Sympathetic Deficits Research Articles

Sudomotor deficits in Parkinson's disease with special reference to motor subtypes

IntroductionParkinson’s disease which shows clinically heterogeneous motor derangement may also accompany various autonomic disorders, but results of previous research on incidence and degree of each autonomic dysfunction have been inconsistent. As for sudomotor dysfunction, some investigators emphasize hypo- or anhidrois, whereas others stress hyperhidrosis. Subjects and methodsTo elucidate sudomotor dysfunctions in Parkinson’s disease (PD) with respect to subtypes, 225 clinically probable patients PD patients were stratified by motor phenotype (tremor-dominant group: 33; mixed group: 105; and akinesia-rigidity group: 87) and subjected to thermal and acetylcholine-induced (focal) sweating tests. Thermal sweating was qualitatively assessed with a modified version of Minor’s colorimetric methods. Thermoregulatory and acetylcholine-induced focal sweat rates were measured with capacitance hydrometers. ResultsThermoregulatory sweating was almost normal without anhidrotic area in 29.8% of PD patients, slightly defective in 38.7%, with anhidrotic area across <1/4 of the body surface, moderately defective in 22.2% with anhidrotic area across approximately 1/2 of the body surface, and extremely defective in 9.3% with anhidrotic area across more than 3/4 of the body surface. Patchy sweating was observed in 104 patients, implicating involvement of the hypothalamo-spinal and/or preganglionic systems in the disease process. Hyperhidrosis was seen in 15% of patients. Tremor-dominant group showed least impairment. ConclusionThis study suggests that PD is associated with various patterns and degree of sudomotor abnormalities, and that sudomotor sympathetic deficits may be related with the pathophysiology of akinesia and rigidity rather than that of resting tremor.

Natural history study of MSA in North America: A prospective cohort study

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 ± 8.8 and at enrollment was 61.2 ± 8.04 years old. MiniMental score was 28.9 ± 1.4 indicating normal cognition. Both the E:I ratio (1.09 ± 0.08) and the Valsalva ratio (1.24 ± 0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/DBP)was 146 ± 24/82 ± 15mmHg, and heart rate (HR) was 74 ± 11 bpm (mean± SD). After 3-min head-up tilt, BP fell to 111 ± 23/67 ± 16mmHg andHR increased to 82 ± 11 bpm. Plasma norepinephrine level while supine was 278 ± 163 pg/ml and increased only to 409 ± 229 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. UPSIT score was 32.3 ± 4.1 indicating preserved olfaction. Symptoms suggesting REM behavior disorder were reported by 67%. Conclusions: Our results confirm that: i) symptom onset in MSA is remarkable consistent at 56 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) sleep behavioral problems are frequent. Longitudinal evaluation of these patients will provide additional information on the natural history of the disease.

Baseline Features of Patients with Multiple System Atrophy Enrolled in the U.S. Autonomic Disorders Consortium Natural History Study

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 ± 8.8 and at enrollment was 61.2 ± 8.04 years old. MiniMental score was 28.9 ± 1.4 indicating normal cognition. Both the E:I ratio (1.09 ± 0.08) and the Valsalva ratio (1.24 ± 0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/DBP)was 146 ± 24/82 ± 15mmHg, and heart rate (HR) was 74 ± 11 bpm (mean± SD). After 3-min head-up tilt, BP fell to 111 ± 23/67 ± 16mmHg andHR increased to 82 ± 11 bpm. Plasma norepinephrine level while supine was 278 ± 163 pg/ml and increased only to 409 ± 229 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. UPSIT score was 32.3 ± 4.1 indicating preserved olfaction. Symptoms suggesting REM behavior disorder were reported by 67%. Conclusions: Our results confirm that: i) symptom onset in MSA is remarkable consistent at 56 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) sleep behavioral problems are frequent. Longitudinal evaluation of these patients will provide additional information on the natural history of the disease.

