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.     

Psychotic depression. An atypical initial presentation of multiple sclerosis

The Roussy-Lévy syndrome (MIM #180800) was described in 1926 as a disorder presenting with pes cavus and tendon areflexia, distal limb weakness, tremor in the upper limbs, gait ataxia and distal sensory loss. We report a family with affected members in four generations, showing these clinical signs of Roussy-Lévy syndrome and a partial duplication at chromosome 17p11.2. This genetic defect is commonly found in patients with the hypertrophic form of the Charcot-Marie-Tooth syndrome. Our finding provides evidence against the Roussy-Lévy syndrome as a distinct entity but suggests a close relation with the Charcot-Marie-Tooth syndrome. What causes the additional features of gait ataxia and essential tremor needs further clarification.     

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.     

Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy

The association between hereditary motor and sensory neuropathy (HMSN) and optic atrophy has been termed HMSN type VI. The autosomal dominant inheritance of this syndrome is reported. Three generations were affected with optic atrophy, which differed in some respects from classic dominant optic atrophy, and an asymptomatic, mainly sensory, neuropathy.     

Muscle atrophy is prevented in patients with acute spinal cord injury using functional electrical stimulation

Severe muscle atrophy occurs rapidly following traumatic spinal cord injury (SCI). Previous research shows that neuromuscular or 'functional' electrical stimulation (FES), particularly FES-cycle ergometry (FES-CE) can cause muscle hypertrophy in individuals with chronic SCI (> 1 year post-injury). However, the modest degree of hypertrophy in these already atrophied muscles has lessened earlier hopes that FES therapy would reduce secondary impairments of SCI. It is not known whether FES treatments are effective when used to prevent, rather than reverse, muscle atrophy in individuals with acute SCI. This study explored whether unloaded isometric FES contractions (FES-IC) or FES-CE decreased subsequent muscle atrophy in individual with acute SCI (< 3 months post-injury). Twenty-six subjects, 14-15 weeks post-traumatic SCI, were assigned to control, FES-IC, or FES-CE against progessively increasing resistance. Subjects were involved in the study for 3 or 6 months. Total body lean body mass (TB-LBM), lower limb lean body mass (LL-LBM), and gluteal lean body mass (G-LBM) were determined before the study, and at 3 and 6 months using dual energy X-ray absorptiometry (DEXA). Controls lost an average of 6.1%, 10.1%, 12.4%, after 3 months and 9.5%, 21.4%, 26.8% after 6 months in TB-LBM, LL-LBM and G-LBM respectively. Subjects in the FES-IC group consistently lost less lean body mass than controls, however, only 6 month G-LBM loss was significantly attenuated in this group relative to the controls. In the FES-CE group, LL-LBM and G-LBM loss were prevented at both 3 and 6 months, and TB-LBM loss was prevented at 6 months. In addition, FES-CE significantly increased G-LBM and LL-LBM after 6 months of training relative to pre-training levels. Within the control group, there was no significant relationship between LL-LBM loss (3 and 6 months) and the number of days between injury and baseline measurement. In summary, this study shows that FES-CE, but not FES-IC, training prevents muscle atrophy in acute SCI after 3 months of training, and causes significant hypertrophy after 6 months. The magnitude of differences in regionalized LBM between controls and FES-CE subject raises hopes that such treatment may indeed be beneficial in preventing secondary impairments of SCI if employed before extensive post-injury atrophy occurs.     

Omeprazole 20 or 40 mg daily for healing gastroduodenal ulcers in patients receiving non-steroidal anti-inflammatory drugs

