa protein product of the dystrophin gene), vinculin, talin, vimentin, desmin, spectrin and titin in the sural nerve biopsies of 25 patients with peripheral neuropathies of different origin. 4 patients presented with HMSN type 1, 4 with HMSN type 2, 2 with HNPP, 4 with CIDP, 5 with chronic axonal neuropathy of unknown origin, 3 with vasculitic neuropathy, 3 with diabetic neuropathy. Expression and localization of Dp116, vinculin, vimentin, desmin, spectrin and titin did not differ from normal control cases. Spectrin and titin immunoreactivities were absent and desmin was occasionally found in few epineurial vessels. A thin rim of Dp116 binding surrounded the outermost layer of myelin sheaths. Perineurium and epineurial vessels stained deeply for vinculin. Vimentin immunoreactivity was seen in all endoneurial, perineurial and epineurial cells. Immunoreactivity for talin was normally found at endoneurial and epineurial vessel walls, perineurial cells and epineurial fibroblasts in all the sural nerves except diabetic nerves. In the latter, whereas talin binding was normal in the vessel walls and epineurial fibroblasts, it was markedly reduced in the perineurium. On immunoblot, two bands at 235 and 190 kDa were found in the sural nerves with the antibody anti-talin, and both were reduced only in the patients with diabetic neuropathy. We postulate that decreased perineurium talin in diabetic polyneuropathy may be related to the known alterations of the tight junctions of the perineurial cells, which have been proposed to be a contributory factor to impaired permeability barrier properties. © 1997 Elsevier Science B.V. All rights reserved.

Central motor Pathway Evaluation using magnetic coil stimulation in hereditary motor and sensory neuropathy type I (HMSN type I, Charco-Marie-Tooth disease

Central Motor Conduction Time (CMCT) was investigated in 18 patients (5 m, 13 f; age range: 11–69 yrs) with clinical and electrophysiological features of HMSN type I, using Magnetic Coil (MC) stimulation. No one exhibited clinically pyramidal signs. Brain stimulation Motor Evoked Potential (MEPs), recorded monolaterally from the left abductor digiti minimi (ADM) and tibialis anterior (TA) muscles, were evoked in all patients from upper extremities and absent in 11.1% from lower limbs. Total Motor Conduction Time (TMCT), as well as Peripheral Motor Conduction Time estimated by either magnetic nerve root stimulation (mag-PMCT) or F-wave latency values (F-PMCT), were markedly delayed in all patients. Central Motor Conduction Time was calculated by subtracting both the latency of mag-PMCT (mag-CMCT) and F-PMCT (F-CMCT) from that one obtained by cortical stimulation. F-CMCT was abnormal in 22.2% from ADM muscles and in 33.3% from TA muscles. Furthermore, CMCT to both methods was not possible to evaluate in 5.6% from upper and lower extremities and following magnetic root stimulation in 11.1% from lower limbs. These findings prove lower motor neuron involvement, in agreement with electroneurographic data, and suggest a possible central motor pathways impairment, even in patients without any clinical evidence, but they cannot explain which is the underlying pathophysiological mechanism, a true motor neuron involvement or an abnormal spinal motor neuron excitability.

Motor involvement in Charcot-Marie-tooth disease (HMSN type I): electrophysiological findings

Motor involvement in Charcot-Marie-tooth disease (HMSN type I): electrophysiological findings

Evaluation of phrenic nerve involvement and respiratory activity in Charcot-Marie-Tooth disease (HMSN type I)

Evaluation of phrenic nerve involvement and respiratory activity in Charcot-Marie-Tooth disease (HMSN type I)

The status of HMSN type III

The indistinctness of the HMSN type III concept of Dyck (1975) prompted us to evaluate the diagnostic criteria. Based on a literature review and the observations in five of our own cases, restricted criteria are formulated. We conclude that at present the diagnosis of AR HMSN type III can be applied reasonably to the condition of “congenital hypomyelination”, which shows a congenital or early childhood onset, extremely slow motor nerve conduction velocities of less than 6–7 m s −1 in upper limbs, and in nerve biopsy only fibres with no or hardly any myelin and “onion bulbs” of basal lamina. Amyelination might be the most severe or earliest expression of congenital hypomyelination. The existence of an inherited type III with mainly classical onion bulbs is uncertain, as only sporadic cases have been described.

