Congenital central diabetes insipidus and optic atrophy in a Wolfram newborn: is there a role for WFS1 gene in neurodevelopment?
Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus (DM), optic atrophy (OA), central diabetes insipidus (CDI) and deafness (D).
The phenotype of the disease has been associated with several mutations in the WFS1 gene, a nuclear gene localized on chromosome 4. Since the discovery of the association between WFS1 gene and Wolfram syndrome, more than 150 mutations have been identified in WS patients.
We previously described the first case of perinatal onset of Wolfram syndrome newborn carrying a segmental uniparental heterodysomy affecting the short arm of chromosome 4 responsible for a significant reduction in wolframin expression.
Here we review and discuss the pathophysiological mechanisms that we believe responsible for the perinatal onset of Wolfram syndrome as these data strongly suggest a role for WFS1 gene in foetal and neonatal neurodevelopment.
We described a male patient of 30 weeks' gestation with intrauterine growth restriction and poly-hydramnios.
During the first days of life, the patient showed a 19% weight loss associated with polyuria and hypernatremia. The presence of persistent hypernatremia (serum sodium 150 mEq/L), high plasma osmolarity (322 mOsm/L) and low urine osmolarity (190 mOsm/l) with a Uosm/Posm ratio < 1 were consistent with CDI. The diagnosis of CDI was confirmed by the desmopressin test and the brain magnetic resonance imaging (MRI) at 34 weeks of age, that showed the lack of posterior pituitary hyperintense signal. In addition, a bilateral asymmetrical optic nerve hypoplasia associated with right orbital bone hypoplasia was observed, suggesting the diagnosis of WF.
During the five years follow-up the patient did not developed glucose intolerance or diabetes mellitus. By the end of the second year of life, primary non-autoimmune central hypothyroidism and mild neurodevelopment retardation were diagnosed.
The analysis of our case, in the light of the most recent literature, suggests a possible role for WFS1 gene in the development of certain brain structures during the fetal period.
Wolfram syndrome should be considered in the differential diagnosis of the rare cases of congenital central diabetes insipidus developed in the neonatal period.
Wolfram syndrome (WS1) (MIM #222300), first described by Wolfram and Wagener in 1938 , is a rare autosomal recessive neurodegenerative disorder with an estimated prevalence of 1: 770.000 live births and a carrier frequency of 1: 354 ,. It is also known by the acronym DIDMOAD in order to include four characteristic clinical abnormalities: central diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA) and deafness (D).
The diagnosis of Wolfram syndrome is based on the presence of the two minimal diagnostic criteria: early onset DM (<15 years) and bilateral progressive OA. DM is usually the first symptom to present at a median age of 6 years, followed by the onset of OA at a median age of 11 years. The incidence of central DI varies considerably, ranging from 48% to 78%, as generally it does not appear until the 2nd or 3rd decade and, initially, it may be partial. Frequently, sensorineural deafness develops at an average age of 16 years (range 4-39 years). A wide spectrum of abnormalities of the endocrine glands, the central nervous system (CNS) and the urogenital tract has been described, comprising hypothyroidism, hypogonadism and ACTH deficiency, anosmia, ataxia, seizures, nystagmus, gaze palsies, dysarthria, dysphagia, psychiatric disorders, cognitive deficits, hypo or areflexia and neurogenic bladder, central sleep apnea, neurogenic upper airway collapse, myoclonus, Parinaud's syndrome -. The leading cause of death, that typically occurs around the age of 30 (range 25-50), is the central respiratory failure resulting from brainsteam atrophy .
The disease phenotype has been associated to mutations in WFS1, a nuclear gene mapped on chromosome 4p16.1, encoding for the endoglycosidase membrane glycoprotein named wolframin. Wolframin plays a protective function against endoplasmic reticulum (ER) stress and it is involved in calcium storage, redox regulation, steroid synthesis, and cell death -. Acquired or inherited ER dysfunction can cause rare genetic diseases as well as common chronic diseases, including DM and neurodegenerative diseases -.
Since the discovery of the association between WFS1 gene and Wolfram syndrome, more than 150 mutations have been identified in WS patients. However, no evident genotype-phenotype correlations were found .
We recently described the first case of Wolfram syndrome perinatal onset, presenting with congenital OA and CDI, in a growth-restricted male infant, born at 30 weeks gestation,. A detailed description of the underlying genetic defect, a segmental uniparental heterodysomy affecting the short arm of chromosome 4 responsible for the significant reduction in wolframin expression, have been previously published .
Here we review the pathophysiological mechanisms possibly responsible for the perinatal onset of Wolfram syndrome according to the recent published evidence of WFS1 role in fetal and neonatal neurodevelopment.
We described a male patient, born to a 38 years old mother at 30 weeks' gestation by emergency Cesarean section, performed because of pre-eclampsia and IUGR associated with poly-hydramnios, detected by 26 weeks. The pregnancy was complicated by maternal type 2 DM, requiring subcutaneous insulin, Antenatal serologies (TORCH, HIV, Treponema and Hepatitis) were protective. Cytogenetic investigation of the fetus by villocentesis confirmed a normal 46,XY karyotype. Paternal medical history was unremarkable. Parents were non-consanguineous Caucasians.
Apgar scores were 6 at 1 minute and 7 at 5 minutes of life. Physical parameters were as follows: weight 1190 g (<10° centile), length 36 cm (<3° centile) and head circumference 26 cm (<10° centile). Physical examination was normal except for a moderate respiratory distress, During the first hours of life, the respiratory status worsened, evolving towards a third-degree hyaline-membrane disease that required surfactant administration, mechanical ventilation for a 24 hour period and non-invasive ventilation for 10 days.
Throughout the first 3 days of life, the patient experienced a significant weight loss (as high as 19% of the birth weight), associated with polyuria (4.7-5.5 ml/kg/h) and hypernatremia (serum sodium 152-159 mEq/l), despite adequate fluid intake. At first, hypernatremia was interpreted as a consequence of the excessive weight loss and treated with large amounts of daily intravenous fluids (180-200 ml/kg/d). The clinical course was complicated by one episode of Serratia Marcescens septic shock during the second week of life and disseminated intravascular coagulation requiring plasma administration, platelet transfusion and aggressive antibiotic therapy.