Differential contribution of afferent and central pathways to the development of baroreflex dysfunction in chronic kidney disease

The effects of chronic kidney disease on baroreflex control of renal sympathetic nerve activity (RSNA) and deficits in afferent and central components of the baroreflex were studied in juvenile and adult male Lewis Polycystic Kidney (LPK) and control Lewis rats under anesthesia (n=35). Blood pressure (BP), heart rate (HR), aortic depressor nerve activity (ADNA), and RSNA were determined after pharmacological manipulation of BP. Responses to ADN stimulation (4.0 V, 2.0 ms, 1-24 Hz) were determined, and the aortic arch was collected for histomorphometry. In juvenile LPK versus age-matched Lewis rats, gain of RSNA (-1.5±0.2 versus -2.8±0.2%/mm Hg; P<0.05) and ADNA (2.5±0.3 versus 5.0±0.6%/mm Hg; P<0.05), but not HR barocurves, were reduced. BP, HR, and RSNA responses to ADN stimulation were normal or enhanced in juvenile LPK. In adult LPK versus age-matched Lewis, the gain and range of RSNA (gain: -1.2±0.1 versus -2.2±0.2%/mm Hg, range: 62±8 versus 98±7%) and HR (gain: -0.7±0.1 versus -3.5±0.7 bpm/mm Hg, range: 44±8 versus 111±19 bpm) barocurves were reduced (P<0.05). The gain and range of the ADNA barocurves were also reduced in adult LPK versus Lewis [1.5±0.4 versus 5.2±1.1 (%/mm Hg) and 133±35 versus 365±61 (%) P<0.05] and correlated with aortic arch vascular remodeling. BP, HR, and RSNA responses to ADN stimulation were significantly reduced in adult LPK. Our data demonstrate a deficit in the afferent component of the baroreflex that precedes the development of impaired central regulation of RSNA and HR in chronic kidney disease, and that progressive impairment of both components is associated with marked dysfunction of the baroreflex pathway.

Differential Contribution of Afferent and Central Pathways to the Development of Baroreflex Dysfunction in Chronic Kidney Disease

The effects of chronic kidney disease on baroreflex control of renal sympathetic nerve activity (RSNA) and deficits in afferent and central components of the baroreflex were studied in juvenile and adult male Lewis Polycystic Kidney (LPK) and control Lewis rats under anesthesia (n=35). Blood pressure (BP), heart rate (HR), aortic depressor nerve activity (ADNA), and RSNA were determined after pharmacological manipulation of BP. Responses to ADN stimulation (4.0 V, 2.0 ms, 1-24 Hz) were determined, and the aortic arch was collected for histomorphometry. In juvenile LPK versus age-matched Lewis rats, gain of RSNA (-1.5±0.2 versus -2.8±0.2%/mm Hg; P<0.05) and ADNA (2.5±0.3 versus 5.0±0.6%/mm Hg; P<0.05), but not HR barocurves, were reduced. BP, HR, and RSNA responses to ADN stimulation were normal or enhanced in juvenile LPK. In adult LPK versus age-matched Lewis, the gain and range of RSNA (gain: -1.2±0.1 versus -2.2±0.2%/mm Hg, range: 62±8 versus 98±7%) and HR (gain: -0.7±0.1 versus -3.5±0.7 bpm/mm Hg, range: 44±8 versus 111±19 bpm) barocurves were reduced (P<0.05). The gain and range of the ADNA barocurves were also reduced in adult LPK versus Lewis [1.5±0.4 versus 5.2±1.1 (%/mm Hg) and 133±35 versus 365±61 (%) P<0.05] and correlated with aortic arch vascular remodeling. BP, HR, and RSNA responses to ADN stimulation were significantly reduced in adult LPK. Our data demonstrate a deficit in the afferent component of the baroreflex that precedes the development of impaired central regulation of RSNA and HR in chronic kidney disease, and that progressive impairment of both components is associated with marked dysfunction of the baroreflex pathway.

