Is disabling fatigue in childhood influenced by genes?

Abstract:

BACKGROUND: Medically unexplained chronic fatigue in childhood may cause considerable disability and (by definition) its cause remains unclear. A study of fatigue in healthy twins has been undertaken to examine whether or not genetic factors play a part.

METHOD: A questionnaire survey of the main carers of an epidemiological population-based sample of 670 twin pairs who were asked about periods of unexplained and disabling fatigue in their twins. Out of 1340 individuals a period of disabling fatigue was reported for 92 (6.9%). Thirty-three (2.5%) reported disabling fatigue for more than 1 month. Zygosity could be confidently assigned in 98% of the sample providing 278 monozygotic (MZ) and 378 dizygotic (DZ) pairs. These data were analysed using a structural equation modelling approach.

RESULTS: The results showed that disabling fatigue in childhood is highly familial with an MZ tetrachoric correlation (rMZ) of 0.81 and a DZ tetrachoric correlation (rDZ) of 0.59, for fatigue lasting at least a week. The most acceptable model using Akaike’s information criteria, was one containing additive genetic effects (A) and shared environment (C) plus residual (or non-shared) environment (E). For fatigue lasting at least a month rMZ was 0.75 and rDZ 0.47. The most acceptable model included just A and E. However, the role of shared environment could not be conclusively rejected.

CONCLUSIONS: Unexplained disabling fatigue in childhood is substantially familial. Both genetic and shared environmental factors are worth further exploration in a search for the causes.

 

Source: Farmer A, Scourfield J, Martin N, Cardno A, McGuffin P. Is disabling fatigue in childhood influenced by genes? Psychol Med. 1999 Mar;29(2):279-82. http://www.ncbi.nlm.nih.gov/pubmed/10218919

 

Unique genetic and environmental determinants of prolonged fatigue: a twin study

Abstract:

BACKGROUND: Prolonged fatigue syndromes have been proposed as prevalent and disabling forms of distress that occur independently of conventional notions of anxiety and depression.

METHODS: To investigate the genetic and environmental antecedents of common forms of psychological and somatic distress, we measured fatigue, anxiety, depression and psychological distress in 1004 normal adult twin pairs (533 monozygotic (MZ), 471 dizygotic (DZ)) over 50 years of age.

RESULTS: Familial aggregation of psychological distress, anxiety and fatigue appeared to be due largely to additive genetic factors (MZ:DZ ratios of 2.12-2.69). The phenotypic correlations between the psychological measures (distress, anxiety and depression) were moderate (0.67-0.79) and higher than that between fatigue and psychological distress (0.38). Multivariate genetic modelling revealed a common genetic factor contributing to the development of all the observed phenotypes (though most strongly for the psychological forms), a second independent genetic factor also influenced anxiety and depression and a third independent genetic factor made a major contribution to fatigue alone. In total, 44% (95% CI 25-60%) of the genetic variance for fatigue was not shared by the other forms of distress. Similarly, the environmental factor determining psychological distress made negligible contributions to fatigue, which was underpinned largely by its own independent environmental factor.

CONCLUSION: This study supports the aetiological independence of prolonged fatigue and, therefore, argues strongly for its inclusion in classification systems in psychiatry.

 

Source: Hickie I, Kirk K, Martin N. Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychol Med. 1999 Mar;29(2):259-68. http://www.ncbi.nlm.nih.gov/pubmed/10218917

 

Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome

Abstract:

Patients with the chronic fatigue syndrome (CFS) complain consistently of delay in recovery of peripheral muscle function after exercise. The purpose of this study was to try to confirm this observation.

A fatiguing exercise test was carried out on the quadriceps muscle group of ten patients and ten control subjects. The test consisted of 18 maximum voluntary contractions (MVCs) with a 50% duty cycle (10 s contraction, 10 s rest), and the force generated by each contraction was recorded using a KinCom dynamometer. This was followed by a recovery phase lasting 200 min in which quadriceps strength was evaluated at increasing intervals, and a follow-up session at 24 h post-exercise involving three 10 s MVCs.

Throughout the exercise period, the MVCs obtained from the control group were significantly higher than those of the patient group (P = 0.006), but both groups showed a parallel decline in force over the 18 contractions, in keeping with a similar endurance capacity.

Recovery was prolonged in the patient group, however, with a significant difference compared to initial MVCs being evident during the recovery phase after exercise (P = 0.001) and also at 24 h (P < 0.001). In contrast, the control group achieved MVCs which were not significantly different from initial values during the recovery phase, and maintained these at 24 h.

These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.