CDI was subsequently suspected as a result of persistent hypernatremia (serum sodium 150 mEq/L), high plasma osmolarity (322 mOsm/L) and low urine osmolarity (190 mOsm/l) with a Uosm/Posm ratio < 1 associated with failure to thrive during the first four weeks of life. The diagnosis of CDI was confirmed by the desmopressin test, showing a normal urine concentrating capability after nasal desmopressin (DDAVP) administration with rapid raise in urine osmolarity and reduced plasma osmolarity and the brain MRI at 34 weeks postmestrual age demonstrating the lack of posterior pituitary hyperintense signal. Bilateral asymmetrical optic nerve hypoplasia associated with right orbital bone hypoplasia was also observed, suggesting the diagnosis of WF . No other abnormalities of the CNS were found.
Ophthalmologic examination revealed eyeball and right optic disc hypoplasia, associated with exotropia. Visual evoked potential confirmed the pathological findings of the right optic pathway, while the electroretinogram resulted normal. Audiological examinations were normal. Borderline TSH values with normal thyroid function were recorded during hospitalization, but no treatment was required until the end of the first year of life, when levo-thyroxine substitutive therapy was started because of primary non-autoimmune central hypothyroidism with a small thyroid gland. During the five years follow-up mild psychomotor and mental retardation were diagnosed. No glucose intolerance or diabetes mellitus have been detected so far.
After the catch-up growth, length and head circumference has stabilized around the 50° centile and, after the first year of life, body weight was above the 97° centile.
Water and electrolyte balance is maintained with standard doses of nasal desmopressin.
No progression of the bilateral asymmetrical OA was noted at the 1-year follow-up MRI. However, new pathological signs (reduced corpus callosus, moderate ventricular dilatation, asymmetric hippocampus and altered occipital peri-ventricular white matter signal intensity)  were noticed.
Genetic investigation of the patient and his relatives revealed a segmental paternal heterodisomy of the chromosome 4 (segmental pat-hUPD4), involving at least part of the promoter and the first exon of WFS1 that we hypothesized could remove splicing regulatory motifs located in intron 1. Direct sequencing analysis of WFS1 cDNA showed a mixed sequencing pattern including the wild-type transcript sequence and two splice variants. The first splice variant was a previously described 4-bp deletion in exon 2, while the second one exhibited the complete skipping of exon 2 and, probably, the loss of the transcription start site. RT-PCR confirmed a normal mRNA expression compared to young controls, while Western blot analysis showed a significantly decreased Wolframin expression . Informed consent for genetic studies was obtained from all subjects involved in the study.
In this report we deepened from the clinical point of view the case of an atypical Wolfram patient, presenting during fetal and neonatal life. As a matter of fact, we discovered DI and OA during the examination performed after the delivery, that occurred long before the term of pregnancy, albeit the antenatal origin of the CDI was suggested by poly-hydramnios, polyuria and rapid body-weight loss occurred since first days of postnatal life. In addition, we speculate that the OA and the hypoplasia of the eyeball were caused by a pathological process originating during fetal life.
The Wolfram syndrome is caused by mutations of the protein Wolframin, essential for the regulation of intracellular calcium homeostasis, the cell cycle progression and the retrieval of homeostasis under conditions such as ER stress -. Indeed, WFS1 is a key element of the ER stress activated signalling cascade, also known as unfolded protein response (UPR). In particular, WFS1 regulates ATF6A activity, one of the ER stress-sensor molecules that induces UPR target genes and prevents cells from apoptosis caused by the imbalance between productive folding of secretory proteins and degradation of misfolded proteins , (Figure 1).
WFS1 is a key element of the ER stress activated signalling cascade, called the unfolded protein response (UPR). WFS1 regulates ATF6 protein through the ubiquitin-proteasone pathway, stabilizing and enhancing the function of its E3 ligase, HRD1 and acts as a negative regulator of this pathway. The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane and is involved in endoplasmic reticulum-associated degradation. In response to ER stress, the cleaved form of ATF6 translocates to the nucleus. The non-cleaved form of ATF6 is degraded by the ubiquitin-proteasome pathway to prevent the hyperactivation of the UPR.
The ER environment can be disrupted by both, physiological (i.e. post-prandial insulin biosynthesis that increases the workload of the ER) and pathological (i.e. hypoxia, hypoglycaemia or mutated proteins) processes, causing the production of toxins, cytokines and mutant proteins expression ,,.
Patients affected by Wolfram syndrome exhibit a dysregulated ER stress signaling. The uncontrolled ATF6α up-regulation determines apoptosis of sensitive cell types, in particular pancreatic β cells and neural cells ,.
Recent insight arising from animal studies led to the conclusion that Wolframin may also be essential for the processing of the arginine vasopressin (AVP)-precursor and for the survival of the supraoptic (SO) and the supraventricular hypothalamic (PV) nuclei neurons . Gabreel and colleagues demonstrated the abnormal processing of AVP-precursor in the SO and PV nuclei and the presence of reactive gliosis in human tissues recovered during the autopsy of patients with longstanding CDI. On the contrary, no gliosis was detected in patients that were symptomatic for a shorter period of time, suggesting that the pathogenesis of CDI in Wolfram patients is characterized by a progressive three-step phase process: 1) a down-regulation of the amount of processed AVP and partial CDI, 2) a complete disappearing of processed AVP, and 3) a complete disappearance of AVP-producing cells in the hypothalamic nucleus .
Investigations in our patient did not allow neither to determine the mechanisms underlying the development of early onset CDI, nor to correlate his rare and previously undescribed mutation to his unique phenotype . The most likely explanation is a specific and severe prenatal/postnatal ER workload in the SO and PVN, that led to a rapid neuronal dysfunction and/or death due to a very low Wolframin level. We speculated that the underlying mechanisms were the rising production of AVP during the second trimester of pregnancy (increase of over 1000 times), the active role of fetal vasopressin in the birth process and the redistribution of the fetal blood flow, contributing to stress adaptation . Moreover, mechanical ventilation and septic shock are known to increase the production of vasopressin, as demonstrated in plasma and urine samples of newborns who received neonatal intensive cares ,. Not to be forgotten that the oxidative stress secondary to pregnancy complications (i.e. pre-eclampsia, maternal insulin-dependent diabetes and growth-restriction) lead to lipid peroxidation, protein and DNA damage, both in the mother and the fetus. These mechanisms may have contributed to the ER overload and, finally, to the apoptosis or the premature cellular senescence ,.
