Taiji Tsunemi

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

AbstractThe 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA; Online Mendelian Inheritance in Man [OMIN] #117210) is one of the most common ADCAs in Japan. Previously, we had reported that the patients share a common haplotype by founder effect and that a C-to-T substitution (−16C>T) in the puratrophin-1 gene was strongly associated with the disease. However, recently, an exceptional patient without the substitution was reported, indicating that a true pathogenic mutation might be present elsewhere. In this study, we clarified the disease locus more definitely by the haplotype analysis of families showing pure cerebellar ataxia. In addition to microsatellite markers, the single nucleotide polymorphisms (SNPs) that we identified on the disease chromosome were examined to confirm the borders of the disease locus. The analysis of 64 families with the −16C>T substitution in the puratrophin-1 gene revealed one family showing an ancestral recombination event between SNP04 and SNP05 on the disease chromosome. The analysis of 22 families without identifiable genetic mutations revealed another family carrying the common haplotype centromeric to the puratrophin-1 gene, but lacking the −16C>T substitution in this gene. We concluded that the disease locus of 16q-ADCA was definitely confined to a 900-kb genomic region between the SNP04 and the −16C>T substitution in the puratrophin-1 gene in 16q22.1.

Marked hypertrophy of the cauda equina in a patient with chronic inflammatory demyelinating polyradiculoneuropathy presenting as lumbar stenosis.

Sirs: Hypertrophy of peripheral nerves and enlargement of nerve roots have been reported in some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [4]. We report a patient with CIDP who suffered from intermittent claudication as a rare manifestation of enlargement of the cauda equina. A 63-year-old male was admitted to our hospital in 2001 complaining of difficulty in walking and recurrent pain in the legs. The patient had noticed slight atrophy of the muscles in the left hand in 1980. In 1996, he noticed numbness of both feet. In March 1999, intermittent claudication appeared: he noticed tingling pain in the lower thigh, which worsened after ambulation for several hundred meters and ameliorated after a rest. He was diagnosed as having lumbar stenosis by an orthopedist. However, his condition continued to worsen and he could not walk without assistance after six months. Physical examinations showed severe wasting of muscles and distal dominant sensory loss. Drop foot was observed. Hypertrophic peripheral nerve trunks were not found. Tendon reflexes were absent without pathological reflexes. Routine laboratory tests including serum autoantibodies against gangliosides and DNA analysis for P0, connexin 32 and PMP 22 genes were normal. Cerebrospinal fluid (CSF) contained a markedly elevated protein (952 mg/dl). Motor nerve conduction velocity of the right median nerve was extremely slowed (28.6 m/s) with marked dispersion of action potentials. Compound muscle action potentials of both lower extremities and all sensory nerve action potentials were not detectable. Needle electromyography showed typical findings of reinnervation without evidence of ongoing denervation. MRI of the lumbar spine showed marked enlargement of the cauda equina and spinal nerve roots (Fig. A, C). The spinal subdural space was occupied with enlarged cauda equina (Fig. A). Patchy enhancement of these hypertrophic tissues was observed (Fig. B). The biopsy specimen of the right sural nerve showed severe depletion of myelinated fibers with onion-bulb formations (Fig. D). Electron microscopy showed myelinated fibers surrounded by several layers of Schwann cells (Fig E). The patient was diagnosed as having definite CIDP [7]. Initial treatment with oral prednisolone was ineffective. The patient received three courses of intravenous immunoglobulin therapy (IVIG, 0.5 g/kg), which ameliorated the weakness of the muscles and the intermittent claudication. A diagnosis as a lumbar stenosis was initially raised when the patient complained of the slowly progressive onset of leg pain and gait disturbance including intermittent claudication. However, absence of tendon jerks and a distal weakness in the upper limbs hinted at a more diffuse neuropathy, and subsequent examinations fulfilled the criteria for the diagnosis of CIDP. Apparent effects of IVIG treatment also supported the diagnosis of CIDP. Hypertrophy of peripheral nerves and spinal nerve roots is a well-known presentation of CIDP. However, CIDP presenting initially with symptoms of lumbar stenosis is rare; only eight cases have been reported so far [2, 3, 5, 6, 8]. Among these patients, two underwent nerve biopsy and the biopsy specimens showed marked onion-bulb formations [3, 5]. Therefore, the pathomechanism of nerve root hypertrophy may be attributed to repeated segmental demyelination and remyelination along with onion-bulb formations. Neurogenic intermittent claudication is one of the characteristic symptoms of lumbar stenosis in which hypertrophy of osseous and soft tissue structures surrounding the lumbar canal causes entrapment of the cauda equina nerve roots [1]. As in our patient, the structures around the lumbar canal were intact in contrast to marked hypertrophy of the cauda equina, that is, occupation of lumbar canal by hypertrophic nerve roots caused relative narrowing of lumbar canal, which led to symptoms similar to “true” lumbar stenosis. In conclusion, this case is of particular interest because it shows that “apparent” lumbar stenosis associated with marked hypertrophy of nerve roots can develop during the course of CIDP.