Amyloid deposition in skeletal muscle is a well-recognized but rare occurrence. Sixteen such cases seen in a 17-year period (1979 to 1996) out of a total of 3,937 muscle biopsy specimens (0.004%) form this study group. Either Congo red or sulfated alcian blue stains were routinely performed in each biopsy to screen for amyloid. Patients in this study (eight men, eight women) ranged in age from 42 to 90 years (mean, 61 years) at initial presentation. The most common symptoms at presentation included weakness/fatigue (n = 10), autonomic symptoms (n = 8), and weight loss/decreased appetite (n = 7). Five patients had a concomitant malignancy (myeloma, n = 3; malignant carcinoid tumor, n = 1; melanoma, n = 1). Two patients had known hereditary forms of amyloidosis. Five patients had amyloid diagnosed on another organ biopsy (excluding peripheral nerve). Histologically, amyloid was deposited in the interstitium or perivascular region in 14 muscles and endomysial region in seven muscles. All cases were confirmed with Congo red staining (apple green birefringence) or by electron microscopic identification of fibrillary amyloid material. Scattered angular atrophic esterase-positive muscle myofibers indicative of acute denervation atrophy were seen in 14 muscles. Eight muscles showed small group atrophy, and seven showed myofiber type grouping. Scattered regenerating muscle fibers were seen in nine cases, degenerating myofibers in six, and foci of chronic endomysial and perivascular inflammation in two. Four muscles showed type II muscle fiber atrophy. A concomitant sural nerve biopsy specimen was evaluated in seven patients; all seven contained amyloid, confirmed either by Congo red staining or electron microscopic examination. In two nerves, there was a mild loss of myelinated axons; four had a moderate loss, and one, severe loss. Six of seven nerves showed predominantly axonopathic changes. In conclusion, (1) the prevalence rate of amyloid myopathy in muscle biopsy specimens was low (in this series, 0.004%); (2) only a minority of patients had multiple myeloma, and most presented with muscle weakness/fatigue or autonomic symptoms; (3) most of the muscles showed neurogenic features histologically; (4) all concomitant sural nerve biopsy specimens contained amyloid, and most showed a predominance of axonopathic changes.     

The influence of recombinant human tumor necrosis factor alpha and its muteins used alone or in combination with 2-chlorodeoxyadenosine on normal and leukemic hematopoiesis in vitro

We report an 80-year-old woman with progressive muscular atrophy predominantly involving her right lower extremity. She was well until 1992 (75 years of age) when she noted an onset of weakness in her right leg which had got progressively worse. She was admitted to our service in July 1994. On admission, general physical examination was unremarkable. She was alert and well oriented without dementia. Higher cerebral functions were normal. Cranial nerves also appeared intact. She dragged her right leg in walking. Mild to moderate weakness (2/5 to 4/5) was noted in muscles in her right lower extremity more in the distal part. Deep tendon reflexes were within normal limits, and the plantar response was flexor bilaterally. Sensation was intact. Laboratory examinations were also unremarkable except for slight increase in CK which was 470 IU/l. CSF was also normal. EMG revealed neurogenic changes in the lower extremities. She was admitted to Aoki Hospital on October 21, 1994, by that time, her weakness in the right lower extremity had gotten worse in that the muscle strength of the right extensor hallucis longus was 0 and tibialis anterior 2; muscle atrophy was also prominent in her right leg; the right ankle jerk could not be elicited. In the subsequent course, weakness and atrophy appeared in her left lower extremity, however, upper extremities and cranial nerves had never been affected. Babinski sign was always negative. In February 1996, she developed delusional ideation of self persecution, and showed difficulty in communication with medical staffs. She developed fever of 38.7 degrees C on June 13, 1996 expired on the next day. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had a form of spinal muscular atrophy. Opinions were divided between ALS and spinal muscular atrophy. Post-mortem examination revealed marked loss of anterior horn neurons in the lumbar area with astrogliosis. Bunina bodies were seen in some of the remaining neurons. No myelin pallor was noted in the pyramidal tracts, however, atrophy and loss of Betz cells were noted in the motor cortex. Other cortical areas were unremarkable. The neuropathologist arrived at the conclusion that the patient had ALS. This patient was unique in that she had asymmetric atrophy and weakness limited to the lower extremities. This is quite unusual as ALS of four years duration. In addition, the patient developed some mental change which was thought to represent dementia by some participants. But no clear morphologic changes were seen to account for her mental change.     

Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency

Impaired exercise capacity is a common finding in chronic obstructive pulmonary disease (COPD) patients. This reduction is not a simple consequence of airflow limitation. Peripheral muscle weakness, deconditioning and impaired gas exchange, were recognized as important contributors to exercise intolerance. In this overview, the contribution of peripheral muscle function and muscle training to exercise performance is discussed by means of three questions: 1) Is peripheral muscle dysfunction contributing to exercise limitation in COPD? 2) How do we measure peripheral muscle function? 3) Are peripheral muscle training modalities effective? At present, there is substantial evidence for peripheral muscle dysfunction. Both reduced force generating capacity as well as impaired muscle metabolism were observed and these findings contributed substantially to the reduced exercise capacity in COPD. Peripheral muscle strength measurements are feasible with mechanical or electronic devices and revealed muscle weakness in COPD patients. However, this weakness is not uniform for all muscle groups. Upper arm and leg muscles were more affected than hand muscles. This may, at least in part, be related to differences in the levels of inactivity between leg and hand muscles. In addition, muscle weakness is associated with impaired exercise capacity and symptoms of increased exertion during exercise. Endurance exercise training, i.e. cycling and treadmill walking, improved exercise capacity and was associated with alterations in muscle metabolism. Strength training of peripheral muscles showed increases in submaximal exercise performance and quality of life measures. These improvements were observed independently of the degree of airflow obstruction. The optimal training regimen (strength or endurance), and the muscle groups to be trained, remain to be determined.     

A family of autosomal dominant facio-limb-girdle muscular dystrophy

A family of autosomal dominant facio-limb-girdle muscular dystrophy was reported. The proband was a 28-year-old male. His father and sister suffered from a similar disease. All patients developed weakness of lower limbs and atrophy of thigh at second to fourth decades. All showed mild facial and neck flexor weakness as well as proximal dominant weakness and atrophy of four limbs. Limb muscle involvement was more severe in lower limbs than in upper limbs in all cases. Interestingly, all showed limitation of ankle dorsiflexion (tight heel cord), although distal muscles of lower limbs were not involved or only mildly involved clinically. On laboratory examination, serum CK increased slightly. Needle EMG revealed low amplitude, polyphasic MUP in limb muscles in all cases. Biopsied muscles taken from the proband showed non-specific myogenic changes. Rimmed vacuoles were not observed. Our cases were different from Bethlem myopathy, because the age of onset was late and joint contractures were mild in our cases, as compared with Bethlem myopathy. Clinical manifestations of our family showed a strong resemblance to the family reported by Girchlist et al, but similar cases were not reported in Japan.     

A pedigree of autosomal dominant limb-girdle myopathy with rimmed vacuole formation

We describe a kindred with autosomal dominant myopathy with preferential proximal limb muscle involvement. This disorder is characterized clinically by early adult onset, slow progression, normal life expectancy, weakness and atrophy of proximal limb muscles, especially in the lower limbs. Laboratory examinations showed myopathic changes mixed with neuropathic components on needle electromyography, slight elevation of serum creatine kinase, and absent cardiac involvement. In biopsied muscle findings of two patients, the presence of rimmed vacuoles was the most striking finding to explain muscle degeneration, though a few necrotic fibers were present. The pathologic and clinical findings in the present family are almost similar to those seen in "adult-onset autosomal dominant limb-girdle muscular dystrophy" reported by Chutkow et al.     

A family with neurogenic atrophy of the distal muscles of the upper limbs: clinical and electrophysiological studies

A Chinese family manifested mild neurogenic atrophy of the distal muscles of the upper limbs. None of the affected members had sensory abnormalities, or pyramidal tract or bulbar involvement. The onset of the illness was in the middle of the second decade of life. The muscle atrophy was more severe in the female members. Electromyographic examination of the atrophic muscles showed evidence denervation. One female patient demonstrated slow motor conduction velocity in the right median nerve.     