WFS1 expression has been fully characterized in the murine CNS. Wolframin presence has been confirmed in several CNS structures, comprising the amigdala, the hippocampal region, the hypothalamic magnocellular neurosecretory system, the brainstem nuclei, the globus pallidus, and the posterior caudate putamen ,. Hilson and colleagues demonstrated that Wolfram patients exhibited abnormalities in various brain regions, including hypothalamus, pituitary, pons, inferior olivary nucleus, lateral geniculate nucleus, thalamus, cerebellum and optic nerve and optic tract .
The neuroimaging evolution of our patient at 1 year of life showed new pathological features such as reduced corpus callosus, moderate ventricular enlargement, asymmetric hippocampus and altered occipital peri-ventricular white matter signal. This suggests a neurodegenerative process affecting brain structures, known to be damaged by the loss of WFS1, but even more widely the white and gray matter. However, we can not exclude that the radiological findings as well as the mild psychomotor and mental retardation may be a consequence of prematurity and co-morbidities; In fact, disabilities affect roughly 30% of patients born between 29 and 32 weeks of gestational age and septic shock is an established cause of white matter damage ,.
The bilateral asymmetrical OA associated with the eyeball hypoplasia and the right orbital bone hypoplasia were evident by the first month of life, suggesting an alteration in the development rather than an involution of optic nerves.
In control mice, Wolframin is expressed in neurons and glial cells of the optic nerve, the SC, the SCN and the visual cortex, while in the retina it was expressed in all neuron subtypes . In humans, it was found that Wolframin is abundant in retinal ganglion cells (RGCs), cell bodies and initial portion of axons, so RGCs could be affected by Wolframin disfunction both at level of the cell body or of the unmyelinated portion of the optic nerve. Such defect could lead to axonal transport deficits and/or perturbations of important cell functions, thus causing OA. Besides, the presence of wolframin in the optic nerve astrocytes suggests that WFS1 mutations may affect their ability to provide nutrients to optic axons when they suffer from ER dysfunction .
In our patient, the presence of optic nerve hypoplasia with orbital bone hypoplasia long before term corrected age allowed new speculations about the underlying pathogenetic mechanisms, supported by recently published work. The vast majority of the critical processes involved in the retinal development occur between 24 weeks gestation and 3 to 4 months of postnatal life, while the axonal development of the optic tract occurs between 20-30 weeks of gestation . A recent study by the Washington University Wolfram Study Group found a smaller intracranial volume, mainly due to reduced brainstem, cerebellum and optic radiation volume, starting from the earliest stages of the disease in Wolfram patients as compared to healthy controls and type 1 diabetic patients, , Such findings were considered more severe than neurobehavioural findings tested in their cohort of patients. The authors' conclusions stated that these brain abnormalities exacerbated by a neurodegenerative process, originally result from a neurodevelopmental disruption dating back to the early stages of the CNS development. Similar conclusions were drawn thanks to post-mortem examination of Wolfram patients, as a discrepancy between the atrophic component of some brain regions (pons and medulla) and the neuronal loss was documented .
Heterozygous missense mutations in WFS1 have been linked to autosomal dominant low frequency neurosensory hearing impairment and psychiatric disorders . Eight families with OA and deafness carrying a single, recurrent heterozygous missense mutation in WFS1 gene leading to reduced levels of mutant wolframin have been described . More recently, Chaussenot et al. described a cohort of 96 Wolfram patients with a wide spectrum of phenotypes. In particular, about 14% of the patients showed late-onset symptoms (after 15 years of life) and one patient (WS9), affected by IUGR, cataract and psychomotor delay developed OA and hearing impairment by 6 months of life. Type 2 Wolfram syndrome, caused by mutations of the CISD2 gene on the chromosome 4q22, has been diagnosed in three large Jordanian families. The phenotype is similar to the type 1- syndrome although diabetes insipidus has not been described ,. These reports underline our incomplete knowledge of wolframin functions.
The analysis of our case reinforces the intriguing hypothesis that the WFS1 plays a role in the development of neural structures, such as the optic nerve and the neuro-hypophyseal tract. After a careful examination of the patient and the extensive review of the literature, we speculate that this early and severe OA cannot be entirely explained by a progressive degenerative mechanism, although further studies are needed in order to identify all cerebral structures expressing Wolframin during embryogenesis and fully elucidate its role in the neurodevelopment.
Written informed consent was obtained from both parents for the publication of this Case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
No ethical approval was required for this case-report.
SG managed the patient, ideated and drafted the manuscript. ED managed the patient, revised the initial manuscript. BC revised the initial manuscript. MF critically reviewed and revised the initial manuscript. FM critically reviewed and revised the initial manuscript. All authors read and approved the final manuscript.


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Three Cheers for MP Daniel J Hannon: Why Not a Better Brexit Deal For Everyone?
The EU values political correctness more than jobs.
The result was a collapse in support for Angela Merkel, and the rise of AfD and FDP in Germany. Let's not forget Marine Le Pen in France, Beppe Grillo in Italy, and the far right in Austria.
For the sake of political correctness, the EU is bound and determined to punish the UK for Brexit even though new studies suggest that a Hard Brexit Will hurt the EU More Than Britain.
The European Union will lose more than twice as many jobs as Britain after a hard Brexit, research by one of the world's leading universities found as tough UK-EU divorce talks begin in Brussels.
Hard Brexit describes what will happen if the UK and EU fail to reach a divorce deal by 29 March 2019. Britain would revert to WTO tariffs on imports and exports to and from the EU rather than the zero tariffs afforded by membership of the bloc.
The return of tariffs to goods and services would cost 526,830 British jobs and 1.209 million jobs in the remaining 27 EU member states, according to researchers at Belgium's University of Leuven, one of the top 50 global universities. The damage would lead to a 4.48% drop in UK GDP and 1.54% in EU GDP, researchers found.
Free Trade Benefits
As I have pointed out previously, a free trade agreement can fit on a napkin. Her is my proposal once again: "Effective immediately all subsidies and tariffs cease regardless of what any other nation does."
The first nation that adopts that policy will see an enormous economic benefit.
Very few people fully understand free trade. Even fewer politicians understand free trade. One of the few who does understand is British MP Daniel J Hannon.
