Hereditary motor and sensory neuropathies. Clinical and molecular genetic aspects

Hereditary motor sensory neuropathies are a heterogeneous group of inherited diseases of the peripheral nerves. In this review the clinical and genetic differences between the sub-groups of this disease will be discussed. Since the discovery of a 1.5 mb duplication on chromosome 17 p11.2-12 in most patients with a hereditary motor sensory neuropathy and a variety of different mutations on chromosomes 1 and X in other patients with a similar disease profile, Dycks' clinical classification needs to be re-evaluated. In this review Dycks' taxonomy of heridihary neuropathies will be compared to a new genetic classification and a relevant diagnostic procedure proposed when a hereditary neuropathy is suspected.     

Genetics and pathophysiology of hereditary motor and sensory neuropathy type 1

Hereditary motor and sensory neuropathy type 1 (HMSN1) is the most common, but genetically heterogenous demyelinating peripheral neuropathy. HMSN1A is caused in most cases by a 1.5-Mb tandem duplication in chromosome 17p11.2. Hereditary neuropathy with liability to pressure palsies is caused by the reciprocal deletion of the 1.5-Mb HMSN1A region. The peripheral myelin protein22 (PMP-22) gene is located within the HMSN1A region and has a point mutation in non-duplicated HMSN1A patients. HMSN1B patients have a mutation in the protein zero (P0) gene located on chromosome 1q22-23 Point mutation in PMP-22 or P0 is also reported in patients with Dejerine-Sottas disease. In X-linked HMSN1 patients (HMSNX1) a mutation occurs in the connexin 32 gene located on chromosome Xq13. The morphological phenotype is different among the genotypes of HMSN1.     

The cortical reactions during sensory and motor activities in healthy children and adults and in depression patients

We recruited 111 patients who were considered to be at significantly increased risk of preeclampsia on the basis of previous obstetric history or preexisting medical disorders. All patients were treated with low dose aspirin (75 mg/day) from the first occasion the patient attended the antenatal clinic, regardless of gestational age. If the maternal mean platelet volume (MPV) increased significantly (by > 0.8 fl) from the baseline, antiplatelet treatment was increased. Five pregnancies were lost during the second trimester and 106 of the treated patients had live infants. The incidence of neonatal death (3/106 infants) was much lower than in the previous pregnancies in these patients (32/134 infants). Patients who were treated from the first trimester of pregnancy (group A, 89 patients) did substantially better than those treated from the second trimester (group B, 17 patients) as assessed by the incidence of pre-eclampsia or intrauterine growth restriction (IUGR), gestational age and birthweight at delivery. These data suggest that longitudinal monitoring of the MPV may identify the women who could benefit from increased antiplatelet treatment, and that antiplatelet treatment may be more effective when initiated in the first trimester rather than later in pregnancy.     

MRI of skeletal muscles in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths

A 33-day-old male infant who developed central diabetes insipitus as a complication of congenital toxoplasmosis is presented. He had polyuria and hypernatremia on admission and responded to Intranasal desmopressin acetate with the normalization of above mentioned findings. Computed tomographic (CT) scan of the brain showed obstructive hydrocephaly with periventricular and right basal ganglion calcification. CT scan of the pituitary gland, thyroid function tests, and serum cortisol levels were all normal. This is the first report of isolated diabetes insipitus with congenital toxoplasmosis in literature and central diabetes insipitus should be remembered if polyuria and hypernatremia develops in a patient with congenital toxoplasmosis.     

Gastric motor and sensory function testing

Structural properties of an equilibrium intermediate formed upon urea-induced unfolding of more ordered staphylococcal nuclease A-forms (A2 and A3) are studied. The effect of association on the structural properties and conformational stability of this unfolding intermediate is also considered. A close structural similarity (including tendency for association) is shown between this intermediate and the least ordered A1-form, induced in the acid-unfolded nuclease by moderate sulfate or chloride concentrations.     