Pulmonary vein isolation in patients with paroxysmal atrial fibrillation is associated with regional cardiac sympathetic denervation

BackgroundCircumferential pulmonary vein isolation (PVI) is the cornerstone of the current state-of-the-art management of atrial fibrillation (AF). However, the precise mechanisms behind AF relapses post PVI are still unknown. Since the activity of the autonomous nervous system is crucial in triggering paroxysmal AF, we hypothesized that PVI is associated with changes of cardiac sympathetic activity.MethodsSixteen patients with paroxysmal AF underwent cardiac iodine-123-meta-iodobenzylguanidine (123I-mIBG) planar cardiac imaging and single-photon emission computed tomography with low-dose computed tomography (SPECT/CT) for attenuation correction before and 4 weeks after PVI. The heart-to-mediastinum ratio (H/M ratio), washout rate (WR), regional myocardial uptake, and regional washout were analyzed.ResultsThe late H/M ratio was unchanged by PVI (pre, 2.9 ± 0.5 vs. post, 2.7 ± 0.6, p = 0.53). Four of the 16 patients (25%) displayed regional deficits before PVI. After PVI, regional deficits were present in ten patients (62.5%) with newly emerging deficits localized in the inferolateral wall. In a 6-month follow-up, four out of the ten patients (40%) with regional 123I-mIBG defects suffered from a recurrence of AF, while only one of the six patients (16.7%) without a regional 123I-mIBG defect experienced a recurrence.ConclusionA significant number of patients with paroxysmal AF show regional cardiac sympathetic innervation deficits at baseline. In addition, PVI is associated with newly emerging defects. The presence of regional sympathetic denervation after PVI may correlate with the risk of AF relapses.

Peripheral vascular response to inspiratory breath hold in paediatric homozygous sickle cell disease

New Findings• What is the central question of this study?Autonomic nervous dysfunction is implicated in complications of sickle cell anaemia (SCA). In healthy adults, a deep inspiratory breath hold (IBH) elicits rapid transient SNS- mediated vasoconstriction detectable using Laser Doppler Flux (LDF) assessment of the finger-tip cutaneous micovasculature.• What is the main finding and its importance?We demonstrate significantly increased resting peripheral blood flow and sympathetic activity in African children with SCA compared to sibling controls and increased sympathetic stimulation in response to vasoprovocation with DIG.This study is the first to observe an inverse association between resting peripheral blood flow and haemoglobin oxygen saturation (SpO2). These phenomena may be an adaptive response to the hypoxic exposure in SCA.There is increasing evidence that autonomic dysfunction in adults with homozygous sickle cell (haemoglobin SS) disease is associated with enhanced autonomic nervous system-mediated control of microvascular perfusion. However, it is unclear whether such differences are detectable in children with SS disease. We studied 65 children with SS disease [38 boys; median age 7.2 (interquartile range 5.1–10.6) years] and 20 control children without symptoms of SS disease [8 boys; 8.7 (5.5–10.8) years] and recorded mean arterial blood pressure (ABP) and daytime haemoglobin oxygen saturation (). Cutaneous blood flux at rest (RBF) and during the sympathetically activated vasoconstrictor response to inspiratory breath hold (IBH) were measured in the finger pulp of the non-dominant hand using laser Doppler fluximetry. Local factors mediating flow motion were assessed by power spectral density analysis of the oscillatory components of the laser Doppler signal. The RBF measured across the two study groups was negatively associated with age (r=−0.25, P < 0.0001), ABP (r=−0.27, P= 0.02) and daytime (r=−0.30, P= 0.005). Children with SS disease had a higher RBF (P= 0.005) and enhanced vasoconstrictor response to IBH (P= 0.002) compared with control children. In children with SS disease, higher RBF was associated with an increase in the sympathetic interval (r=−0.28, P= 0.022). The SS disease status, daytime and age explained 22% of the variance in vasoconstrictor response to IBH (P < 0.0001). Our findings suggest that blood flow and blood flow responses in the skin of young African children with SS disease differ from those of healthy control children, with increased resting peripheral blood flow and increased sympathetic stimulation from a young age in SS disease. They further suggest that the laser Doppler flowmetry technique with inspiratory breath hold manoeuvre appears to be robust for use in young children with SS disease, to explore interactions between , ABP and autonomic function with clinical complications, e.g. skin ulceration.