Copyright 1999 Lippincott Williams & Wilkins

 

Source: Paul L, Wood L, Behan WM, Maclaren WM. Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. Eur J Neurol. 1999 Jan;6(1):63-9. http://www.ncbi.nlm.nih.gov/pubmed/10209352

 

Managing chronic fatigue syndrome: overview and case study

Abstract:

1. The basic principles of envelope theory are explained. By not overexerting themselves, people with CFS can avoid the setbacks and relapses that commonly occur in response to overexertion while increasing their tolerance to activity. 2. By collecting time series data on fluctuations in energy levels, important clinical observations can be made in respect to a client’s unique condition and experience with CFS.

 

Source: Jason LA, Melrose H, Lerman A, Burroughs V, Lewis K, King CP, Frankenberry EL. AAOHN J. 1999 Jan;47(1):17-21. http://www.ncbi.nlm.nih.gov/pubmed/10205371

 

Cardiovascular response during head-up tilt in chronic fatigue syndrome

Abstract:

This study examined the cardiovascular response to orthostatic challenge, and incidence and mechanisms of neurally mediated hypotension in chronic fatigue syndrome (CFS) during a head-up tilt test. Stroke volume was obtained by a thoracic impedance cardiograph, and continuous heart rate and blood pressure were recorded during a 45-min 70 degrees head-up tilt test.

Thirty-nine CFS patients and 31 healthy physically inactive control subjects were studied. A positive tilt, i.e. a drop in systolic blood pressure of > 25 mmHg, no concurrent increase in heart rate and/or development of presyncopal symptoms, was seen in 11 CFS patients and 12 control subjects (P > 0.05). During baseline and the first 5 min of head-up tilt, CFS patients had higher heart rate and smaller pulsatile-systolic area than control subjects (P < 0.05). Among subjects who completed the test, those with CFS had higher heart rate and smaller stroke volume (P < 0.05) than corresponding control subjects.

When comparing those who had a positive test outcome in each group, CFS patients had higher heart rates and lower pulse pressure and pulsatile-systolic areas during the last 4 min before being returned to supine (P < 0.05).

These data show that there are baseline differences in the cardiovascular profiles of CFS patients when compared with control subjects and that this profile is maintained during head-up tilt. However, the frequency of positive tilts and the haemodynamic adjustments made to this orthostatic challenge are not different between groups.

 

Source: LaManca JJ, Peckerman A, Walker J, Kesil W, Cook S, Taylor A, Natelson BH. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol. 1999 Mar;19(2):111-20. http://www.ncbi.nlm.nih.gov/pubmed/10200892

 

Chronic fatigue syndrome

Comment on: Phosphate diabetes in patients with chronic fatigue syndrome. [Postgrad Med J. 1998]

 

Sir, De Lorenzo and colleagues’ report a previously undefined relationship between chronic fatigue syndrome (CFS) and phosphate diabetes. They also report that mean serum phosphate concentration was found to be significantly lower in CFS patients than in control subjects. They explain their findings by the hypothesis that CFS patients have a metabolic defect that is secondary to their chronic underutilisation of skeletal muscle. Another hypothesis can, however, be proposed.

Hypophosphataemia in sepsis has been recently reported to be associated with high levels of tumour necrosis factor-a and interleukin-6.’ However, these inflammatory cytokines are also produced to excess in both CFS patients 3 and hypocortisolaemic subjects.4 De Lorenzo and colleagues’ findings,’ therefore, may simply reflect the hypocortisolism of CFS patients, 5 which is one of the 20 features that CFS shares with Addison’s disease.5

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431605/pdf/postmedj00143-0063a.pdf

 

Source: Baschetti R. Chronic fatigue syndrome. Postgrad Med J. 1998 Nov;74(877):701. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431605/ (Full article)

 

Downregulation of RNase L inhibitor correlates with upregulation of interferon-induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome

Abstract:

Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) is a disorder characterized by debilitating fatigue associated with immunological abnormalities and cognitive impairments. The recently cloned RNase L Inhibitor (RLI) gene encodes a specific protein which is believed to regulate 2-5A synthetase and RNase L activity via the formation of a latent heterodimeric protein complex.

In the present study, we investigated the levels of 2-5A synthetase, RNase L and RLI in patients with CFIDS as compared to healthy controls. Quantitative Competitive PCR (Q/C PCR) analysis showed a statistically significant decrease in RLI mRNA present in the peripheral blood lymphocytes (PBL) of patients with CFIDS (n = 25, mean = 569, S.E = 154) as compared to RLI mRNA level present in peripheral blood lymphocytes (PBL) of healthy controls (n = 15, mean = 2296, S.E = 506; p < 0.0001).

The decrease in RLI mRNA in CFIDS individuals correlated directly with RLI and RLI: RNase L protein ratio while showing an inverse relationship to the 2-5A synthetase and RNase L activity. This RLI mRNA and protein deficiency in CFIDS patients may explain the increase in activity of RNase L found in CFIDS patients.

The unidirectional decrease in RLI message and protein levels in CFIDS individuals may contribute to the destabilization of the latent RLI:RNase L heterodimeric protein complex, resulting in the excessive activation of RNase L shown in this study.