In a Telegraph Op-Ed Hannan writes By embracing free trade, we can use Brexit to make everyone better off.
Free trade is actually between individuals, not nations.
The following caption is correct.
Institute for Free Trade
On September 27, Hannan launched the Institute for Free Trade (IFT).
We want to use Brexit to boost global commerce. We have an International Advisory Panel made up of statesmen who successfully pursued liberalisation in their own countries, from Spain's José María Aznar to Australia's Tony Abbott. Brexit, after all, shouldn't just be about having an engaged and global Britain; it should be about reviving a stalled world trading system.
Why does such an institute need to exist? Largely because, however successful free trade has been in practice, it remains counterintuitive.
In rich countries, people fear being undercut by lower wages. In poor countries, conversely, they fear being overwhelmed by superior technology. Logically, these worries cannot both be justified; and, in truth, neither of them is. Free trade between a rich and a poor country, as between any two countries, benefits both.
Excellent Set of Hannan Tweets
Does it ever occur to @Keir_Starmer to ask WHY no one in Norway, Switzerland or Iceland wants to join the customs union? https://t.co/APAgq8vmL5
— Daniel Hannan (@DanielJHannan) September 25, 2017
The world is moving toward smaller and more democratic countries. The EU is going in the opposite direction. https://t.co/55HlU6oGiC
Support for the far Right is lower in the UK than almost anywhere in Europe. Brexit, contrary to what we were told, acted as a safety valve.
Scots vote on leaving UK? Democracy.
Kurds on leaving Iraq? Democracy.
Catalans on leaving Spain? Democracy.
Brits on leaving EU? Racism!
Tomorrow, alongside @LiamFox and @BorisJohnson, I'll be launching the Institute for Free Trade – @IFTtweets. Brexit is a unique opportunity.
Donald Trump gets one thing right: the nation-state is indeed the most secure vessel for human freedom and happiness.https://t.co/Uq5Y0CMuKx
1. Why I'm launching @IFTtweets.
2. The PM gets it right on the EU.
3. Actors! Stick to acting!
My @Telegraph columnhttps://t.co/DoRHa0ru2s
Labour is hip and street and down with the kids – until it comes to embracing some new technology. #Uber pic.twitter.com/7YvKDpC8fo
So much utter bilge on Twitter this afternoon. The PM's #FlorenceSpeech was well-judged, sensible, optimistic and statesmanlike. pic.twitter.com/Vr5XQZ25z6
"No country should have a better deal than as a current EU member!" Why not? Surely all 28 countries should want better terms than now?
Better Deal For Everyone
Hannan's last Tweet is my favorite of the group. Why not a better deal for everyone?
The EU is a customs union, not a free trade union. It promotes clean energy but puts tariffs and restrictions on solar panels and countless other items.
EU Hypocrites on Free Movement of Goods
Think goods move freely? Then think again. Please consider French Farmers Dump 90,000 Bottles Worth of Spanish Wine Because…Spanish!
EU Hypocrites on Free Movement of Services and Freedom of Establishment
In Germany, a license to bake cupcakes does not allow one to bake pretzels or donuts.
Freedom of movement is a downright lie. A prime case in point is Germany's Apprenticeship System.
After 18 months of study, $2,200 in tuition and three exams, Ewa Feix is now permitted by German law to bake two variations of cupcakes.
"Not pretzels, not Black Forest gâteau, not bread," said Ms. Feix, a Canadian who moved to Germany in 2009. Becoming a professional bread baker entails a three-year apprenticeship and more exams.
Germany's thicket of rules and standards shields roughly 150 professions from competition, from ski instructors to well-diggers. Stiff fines await uncertified practitioners. German authorities conduct thousands of enforcement raids each year.
Ridiculous EU Rules
There are a lot of claims and counter-claims over Ridiculous EU Rules but Business Insider investigated. Here are the ones labeled true.
Banana's cannot be too bendy.
It is illegal to claim water hydrates you on a bottle of water.
Prunes cannot be promoted for a bowel function effect.
Turnips cannot be labeled "swedes", except in one place.
Diabetics are banned from driving (passed but not enforced).
Eggs cannot be sold by the dozen, they have to be sold by weight.
In regards to prunes, the EU ruled "The evidence provided is insufficient to establish a cause and effect relationship between the consumption of dried plums of 'prune' cultivars (Prunus domestica L.) and maintenance of normal bowel function."
In regards to eggs, they can be packaged by the dozen, but the package has to include the weight. This is nothing but needless red tape.
The UK does not need any of this madness.
Fair Trade is Unfair
In response to every article like this one, I get slews of emails and comments along the lines of "I support fair trade".
Such arguments are presented by people who want to drive up prices or protect their jobs at your expense.
Here is my counter-reply: Fair Trade is Unfair; In Praise of Cheap Labor; Are Bad Jobs at Bad Wages Better than No Jobs at All?
The unions howl they want "fair trade". Fair to whom? The answer is fair to their self-interests, damn the enormous costs to everyone else.
China Doesn't Play Fair!
Also consider Reflections and Reader Comments on Free Trade: "China Doesn't Play Fair!"
My inbox and comment box are filled with reader comments and emails telling me "China doesn't play fair".
As part of that allegation, many point out Chinese pollution. I've written about that many times myself. Yes, it's disgusting.
Let's assume for a second that China is the one and only nation that plays unfair, or if you prefer plays the "most unfair." Let's also assume China subsidizes its manufacturers.
Who Benefits, Who Loses?
The logical conclusion of such an arrangement is the Chinese government is robbing its people for the express benefit of citizens of the United States.
There is no other logical conclusion. To subsidize exports, every person in China has to pay a cost, via taxation, pollution or both.
The winners are US consumers.
Reader Stuki eloquently explained the math in response to one of my free trade posts. He writes …
In order for a foreign government to subsidize one sector, it must necessarily pull the money from others, rendering them less competitive. Conversely, by subsidizing steel, the Chinese government is indirectly subsidizing each and every industry that uses steel as an input, in the US and elsewhere. While simultaneously taking that subsidy back from their home market companies, in order to pay for the steel subsidies.