Gene for hereditary neuropathy with liability to pressure palsies (HNPP) maps to chromosome 17 at or close to the locus for HMSN type 1.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder with an increased susceptibility of peripheral nerves to mechanical lesions resulting in transient nerve palsies. Many carriers remain asymptomatic but can be traced by electrophysiological examination, thereby demonstrating that HNPP is a generalised polyneuropathy. By using highly polymorphic markers linkage analysis was performed in a large family with HNPP. This resulted in a maximum lod score of 4.20 at theta = 0.10 with D17S520. Three-point linkage suggests that the gene for HNPP is located on chromosome 17 in the region between D17S250 (q11.2-q12) and D17S520 (p12), a region that has recently been shown to encompass a locus for another hereditary neuropathy, hereditary motor and sensory neuropathy type 1 (HMSN type 1). This raises the possibility that HNPP and this form of HMSN type 1 are allelic. In keeping with this speculation is our recent finding that D17S122, another marker from the HMSN type 1 region, displays apparent loss of heterozygosity in this family.

Duplication of part of chromosome 17 is commonly associated with hereditary motor and sensory neuropathy type I (Charcot-Marie-Tooth disease type 1).

Hereditary motor and sensory neuropathy type I (HMSNI), also known as Charcot-Marie-Tooth disease type 1 (CMT1), has been shown to be genetically heterogeneous. A major gene maps to chromosome 17 (CMT1A). A set of loci, D17S122, D17S125, and D17S124, show tight linkage to the CMT1A locus, and a duplication of D17S122 has been detected in some families. We show that the locus D17S122 is duplicated in affected individuals from 7 informative families with HMSNI. The duplication was demonstrated either by differences in hybridization densities between two bands of a restriction fragment length polymorphism or by the presence of all three alleles. No normal individual had the duplication. A single recombinant exists between the MspI polymorphism of D17S122 and the duplicated band, suggesting that the duplication is of considerable size. Patients with HMSN type II do not show the duplication. These findings will have considerable impact on the diagnosis of chronic demyelinating neuropathies, in patients with or without similarly affected relatives.

Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I)

Seventeen cases of dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I) with infantile onset were studied. Not only clinical and electrophysiological data, but also the g ratio (axon diameter to fibre diameter), considered to be a distinguishing feature between HMSN type I and HMSN type III, showed overlap. Morphological and morphometrical investigations already revealed a lack of small and large diameter myelinated axons at an early stage, and a demyelinating process most active in early childhood followed later by axonal loss. It was concluded that the histopathology of HMSN type I cannot be sufficiently explained by axonal atrophy with secondary demyelination.

Three modality evoked potentials in Charcot-Marie-Tooth disease (HMSN-1)

Sixteen patients with dominant hereditary motor-sensory neuropathy type I (HMSN I), members of 5 families, underwent trimodality evoked potential studies. All patients had clinically normal optic nerves. History of deafness was present in 3 patients and sensory-neural hearing defect was found in 5 of 7 patients in whom audiometry was obtained. In 43.7 percent of the subjects significant prolongation of P100 of the VEP was found. Prolongation of N19 of the SEP was found in all 12 subjects examined. Significant bilateral prolongation of peak I of the ABEP was found in 37.5 percent of the subjects and in 50 percent of the ears examined: these findings indicated that in addition to peripheral nerves, the myelin of the optic and cochlear nerves is also affected in HMSN type I.

HEREDITARY MOTOR AND SENSORY NEUROPATHY OF NEURONAL TYPE WITH ONSET IN EARLY CHILDHOOD

Eighteen cases of a chronic progressive motor and sensory neuropathy of neuronal type with early onset are described. Based on the presented data and literature reports a condition is distinguished, which is in clinical, genetic and morphological aspects different from autosomal dominant HMSN type II. The condition corresponds to that described by Ouvrier et al. (1981). It shows a congenital or early childhood onset and causes a severe disability usually with wheelchair dependency already in puberty or later in adult life. The condition is probably transmitted by an autosomal recessive gene. Morphological features of biopsied nerves are an extensive loss of large diameter fibres with a shift to smaller diameters in the histogram. Regenerative features are almost absent in contrast to the distinct cluster formation in autosomal dominant HMSN type II. A maturation disturbance of peripheral motor and sensory neurons with a concomitant or secondary process of chronic neuronal degeneration is suggested. One dominantly inherited case in our group with an infantile onset exhibits clinical and morphological features consistent with an autosomal dominant HMSN type II.

P105 Somatosensory evoked potentials (SEPs) in hereditary motor-sensory neuropathies (HMSN type I and II)

P105 Somatosensory evoked potentials (SEPs) in hereditary motor-sensory neuropathies (HMSN type I and II)