Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation

OBJECTIVE: To report the clinical manifestations and functional aspects of Tuberous Sclerosis Complex (TSC), resulting from Codon 905 mutations in TSC2 gene. METHODS: We performed a detailed study of the TSC phenotype and genotype in a large French-Canadian kindred (Family A). Subsequently, clinical and molecular data on 18 additional TSC families with missense mutations at the same codon of TSC2 were collected. Functional studies were performed on the different missense changes and related to the phenotype. RESULTS: A 2714G>A (R905Q) mutation was identified in Family A. The TSC phenotype in this family was unusually mild and characterized by hypomelanotic macules or focal seizures that remitted spontaneously or were easily controlled with medication. Diagnostic criteria were met in only a minority of mutation carriers. Other families with the R905Q mutation were found to have a similar mild phenotype. In contrast, patients with a 2713C>T (R905W) or a 2713C>G (R905G) mutation had more severe phenotypes. Although all three amino acid substitutions were pathogenic, the R905W and R905G substitutions affected tuberin function more severely than R905Q. INTERPRETATION: Codon 905 missense mutations in TSC2 are relatively common. The TSC2 R905Q mutation is associated with unusually mild disease, consistent with functional studies. Combined with previous reports, it is apparent that certain TSC2 missense mutations are associated with a mild form of tuberous sclerosis, which in many patients does not meet standard diagnostic criteria. These findings have implications for the large number of patients with limited clinical features of TSC and for genetic counseling in these families.     

Acute intermittent porphyria presenting as acute pancreatitis and posterior reversible encephalopathy syndrome

Acute intermittent porphyria (AIP) is an inherited metabolic disease that can affect the autonomic, peripheral and central nervous systems. Pancreatic diseases assocated with AIP is rarely reported. We report here a 60-year-old non-alcoholic male who had typical manifestations of AIP, including abdominal pain, constipation, tachycardia, hypertension, mental disturbances, psychiatric manifestations, seizures, peripheral neuropathy, and excessive excretion of porphyrin precursors in urine. Increases of serum amylase and lipase, as well as mild pancreatic edema on ultrasonography, were noted during the acute attack of AIP, suggesting concomitant acute pancreatitis. In this patient, brain magnetic resonance imaging revealed reversible multifocal cerebral lesions resembling a posterior reversible encephalopathy syndrome (PRES) during the acute attack of AIP. Because the clinical manifestations of acute pancreatitis could be present with an acute attack of AIP, early confirmation of diagnosis is mandatory to effectively manage the attack and avoid inappropriate treatment.     

Ischemia may be the primary cause of the neurologic deficits in classic migraine

This study investigates whether the cerebral blood flow reduction occurring in attacks of classic migraine is sufficient to cause neurologic deficits. Regional cerebral blood flow measured with the xenon 133 intracarotid injection technique was analyzed in 11 patients in whom a low-flow area developed during attacks of classic migraine. When measured with this technique, regional cerebral blood flow in focal low-flow areas will be overestimated because of the effect of scattered radiation (Compton scatter) on the recordings. In this study, this effect was particularly taken into account when evaluating the degree of blood flow reduction. During attacks of classic migraine, cerebral blood flow reductions averaging 52% were observed focally in the 11 patients. Cerebral blood flow levels known to be insufficient for normal cortical function (less than 16 to 23 mL/100 g/min) were measured in seven patients during the attacks. This was probably also the case in the remaining four patients, but the effect of scattered radiation made a reliable evaluation of blood flow impossible. It is concluded that the blood flow reduction that occurs during attacks of classic migraine is sufficient to cause ischemia and neurologic deficits. Hence, this study suggests a vascular origin of the prodromal neurologic deficits that may accompany attacks of classic migraine.     