So, the net result is the Chinese government subsidizing a low value add, albeit politically well connected, industry at home, while disproportionately subsidizing higher valued add industries abroad. Any way you look at it, it's a better deal for foreigners than for the domestic Chinese. Which shouldn't come as a surprise, because, as Friedman has pointed out, the Chinese government is taxing it's own people, in order to pay for free gifts to foreigners.
If we would only be so lucky…… Of course, the Chinese collectively aren't nearly stupid enough to not understand that. So the whole "subsidize" gift we're supposed to be getting from China is, in reality, nothing more than the figment of some congressman-on-the-take's imagination, planted there by the lobbyists for whatever LBO shop happens to have bought the steel maker that paid for his campaign.
Problems with Free Trade?
There are no problems with free trade, but there are two rules that prevent free trade.
Every country wants free trade for exports
No country wants free trade for imports
"Fair Trade" is a concoction by industries that seek or need protection via tariffs and import restrictions, to the damage of everyone else.
It is absurd to have everyone pay triple for underwear to "save 500 underwear manufacturing jobs" but that is precisely what the "fair trade" advocates seek.
Steel tariffs, Trump's current hot button, constitute a similar story.
Steel tariffs may protect a small percentage of jobs in the steel industry (at best), but that is at the expense of auto manufacturing, fence manufacturing, etc. jobs, as prices rise everywhere else.
Fair Trade Irony
Finally, think of all the trucking, shipping, and shelf-stocking, and refueling jobs lost when trade slows because of protectionism.
The irony of the "fair trade" argument is that it costs jobs. Ultimately, the only "fair trade" is "free trade".
https://t.co/l5rRpJqrmO
— Mike Mish Shedlock (@MishGEA) September 26, 2017
Ultimately, the only "fair trade" is "free trade".
46 thoughts on "Three Cheers for MP Daniel J Hannon: Why Not a Better Brexit Deal For Everyone?"
Michael Surkan said:
Sure, the EU will suffer more economically from a hard Brexit than the UK. However, a successful Brexit (where the UK prospers) threatens the very continued existence of the EU since it would encourage other EU member states to bolt.
It is the disintegration of the EU that is by far the biggest threat to EU policy makers, not economic harm.
@formula57 – Yes, there is not a great enthusiasm for leaving the EU amongst the remaining EU member states at present. However, that might change if the UK had a successful exit and prospered outside the EU. EU policy makers can't allow that to happen.
3 out of 4 Italian political parties want to leave the Euro and/or the EU.
The second place finisher in France wants to leave the EU.
The 3rd place party, and fastest growing party, in Germany wants to leave the EU.
Austria and Poland have governments that are openly defiant of Brussels.
For all the media spin, Greece, Spain, and Portugal defy Brussels as well. They nod their heads and sign EU agreements — but then they just do as they please, ignoring EU agreements. Greece keeps demanding more and more subsidies from Brussels as tribute not to leave.
… but other than the three anchor countries having major parties wanting to leave, and other than a half dozen smaller economies openly ignoring Brussels… other than that there is "no impetus to leave"
HT said:
Wrong but why preach to the "unpreachable".
If you want to have some BREXIT fun, here is one simple transaction before and after BREXIT: the curious case of the pellets:
https://www.nakedcapitalism.com/2017/09/brexit-denialism-the-customsborder-problem-and-the-curious-case-of-the-pallets.html
The EU can throw in so much sand into the UK export efforts if they don't knee down and say "Bitte, bitte…" LOL and it is all totally legal since everything had been agreed on year's ago.
I've been saying for months that UK PM May should just ignore Brussels and focus 100% of her energy on two-way free trade deals with the former British commonwealth, and as many African, Latin American, and southeast Asian countries as she can get on board.
Every minute wasted negotiating with Brussels has opportunity costs that dwarf all benefits.
As June 2019 approaches, the EU will probably come to England on bended knee begging for a settlement — because the EU's continued existence depends on it. But there is no downside risk to England if the EU remained stubborn — the EU is failing as a political entity anyway, and there is zero economic growth.
It makes no sense to waste time battling for a tiny piece of a shrinking pie — especially when there are dozens of better opportunities all over the world. There are only 24 hours in a day, shouldn't the British government focus on the best risk/reward opportunities? Why waste time on Brussels?
Unfortunately, May only has a very small working parliamentary majority that is highly vulnerable. The pro EU members of the Tory party would desert May if they thought she was not hell bent on getting a trade agreement with the EU. Worse, most of the business community is also lobbying hard for an EU agreement.
May would find herself tossed from government if she followed Medex Man's suggestion.
The sad fact is that the UK populace is so terribly divided by Brexit that it is impossible to either negotiate a good deal or even to walk away cleanly.
The Tories will not abandon May because it would put Labour in power.
formula57 said:
May's purpose at present for the Conservative Party is to take the blame, for she is damaged goods so far as the public is concerned. Once she has done that (which will be complete when she delivers Brexit), she can be ousted as party leader without jeopardizing her party's hold on goverment (the mechanics being aking to the case of M. Thatcher when she was replaced by Major).
May benefits from the fact that at present there is no agreement within the party on who is to succeed her as leader and of course an early appointment of a successor would leave such person tarnished by the blame that is still to be layed.
What the Eurocrats wish is indeed to see their European dreams furthered even if the price is harming member states economically and in other ways but the pressures they are under do not really arise from other members wishing to follow the UK's lead.
Recall that none of the other EU countries took the same view as the UK about EU reform, none supported its efforts to renegotiate and redefine and so we must question to notion that any of the others are incipient leavers. Those in the Euro currency would face high barriers to exit.
(As an aside, Mr. Hannon is a member of the European Parliament (pro tem) and would normally be described as an M.E.P. rather than as an M.P. (usually reserved for members of the UK parliament).)
The above was meant as a rejoinder to the first reply above by Mr Surkan.
@formula – "Recall that none of the other EU countries took the same view as the UK about EU reform … that any of the others are incipient leavers."
Three out of the four leading political parties in Italy want to leave the Euro and/or leave the EU.
Le Pen came very close to winning in France, but for some rather shady electoral shenanigans.
AfD went from a bunch of outliers to having the 3rd most seats in the Bundestag — and they aren't subtle about saying the EU should go stuff it.
Austria and Poland both have governments that have told Brussels they will not be adhering to Brussels edicts.
… how do you look at these facts and conclude there are "no incipent leavers"??? The three anchor countries all have top 3 candidates that want to leave, but you want to ignore that?
