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.     

Small cell lung cancer associated with subacute sensori-motor neuropathy in a patient whose symptoms subsided during chemotherapy

A 71-year-old man was referred to us with diplopia, left peripheral facial nerve dysfunction, ataxic gait and dysesthesia of the extremities. Neurological examination revealed mild reduction of sensation to pinprick and light touch in the left dominant lower leg. His standing position was wide based, and he showed Romberg's sign. The patient also presented signs of left peripheral facial, bilateral abducent, and left oculomotor nerve dysfunction. Serum levels of CEA, CA 19-9, and proGRP were high. 67Gallium scintigraphy showed an accumulation of radioactivity at the hilum of the right lung, and the findings of bronchofiberscopy were compatible with the diagnosis of small cell lung cancer. Because the symptoms gradually worsened to the point that the patient could not move by himself, chemotherapy and radiotherapy were initiated 3 months after the onset of symptoms. While under chemotherapy, symptoms of neuropathy subsided and the patient was able to walk with the aid of a walking stick. Although all symptoms were indicative of carcinomatous neuropathy, no antineuronal antibodies were detected in the patient's serum by immunohistochemical techniques. However, because the lung cancer deteriorated gradually despite therapy, the patient died of respiratory failure. At autopsy, tumor metastases were found in the pericardium, left lung, both adrenal glands, right hilum lymph nodes, and mediasternal lymph nodes. No microscopic signs of metastases were found in the frontal, parietal, temporal, or occipital lobes, or in the basal ganglia, thalamus, midbrain, pons, cerebellar vermis and hemispheres, or upper medulla. Histopathologically, there was no degeneration of neuronal cell bodies in cerebellar or cervical dorsal root ganglia; however, almost total loss of myelinated fibers or variegated demyelination of myelinated fibers was observed in the anterior, lateral and posterior funiculus at both cervical segments of the spinal cord. The number of myelinated fibers was smaller in the 5th and 6th cervical left ventral roots. The reason why the patient's symptoms subsided during chemotherapy was probably a suppression of antineuronal antigen by chemotherapy and the repair of myelinated fibers.     

Familial amyloid polyneuropathy related to transthyretin mutation Val30 to Leu in a Japanese family

A rare variant transthyretin that has a leucine-for-valine substitution at position 30 was reported in a sporadic case of type 1 familial amyloid polyneuropathy (FAP). We found the same substitution in members of a Japanese family with FAP. Three individuals in this family had a guanine-to-cytosine mutation at the first base of codon 30 in exon 2. This family shows a direct link between a valine-to-leucine substitution at position 30 and type 1 FAP.     

Transthyretin amyloidosis (serine 44) with headache, hearing loss, and peripheral neuropathy

A 32-year-old man of Irish descent presented with severe progressive headache and sensorineural hearing loss. MRI/magnetic resonance angiography head scans were normal. A length-dependent sensorimotor peripheral neuropathy with autonomic dysfunction predated these symptoms. Systemic organ involvement and transthyretin (TTR) amyloid immunostaining of bone marrow and fat aspirate were documented. Direct DNA sequencing revealed both the normal TTT (phenylalanine) and a new variant TCT (serine) at position 44 of the TTR gene. This case expands the genotypic and phenotypic variability within TTR amyloidosis.     

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.     

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.     

Hereditary motor and sensory neuropathy with calf hypertrophy is associated with 17p11.2 duplication

The demyelinating type of hereditary motor and sensory neuropathy (HMSN I) is characterized by progressive weakness and atrophy of leg muscles. Six patients (age, 25-79 yr) belonging to three generations had calf hypertrophy (6 of 6), foot drop or difficulty with heel walking (4 of 6), pes cavus (3 of 6), absent or depressed tendon jerks in the lower limbs (4 of 6), and mild distal sensory loss (3 of 6). No other family member had leg atrophy. Motor conduction velocities ranged from 20 to 40 m/sec. Sural nerve biopsy showed loss of large myelinated fibers, numerous onion bulbs, and segmental demyelination and remyelination. Computed tomographic scans of leg muscles and histological and morphometric findings in gastrocnemius revealed true muscular hypertrophy. Southern blot and fluorescence in situ hybridization documented the duplication of the entire 17p11.2 segment associated with classical HMSN IA. The pathogenesis of muscle hypertrophy in our cases is unclear. Chronic leg muscle weakness and long-standing partial denervation might cause calf enlargement by a combination of compensatory "work-induced" and "stretch-induced" fiber hypertrophy. Alternatively, that all the affected family members presented calf hypertrophy might suggest the action of a genetic factor associated with the duplication at 17p11.2.     