Reversible central neurogenic hyperventilation in an awake patient with multiple sclerosis.

Sirs: Central neurogenic hyperventilation (CNH) is a rare respiratory condition characterized by sustained hyperventilation. We present the first report of CNH successfully treated in an awake patient in multiple sclerosis (MS). A 43-year-old woman was admitted because of sudden gait disturbance, dysarthria and worsening of visual acuity. She had suffered from left and right optic neuritis 6 months and 18 months before admission, respectively. Steroid treatment partially improved her visual acuity. On admission she was fully awake. Her respiratory pattern was sustained, rapid (24 breaths/min), regular, deep, and unchanged during sleep but voluntarily changeable. Restricted left eye movement in all directions, horizontal gaze nystagmus in both eyes and ataxic speech was observed. Deep tendon reflexes were increased in four limbs without pathological reflexes. Arterial blood gas (ABG) values were PaO2 95.9 mm Hg, PaCO2 28.2 mm Hg, and pH 7.486. The patient’s hyperventilation was not psychogenic, because hyperpnea and respiratory alkalosis had been continued during sleep, after receiving intravenous 10 mg midazolam, and after breathing into a paper bag for 5 min. Chest X-ray, pulmonary function test and blood sample analysis revealed no abnormalities. Lactate concentrations in serum and cerebrospinal fluid (CSF) were within reference intervals. CSF analysis revealed cell count 11/mm3 without malignant cell, protein concentrations 0.35 g/L, pH 7.661. Multiple oligoclonal bands were detected in CSF but not in serum. The brain MRI showed many lesions spreading throughout the pons and midbrain (Fig.1A, B) and small number of supratentorial lesions (Fig.1C). The spinal cord was intact. We excluded other differential diagnosis and diagnosed the patient’s illness as MS, according to McDonald criteria [1]. After treatment with high-dose intravenous methylprednisolone, some of her symptoms improved but visual acuity and hyperventilation did not. Although there is not much evidence that plasma exchange is effective for an acute attack in MS [2], plasma exchange was reported to be effective for severe optic neuritis [3], or neuromyelitis optica (Davic’s disease) [4]. To prevent complete blindness, we performed plasma exchange six times. After these therapies, her visual acuity and hyperventilation gradually improved. After 52 days from admission, respiratory rate normalized to 16 breaths per minute and ABG values were PaO2 95.5 mm Hg, PaCO2 38.8 mm Hg, and pH 7.403. Lesions previously detected on brain MRI were markedly decreased (Fig.1D–F). CNH is defined as sustained hyperventilation persisting during sleep, normal or increased arterial oxygen tension, decreased arterial carbon dioxide tension, and respiratory alkalosis in the absence of cardiac disease, pulmonary disease, and respiration-stimulating drugs [5]. Our patient’s hyperventilation met the definitive criterion for CNH. CNH is usually seen in deeply comatose patients and rarely in conscious patients [5]. To the best of our knowledge, 27 cases in conscious patients have been reported. All reported cases were associated with brainstem tumor [6, 8–12], except a case after bilateral medial thalamic infarction [7]. The pathophysiological mechanisms that lead to CNH are still unknown. From the fact that CNH are frequently associated with brainstem tumors, both structural and chemical factors have been considered. One hypothesis is that a destructive lesion in the medial pons would interrupt descending inhibitory impulses to the medullary respiratory centers and produce CNH. The alternate hypothesis is local lactate production could stimulate medullary chemoreceptors and cause CNH. However, these two hypotheses did not account for all cases with CNH. Recently, a third hypothesis was reported. From a study using rats or cats, chemical stimulation of lateral parabrachial neurons in the pons increased respiratory rate, tidal volume or both [13]. Tarulli et al. reported that tumorous infiltration in these neurons caused CNH [6]. The current lesions are diffusely distributed in pons including parabrachial neurons; therefore, the mechanism of CNH in this case can be explained by all three explanations. Respiratory complications are relatively uncommon in MS [14] and CNH has not been reported. LETTER TO THE EDITORS