血卟啉病的神经系统表现分析

为了探讨血卟啉病神经系统表现规律,增加对本病的认识,并给临床医生提供一个实用的临床诊断和治疗方法。笔者报道了2例,加上国内近10年报道的13例,本文对此15例进行了全面的分析,对该病的发病机制、分类、临床表现、诊断、治疗及预后进行了系统的讨论。结果发现血卟啉病神经系统表现为周围感觉运动神经病4例、内脏自主神经病9例、抽搐发作4例及精神症状6例。我们报道的例2中有枕叶梗塞所致的皮层盲,国外少见,国内未见报道。血、尿中尿卟啉、粪卟啉及前体的测定是诊断有关键,避免诱因、静脉滴注血红素及葡萄糖是主要的治疗手段。     

Seizure phenotypes of a family with missense mutations in SCN2A

The seizure phenotypes of a Japanese family with missense mutations in SCN2A are described. The proband of the family had partial epilepsy after febrile seizures plus. He had three missense mutations of SCN2A (R19K, R188W, and R524Q). The R188W mutation was suggested by electrophysiologic studies to be the main disease mutation. However, it is suggested that the penetrance rate of this pedigree is extremely low, or that other genes may have modified the phenotype of the proband.     

Prenatal stroke in a neonate heterozygous for factor V Leiden mutation

The authors report an infant with congenital hemiplegia associated to heterozygosity for factor V Leiden. Prenatal stroke in the left cerebral hemisphere was diagnosed by ultrasonography at the 28th week of pregnancy, and followed up until birth. Although neonatal neurologic examination was normal, a moderate right hemiparesis developed along the 1st months of life. Coagulation studies performed in the neonatal period and at the age of 18 months revealed activated protein C resistance due to factor V Leiden mutation (R506Q). There are some previous reports of stroke associated to this mutation in near or at term neonates, but to our knowledge this is the stroke detected at the most early stage of fetal development.     

Cerebral blood flow variations in CNS lupus

We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery.     

脑出血患者屏氧酶1基因192位Gln-Arg多态性的研究

目的　探讨屏氧酶 1( PON1)基因 192位 Gln- Arg( Q/ R192 )多态性与脑出血关系。方法　应用聚合酶链式反应 -限制性片段长度多态性 ( PCR- RFL P)方法 ,对 30 5例脑出血患者和 339例正常对照者 PON1Q/ R192基因多态性进行研究。结果　在脑出血组中 ,PON1Q/ R192 3种基因型频率分别为 QQ13.1%、QR4 8.2 %、RR38.7%。PON1Q/ R192基因型和等位基因频率分布在脑出血组与对照组之间无显著性差异 ( P>0 .0 5 ) ;各基因型之间血脂水平无显著性差异 ( P>0 .0 5 )。结论　研究未发现 PON1Q/ R192基因多态性与脑出血存在相关关系     

Cortical amaurosis and status epilepticus with acute porphyria

The most common neurologic manifestations of acute intermittent porphyria (AIP) are autonomic visceral neuropathy, peripheral motor neuropathy, and CNS dysfunctions including seizures and neuropsychiatric disturbances. In rare instances, however, AIP patients have presented with acute cortical blindness. We present a 20-year-old woman who suffered her first attack of AIP. Following 1 week of abdominal pain, she was transferred from a surgical department because of sudden visual loss and deterioration of consciousness. On admission, she developed several generalized seizures. Magnetic resonance imaging showed bilateral DWI lesions occipitally and in the left anterior circulation. Cerebrospinal fluid, MR angiography, and duplex ultrasound were normal. On the following day, sedation and intubation became necessary because of a generalized status epilepticus. Analysis of porphyrinogens in blood, urine and stool showed significantly elevated values. Intravenous therapy with h?m-arginate was initiated and antiepileptic therapy was changed to gagabentine. Under this therapeutical regime she remained stable and extubation was possible 48 h later.     

Regional cerebral blood flow characteristics of the Sturge-Weber syndrome

Four patients with the Sturge-Weber syndrome were studied using the non-invasive Xenon-133 inhalation technique. All four patients had decreased regional cerebral blood flow in the area of their lesion, and in two patients who were subsequently tested with 5% carbon dioxide inhalation, impaired vasomotor reactivity was documented. Diminished regional cerebral blood flow is consistent with previously described nuclide flow studies which demonstrated a delay in the initial perfusion blush in the region of the abnormal vasculature. The focal decrease in blood flow was greatest in the most severely affected patient, but was also prominent in the two younger patients, both of whom have excellent neurologic function. These studies suggest that localized decrease in blood flow and vasomotor dysfunction in Sturge-Weber syndrome can precede the occurrence of severe neurologic impairment and extensive cerebral atrophy and possibly be a major contributing factor in progressive dysfunction. A secondary observation was that the blood flow in the unaffected hemisphere was significantly greater in two children compared to the two adults and was similar to the age-related differences reported for normal children and adults.     