@formula — "(As an aside, Mr. Hannon is a member of the European Parliament (pro tem) and would normally be described as an M.E.P. rather than as an M.P. (usually reserved for members of the UK parliament).)"
As an aside, none of the M.E.P.'s were elected by anyone. They are all political appointees. There is nothing parliamentary about them.
Definition of "Parliament" — "A national representative body having supreme legislative powers within the state."
EU bureaucrats are not representatives at all. "M.E.P." is a silly title they awarded themselves.
If facts are important to you consider neither AfD nor Le Pen (both of whom are probably spent forces) want their countries to leave the EU. As for Italy, the 5 Star movement has shifted its ground on Euro membership (which of course is distinct from EU membership) – as have all others (most starkly Greece's Syriza) who have given serious contemplation to how abandoning that currency would work for them – and do not wish for exit from the EU. Even Italy's Northern League has recently softened its approach – see http://www.politico.eu/article/italys-northern-league-goes-soft-on-the-euro/ for example. The Forza Italia of Berlusconi has limited itself to callig for introduction of a parallel currency to the Euro (somehow using it contemporaneously with continued use of the Euro) and it too does not wish to leave the EU.
The EU is in difficulties I would agree but not to the point where members are likely to exit.
Roger said:
Short of a depression Marine L Pen will never make it.
Le Pen almost did make it… a lot of shady tactics were used to put the pretty boy into office instead (and he isn't very popular if you believe the French media).
That is not an endorsement of Le Pen (I think she is a little nuts). Just pointing out that the EU has pushed a lot of people into her circle.
I don't know how many Germans support AfD per se… but every time Angela Merkel opens her mouth to praise Brussels / bash Germany, she puts a few more German voters into the AfD camp.
The EU and their puppets in Paris / Berlin are their own worst enemies
A proper mix of ideology from years of indoctrination…and guilt for Hitler, and a substantial dependency on government, will keep them voting for what they have. Most are afraid of change, even in the face of disaster. The race is on to get the EU locked down and fully dependent…before the immigration influx becomes an apparent financial disaster. BREXIT screwed that up royal, and Spain's difficulties will fall right behind them.
Sometimes I think the whole world is devolving into one big civil war. The hungry unproductive mindless eaters against those resisting theft and dependency.
Winston said:
"A capitalist will sell you the rope you hang him with."
China's Intellectual Property Theft Must Stop
https://www.nytimes.com/2017/08/15/opinion/china-us-intellectual-property-trump.html
China must stop forcing U.S. firms to share intellectual property –
When a U.S. company turns over technology in exchange for access to today's Chinese market, it creates a Chinese competitor in tomorrow's global markets
https://www.usatoday.com/story/opinion/2017/08/14/china-must-stop-forcing-us-firms-share-intellectual-property-peter-navarro-column/563151001/
Let me correct that second headline – "U.S. companies should stop turning over technology in exchange for access to today's Chinese market". That correction fixes the problem found in the first sentence of this post.
Andrew said:
This is my biggest concern too. It takes time to develop an industry that can become globally competitive and it can require government intervention to foster the innovation, capacity and specialized skills. Once those skills are gone they do not easily come back. For example the Australian car industry was destroyed by the liberal government and the high dollar courtesy of the RBA. The US subsidizes its industries amongst many other nations – this is because the US and Germany believe that having heavy manufacturing is in the national interest. Now the Australian economy is a country of only mining and real estate investment supported by a population ponzi.
Governments need to play a role in fostering an industry and in some cases protecting it long enough to transform. Look at India's pharma industry for example. Indians protected their industry and now they have a viable global industry.
Mish would love your thoughts on this argument.
1. If it's good for the consumer I support it.
2. Protectionism and higher prices are not good for the consumer
3. Standards of living go up when prices fall
4. Letting governments pick winners and losers (that's what subsidies and tariffs do) is a bad idea. How can a bunch of bureaucrats possibly know what to do? Central planning is a failure.
5. Governments have a role: Get the hell out of the way
Our reality is that we have no reality. How is it possible to speak of free trade when there are so many interventions already in place,with many have far reaching effects. Are not taxes and debt considerations as well as interventions by domestic government in our own production? Are we oblivious to short term destruction as long is it is not ours? Have we ever in history seen such rapid growth in technology, combined with world wide internet trade and universal financial instability?
So we assume no risk, as with so many other hypothesizers who will casually impose rules that could have disastrous effect on millions, and it is simply the necessary collateral damage of "growth"?
Why are we pretending that we know what we do? Can anyone really say it is the same as before given the massive acceleration of trends?
If so, I will posit that we had a positive trade balance, very low national debt, a booming economy and our federal government was funded 90% with PROTECTIONIST TARIFFS in 1900. No taxes on our production, no sales tax, no income tax. If we can "imagine" what a free trade world would look like, why is it not at least as rational to consider something with historical precedence?
Andy said:
I an understand Mish's points but my concern is the lack of know how and the surrounding economy that are based on some core industries as well as IP theft changing the balance. Government has a role to play in markets and as to your point Madshellowell – Americans used protectionist tariffs well at the expense of the British.
Your point on the inability of the government to pick winners or losers is a sound one which works against this argument but the core investments that governments made in science (for example) drove amazing technological developments that may not have been possible without the government getting involved.
Carl R. said:
I totally agree with your stance on free trade. and great article. My one comment is that per my understanding a turnip is not a "swede". I believe a rutabaga is a "swede". Thus, a rule preventing a turnip from being called a "swede" is as reasonable as a rule saying that you can't call a broccoli a cauliflower, or call a grapefruit an orange.
bilejones said:
"Free trade between a rich and a poor country, as between any two countries, benefits both."
Rubbish. The loss of a job in the rich country will simultaneously reduce the governments funding from loss of taxation while increasing the demands on the inevitable welfare system.
Free trade must simultaneously assume a single world government with one set of world wide rules, a level playing field, and if you can believe THAT will not be corrupted to benefit the few, I have some beach front property in Puerto Rico to sell you.
We know why our jobs left. We refused to buy our own production. Now we tax our corporations, our personal labor and everything we consume to help pay for those who's production we refused to buy. WHAT A BARGAIN.
"Free Trade" doesn't "assume" anything about government at all. Much less a single world one.