Atypical parkinsonism in a family of Portuguese ancestry: absence of CAG repeat expansion in the MJD1 gene

We studied the clinical features and molecular genetics of a family, afflicted with a form of atypical parkinsonism, originating from the Madeira Islands of Portugal. We examined four affected individuals and reviewed clinical information on one other affected family member. Mean age at onset was 31 years. Parkinsonism (akinesia, rigidity, gait disturbance) was the most prominent feature in advanced disease. Levodopa responsiveness with peak-dose dyskinesia was present in one individual. Initial symptoms and other clinical features were variable and included other extrapyramidal signs (dystonia, action tremor of the limbs and bulbar muscles, synkinesis), ophthalmologic abnormalities (ptosis, slow saccades, progressive external ophthalmoplegia, hypometric saccades, saccadic pursuit movements), speech abnormalities (dysarthria, hypernasality), cortical impairment (dementia, frontal lobe dysfunction, palilalia, perseveration), minor cerebellar signs (dysmetria, gait ataxia), pyramidal abnormalities (spasticity, hyperreflexia), and peripheral nervous system abnormalities (propioceptive loss, areflexia, distal weakness, atrophy). The length of trinucleotide repeats in the MJD1 gene was in the normal range for all affected individuals.     

A trinucleotide deletion in the transthyretin gene (delta V 122) in a kindred with familial amyloidotic polyneuropathy

A 63-year-old white man of Ecuadorian origin had a subarachnoid hemorrhage at age 57 followed by numbness and paresthesia in his lower extremities. He subsequently developed sexual impotence, alternating constipation and diarrhea, urinary frequency, and difficulty in walking. Rectal biopsy revealed amyloid deposits immunohistochemically reactive with antitransthyretin antisera. Direct DNA sequencing of the transthyretin gene of the patient showed a trinucleotide deletion in exon 4. This deletion resulted in the loss of one of two valines at position 121 or 122. DNA analysis on 11 family members at risk revealed four mutant gene carriers. Plasma transthyretin levels in the mutant gene carriers measured by nephelometry were very low. Peptide sequence analysis revealed that most of plasma transthyretin was normal with only a small amount of variant protein. This is the first report of a DNA deletion in the transthyretin gene. We speculate that the loss of valine in the carboxyl terminal region of the transthyretin monomer alters stability of the tetrameric protein, which leads to rapid clearance from the plasma and amyloid deposition in the tissue.     

Functional differentiation of human naive helper T cells

Here we report a case of a 56-year-old male with post-poliomyelitis muscular atrophy (PPMA), who presented with cranial nerve signs and widespread atrophy of the extremities. He had suffered from poliomyelitis at the age of 2 years. After recovery from the acute stage, the paralysis remained in his left arm. He noticed muscle weakness of the right upper and lower extremities at the age of 45 years and the muscle atrophy progressed to his arms, hip and thigh at the age of 55 years. Neurological examination revealed muscle atrophy of the neck and disturbance of left V, VIII, IX, X and bilateral XI cranial nerves. We diagnosed this case as PPMA from his history and electromyographic and muscle biopsy findings which suggested chronic denervation. Among the 21 PPMA cases in the past in which the acute poliomyelitis had resulted in paralysis of the only one limb, ours was the only case that had muscle atrophy of all the limbs. Cranial nerve involvement is known to occur in acute poliomyelitis; therefore, there is a possibility that the involvement of the cranial nerves in our case might be a delayed progressive symptoms.     

Charcot-Marie-Tooth disease. Clinical study in 45 patients

Charcot-Marie-Tooth (CMT) disease is the commonest inherited peripheral neuropathy. The clinical study of 45 patients with CMT is presented. They were derived from Antonio Pedro Hospital of Universidade Federal Fluminense in Niteroi, RJ, Brazil. Such patients could be divided by the motor conduction velocity in two types: a demyelinating form or type I (11 cases) and an axonal form or type II (34 cases). The disease was inherited as an autosomal dominant trait in 23 patients and as an autosomal recessive trait in 7 cases. In 15 patients the disorder was sporadic. The age of onset was in most of our cases before the 20 years. All of them had distal weakness in lower limbs. 38.2% had also distal weakness in upper limbs. 80% had distal wasting of the lower limbs and 50% had distal wasting of upper limbs. The tendon reflexes were absent in 64% in lower limbs and in 28% in upper limbs. The sensitive impairment in the distal regions of the extremities was mild in most patients. We found enlargement of peripheral nerves in 7 patients of type I. Pes cavus was present in 21 cases and scoliosis in 7. We found postural tremor of hands in 6 patients. In 9 cases there were rare features as mental retardation, trigeminal nevralgia, optic atrophy, deafness and calf enlargement. In most of our cases the clinical course was very slow progressive. A greater severity was seen in our sporadic cases.     