Complex neurologic syndrome associated with the G1606A mutation of mitochondrial DNA

OBJECTIVES: To confirm the pathogenicity of the G-to-A substitution at nucleotide 1606 (G1606A) mutation in the mitochondrial DNA (mtDNA) tRNA(Val) gene, and to characterize genotype-phenotype correlation. PATIENT AND METHODS: A 37-year-old man since childhood developed a complex clinical picture characterized by hearing loss, migraine, ataxia, seizures, cataracts, retinitis pigmentosa, mental deterioration, and hypothyroidism. Magnetic resonance imaging revealed diffuse calcification of the basal ganglia and cerebral cortical atrophy. Morphologic and biochemical studies of respiratory chain complexes were performed in skeletal muscle. All 22 mitochondrial tRNA genes were screened for mutations by direct sequencing. RESULTS: Biochemical analysis showed normal activities of respiratory chain enzymes and citrate synthase; morphologic examination showed scattered ragged-red fibers and poor or absent cytochrome c oxidase staining in 10% of the fibers. A heteroplasmic G1606A transition in the mtDNA tRNA(Val) gene was found. Mutant DNA was 70% of the total in the proband's muscle. The mutation was absent in blood samples and urinary sediment from his healthy brother and mother. CONCLUSION: This second patient with the G1606A mutation confirms both the pathogenicity of the mutation and its association with a characteristic complex neurologic phenotype.     

The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice

Gaucher disease (GD), caused by a defect of acid β-glucosidase (β-Glu), is one of the most common sphingolipidoses. Recently, ambroxol, an FDA-approved drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified as a chemical chaperone for GD. In the present study, we investigated the chaperone activity and toxicity of ambroxol on both cultured GD patient cells and normal mice. We found that ambroxol treatment significantly increased N370S, F213I, N188S/G193W and R120W mutant β-Glu activities in GD fibroblasts with low cytotoxicity. Additionally, we measured the β-Glu activity in the tissues of normal mice which received water containing increasing concentrations of ambroxol ad libitum for one week. No serious adverse effect was observed during this experiment. Ambroxol significantly increased the β-Glu activity in the spleen, heart and cerebellum of the mice. This result showed its oral availability and wide distribution and chaperone activity in the tissues, including the brain, and its lack of acute toxicity. These characteristics of ambroxol would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations.     

Zur Diagnostik der akuten intermittierenden Porphyrie: Ergebnisse neurologischer,biochemischer und genetischer Untersuchungen

Zusammenfassung An vier AIP-Familien mit 21 Mitgliedern führten wir neurologisch klinische und biochemische Untersuchungen durch. Fünf Patienten litten an manifester AIP (Uroporphyrinogen-Synthase-Defekt und charakteristische Urinbefunde), unter ihren Angeh?rigen fanden wir fünf Personen mit latenter AIP und acht Tr?ger des genetisch-enzymatischen Defektes (Uroporphyrinogen-Synthase-Defekt). Internistische und neurologische Symptome konnten i. S. einer Panneuropathie gedeutet werden. Neben akuten und chronischen Polyneuropathien sahen wir auch Myelopathien und encephale Mitreaktionen. Ein h?ufiges Symptom der Krise und Latenzphase waren ?tiologisch unklare Myalgien. Die AIP-Verlaufsform ist unterschiedlich: neben sog. „klassischen“ Verl?ufen mit intermittierenden porphyrischen Krisen sahen wir einen Fall, der durch eine permanente Krisensituation gekennzeichnet war, und einen zweiten Fall, der sich durch einen langsam chronisch-progredienten Verlauf ohne jegliche porphyrische Krise auszeichnete.