All that is required for free trade to result in better outcomes than lack thereof, is that someone able to pick the most suitable product, for him, from a strict superset of the ones produced domestically, is better off than if he was restricted to the domestically produced subset. Which is trivially true.
And it's trivially true whether that someone is an end consumer, or a producer competing with other producers. The latter is why steel tariffs is such a disaster, as steel is an input in so many higher value add products made by American companies. Each and every one of whom will face higher costs than international competitors if steel tariffs are enacted, due to then having to pay a higher prices for one of their key inputs. So then, in order to make up for that cost disadvantage, they have to pay lower wages to American workers than they otherwise could…… And so on and so on…..
"Our jobs" leaving, has nothing at all to do with "free trade." Instead, they left because it is too expensive to produce anything in America. Because every American who produces something, has to carry on his back, an army of produce-nothing-consume-a-lot banksters, lawyers, bureaucrats and zero-value-adders who "make money" by having the Fed and regulators pumping up the "value" of their house, stocks and other idle "assets."
Sitting idly around "owning" something produces no new value at all. So, inevitably, whatever purchasing power someone gains by doing so, has to be taken from that produced by someone else, who happens to be producing something. Driving up his cost. Reducing his competitiveness. Until he is no longer able to compete against less so burdened international competition.
And sitting idly around "owning something," is all that the "ownership society" drivel propagated since Nixon went off gold, have encouraged Americans to do for the past 4 decades. Which happens to be exactly the same 4 decades over which America's manufacturing base has been shipped abroad, for those starry eyeds who insists on believing economics is some sort of an empirical discipline.
John said:
You might enjoy this parable from a friend:
Genie: I will grant you one wish.
EU: I want everyone to be equal.
Genie: Granted! You have no wishes.
Ethics go out the window when profits are involved there is no clean country,they all spy and cheat,wars are the continuation of economic struggle.
Motivation goes out the window when profit is absent.
Clean open competition under rules administered by the court system can function without the destruction Of profits.
daveyone1 said:
Reblogged this on World4Justice : NOW! Lobby Forum..
fedwatcher said:
As long as Merkel remains, the EU remains on a path to destroy itself.
Looks like Great Britain has a chance to save itself while the rest of Europe commits suicide.
Protectionism is a symptom of individual and policy failure, just like war is. Are we to deny our failure and insist on a pure and just world, pacifist in nature to the extent that we stand defenseless against the onslaught of our own making? To insist on "free trade" when we KNOW our trading partners have NEVER played fair, is asking for defeat. How many years of massive trade deficits can we accumulate before the system breaks? Are we going to bet on "the something for nothing" lasting forever? Do we really think China's giveaway prices will continue once they have concurred all of their competition?
The Chinese not only dominate world manufacturing, but they are quickly becoming dominant in the production of the machines used to manufacture.How will America rebuild their productive capacities if needed if they must purchase those machines and technology from China?
I'm sorry, but I just don't get it. Maybe because I've worked too many years actually making things and can't imagine a prosperous world where we are simply consultants and resellers. Looks mighty fragile to me. It feels like we are eating our seed corn.
I really liked Stuki's argument.
So the Chinese can create trillions of dollars from thin air to subsidize their industries competitively to the rest of the world. Their failing debt continues to be rolled over while their profligate printing leaks all over the world pushing up real estate and other asset prices so high that domestic citizens can no longer afford to live in their own neighborhoods. Meanwhile they decimate the rest of the world's productive capacities. As US business suffers greater and greater losses, they are left with no choice but to buy Chinese steel or whatever in order to even begin to compete….which they can't.
All I can say to foreign competitors regarding free trade is "you first".
harald said:
Mish, it seems that Stuki's and your arguments pro free trade lack information regarding the long term (20 years+?) effects of the type of free trade in which the US and China are currently engaged. If you have the time, I think it would be interesting if you could research and report on the following:
– What are the long term economic effects on business viability, both small and large, when nations engage in free trade similar to that currently happening with US and China?
– What are the long term economic effects on employment when nations engage in free trade similar to that currently happening with US and China?
– What are the long term economic effects of IP transfer/theft from one nation to another due to free trade?
– If there are negative long term consequences, what are the costs to society? Do these costs negate the short term benefits of free trade?
Please include data from any historical precedent you might find. Thanks!
Rick said:
Hi Mish;
As an American living in France, I enjoy your European coverage.
I understand your position on free trade but there is something perhaps you could clarify. How does a country such as France with high social charges and an aging population directly compete with one that doesn't have those handicaps?
Thanks for your time and your work.
It is tough for socialists to compete.
It needs something like the EU with all its rules and regulations.
But that is a path to very anemic growth if any growth at all. Musch of the growth is in Germany. Italy is a basket case and so is Greece.
French-sponsored agricultural tariffs to save the small farm and the French way of life are an absolute disaster for the sole benefit of French farmers at the expense of everyone else in the EU. To his credit, this is the one positive of Macron (I think). He says he wants to liberalize French work rules. Will he?
Is it me, or is the caption on that second picture ironic? The man is literally doing backbreaking toil in what can clearly not be characterised as "subsistence" farming, and free-trade will only increase that by increasing demand for his produce, unless you are suggesting he will be able at some point to automate it … which we won't, because even he will be undercut by cheaper producers elsewhere and will not be able to accumulate the capital to keep himself competitive.
Freedom of movement is not a lie: It is an aspiration. Article 45 TFEU specifically provides for the freedom of movement workers, but this is subject to limitations justified on grounds of public policy, public security or public health. The apprenticeship system has a private aspect of ensuring an appropriate pipeline of talent is in training, and a public aspect in ensuring appropriately qualified persons are doing the job.
The authorities do try to be accomodating: One of the funnier stories I ever heard about the German apprenticeship system was the authorities in Dresden trying to figure out how to qualify one of their Beamters (officials) to be up to speed on assessing the skills of and licensing a couple of Italians who had started a Gondola service on the River Elbe. They eventually worked through it by getting him up to speed on licensing operators of flat-bottom boats and then deeming that equivalent to driving a gondola. This is not exactly a trivial matter, since ensuring that persons carrying paying passengers on a public waterway can do so safely is reasonably a function of the state within its competence to safeguard health and safety.