Impaired cerebral and systemic hemodynamics under cognitive load in young hypotensives: a transcranial Doppler study

Reduced sympathetic outflow and deficits in cerebral hemodynamics have been considered as possible factors mediating the impaired cognitive performance in essential hypotension. However, the relationship between systemic blood pressure (BP), cerebral blood flow and cognitive functioning is still poorly understood. The present study was aimed at clarifying the physiological processes underlying cerebral and systemic hemodynamics in young hypotensives during cognitive engagement. Doppler sonography blood flow velocities in both middle cerebral arteries were measured from 17 hypotensives and 15 normotensives during a working memory task. Impedance cardiographic and BP measures were also recorded continuously. Lower increases in systolic and diastolic BP were observed in hypotensives. However, no evidence of lower sympathetic control was found for this group, as assessed by pre-ejection period. Flow velocity in middle cerebral arteries showed a lower increase in hypotensives throughout the task. Moreover, significant positive correlations between BP changes and blood flow velocities in middle cerebral arteries during the task were obtained for this group only, suggesting a less effective cerebral autoregulation. No difference was found between groups in task performance. Results suggest that during cognitive challenge hypotensives show impaired hemodynamic adjustments, both central and peripheral. However, such alterations do not directly affect cognitive performance, at least under moderate cognitive load.

Pupillometry in congenital central hypoventilation syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation

Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation, autonomic nervous system (ANS) dysregulation (ANSD), and mutations in the paired-like homeobox 2B (PHOX2B) gene. ANSD in CCHS affects multiple systems and includes ophthalmologic abnormalities. We hypothesized that quantitative pupil measures, obtained using pupillometry, would vary between cases with CCHS and controls and within those with CCHS by PHOX2B genotype. Measures known to be illustrative of sympathetic and parasympathetic response (prestimulus, maximum pupil diameter, percentage of pupil constriction after light stimulus, and average constriction and dilation velocities) were significantly reduced in those with CCHS as compared with controls (all P < 0.05). These reductions are indicative of both sympathetic and parasympathetic deficits in CCHS, which is in keeping with the role of PHOX2B in ANS development. An inverse linear relationship was apparent in pupil diameter and velocity measurements among the cases with CCHS with the most common heterozygous PHOX2B polyalanine expansion repeat mutations, suggesting a graded phenotype/genotype dose response based on polyalanine repeat length. These results confirm our central hypotheses while offering the first objective measures of pupillary dysfunction and ophthalmologic-specific ANSD in CCHS. A total of 316 monocular measurements were taken under dark-adapted conditions with a fixed light stimulus from 22 PHOX2B mutation-confirmed cases with CCHS and 68 healthy controls.

Managements of vagal paragangliomas: a report of 11 cases

To study the clinical characters, diagnosis, surgical outcomes and treatment strategies of vagal paraganglioma (VP). A retrospective review was performed on 11 patients with VP confirmed by surgery and pathology between January 2000 and July 2010. Although the combined application of ultrasonography, enhanced computed tomography (CT), magnetic resonance imaging (MRI) and digital subtraction angiography (DSA), the preoperative diagnostic accuracy rate was only 27.2%. All patients were managed by surgical resection (one malignant case with postoperative radiotherapy). All patients either had or developed a vagal palsy and additional cranial nerve or sympathetic nerve deficits were sustained in 8 patients after operation. With a median follow-up time of 41 months (range: 4 - 132 months), one case lost and the others survived without local recurrence or distant metastasis. VP are rare and liable to misdiagnose. For increasing the preoperative diagnosis rate of VP, the combined application of imaging tests is important and clinicians and radiologists should also enhance the awareness of this disease. Postoperative complications including nerve injury are inevitable and individual treatment is required.