Dominant T-cell clones of unknown significance in patients with idiopathic sensory neuropathies

The aim of this study was to describe an high-performance liquid chromatographic assay for the simultaneous determination of two HIV protease inhibitors, saquinavir and ritonavir, in human serum. The method involved extraction of ritonavir and saquinavir from serum with the aid of solid-phase extraction C18 cartridges followed by high-performance liquid chromatography with a C8 column and ultraviolet detection set at a wavelength of 240 nm. The assay was linear and has been validated over the concentrations range of 0.5-32 microg/ml for ritonavir and 0.075-4.8 microg/ml for saquinavir, from 600 microl serum extracted. In future, the assay will be used to support human population pharmacokinetic studies, and therapeutic drug monitoring for ritonavir and saquinavir.     

Multifocal motor neuropathies with conduction blocks. 39 cases

Clinical, biological and electrophysiological features from a cohort of 39 multifocal motor neuropathies with conduction blocks (NMM with CB) have been studied. There were 29 males and 10 females with an average of 47.3. At the first evaluation, the mean duration of the symptoms was of 8 years with extremes between 1 and 28. Pain and paresthesias were present in respectively 10 and 18 p. 100 of the patients. Fasciculations and cramps were observed in more than 2/3 of the cases. Three patients had tremor at rest. Upper limb muscular weakness was the predominant initial symptom (84.6 p. 100). The weakness always affected distal and unilateral muscles. Radial and cubital nerve distribution are mainly affected and in half of the cases an unilateral motor deficit in the lower limb was associated. Muscle atrophy was frequent (74 p. 100) and rapidly developed in the first 2 years. Reflexes were decreased or absent in 64 p. 100. In 78 p. 100 of cases, biological study showed normal serum immunoelectrophoresis and CSF. IgM anti-GM1 antibodies were found in 24/36 patients. Very high titres were found in 5 cases. All patients had CB in upper limbs. The preferential localizations of the CB were equally at the median and ulnar nerves. Only 7 patients had CB localized to the lower limbs. In many cases, marked reduction of the motor amplitude prevented the detection of CB, marked reduction of the motor amplitude prevented the detection of CB. Moderate fibrillation potentials were found in 28 p. 100 of patients. Giant muscular unit potentials were frequent (21/39). F-waves in nerve with CB were always abnormal with marked increased latencies. Late responses sometimes seemed to be repeater F-waves. Axon reflexes were detected in 5 cases. The late responses abnormalities could precede the block. Clinical, biological and electrophysiological described arguments could may distinguish NMM with CB from motor neuron disease and relate them to the group of chronic demyelinating neuropathies.     

Hand and foot infections in children

Hand and Foot anatomic and physiologic characteristics make the infections, located there, acquire specific aspects. Seventy seven in-patients admitted and/or with follow-up at the out-patient clinic of Dona Estef?nia Hospital with Hand (25) and Foot (52) infections, were reviewed during the period between January 1991 and January 1994. We treated, out-patients with paronychia (7 of the hand and 42 of the foot), one patient with hand pulpitis, and one with dorsum hand cellulitis. The remaining 16 with hand infection (64%) and 15 with foot infection (29%) were being treated with splint in the position of rest, elevation of the affected limb and endovenous antibiotic therapy. In all abscess cases, surgical drainage was conducted, 16 the of hand and 22 of the foot. There were no sequels in hand infection. In foot infection there was one osteitis of the first metatarsus and a cutaneous fistula.     

