Vitamins, genes and language

Thiamine chloride  (source: Wikipedia)

In November 2003, a six-month-old boy was admitted to the emergency department of  a children’s hospital in Tel Aviv. He had been vomiting daily for two months, was apathetic, and had not responsed to anti-emetic drugs. The examining doctor noticed something odd about the child’s eye movements and referred him on to the neuro-ophthalmology department. A brain scan failed to detect any tumour. The doctors remembered a case they had seen 18 months earlier, where a 16-year-old girl had presented with episodic vomiting and abnormal eye movements due to vitamin B1 deficiency.  They injected the child with thiamine and saw improvement after 36 hours. The vomiting stopped, and over the next six weeks the eye movements gradually normalised. When followed up 18 months later he was judged to be completely normal.

This was not, however, an isolated case. Other babies in Israel were turning up in emergency departments with similar symptoms. Where thiamine deficiency was promptly recognised and treated, outcomes were generally good, but two children died and others were left with seizures and neurological impairment. But why were they thiamine deficient? All were being fed the same kosher, non-dairy infant formula, but it contained thiamine. Or did it? Analysis of samples by the Israeli Ministry of Health revealed that levels of thiamine in this product were barely detectable, and there was an immediate product recall. The manufacturer confirmed that human error had led to thiamine being omitted when the formula had been altered.

The cases who had been hospitalised were just the tip of the iceberg. Up to 1000 infants had been fed the formula. Most of these children had shown no signs of neurological problems. But a recent study reported in Brain describes a remarkable link between this early thiamine deprivation and later language development. Fattal and colleagues studied 59 children who had been fed thiamine-deficient formula for at least one month before the age of  13 months, but who were regarded as neurologically asymptomatic. Children who had birth complications or hearing loss were excluded. The authors stress that the children were selected purely on the basis of their exposure to the deficient formula, and not according to their language abilities. All were attending regular schools.  A control group of 35 children was selected from the same health centres, matched on age.

Children were given a range of language tests when they were 5 to 7 years of age. These included measures of sentence comprehension, sentence production, sentence repetition and naming. There were dramatic differences between the two groups of children, with the thiamine-deficient group showing deficits in all these tasks. The authors argued that the profile of performance was identical to that seem in children with a diagnosis of specific language impairment (SLI), with specific problems with certain complex grammatical constructions, and normal performance on a test of conceptual understanding that did not involve any language.

Figure 1 An example of a picture pair used in the comprehension task. 

The child is asked to point to the picture that matches a sentence, 

such as ‘Tar’e li et ha-yalda she-ha-isha mecayeret’ 

(Show me the girl that the woman draws). From Fattal et al, 2011.

I have some methodological quibbles with the paper. The authors excluded three control children who did poorly on the syntactic tests because they were outliers - this seems wrong-headed if the aim is to see whether syntactic problems are more common in children with thiamine-deficiency than in those without. The non-language conceptual tests were too easy, with both groups scoring above 95% correct. To convince me that the children had normal abilities they would need to demonstrate no difference between groups on a sensitive test of nonverbal IQ. My own experience of testing children’s grammatical abilities in English is that ability to do tests such as that shown in Figure 1 can be influenced by attention and memory as well as syntactic ability, and so I think we need to rule out other explanations before accepting the linguistic account offered by the authors. I’d also have liked a bit more information about how the control children were recruited, to be certain they were not a ‘supernormal’ group - often a problem with volunteer samples, and something that could have been addressed if a standarized IQ test had been used. But overall, the effects demonstrated by these authors are important, given that there are so few environmental factors known to selectively affect language skills. These results raise a number of questions about children’s language impairments.

The first question that struck me was whether thiamine deficiency might be implicated in other cases outside this rare instance. I have no expertise in this area, but this paper prompted me to seek out other reports. I learned that thiamine deficiency, also known as infantile beriberi, is extremely rare in the developed world, and when it does occur it is usually because an infant is breastfeeding from a mother who is thiamine deficient. It is therefore important to stress that thiamine deficiency is highly unlikely to be implicated in cases of specific language impairment in Western societies. However, a recent paper reported that it is relatively common in Vientiane, Laos, where there are traditional taboos against eating certain foods in the period after giving birth. The researchers suggested that obvious cases with neurological impairments may be the extreme manifestation of a phenomenon that is widespread in milder form. If so, then the Israeli paper suggests that the problem may be even more serious than originally suggested, because there could be longer-term adverse effects on language development in those who are symptom-free in infancy.

The second question concerns the variation in outcomes of thiamine-deficient infants. Why, when several hundred children had been fed the deficient formula, were only some of them severely affected? An obvious possibility is the extent to which infants were fed foods other than the deficient formula. But there may also be genetic differences between children in how efficiently they process thiamine.

This brings us to the third question: could this observed link between thiamine deficiency and language impairment have relevance for genetic studies of language difficulties? Twin and family studies have indicated that specific language impairment is strongly influenced by genes. However, one seldom finds genes that have a major all-or-none effect. Rather, there are genetic risk variants that have a fairly modest and probabilistic impact on language ability.

Robinson Crusoe Island

A recent study by Villanueva et al illustrates this point. They analysed genetic variation in an isolated population on Robinson Crusoe Island, the only inhabited island in the Juan Fernandez Archipelago, 677 km to the west of Chile. At the time of the study there were 633 inhabitants, most of whom were descended from a small number of founder indviduals. This population is of particular interest to geneticists as there is an unusually high rate of specific language impairment.  A genome-wide analysis failed to identify any single major gene that distinguished affected from unaffected individuals. However, there was a small region of chromosome 7 where there genetic structure was statistically different between affected and unaffected cases, and which contained genetic variants that had previously been found linked to language impairments in other samples. One of these, TPK1 is involved in the catalysis of the conversion of thiamine to thiamine pyrophosphate. It must be stressed that the genetic association between a thiamine-related genetic variant and  language impairment is probabilistic and weak, and far more research will be needed to establish whether it is generalises beyond the rare population studied by Villanueva and colleagues. But this observation points the way to a potential mechanism by which a genetic variant could influence language development.

To sum up: the importance of the study by Fattal and colleagues is two-fold. First, it emphasises the extent to which there can be adverse longer-term consequences of thiamine deficiency in children who may not have obvious symptoms, an observation which may assume importance in cultures where there is inadequate nutrition in breast-feeding mothers. Second, it highlights a role of thiamine in early neurodevelopment, which may prove an important clue to neuroscientists and geneticists investigating risks for language impairment.

References

Fattal I, Friedmann N, & Fattal-Valevski A (2011). The crucial role of thiamine in the development of syntax and lexical retrieval: a study of infantile thiamine deficiency. Brain : a journal of neurology, 134 (Pt 6), 1720-39 PMID: 21558277  

Villanueva P, Newbury DF, Jara L, De Barbieri Z, Mirza G, Palomino HM, Fernández MA, Cazier JB, Monaco AP, & Palomino H (2011). Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. European journal of human genetics : EJHG, 19 (6), 687-95 PMID: 21248734