Correction for Bengoechea et al., p75 reduces β-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model

Correction for Bengoechea et al., p75 reduces β-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model

P75 reduces β-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model

Beta-amyloid (Abeta) has adverse effects on brain cells, but little is known about its effects on the peripheral nervous system in Alzheimer's disease (AD). Several lines of in vitro evidence suggest that the neurotrophin receptor p75 mediates or exacerbates Abeta-induced neurotoxicity. Here, we show that p75-deficient sympathetic neurons are more sensitive to Abeta-induced neurite growth inhibition. To investigate the role of p75 in the sympathetic nervous system of AD, p75 mutant mice were crossed with a mouse line of AD model. The majority of p75-deficient AD mice died by 3 weeks of age. The lethality is associated with severe defects in sympathetic innervation to multiple organs. When 1 copy of the BACE1 gene encoding a protein essential in Abeta production was deleted in p75-deficient AD mice, sympathetic innervation was significantly restored. These results suggest that p75 is neuroprotective for the sympathetic nervous system in a mouse model of AD.

Cardiac sympathetic denervation and its association with cognitive deficits in Parkinson's disease

BackgroundThere is growing evidence to suggest that cognitive decline in patients with Parkinson's disease (PD) is associated with autonomic involvement, although the clinical and pathological correlations have not been firmly established. ObjectiveWe prospectively investigated the pattern of myocardial sympathetic denervation deficits in PD and its correlation with cognitive decline. MethodsTwenty-eight patients with PD who underwent myocardial 123I-metaiodobenzylguanidine (MIBG) scintigraphy, clinical assessment of stage and severity of PD and detailed neuropsychological investigation were included in the study. ResultsThere were significant differences in the MIBG uptake between the PD patients with cognitive deficits and those who did not have cognitive deficits. ConclusionThese findings confirm that cognitive decline in patients with PD is associated with autonomic involvement and raises the possibility that the topographical spread of synuclein pathology involving the neocortical areas might be linked to the autonomic system in PD.

Pupil evaluation as a test for autonomic disorders

Pupil tests provide a convenient and simple method for evaluation of autonomic function. Most patients with autonomic disorders show evidence of sympathetic or parasympathetic deficits in the pupil, and these can be detected using a combination of clinical signs, pupillometric tests (measuring the responses to light, or an accommodative effort, or a sudden noise) and pharmacological tests (using topically applied drugs both to confirm a deficit and to localize the lesion). Caution is needed in the interpretation of these tests, particularly if the deficits are mixed (i.e. sympathetic and parasympathetic) or bilateral. The pattern of autonomic disturbance in the pupils often correlates poorly with autonomic function elsewhere, but may have diagnostic value in discriminating between different underlying conditions.

Harlequin Syndrome: Still Only Half Understood

Sympathetic vasodilatory and sudomotor fibers from the stellate ganglion mediate the principal reflex control of human facial thermoregulatory flushing and sweating (1,2). Heat stress, exercise, or sudden emotion in the patient with hemifacial cutaneous sympathetic denervation may elicit a dramatic

Pupil Abnormalities in Selected Autonomic Neuropathies

Examination of the pupil provides an opportunity to detect disturbances in the autonomic innervation of the eye. The pupil is frequently affected in patients with generalized autonomic neuropathies. This literature review confirms a high prevalence of sympathetic deficits and parasympathetic deficits in acute or subacute dysautonomia, diabetes, amyloidosis, pure autonomic failure, paraneoplastic syndromes, Sjögren syndrome, familial dysautonomia, and dopamine beta-hydroxylase deficiency. It confirms the relative scarcity of a pupil abnormality in patients with multiple system atrophy. There are difficulties in clinical diagnosis of pupil abnormalities and interpretation of pupil pharmacologic tests, particularly when combined sympathetic and parasympathetic deficits are present.