Calcium channel subtypes in lamprey sensory and motor neurons

Pharmacologically distinct calcium channels have been characterized in dissociated cutaneous sensory neurons and motoneurons of the larval lamprey spinal cord. To enable cell identification, sensory dorsal cells and motoneurons were selectively labeled with fluorescein-coupled dextran amine in the intact spinal cord in vitro before dissociation. Calcium channels present in sensory dorsal cells, motoneurons, and other spinal cord neurons were characterized with the use of whole cell voltage-clamp recordings and specific calcium channel agonist and antagonists. The results show that a transient low-voltage-activated (LVA) calcium current was present in a proportion of sensory dorsal cells but not in motoneurons, whereas high-voltage-activated (HVA) calcium currents were seen in all neurons recorded. The different components of HVA current were dissected pharmacologically and similar results were obtained for both dorsal cells and motoneurons. The N-type calcium channel antagonist omega-conotoxin-GVIA (omega-CgTx) blocked >70% of the HVA current. A large part of the omega-CgTx block was reversed after washout of the toxin. The L-type calcium channel antagonist nimodipine blocked approximately 15% of the total HVA current. The dihydropyridine agonist (+/-)-BayK 8644 markedly increased the amplitude of the calcium channel current. The BayK-potentiated current was not affected by omega-CgTx, indicating that the reversibility of the omega-CgTx effect is not due to a blockade of L-type channels. Simultaneous application of omega-CgTx and nimodipine left approximately 15% of the HVA calcium channel current, a small part of which was blocked by the P/Q-type channel antagonist omega-agatoxin-IVA. In the presence of the three antagonists, the persistent residual current (approximately 10%) was completely blocked by cadmium. Our results provide evidence for the existence of HVA calcium channels of the N, L, and P/Q types and other HVA calcium channels in lamprey sensory neurons and motoneurons. In addition, certain types of neurons express LVA calcium channels.     

Symmetry of normal motor and sensory nerve conduction measurements

Nerve conduction measurements in normal subjects are assumed to be symmetric, but the normal limits of symmetry have not been determined. Full data on the limits of symmetry for commonly studied nerves are important in the clinical interpretation of nerve conduction data. We selected normal electrodiagnostic studies from archived electromyographic laboratory reports that included bilateral measurements of motor and sensory nerves. Symmetry of nerve conduction measures was confirmed, and only the median and ulnar sensory nerves had significant deviations from symmetry, supporting subclinical nerve damage in the most common dominant hand. The limits of symmetry were determined by calculating the 95th percentile for the differences between sides. For motor and sensory nerves, the range of 95th percentile limits was narrower for measures in upper extremity nerves compared to lower extremity nerves. Several reasons are offered for the wider limits of symmetry in lower extremity nerves.     

Immunocytochemical and electron-microscopic features of tooth pulp innervation in hereditary sensory and autonomic neuropathy

Increases in urine drug concentration that result from changes in urinary output may be mistakenly interpreted as new drug use rather than carryover from previous drug exposure. Normalization of drug excretion to urine creatinine concentration reduces the variability of drug measurement attributable to urine dilution. A specimen ratio of 1.5 or greater between two creatinine normalized positive urine cannabinoid tests was previously proposed as an indicator of new marijuana use. This approach has received wide attention for potential use in treatment and employee assistance programs associated with workplace drug testing. Unfortunately, there has been limited evaluation of the usefulness of this ratio under controlled-dosing conditions with marijuana smokers. A controlled clinical study was conducted to examine the excretion profile of creatinine and marijuana metabolites in a group of six marijuana users who smoked two different doses of marijuana over a 4-week period. A relative operating characteristic curve was constructed from sensitivity and specificity data for 26 different specimen ratios ranging from 0.1 to 2.0. The most accurate specimen ratio (85.4%) for differentiating new use from residual excretion was 0.5. Use of this ratio provided a sensitivity of 80.1%, a specificity of 90.2%, and 5.6% false-positive and 7.4% false-negative predictions. To substantiate the validity of the 0.5 specimen ratio, urine cannabinoid and creatinine data from a controlled clinical trial specifically addressing water dilution as a means of specimen adulteration were evaluated. Sensitivity, specificity, accuracy, and percent false-positive and percent false-negative predictions were 71.9%, 91.6%, 83.9%, 5.4%, and 10.7%, respectively. These data compared favorably with the results from the first clinical study, with the exception of slightly lower sensitivity and higher false-negative percentages in the water dilution study. This would be expected because of the ingestion of large amounts of water and consequent dilution of urine drug concentration. These data indicated that selection of a specimen ratio to evaluate sequential creatinine normalized urine drug concentrations can improve the ability to distinguish residual excretion from new marijuana usage. The selection of an appropriate specimen ratio can be made based on the needs of a specific urine drug-testing program taking into account sensitivity, specificity, and accuracy data.     