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Diagnosis of acute intermittent porphyria: Results of neurological, biochemical, and genetic studies

Summary Neurological and biochemical studies have been performed on four AIP families with 21 members. Five patients suffered from manifested AIP (Uroporphyrinogen Synthase defect and characteristic urine findings); among their relatives five persons with latent AIP were detected and eight carriers of the genetic-enzymic defect (Uroporphyrinogen Synthase defect). Internal and neurological symptoms could be interpreted as a panneuropathy. Acute and chronical polyneuropathies could be observed as well as myelopathies and cerebral co-reactions. A frequent symptom dominating the crisis and the latent state of AIP were etiologically abscure ‘myalgias.’ The character of the course of AIP is various and dubious: beyond the ‘classical’ courses with its intermittent porphyric crises we observed one case which was characterized by a permanent crisis and a second case marked by a chronical, slow progredient course without any porphyric attacks.

     

Focal chronic ischemia and concomitant migraine: an atypical form of Sturge-Weber angiomatosis?

A young man with a left hemifacial hemangioma had during a six months period about forty left hemispheric neurologic attacks suggestive of classic migraine. The neurologic examination was normal during the attack-free period. The CT scan (fig. 1) and the M.R.I. study (fig. 2) only showed a moderate interhemispheric asymmetry. The left internal carotid angiogram showed subtle anomalies of the venous system (fig. 3). All the neurologic manifestations ceased as soon as therapy by aspirin was initiated. A Positron Emission Tomography (PET) study with the oxygen 15 continuous inhalation technique was performed 7 months after the last attack in order to measure the regional Cerebral Blood Flow (rCBF), Oxygen Extraction Fraction (rOEF) and Oxygen Consumption (rCMRO2). Striking, statistically significant, alterations were observed in the left temporo-parieto-occipital area (fig. 4) consisting of a "misery perfusion" syndrome (rCBF = 28-38 ml/100 g/mn; rOEF = 0.64-0.80), without alteration in the rCMRO2 (Table). A repeated PET study 12 months later was unchanged. The association of local chronic oligemia and ipsilateral facial hemangioma, ipsilateral cerebral hypotrophy and venous anomalies suggested the diagnosis of atypical leptomeningeal angiomatosis of the Sturge-Weber type. The importance and persistence of the hemodynamic alterations suggest that chronic oligemia and, hence, tissue hypoxia may participate in the pathogenesis of the migraine-like attacks. Moreover, local circulatory stasis with thrombotic events may be implicated, as suggested by the apparent efficacy of aspirin.     

Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy

Introduction: A case series of acute intermittent porphyria (AIP) is described that focuses on the clinical course of the disease with regard to neurological manifestations of the peripheral nervous system. Methods: Eight patients were diagnosed with AIP on the basis of characteristic clinical findings, erythrocyte porphobilinogendeaminase activity, neuropathic patterns, serial changes in nerve conduction studies (NCS), and temporal relationship of central nervous system involvement. Results: Six patients diagnosed with AIP <2 months after symptom onset had neuropathy that was predominantly upper extremity, motor, and proximal. NCS recovery rates were slower in the lower than the upper limbs. Two patients diagnosed >2 months after symptom onset had distal sensorimotor polyneuropathy. Conclusions: The findings from this case series suggest that the peripheral nerves may be differentially and selectively involved in different diagnostic stages of porphyric neuropathy. Muscle Nerve 51 : 363–369, 2015     

A review of neurological sequelae and cognitive deficits associated with antiphospholipid antibodies.

Antiphospholipid Antibodies (aPAs) are specific circulating immunoglobulins that lead to a hypercoagulant state and recurrent arterial and venous thromboembolic events. The cerebral circulation is the most common site of arterial occlusion in aPAs, and neurologic events include amaurosis fugax, migrainous cephalalgia, transient ischemic attacks (TIA), stroke, ischemic encephalopathy, and vascular dementia. A review of the literature yields numerous studies citing neurocognitive and neuropsychiatric symptoms associated with this syndrome in a much younger population than is seen in other cerebrovascular disorders. These associated features include focal and generalized cognitive deficits, early-onset vascular dementia, and neuropsychiatric symptoms such as affective and thought disorders. These neurocognitive and neurobehavioral manifestations may be underemphasized in this population and aPAs should be considered in a differential diagnosis. Largescale prospective studies are needed to quantify psychiatric and neuropsychological sequelae of this disorder.     