Harlequin Syndrome with Crossed Sympathetic Deficit of the Face and Arm

Harlequin syndrome is characterized by unilateral hyperhidrosis and flushing, which are predominantly induced by heat or exercise. Usually, the sympathetic deficits confine to the face. Rarely, the autonomic deficits involve the arm or the parasympathetic neurons in the ciliary ganglia. We report a 43-yr-old woman who presented with facial flushing and sweating in the right side, which were mainly induced by exercise. The facial flushing accompanied relative coldness in the right arm. Valsalva maneuver, cold pressure and 0.125% pilocarpine test, and computed tomography of the chest were normal. The crossed sympathetic deficit in the left face and right arm suggested that the lesions were multifocal. The sympathetic impairment in our patient may lie on a spectrum of pre- and postganglionic autonomic dysfunction, which was observed in Holmes-Adie, Ross, and Guillain-Barré syndrome.

Inactivation of one copy of the mouse neurotrophin-3 gene induces cardiac sympathetic deficits

Whether two copies of the neurotrophin-3 (NT3) gene are necessary for proper development of cardiac sympathetic innervation was investigated in mice carrying a targeted inactivation of the NT3 gene. Heterozygous (+/-) and null (-/-) mutant mice had fewer stellate ganglion neurons than did wild-type (+/+) mice at postnatal day 0 (P0 or birth), and this deficit was maintained between adult (P60) +/- and +/+ mice. The sympathetic innervation of the heart matured postnatally in +/+ and +/- mice. Tyrosine hydroxylase (TH)-positive axons were restricted largely to the epicardium at P0, were concentrated around large blood vessels in the myocardium at P21, and were present among cardiac myocytes at P60. Cardiac norepinephrine (NE) concentrations paralleled the growth of the sympathetic axons into the heart. NE concentrations were equivalent among +/+, +/-, and -/- mice at birth, but differences between +/- and +/+ mice increased with age. Adult +/- mice also exhibited lower resting heart rates and sympathetic tonus than +/+ mice. Thus deletion of one copy of the NT3 gene translates into anatomical, biochemical, and functional deficits in cardiac sympathetic innervation of postnatal mice, thereby indicating a gene-dosage effect for the NT3 gene.

A New Method for Detecting Bilateral Horner's Syndrome

Unilateral sympathetic deficits (i.e., miosis, ptosis, and redilatation lag) make unilateral Horner's syndrome recognizable, but bilateral Horner's

Effects of nerve growth factor on splenic norepinephrine and pineal N-acetyl-transferase in neonate rats exposed to alcohol in utero: Neuroimmune correlates

Prenatal alcohol exposure (FAE) has been associated with multiple anomalies, including a selective developmental delay of sympathetic innervation in lymphoid organs. Sympathetic neurons require nerve growth factor (NGF) for their development and maintenance, and recent evidence has suggested that alcohol impairs the synthesis and/or biological activity of NGF in selected central and peripheral neurons. Thus, the present study examined the hypothesis that NGF administration to FAE rats during early postnatal development would reverse some of the peripheral sympathetic deficits. Neonate rats, FAE and the corresponding control cohorts, received daily treatments of NGF or cytochrome C (0.3 mg/kg; s.c.) for various time intervals, and were killed 24hr or 10 days after the last treatment. The measured parameters included norepinephrine (NE) concentrations in the spleen and heart, which receive noradrenergic innervation from the coeliac ganglion and the superior cervical ganglion (SCG), respectively. In addition, we measured the activity of pineal N-acetyltransferase (NAT), the rate-limiting enzyme of melatonin biosynthesis, which depends on sympathetic innervation from the SCG. The data show that chronic, but not acute, NGF treatments reversed the FAE-related deficits in splenic NE concentrations as well as in pineal NAT activity in a time- and age-dependent manner. Sympathetic neurons play an important role in immune modulation. Thus, the altered splenic NE levels and pineal NAT activity may play a role in immune deficits associated with exposure to alcohol in utero.