Why does galactosemia cause mental retardation

Jaundice was the main presentation Other presentations included; convulsions Duration to diagnosis and exposure to galactose in diet correlated with liver pathology severity i. Its complications are potentially preventable. Early detection is mandatory to prevent serious morbidity and mortality. Initiation of neonatal screening for galactosemia in Egypt is recommended. Classic galactosemia results from deficiency of galactosephosphate uridylyltransferase GALT activity, while partial enzymatic impairment results in the more common clinical variant, Duarte galactosemia [1].

Deficiency of GALT results in accumulation of galactose, production of galactitol, defective galactosylation and glycosylation [2]. If undiagnosed and untreated this metabolic derangement causes progressive morbidities that compromise quality of life and threatens it. The derangement varies from jaundice, liver cell failure, sepsis, minor neurologic mental and motor derangements to severe handicapping, renal tubular dysfunction, ovarian dysfunction, cataracts and death [3] , [4] , [5] , [6].

Prompt diagnosis is essential to institute galactose-restricted diet to halt March of galactosemia. While compliance to galactose restricted diet does not promise cure, it is the treatment that reduces acute, short and long-term morbidity and mortality significantly.

Galactosemia complications are potentially preventable [7] , [8] , [9]. Some countries provide neonatal screening programs to allow early detection and management of galactosemia [10] , [11]. The neonatal screening programs for galactosemia allowed early detection of the classic galactosemia, which is fatal, and the Duarte type.

It allowed further identification of molecular defects in galactosemia. Partial GALT deficiency clinical spectrum ranges from clinically silent to milder clinical spectrum with potentially problematic developmental deficits rather than life threatening complications [13]. In countries where newborn screening is not available, health system depend on the diagnosis made by neonatologists or clinicians at large.

In Egypt screening for galactosemia is not included in neonatal screening program. This work aimed to define clinical presentation s of galactosemia that should raise clinicians high index of suspicion to diagnose galactosemia in communities in which neonatal screening programs are not feasible. This is an observational study that included a cohort of 37 infants and children who were followed up for 2-years during the period from to at the Pediatric Hepatology Clinic New Children Hospital, Cairo University, Egypt.

Parents consented to trial. Inclusion criteria: patients fulfilling the diagnosis of classic galactosemia confirmed by reduced erythrocyte galactosephosphate uridylytransferase GALT activity by C14 radioactive assay [14].

Anthropometric measures were plotted against Egyptian Percentiles for weight and height [15] and recorded as percentiles for age. Outcome was graded into: resolved where the condition resolves without sequela, improved where the condition improves but did not resolve completely, stationary, progressive and death.

The studied cohort comprised 37 infants with a male preponderance; 22 Eight Only one child with galactosemia presented by self-mutilation and mental subnormality, he had normal uric acid level, and was not found to suffer from other causes of self-mutilation apart from galactosemia.

GALT enzyme activity was quantitative in 36 of the cohort, where 10 There was no statistically significant association between age at onset, age at presentation with any symptom, sign or complication. There was no statistically significant association between GALT residual activity and amount of reducing substance in urine or with outcome of neurologic or liver disease as illustrated in Table 3 , Table 4 , Table 5.

Nine children underwent liver biopsy as deemed indicated. Duration to diagnosis and longer duration of exposure to galactose in diet correlated with liver pathology severity i. One child had semi-quantitative assessment of GALT, and was not included in this comparison. The child with jaundice who had semi-quantitative assessment of GALT resolved the jaundice.

Biopsy was performed in only 9 children as indicated by clinical condition. One infant who presented by liver cell failure at one month of life had a complete remission on galactose-restricted diet. The other progressed to death. Among the 7 with portal hypertension, the portal hypertension was not reversible and only one child underwent liver transplantation, while the others had a stationary course.

Among the 25 with cholestasis, only 8 resolved the cholestasis completely on galactose-restricted diet as in Table 5. Renal tubular acidosis was not reversible by galactose-restricted diet and was very challenging to control, as phosphorous doses tailored according to needs were difficult to tolerate by the affected children. Among the 11 children who presented by epilepsy that was difficult to control, 4 had a stationary course and 5 were controlled on anti-epileptic medications of them 4 were weaned successfully off anti-epileptic medications.