The increased activation of RNase L may result in an increased cellular RNA turnover and subsequent inhibition of protein synthesis; thus resulting in general fatigue, myalgia muscle weakness and other symptomatologies shown in CFIDS patients.

Furthermore, this data supports the hypothesis that the antiviral 2-5 oligoadenylate synthetase (2-5OAS) overexpression in individuals with CFIDS correlates with an increase in RNase L activity and with a decrease in RNase L inhibitor.

 

Source: Vojdani A, Choppa PC, Lapp CW. Downregulation of RNase L inhibitor correlates with upregulation of interferon-induced proteins (2-5A synthetase and RNase L) in patients with chronic fatigue immune dysfunction syndrome. J Clin Lab Immunol. 1998;50(1):1-16. http://www.ncbi.nlm.nih.gov/pubmed/10189612

 

Orthostatic intolerance in the chronic fatigue syndrome

Abstract:

This study aims to investigate the prevalence and pathophysiology of orthostatic intolerance (OI) and its potential contribution to symptoms of a group of unselected patients with chronic fatigue syndrome (CFS).

Seventy five patients (65 women, 10 men) with CFS were evaluated. During an initial visit, a clinical suspicion as to the likelihood of observing laboratory evidence of OI was assigned. Laboratory investigation consisted of beat-to-beat recordings of heart rate, blood pressure (Finapres), and stroke volume (impedance cardiograph) while supine and during 80 degrees head-up tilt (HUT), during rhythmic deep breathing (6 breaths/min) and during the Valsalva maneuver. The responses of 48 age-matched healthy controls who had no history of OI were used to define the range of normal responses to these three maneuvers.

Forty percent of patients with CFS had OI during head-up tilt. Sixteen exhibited neurally-mediated syncope alone, seven tachycardia (> 35 bpm averaged over the whole of the head-up tilt) and six a mixture of tachycardia and syncope. Eight of 48 controls exhibited neurally-mediated syncope. The responses to the Valsalva maneuver and to deep breathing were similar in controls and patients. On average, the duration of disease and patient age were significantly less and the onset of symptoms was more often subacute in patients with OI than in those without OI.

We conclude that there exists a clinically identifiable subgroup of patients with CFS and OI that differs from control subjects and from those with CFS without OI for whom treatment specifically aimed at improving orthostatic tolerance may be indicated.

 

Source: Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst. 1999 Feb 15;75(2-3):192-201. http://www.ncbi.nlm.nih.gov/pubmed/10189122

 

What causes chronic fatigue?

Comment on:

Chronic fatigue syndrome comes out of the closet. [CMAJ. 1998]

Chronic fatigue syndrome or just plain tired? [CMAJ. 1998]

Chronic fatigue syndrome get court’s nod of approval as legitimate disorder. [CMAJ. 1998]

 

The 3 excellent articles on chronic fatigue syndrome 1–3 reminded me of the desperate need for a discussion of the ethics — or lack thereof — related to independent medical examinations of patients with this condition.

A recent 21-page report from an independent medical examination of one of my patients with chronic fatigue syndrome included 2 pages of error-riddled history and the results of only a cursory physical exam, along with a bold admission that a full physical examination had not been done. The other 19 pages, clearly based on a word-processor template, were peppered with such clichés as “illness-seeking behaviour,” “somatization syndromes” and “preconscious motives.” The fee assessed for this report was $1200.

I used to be asked by insurance companies to perform independent medical examinations (for the standard fee suggested by the Alberta Medical Association), requests that I always accepted. However, when it became known that, in appropriate circumstances, I might support a diagnosis of chronic fatigue syndrome, such requests ceased abruptly.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1230108/pdf/cmaj_160_5_638.pdf

 

Source: Voth A. What causes chronic fatigue? CMAJ. 1999 Mar 9;160(5):638. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1230108/pdf/cmaj_160_5_638.pdf (Full article)

 

What causes chronic fatigue?

Comment on:

Chronic fatigue syndrome comes out of the closet. [CMAJ. 1998]

Chronic fatigue syndrome or just plain tired? [CMAJ. 1998]

Chronic fatigue syndrome get court’s nod of approval as legitimate disorder. [CMAJ. 1998]

 

Even though the 3 articles on chronic fatigue syndrome 1–3 in the Sept. 8 issue commendably demolish the obsolete claim that chronic fatigue syndrome is a psychiatric illness, they also offer outdated biological explanations for the syndrome, namely, either a chronic viral infection or a weakened immune system. Although the first of these explanations seemed convincing until a few years ago, it is hardly tenable now, because no specific virus has been identified in these patients.4

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1230107/pdf/cmaj_160_5_636.pdf

 

Source: Baschetti R. What causes chronic fatigue? CMAJ. 1999 Mar 9;160(5):636, 638. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1230107/pdf/cmaj_160_5_636.pdf (Full article)