A Japanese familial ALS patient with autonomic failure and a p.Cys146Arg mutation in the gene for SOD1 (SOD1).

We describe a Japanese man with familial amyotrophic lateral sclerosis (ALS) associated with a p.Cys146Arg mutation in the copper/zinc superoxide dismutase gene (SOD1). The patient developed bulbar signs followed by rapidly progressive limb muscle weakness. The prominent clinical feature was orthostatic hypotension due to autonomic failure, which occurred after he underwent tracheostomy 1 year and 3 months after the onset. Thereafter, he required mechanical ventilation and progressed to communication stage V (totally locked-in state) 7 years after the onset. Neuropathology showed ALS with posterior column degeneration and multiple system degeneration. Severe neuronal loss in the intermediolateral nucleus was also observed. Two previously reported cases of ALS patients with autonomic failure showed severe neuronal loss in the intermediolateral nucleus in addition to degeneration of the motor neurons. Thus, autonomic failure due to neuronal loss in the intermediolateral nucleus could present in patients with ALS associated with certain mutations in SOD1.

ß-1 and ß-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening.

Variation in the beta-1 and beta-2 adrenergic receptor genes (ADRB1 and ADRB2, respectively) may influence cardiovascular reactivity including orthostatic stress. We tested this hypothesis in a head-up tilt (HUT) screening protocol in healthy young adults without history of syncope. Following brachial arterial catheter insertion, 120 subjects (age 18-40, 72 females, Caucasian) underwent 5min 60° HUT. Polymorphisms tested were: Ser49/Gly and Arg389/Gly in ADRB1; and Arg16/Gly, Gln27/Glu, and Thr164/Ile in ADRB2. Three statistical models (recessive, dominant, additive) were evaluated using general linear models with analysis for each physiologic variable. A recessive model demonstrated a significant association between Arg16/Gly and: absolute supine and upright HR; HUT-induced change in cardiac index (CI), stroke index (SI) and systemic vascular resistance (SVR); and supine and upright norepinephrine values. Blood pressure was not influenced by genotype. Fewer associations were present for other polymorphisms: Ser49/Gly and the change in SI (dominant model), and Arg389/Gly and supine and HUT norepinephrine (additive model). We conclude that in this population, there is a robust association between Arg16/Gly and HUT responses, such that 2 copies of Arg16 increase supine and upright HR, and greater HUT-induced decreases in CI and SI, with greater increases in SVR and norepinephrine. ADRB1 gene variation appears to impact SI and plasma NE levels but not HR. Whether ADRB2 gene variation is ultimately disease-causing or disease-modifying, this study suggests an association between Arg16/Gly and postural hemodynamics, with sympathetic noradrenergic activity affected in a similar direction. This may have implications in the development of orthostatic disorders.

The Lewis family revisited: no evidence for autosomal dominant multiple system atrophy.

In 1964, Lewis reported a familial ataxia-dysautonomia syndrome reminiscent of Shy-Drager syndrome subsequently known as multiple system atrophy (MSA). Here we review this report and propose that the Lewis family may represent an unusual form of autosomal dominant cerebellar ataxia type I, which might be categorized either as SCA3 (Machado-Joseph disease) or a new SCA subtype. There remains no conclusive evidence to support the notion of hereditary MSA.

Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression.

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease.

Mutations in the PINK1 gene cause autosomal recessive parkinsonism characterized by early onset and a variable phenotypic presentation. A patient homozygous for the Ala168Pro mutation has been fully characterized clinically. Apart from onset at age 39 years and the excellent and sustained response to levodopa, all clinical and laboratory features, including SPECT and assessment of autonomic function, were indistinguishable from typical idiopathic Parkinson disease.

Structure of the human histamine H3 receptor gene (HRH3) and identification of naturally occurring variations.

Neurotransmitter release is modulated by presynaptic histamine H(3) receptors located on histaminergic, noradrenergic and other nonhistaminergic neurons of the central and peripheral nervous system. Here, we report the determination of the structure of the human histamine H(3) receptor gene (HRH3) and the identification of a missense mutation (Ala280Val) in a patient with Shy-Drager syndrome. The coding region of the gene consists of three exons interrupted by two introns of approximately 1 kb in size. Exon boundaries only partly correspond to transmembrane domain organization. The homozygous Ala280Val variation in the third intracellular loop of the histamine H(3) receptor of a patient with Shy-Drager syndrome may be related to the etiology of the illness due to altered norepinephrine release. Furthermore, knowledge of the gene structure allows the verification of alternative splicing of the receptor. The corresponding histamine H(3) receptor isoforms as reported for the guinea pig and rat histamine H(3) receptor in different brain regions are not found in the human brain.

Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Neurolab Autonomic Team.

Orthostatic intolerance is a common problem for inbound space travelers. There is usually tachycardia on standing but blood pressure may be normal, low or, rarely, elevated. This condition is analogous to the orthostatic intolerance that occurs on Earth in individuals with orthostatic tachycardia, palpitations, mitral valve prolapse, and light-headedness. Our studies during the Neurolab mission indicated that sympathetic nerve traffic is raised in microgravity and that plasma norepinephrine is higher than baseline supine levels but lower than baseline upright levels. A subgroup of patients with familial orthostatic intolerance differ from inbound space travelers in that they have an alanine-to-to-proline mutation at amino acid position 457 in their norepinephrine transporter gene. This leads to poor clearance of norepinephrine from synapses, with consequent raised heart rate. Clinical features of these syndromes are presented.

Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy.

Glial cytoplasmic inclusions (GCI) characteristically occur in the oligodendrocytes of patients with multiple system atrophy (MSA). However, the molecular mechanisms underlying GCI formation are unknown. To investigate whether these inclusions are related to proline-directed protein kinases that have been associated with neuronal inclusion bodies in some other neurodegenerative diseases, we immunohistochemically probed tissue samples from MSA brains with a panel of antibodies against cyclin-dependent kinases and mitogen-activated protein kinase. We unexpectedly detected cyclin-dependent kinase 5- (cdk5) and mitogen-activated protein kinase- (MAPK) immunoreactivities in GCI. We also found TAU1 immunoreactivity in GCI, and a strong expression of microtubule-associated protein (MAP) 2 immunoreactivity in oligodendrocytes of MSA brains. This immunoreactivity was not observed in the normal or neurological controls. The accumulated evidence suggest a close association between GCI and the microtubular cytoskeleton. Cdk5 phosphorylates tau and MAP2, and MAPK is capable of phosphorylating MAP2. The present results suggest that the aberrant or ectopic expression of cdk5 and MAPK causes abnormal phosphorylation of microtubular cytoskeletal proteins, thus leading to GCI formation in affected oligodendrocytes.

Facial myokymia in multiple system atrophy.

Two patients are described with clinical and neuroimaging features consistent with a diagnosis of multiple system atrophy (MSA). The patients are unusual in that facial myokymia became apparent clinically at some stage in their illness. In each patient, the nature and severity of the involuntary facial movements evolved over the course of the illness. Electrophysiologically the movement pattern was consistent with myokymia, and studies of blink-reflex responses suggested that the myokymic discharges were of brainstem origin. Involuntary facial movements described as facial action myoclonus with electrical characteristics consistent with myoclonus have been described previously in hereditary olivopontocerebellar atrophy (OPCA). Our report describes electrical and clinical features of facial myokymia in MSA with electrical features suggesting hyperexcitability of the facial motorneurons in the brainstem. Such myokymic movements may occur more frequently in MSA than previously recognised but may be missed clinically because of their evolving nature.

Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation.

We studied 60 patients with multiple system atrophy and autonomic failure and 60 control subjects matched for age, sex and race. Their psychosocial history, pedigree and occupation were obtained by personal interview. An inventory of autonomic and neurologic symptoms was obtained from 148 first-degree relatives of the patients and 80 controls by a self-administered questionnaire. Patients with multiple system atrophy had significantly more potential exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides than the control population. The potential exposures were determined in most subjects by their reported usual occupation. Clinical symptoms of multiple system atrophy were reported by a significantly larger group of patients' relatives than controls. These findings are possibly consistent with the hypothesis that multiple system atrophy develops as a result of a genetically determined selective vulnerability in the nervous system. Specific neuronal systems may become targets for environmental insults or toxins, and the disease state may occur when ageing neuronal systems can no longer sustain functional capacity. This preliminary study supports the need to further explore possible environmental, occupational, and familial contributions to the aetiology of multiple system atrophy.