Progressive central and peripheral demyelinating disease of adult onset in a Norwegian family

OBJECTIVE: To describe the clinical features of a Norwegian family with a combined central and peripheral demyelinating disease. DESIGN: Multiple case report. SUBJECTS AND MATERIALS: Three generations of a Norwegian family. Medical records were available for all 9 members of the second generation and 5 affected members in the third generation. RESULTS: At least 5 members had clinical features, neuroimaging findings, and electrophysiologic signs indicating a chronic progressive disorder affecting both the central and peripheral nervous systems. The clinical symptoms developed between the ages of 30 and 70 years in affected family members, who gradually developed sensory loss, muscle deterioration, and distal weakness in all extremities, unsteady gait, and dysarthria. Five of 9 persons in the second generation had strokes and experienced mental deterioration. The initial stroke episodes were recognized between the ages of 54 and 68 years, and death occurred between the ages of 62 and 75 years. In 7 subjects, cerebrospinal fluid protein levels were increased, and in 5 agar gel electrophoresis indicated blood-brain barrier dysfunction. Seven family members had neuroimaging signs of a widespread white matter disorder. In 4 subjects, neurophysiological investigations indicated a polyneuropathy, and in 3 subjects, results from a sural nerve biopsy showed a demyelinating neuropathy. There was no evidence of co-inheritance with genetic markers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (19p), PMP22 (17q), APP (21q), CMTX1 (Xq), or PLP (Xq). CONCLUSIONS: Progressive central and peripheral demyelinating disease seems to be a distinct type of hereditary adult-onset demyelinating disorder affecting both the peripheral and central nervous systems. Its exact nature remains unknown.     

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We report a case of transient left lateral gaze paresis due to a hemorrhagic lesion restricted in the right precentral gyrus. A 74-year-old female experienced a sudden clumsiness of the left upper extremity. A neurological examination revealed a left central facial paresis, distal dominant muscle weakness in the left upper limb and left lateral gaze paresis. There were no other focal neurological signs. Laboratory data were all normal. Brain CTs and MRIs demonstrated a subcortical hematoma in the right precentral gyrus. The neurological symptoms and signs disappeared over seven days. A recent physiological study suggested that the human frontal eye field (FEF) is located in the posterior part of the middle frontal gyrus (Brodmann's area 8) and the precentral gyrus around the precentral sulcus. More recent studies stressed the role of the precentral sulcus and the precentral gyrus. Our case supports those physiological findings. The hematoma affected both the FEF and its underlying white matter in our case. We assume the lateral gaze paresis is attributable to the disruption of the fibers from the FEF. It is likely that fibers for motor control of the face, upper extremity, and lateral gaze lie adjacently in the subcortical area.     

A Japanese family with paramyotonia congenita which has a mutation in the muscle sodium channel gene

We report here a Japanese family with paramyotonia congenita. The proband was a 42-year-old woman (case 1), who noticed muscle stiffness and weakness in the cold since the age of 7 years. These symptoms were alleviated by warming. Her eldest son (case 2) also experienced similar symptoms, while her younger son and daughter were healthy. Neurological examination in case 1 revealed mild weakness in facial and neck muscles. Cold-induced muscle stiffness and weakness were present. Electromyography showed myotonic discharges, intensified by cooling or repetitive exercise. The amplitude of the compound muscle action potentials was also reduced by the repetitive exercise and cooling. Serum chemistry including potassium and CK was normal. Molecular analysis of SCN4A (exon22-24) by SSCP and nucleotide sequencing revealed a C-to-T transition at nucleotide 3,938, causing a substitution of 1313methionine of threonine in case 1. This mutation was confirmed by PCR-RFLP with a mismatched primer; the proband (case 1) and her eldest son (case 2) had a heterozygous mutation, while the other family members did not. This is the first report that a mutation in SCN4A was identified in a Japanese family with paramyotonia congenita.     