I like the apprenticeship system. Yes, it is a collar on free trade and free movement, but it is ultimately more fair to the people of a nation-state than the Anglo-American system of pushing everyone toward college and the accumulation of mountains of debt that will follow them through lives, or pushing them into welfare, all the while importing masses of unskilled foreigners to do the trade work that would have been done by the locals but for either being pushed into debt serfdom which makes it financially untenable to do a trade or welfare serfdom, which financially pays better than doing trade or menial labour.
Further, you trivialise the debate by offering up the lame story of becoming a master baker. Yeah, it seems absurd on the surface, but there are a lot of things learned in the course of being an apprentice, like proper hygiene. I've been served baked goods in the US and EU, and the standards of hygiene in the EU are significantly better. I've also had hot-water heaters installed on both continents: In Germany, by a Pole who qualified as a master plumber and who confidently and competently installed the heater in short order, and in Florida, by a Mexican of questionable legality and whose skill was dubious.
I wouldn't make too much of the French farmers dumping Spanish wine, because that is not a function of the EU (under Articles 34 & 35 TFEU and in numerous CJEU cases, these kinds of actions are illegal, and member states have been dinged for not doing enough to stop these sorts of actions): It is, rather, French farmers being French farmers.
Seenitallbefore said:
Politicians are not smart people. They are ruthless driven people who seek power. Such people seldom make sound decisions especially when their greed for money and more control get in the way. Thus why question the wisdom of anything they do. Most of it is sheer lunacy.
Stuki smart !
Suki should reboot by reading :
"Bad Samaritans" by Ha – Joon Chang.
S.Korea started with steel and moved, one step at a time, to high end industrial products.
China started with low end electronic components assembly, but when AAPL project engineers ( email, or two way conference call, from 6,000 miles are not good enough)
want to design a new phone, they have to fly to China to get an advise. A country
that don't Produce lose their advantage & skills and the minute tech know how. It will be taken over by those who are Producing the next generation of products.
The non productive nation, can benefit for a while, but their citizens are
basically useless people until they expire.
CautiousObserver said:
Your point is exactly the problem that I keep mentioning.
Stuki's comment in the original post, that a country which subsidized one industry is effectively taxing itself elsewhere, is true as far as it goes but ignores the strategy behind a decision to be dominant in certain types of production.
For example, what reasons could China have for subsidizing its steel production besides that of giving a gift to foreigners? Could it be that steel manufacturing technology is a vital component in infrastructure and defense? Meanwhile, other countries who open themselves to total dependence on low cost Chinese made steel may become unable to reliably produce their own supply. I think it is a narrow view to look at trade exclusively from the point of view of lowest front-end cost to consumers.
I am open to a convincing counter argument.
Emanon said:
Fun fact: from 1942 to 1945, the city of Pittsburgh and the area around it (Monongahela Valley, etc.) produced more steel than the Third Reich.
The fact that we weren't being bombed by the British or invaded by the Russians made our job a bit easier than the Germans'.
Today China's steel industry has a productive capacity about ten times that of the USA. They produced 808.4 metric megatons in 2016 versus 78.6 by the USA.
https://en.wikipedia.org/wiki/List_of_countries_by_steel_production
If there's another prolonged world war requiring the mass production of weapons, the US will lose to China.
Thanks for that.
That's a striking contrast and I dearly hope the US will not be facing a war with China any time soon.
I imagine a large scale war today would destroy assets much faster than anything previously seen in history. Possibly neither 78 megatons or 808 megatons of steel fabrication would make much difference.
And the US pisses $5 billion on Elon Musks lunacies.
canadavid said:
Hi Mish.
Thanks for all your posts!
I agree in theory with zero tariffs and subsidies. Let's assume the US follows this route and China subsidizes their steel works until all the US steelworks go out of business. China then increases their steel prices to become profitable again. At that stage the US will not commit new capital to start up the steelworks again in fear of future subsidies. How do you square theory with practice?
In practice, it will not happen.
China would go broke and interest rates would soar before it could give too much free steal away.
Free "steal?" Did you do that on purpose? My comments, such as they are:
The steel does not need to be free. It only needs to be significantly cheaper. In return, China gains economy of scale in steel manufacturing which is difficult to challenge and, as long as China is a huge consumer of steel, much of the steel itself and the subsidy spent paying for that steel presumably end up somewhere else within China's economy (assuming they use it to build productive assets and that the Chinese citizens being paid to make the steel spend their subsidized earnings locally).
In the pure free trade argument, other countries should be grateful for the windfall of cheap steel coming from China and they should use as much of it as they can to lower their own costs. Fine, except (1) steel manufacturing technology is a strategic asset and, (2) western governments consistently enact regional economic policies that hobble the ability of their local industries to compete.
The pure free trade model only works well if countries in the group are guaranteed never to have military conflicts with the others, every country follows a pure free trade policy, and every country is willing to shutter their own production whenever their supposedly egalitarian regulations make their local production noncompetitive. I think there are a number of famous social psychology experiments that say human nature is not consistent with that.

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Schroders in talks to buy stake in green investor Greencoat - Copyright Thomson Reuters 2021
LONDON -British fund manager Schroders said on Thursday it was in advanced talks to buy a significant stake in renewables investment firm Greencoat Capital.
Schroders issued the statement after a report by Sky News that it was close to taking a 75% stake for about 360 million pounds ($478 million), with a potential option to buy the remainder of the firm.
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Guy Hatton clocked his first sub-four-hour marathon as he completed race number 42 of his 100 marathon target.
He did so at the Brexit Challenge, organised by Its Grim up North.
The race was a mentally tough one, consisting of a whopping 106 laps of the course at Tadcaster Grammar School.
Members of Skegness and District Running Club competed at the Grantham Cup 10k cross-country run on Sunday.
Across the testing grounds of Belton House Estate, Helena Shelton entered the popular canicross event with her four-legged partner Totty, whilst Rob Goddard and Olivia Brown opted to go it alone.
Runners were treated to stunning views from the vantage point of Belmont Tower as well as enjoying trails through the deer park.
Rob was first home in 1:06.50, followed by Olivia in 1:19.17.
Helena and Totty crossed the line in 1:19.16.
The Peterborough Spring 10k, part of the four seasons 10k series, gave five SADRC ladies a chance to show just what mummies are made of on Mothering Sunday.
Lisa Smith was next up in 1:06.07, closely followed by Denise Andrews (1:07.23).