Myelinated sensory and alpha motor axon regeneration in peripheral nerve neuromas

Histochemical staining for carbonic anhydrase and cholinesterase (CE) activities was used to analyze sensory and motor axon regeneration, respectively, during neuroma formation in transected and tube-encapsulated peripheral nerves. Median-ulnar and sciatic nerves in the rodent model permitted testing whether a 4 cm greater distance of the motor neuron soma from axotomy site or intrinsic differences between motor and sensory neurons influenced regeneration and neuroma formation 10, 30, and 90 days later. Ventral root radiculotomy confirmed that CE-stained axons were 97% alpha motor axons. Distance significantly delayed axon regeneration. When distance was negligible, sensory axons grew out sooner than motor axons, but motor axons regenerated to a greater quantity. These results indicate regeneration differences between axon subtypes and suggest more extensive branching of motor axons within the neuroma. Thus, both distance from injury site to soma and inherent motor and sensory differences should be considered in peripheral nerve repair strategies.     

A case of hereditary motor and sensory neuropathy type I with a new type of peripheral myelin protein (PMP)-22 mutation

A 16-year-old school boy suffered from an insidious foot deformity. Slight degrees of symmetrical muscular weakness of the distal lower limb muscles were observed. In addition, slight degrees of atrophy of the anterior tibial muscles with moderate degrees of pes cavus deformity and flexion contracture of the toes of both feet were observed. In the upper and lower limbs muscle stretch reflexes were decreased and absent, respectively. Vibratory and touch sensations were moderately and slightly decreased, respectively, in the toes. The median and ulnar motor conduction velocities (m/sec) were 21.1 and 13.2, respectively, with markedly prolonged distal latencies. The median and ulnar sensory conduction velocities (m/sec) were 21.5 and 10.1, respectively. No M-waves were recorded by stimulation of the tibial and peroneal nerves. Also no nerve action potential was elicited by stimulation of the sural nerve. A fascicular biopsy of the sural nerve was performed. The myelinated fibers showing segmental de- and re-myelination were frequently found in teased fiber preparations. The density of myelinated fibers was markedly decreased, and both demyelinated axons and onion-bulbs were also observed by light and electron microscopy in the Epon-embedded sections. Based on the neurological examination and nerve conduction studies, although other family members were not examined, a diagnosis of HMSN type I was made. To clarify the genetic abnormality, a systematic study of the genomic DNA was made. A DNA duplication in the chromosome 17p11.2-12 was not observed. The single-strand conformational polymorphism method showed an abnormal extra band in the exon 3 encoding peripheral myelin protein (PMP)-22 gene of the patient compared with the control. The direct sequencing analysis of the exon 3 revealed a guanine to cytosine substitution that caused a substitution of arginine for glycine at amino acid position 93 of PMP-22. The digestion of the exon 3 with Sty I showed the presence of a mutant and normal allele of the PMP-22 gene indicating autosomal dominant heredity. This type of PMP-22 gene mutation is different from any type of PMP-22 mutations reported in the literature. The mutation is located in the intracellular domain of PMP-22. The mechanism by which the mutation induce demyelination of the peripheral myelin remains to be elucidated. Reports of patients with a point mutation of amino acids of PMP-22 are rare in the literature. This is the first Japanese patient with a new type of mutation of the PMP-22 gene.     

REM-sleep motor disorder in children

Beta-thalassemia (thal) is a common single-gene disease worldwide. However, the prevalence of beta-thal and the spectrum of beta-globin gene mutations in Filipinos remain unclear. This study sought to answer these two questions. A total of 2954 apparently healthy Filipinos in Taiwan were recruited for a prevalence study. A complete blood count was done in every subject. Those with microcytosis were studied with hemoglobin (Hb) high-performance liquid chromatography to determine the levels of Hb A2 and Hb F. Twenty-seven subjects had elevated levels of Hb A2 (>4.0%). These 27 suspected beta-thal carriers and another 16 beta-thal major patients who were being treated in the Philippines were studied to determine the spectrum of beta-globin gene mutations. Gap-PCR was used to detect the Filipino deletion of beta-thal, and direct sequencing was used to detect point or small mutations in the beta-globin gene. All of the 27 suspected beta-thal carriers had one mutation in the beta-globin gene, resulting in an overall prevalence of 0.9%. The spectrum of beta-thal mutations was similar in the carrier and patient groups. Analysis of the pooled identified seven different mutations in the study population. The Filipino deletion was the most common mutation, accounting for 45.8% (27/59) of the alleles, followed by codon 67 (-TG) (16 alleles), and Hb E (11 alleles). These three mutations accounted for 92% of the Filipino beta-thal alleles. Elucidation of the beta-thal mutations in Filipinos is useful for the genetic counseling and prenatal diagnosis of this disease.     