A case of juvenile muscular atrophy of the upper limb with intraspinal cavity formation

The patient was a 23-year-old man. He had no history of trauma in the head and neck. When he was 20 years old (in 1992), he noticed muscle atrophy and weakness in the right hand. In a hospital, he had cervical MRI study and other examinations. The diagnosis was juvenile muscular atrophy of the upper limb (Hirayama's disease). After that the symptoms became worse in the bilateral forearms and hands. The neurological examination showed severe atrophy in bilateral C7 to Th1 innervated muscles, right pyramidal sign, mild superficial and deep sensory disturbance in the dermatome of C7-Th1, and right Horner's sign. Cervical MRI and myelography revealed the atrophy of cervical cord and intraspinal cavity formations from C5 to Th1. We concluded that chronic and intermittent compression to cervical cord with flexion position made the cavities during the clinical course because these cavities were not found in the MRI taken in 1992.     

Amyloid neuropathy simulating lower motor neuron disease

We report a 57-year-old man with progressive symmetric weakness and fasciculation affecting the legs. Electromyography revealed fibrillations and neurogenic motor unit potentials in the leg muscles. Biopsy of a motor branch of the obturator nerve revealed axonal degeneration, loss of myelinated nerve fibers, and amyloidosis with deposits of lambda light chains. At 6-month follow-up, the patient manifested sensory and autonomic symptoms, and lambda light chains were first detected in the serum. In this case, diagnosis of amyloidosis remained elusive until motor nerve biopsy.     

Peripheral neuropathy and testosterone

A 265 lb. (body mass index, 38.1) male elite bodybuilder suffered focal muscle atrophy that developed in his right vastus lateralis muscle within a month following a painful self-administered injection of testosterone. The subject did not lose any sensory or motor function immediately after the injection; however after several days to weeks, muscle atrophy and paresthesia ensued. The subject had an obvious atrophic zone in the right vastus lateralis muscle with approximately 40% loss of strength when compared to the left leg. In our view, the neuropraxia developed from direct neurotoxic effect of androgens or pressure exerted upon the nerve following injection of a bolus of liquid. This report is indicative of the many potential dangers associated with unsupervised androgen use which may include androgens as potential neurotoxins.     

Acute brachial neuritis (Parsonage-Turner syndrome): MR imaging appearance--report of three cases

Magnetic resonance (MR) imaging findings in three patients with acute onset of neuritic shoulder pain and weakness included high signal intensity in supra- and infraspinatus muscles (n = 2), partial involvement of infraspinatus muscle (n = 1) and of deltoid muscle (n = 1), and atrophy of supra- and infraspinatus muscles (n = 2). Clinical diagnosis of acute brachial neuritis (Parsonage-Turner syndrome) correlated with MR imaging results in all cases.     

Magnetic resonance imaging of lower extremity muscles and isokinetic strength in foot dorsiflexors in patients with prior polio

The thigh and lower leg of six patients with prior polio were examined using magnetic resonance imaging (MRI), and the strength of their weak foot dorsiflexors was measured isokinetically. Spinecho images of the lower extremities were visually evaluated on a semi-quantitative four-point scale, and T1 and T2 relaxation times of the lower leg anterior compartment were analysed. There were prominent MRI signs of randomly distributed muscle degeneration. The high signal intensity changes in the affected muscles on T1-weighted images and T1 and T2 values indicated replacement of muscle fibres with fat and the accumulation of tissue water, respectively. MRI findings were compared with isokinetic strength in foot dorsiflexor muscles. Foot dorsiflexor peak torque values at 30 deg/s ranged from 6 to 29 Nm. There was no significant correlation between MRI visual scoring, T1 and T2 relaxation times and peak torque values at 30 deg/s. However, the most severe MRI changes with visual scoring and T2 relaxation times were observed in the patients with the most pronounced muscle weakness.     