Creutzfeldt-Jakob disease after jannetta's operation with cadaveric dura mater graft: initial manifestations related to the grafted site

Sirs: Patients with CreutzfeldtJakob disease (CJD) may be associated with iatrogenic transmission including brain or eye surgery, cadaveric pituitary extracts for growth hormone or gonadotropin therapy, and implantation of cadaveric dura mater grafts during neurosurgical procedures [2]. In recent years dural graft-associated cases have been increasing in number, especially in Japan [4, 11]. We describe an autopsy-confirmed case of CJD, in which cadaveric dura mater graft was implanted in the right posterior cranial fossa for Jannetta’s operation 167 months before the onset. The patient presented with vertigo and nystagmus as initial manifestations, and neuro-otological examinations suggested an initial lesion adjacent to the grafted site. A 69-year-old woman developed vertigo in the middle of May 1998. On 19 July 1984, 167 months before the onset of the vertigo, the patient underwent Jannetta’s operation for right hemifacial spasm to reduce vascular compression to the right facial nerve, and received a lyophilized cadaveric dural patch (Lyodura®) for the repair of a dural defect covering the surface of the right cerebellar hemisphere. The operation was successful and she left the hospital with neither facial spasm nor other neurological symptoms. Since her vertigo worsened, the patient was admitted to our Otorhinolaryngological Clinic on 14 July 1998. On admission, her mental status appeared normal. Neurological examinations showed no abnormalities except for neurootological findings. In the ocular movement, smooth pursuit was impaired bilaterally (Fig. 1a). The response to optokinetic stimulation was also impaired. There was spontaneous nystagmus toward right direction under calculation task with eyes open in the dark room. Saccadic eye movement was not impaired. The patient occasionally complained of diplopia when she was gazing toward right or upward, although there appeared to be no limitation in the range of the eye movement. These findings suggested that the right side of flocculus and paraflocculus would be damaged with mild involvement of the right oculomotor nucleus [9], and that the cerebellar vermis was not affected [9]. On 21 July, up-beat nystagmus was observed in a positioning test, and visual suppressions in bilateral caloric tests were disturbed. Impairment of smooth pursuits (Fig. 1b), visual suppression, and the response to optokinetic stimulation rapidly worsened, and dysmetria in the saccade test was observed. These suggested that cerebellar vermis and fastigial nucleus were also impaired [9]. On 4 August, fast phase velocity toward the right was revealed to be slow. Thereafter, her spontaneous speech much decreased, and abnormal behavior appeared. The patient was admitted to our Neurological Clinic on 13 August. On admission, she was alert, however orientation for time and place and calculation were severely impaired; other cognitive functions could not be evaluated. The patient showed no vertigo, diplopia, or nystagmus. Although movements were generally slow, muscle tone and power were normal. There was no involuntary movement including myoclonus. Tendon reflexes were all normal. Babinski’s sign was negative bilaterally. Her gait was ataxic; however, the finger-to-nose test, pronation-supination movement, and heel-to-knee test were normal. Romberg sign was negative. Sensory and autonomic systems were normal. Blood and urinary examinaLETTER TO THE EDITORS

Direct and accurate measurement of CAG repeat configuration in the ataxin-1 (ATXN-1) gene by “dual-fluorescence labeled PCR-restriction fragment length analysis”

AbstractSpinocerebellar ataxia type 1 (SCA1; OMIM: #164400) is an autosomal dominant cerebellar ataxia caused by an expansion of CAG repeat, which encodes polyglutamine, in the ataxin-1 (ATXN1) gene. Length of polyglutamine in the ATXN1 protein is the critical determinant of pathogenesis of this disease. Molecular diagnosis of SCA1 is usually undertaken by assessing the length of CAG repeat configuration using primers spanning this configuration. However, this conventional method may potentially lead to misdiagnosis in assessing polyglutamine-encoding CAG repeat length, since CAT interruptions may be present within the CAG repeat configuration, not only in normal controls but also in neurologically symptomatic subjects. We developed a new method for assessing actual CAG repeat numbers not interrupted by CAT sequences. Polymerase chain reaction using a primer pair labeled with two different fluorescences followed by restriction enzyme digestion with SfaNI which recognizes the sequence “GCATC(N)5”, lengths of actual CAG repeats that encode polyglutamine were directly detected. We named this method “dual fluorescence labeled PCR-restriction fragment length analysis”. We found that numbers of actual CAG repeat encoding polyglutamine do not overlap between our cohorts of normal chromosomes (n = 385) and SCA1 chromosomes (n = 5). We conclude that the present method is a useful way for molecular diagnosis of SCA1.