Effects of sex steroids on sensory and motor spinal mechanisms

The male copulatory pattern uses muscles in the penis for erection and penile insertion, the lower trunk for pelvic thrusting, and the sex accessory organs for seminal emission. Organization of the nuclei controlling penile muscles is achieved through cell growth, dendritic arborization, and synaptogenesis, actions dependent on androgen but not estrogen. Testosterone (T) and dihydrotestosterone (DHT) but not estradiol (E2), stimulate pelvic thrusting vigor by synchronizing discharge of motoneurons innervating pelvic muscles. Pelvic thrusting rhythmicity, regulated by spinal interneurons, is produced in female rabbits by E2 or T but not by DHT. Reflex contraction of the seminal vesicles, due to penile insertion, is facilitated by androgen presumably by its effect on preganglionic neurons of the hypogastric nerve, located in the dorsal commissural nucleus.     

Limb laterality and motor proficiency in children

This investigation examined the premise derived from recent reports, that children who are consistent right-handers are better coordinated than their left- and mixed-sided (inconsistent) peers. The observation of limb laterality was extended to include footedness. Two samples of children (N = 273) (foot laterality/hand laterality), matched for age and sex, were assessed for motor proficiency and compared according to limb preference (right, mixed, left). Overall, results indicated no significant group differences (ps > .05) in composite scores (upper-limb, lower-limb, combination) and total performance, within foot and hand laterality. In view of recent studies (noting differences between laterality groups) and these nonsupportive results, it appears that additional inquiry is warranted before any consensus regarding the association between limb laterality and motor coordination can be established. Suggestions for further inquiry are presented.     

Peripheral nerve repair in the hand with and without motor sensory differentiation

To investigate the value of motor sensory differentiated nerve repair, we examined a group of 9 patients with motor sensory differentiated nerve repair and a group of 13 patients without motor sensory differentiated nerve repair. The clinical and electroneurographic findings were compared. For the clinical examination, Millesi's scoring system was used. The hand function after motor sensory differentiated median nerve repair was 72% +/- 16% compared with 57% +/- 14% without motor sensory differentiation. The hand function after motor sensory differentiated median and ulnar nerve repair was 53% +/- 12% compared with 43% +/- 24% without motor sensory differentiation. After ulnar nerve repair the achieved values for hand function were high even without motor sensory differentiation. Our results indicate that intraoperative motor sensory differentiation of injured nerves is helpful to reestablish particularly the sensory function in median nerve injuries.     

Hereditary motor and sensory neuropathy Lom type in an Italian Gypsy family

We describe a form of hereditary motor and sensory neuropathy (HMSN) affecting four siblings in an Italian family of Gypsy ethnic origin with both clinical and pathological findings very reminiscent of the HMSN Lom type (HMSNL), recently described in a group of Bulgarian Gypsies. Genetic analysis demonstrated linkage to chromosome 8q24 and conserved haplotypes in the HMSNL region, thus confirming that this is the first Gypsy family outside the Balkans suffering from the same disorder.     

Autocontrol of sensory reinforcement in children.

Conducted 2 experiments with 7-yr-olds (N = 96) from schools in a black lower socioeconomic status neighborhood to test the hypothesis that self-production of sensory reinforcement enhances its effect relative to identical reinforcement which is externally provided. Completion of an FR-50 work period led to a 30-sec reinforcement period, where different groups either controlled visual input or received the same input externally controlled. It was found that, over extended trials, the group with autocontrol of visual input completed more trials before dropping out and responded at a higher rate during the reinforcement period than did groups with the externally-produced input. It is concluded that self-production is an important factor in determining the effectiveness of sensory reinforcement. (16 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)