抑肽酶佐治脑出血的临床研究

目的　观察抑肽酶辅助治疗脑出血脑水肿的疗效及安全性。方法　收集脑出血患者 41例 ,分为 2组 ,抑肽酶治疗组 2 1例 ;对照组 2 0例。治疗前后进行神经功能评分 ,CT下测量水肿体积。结果　 (1 )入院后 1、2、3周用欧洲脑卒中量表进行神经功能评分 ,抑肽酶治疗组分值高于对照组 (P <0 .0 5)。 (2 )水肿产生量治疗组少于对照组 (P <0 .0 5)。结论　脑出血急性期加用抑肽酶可以抑制脑水肿的形成 ,提高脑出血患者神经功能评分 ,抑肽酶佐治脑出血脑水肿优于单独使用甘露醇     

Cyclosporine A neurotoxicity among bone marrow transplant recipients

Cyclosporine A (CsA) neurotoxicity is an iatrogenic disease with significant morbidity and occasional mortality. We retrospectively reviewed the cases of CsA neurotoxicity among bone marrow transplant recipients at our institution, and summarized the current literature on the subject. The neurologic presentation is varied and the neurologic manifestations are reversible, even after prolonged toxicity, in most instances. Serum CsA level is useful in evaluation, as the level is high in most instances. However, in a case of suspected neurotoxicity, withdrawal of the drug is the only way of determining presence or absence of such toxicity. The electrophysiologic studies, especially electroencephalogram (EEG), is very sensitive in identifying the problem, but lacks specificity. On the other hand, the neuroimaging studies are helpful in making a diagnosis if they show characteristic findings of hyperintense lesions affecting posterior cerebral regions on T2 weighted magnetic resonance images (MRI) or white matter hypodensities on computed tomographic (CT) scan. These lesions are probably due to breakdown of blood-brain barrier resulting in leakage of fluid in interstitial space. The breakdown could be serious enough to cause microhemorrhages that may coalesce to produce macrohemorrhages.     

Safety of fluoxetine treatment in a case of acute intermittent porphyria

Acute intermittent porphyria (AIP) is a metabolic disease characterized by recurrent attacks of neurological and psychiatric dysfunction. It is a rare disorder of heme metabolism that usually presents with abdominal pain, gastrointestinal symptoms and autonomic nervous system disturbances. Exposure to certain drugs, dieting, starvation and infection during pregnancy may precipitate AIP attacks. Psychiatric manifestations of AIP include mood changes, organic brain syndrome and psychosis. Here, we present a 21-year-old female patient with AIP and major depression. She had a caesarean section under general anesthesia with pentothal and her recovery time from anesthesia took longer than usual. She had a blood transfusion because of severe anemia following the operation. Three days after her discharge she was readmitted to the hospital with confusion and seizure. It was her first AIP attack and it started 6 days after caesarean section. Two months after her first attack, we saw her for anxiety and depressive symptoms. She was in severe anxiety and depression and she was put on fluoxetine (20 mg/day liquid form). Following the treatment she did not develop any other porphyria attack. Her symptoms vanished and she improved functionally. She stayed on fluoxetine for 6 months without any new AIP attack. Despite limited data regarding fluoxetine therapy in porphyria patients, it seems to be safe for the treatment of depressive and anxiety symptoms in these patients.     

Kearns-Sayre syndrome with a novel mitochondrial DNA deletion

We describe a 17-year-old boy with a clinical neurologic picture consistent with Kearns-Sayre syndrome. His manifestations included progressive external ophthalmoplegia, bilateral ptosis, retinitis pigmentosa, and muscle weakness. He was found to harbor an abundant novel deletion in skeletal muscle mitochondrial DNA. Biochemical analysis of the patient's biopsied skeletal muscle showed that the specific activities of all four respiratory complexes with mitochondrial DNA-encoded subunits were markedly reduced in contrast to normal activity levels of entirely nuclear DNA-encoded enzyme activities (eg, complex II and citrate synthase). Ultrastructural analysis also indicated the presence of strikingly abnormal mitochondria with both unusual cristae and frequent paracrystalline inclusions. The great amount of the deleted mitochondrial DNA in this patient's muscle, as well as the concomitant reduction in specific respiratory complex activity, suggests that the mitochondrial DNA deletion plays a role in the pathogenesis of this neurologic disease.