Magnetic resonance imaging findings of the skeletal muscle of a patient with nemaline myopathy

This is the first magnetic resonance imaging (MRI) report of nemaline myopathy in which muscle atrophy was not apparent clinically in the lower extremities because of subcutaneous fat. The patient is a 38-year-old woman who was admitted to our hospital because of muscle weakness of the four extremities. Until the age of 17 years, she was asymptomatic except that her running speed was slow. The T1-weighted image of muscle MRI at the mid-thigh level showed hyperintensity of the quadriceps femoris muscle and relatively spared hamstring muscle. The T2-weighted image of muscle MRI at the maximum diameter of the lower leg showed hyperintensity of the tibialis anterior muscle and a relatively spared triceps surae muscle. The biopsy specimen of the right deltoid muscle showed nemaline bodies and type II fiber deficiency.     

A case of X-linked recessive bulbospinal muscular atrophy with demyelinating neuropathy and hypertrophy of the calves

We report a 53-year-old man of X-BSMA with neuropathy. The patient developed slowly progressive muscular weakness and wasting over a 2-year period with an accompanying numbness in the finger tip. He can run normally but not so fast. When he was aged 52-year old, difficulty in running progressed. General physical examination revealed nothing particular except for hypertension and gynecomastia. He showed muscular weakness and atrophy in the tongue, shoulder girdle, and upper and lower limbs. Calf muscle hypertrophies were prominent on both sides. The tendon reflexes were absent. Slight sensory impairment for vibration and pin-prick was present distally in all limbs. Autonomic nerve dysfunction was not observed. Hyperglycemia, elevated HbA1c and elevated serum CK (1,242 IU/l) were seen. The computed tomographic analyses on skeletal muscle showed hypertrophic changes in the calf muscles with a few fatty infiltrations. Electromyography showed a systemic neurogenic pattern. Motor nerve conduction velocities were slightly delayed in the lower limits. Sensory nerve action potentials were not elicited in all nerves tested. Sural nerve biopsy disclosed marked reduction of myelinated fibres for that of large diameter with thin myelin. Teased fibre studies showed a definite increase in the incidence of fibres with segmental demyelination and remyelination. In electron microscopic examination, typical or atypical onion bulb formation was observed on individual fibres. Axonal changes were minimum. We believe that segmental demyelination observed in this patient is not secondary to axonal damage. We, also, investigated AR gene abnormality by polymerase chain reaction (PCR) in this patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated with HNPP. Duplication of the same 1.5-Mb region is known to be associated with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat element (CMT1A-REP) that flanks the 1.5-Mb region involved in the duplication/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, and histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis using a CMT1A-REP probe detected a reduced hybridization signal of a 6.0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating deletion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA)n repeat and with RFLPs corresponding to loci D17S122, D17S125, and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel electrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Italian families included in this study. These findings suggest that a 1.5-Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP.     

Autosomal dominant Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies: detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118Met PMP22 point mutation

Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are the most frequent autosomal dominantly inherited disorders of the peripheral nervous system. The recessive inheritance is observed only exceptionally. Unequal crossing-over of misaligned flanking CMT1A-REP elements on chromosome 17p11.2 is the most frequent cause of the CMT1A duplication and of the reciprocal deletion in HNPP patients. Recently a recombination was noted. In our study 71 Slovene CMT1 patients from 36 families, 12 HNPP patients from 6 families and their 31 healthy relatives were analysed for the presence of these recombination mutations. In 29 of 36 unrelated CMT1 (81%) and in all 6 unrelated HNPP patients the duplication or the deletion, on chromosome 17p11.2-12 was detected. In 26 out of 29 duplication patients (CMT1A) (90%) a 3.2 kb EcoRI/SacI duplication junction fragment was observed. The analogous 7.8 kb EcoRI/EcoRI deletion junction fragment was found in 4 out of 6 unrelated HNPP deletion patients (67%). Overall we found a recombination mutation inside the in 86% of unrelated Slovene CMT1A and HNPP patients. One hundred and thirty-six DNA samples of the CMT1 and HNPP patients and of the healthy controls were negative for the potentially recessive Thr118Met PMP22 amino acid substitution. Dominantly inherited CMT1A duplications and HNPP deletions on chromosome 17p11.2 are thus, as in most other European countries, the most common mutations in Slovene CMT1 and HNPP patients. No signs of polymorphism or of potentially recessive mutation were found at the specific Thr118Met PMP22 site.