Neurologic complications in a case of Werner syndrome

A 39 year old caucasian man was admitted in 1994 to the neurological department with a left pure motor hemiplegia that appeared suddenly. This patient showed typical features of Werner's syndrome. He had a hoarse voice, a diffuse muscle weakness and atrophy in the upper and lower limbs with chronic ulcers on the legs. His scalp and public hair were sparse. Cranial MRI revealed several lesions in the white matter, low signal intensity on T1 weighted images and high signal on T2 weighted images. Cerebrospinal fluid (CSF was inflammatory with hypercytosis and proteinorachia was 0.50 g/l with synthesis of IgG. Sural nerve biopsy revealed muscle atrophy and the loss of myelinated fibers. Thus, central and peripheral nervous systems were affected in this case.     

Progressive juvenile segmental spinal muscular atrophy

Juvenile segmental spinal muscular atrophy (JSSMA) typically involves the distal upper extremities and follows a benign course over 2-4 years then stabilizes. We report 2 males who presented in their teens with insidious distal upper extremity atrophy and weakness as in typical JSSMA but who then progressed to involvement of the lower extremities and hyperreflexia. There was no sensory loss. Electromyography and muscle biopsy demonstrated features consistent with localized anterior horn cell dysfunction. These patients are noteworthy because they demonstrate that some patients with JSSMA also may have involvement of the lower limbs several years after initial presentation. Progressive JSSMA may be categorized in the clinical spectrum between the spinal muscular atrophies and amyotrophic lateral sclerosis.     

Cataract extraction as a means of treating postfiltration hypotony maculopathy

A 13-year-old warmblood mare was presented because of progressive weight loss, general weakness and trembling. On examination the horse stood with its head lowered and the limbs placed under the body. On lifting its head spasms of the neck muscles could be observed. At the same time the horse developed trembling over the lower neck and muscle fasciculations continued over the whole body. Additional signs included frequent recumbency, polyphagia and facial hyperaesthesia. The horse showed no signs of ataxia. Haematology was normal. Blood biochemistry revealed slight increased aspartate aminotransferase (AST: 1060 U/I) and creatine kinase levels (CK: 441 U/I). Based on the clinical findings equine motor neuron disease was diagnosed. The horse was euthanatized due to poor prognosis and the progression of symptoms. The typical neurodegenerative changes found on histological examination of the spinal cord confirmed the diagnosis.     

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.     

Familial amyloidotic polyneuropathy type I with extracellular superoxide dismutase mutation: a case report

We report an autopsy case of familial amyloidotic polyneuropathy (FAP) Type I with mutations in both transthyretin (TTR) and extracellular superoxide dismutase (EC-SOD). This patient started to develop peripheral neuropathy at age 25, followed by cardiac, renal, and autonomic nervous system failure due to massive amyloid deposition. Thirteen years after the initial symptoms, he died of septic shock. Autopsy revealed suppurative peritonitis, multiple abscesses in the bile ducts and urinary tract, and more marked amyloid deposition than commonly seen in FAP. Amyloid deposition occurred in various organs and tissues, especially prominently around blood vessels and in interstitial tissues, and was demonstrated immunohistochemically to be composed of TTR but not amyloid A (AA) and not amyloid L (AL) proteins. The serum EC-SOD content of the patient was 10 fold higher than those seen often in other FAP patients and in healthy controls. Genetic analysis demonstrated the single amino acid substitutions in Val30Met TIR and Arg213Gly EC-SOD. Since these data suggest the dissociation of EC-SOD from the vascular wall, massive amyloid deposition in the present case may be related to increased oxidative stress in loco.     

Primary meningeal lymphoma in a horse

Primary meningeal lymphoma was diagnosed in an 18-year-old Morgan gelding. The horse was examined because of a 3-day history of progressive ataxia and weakness. The gait abnormalities were worse on the left side, and the pelvic limbs were more affected than the thoracic limbs. Additional findings included signs of depression, miosis of the left pupil, ptosis of the left upper eyelid, and areas of muscle atrophy on the left side of the neck and over the dorsal aspect of the left scapula. Inflammatory changes were evident in the CSF. At necropsy, there was diffuse and irregular thickening of the dura mater along the entire spinal cord. Histologic examination revealed infiltration of the leptomeninges with neoplastic lymphocytes.