Four Galactosemia associated morbidities and mortality are potentially preventable. Galactosemia results from deficiency of GALT, galactose epimerase and galactokinase. Accumulation of galactose and galactitol —the alcohol of galactose- are toxic to various tissues, including the liver, nervous system and kidneys [2]. While galactosemia morbidity and mortality is amenable to management by galactose-restricted diet, the chronic morbidity in classic galactosemia in not amenable to management by diet.

The earlier the institution of galactose-restricted diet the better the prognosis, as children with galactosemia are challenged in their early days by life-threatening amounts of galactose, given that breast milk is rich in lactose that is a disaccharide composed of galactose and glucose [16]. Galactose-restricted diet should be implemented as early as possible in children with galactosemia to prevent the early morbidity and mortality associated with early exposure to galactose in nursing milk —whether breast or artificial milk.

This work provides evidence that studies of prevalence and incidence of galactosemia in Egypt are mandatory, and inclusion of galactosemia in neonatal screening is urged. Egypt neonatal screening program does not include neonatal screening for galactosemia.

Thus full-blown picture of galactosemia is still being encountered in Egypt. The studied cohort exhibited serious complications of galactosemia, ranging from failure to thrive, motor development retardation, epilepsy, microcephaly, mental retardation, jaundice, hepatosplenomegaly, portal hypertension, autoimmune hepatitis, portal vein thrombosis, liver cell failure, cataract, renal tubular acidosis, self mutilation, and a severe form of combined immune deficiency that was investigated as severe combined immunodeficiency and death.

No correlation was found between residual GALT activity and clinical picture. This work studied clinical presentation spectrum of known cases of classic galactosemia and not incidence, as the studied cohort was recruited from only those presenting to Cairo University Children Hospitals. The limited number of studies that report incidence of galactosemia in Egypt, reported an incidence that ranged from to [19] , [20] , [21].

The current study demonstrated that GALT residual activity is not a determining factor of clinical phenotype of children with untreated galactosemia. Moreover, it is neither possible to define the attributes responsible for development of liver disease or development of nervous system disease or overlap presentation, nor to determine attributes for timing of onset of disease.

It is suspected that detectable residual activity even if scarce could explain why the studied cohort survived the early neonatal period, and did not suffer early demise, i. Yet this assumption needs a bigger sample size for verification. Incidence and prevalence studies of galactosemia in Egypt will provide answers to questions, pave way for cost-effectiveness studies, and aid in decision making for inclusion of galactosemia in neonatal screening program.

Until then it is important to note that incremental cost effectiveness studies in different countries varied, and justified neonatal screening programs for galactosemia [10] , [17] , [22] , [23] with the exception of United Kingdom that stopped its galactosemia newborn screening program. One of the arguments that lead to this decision was the low incidence of galactosemia among their population [24] , [25].

The current work supports that established morbidities of galactosemia are not reversible but are amenable to improvement or control when galactose restricted diet is initiated. Despite the lack of a flawless completely curative treatment, galactose-restricted diet reduces morbidity and mortality [26]. The numbers or incidence of early deaths due to galactosemia in Egypt are not known, yet the currently studied cohort of neonates and infants with galactosemia had a later age at onset and later age at presentation.

Early restriction of galactose from diet improves mortality and trades sepsis, liver cell failure, epilepsy and renal tubular acidosis with possibility of delayed puberty, ataxia, intention tremor, microcephaly, declined intelligence and other neurologic abnormalities in some children [26]. Neonatal screening for galactosemia is one step for a better outcome of galactosemia. As adherence to galactose-restricted diet needs legislative steps to secure documentation of information about galactose content of foods and food products and needs compliance from community, to allow affected subjects the information that is necessary for their meal planning.

Family counseling for families with index cases and genetic testing for future pregnancies are other valuable tools. Residual GALT activity does not protect against complications of untreated- galactosemia. The current work supports that GALT residual activity is not a determining factor of outcome of children with galactosemia challenged by galactose in diet.

The age dependent endogenous galactose, galactose 1 phosphate formation and galactitol might be an explanation [27] , [28] , [29] , [30]. Moreover, the currently studied cohort does not represent the whole spectrum of disease [31] , as the study assessed the clinical spectrum in known cases with galactosemia only. Effect of amount of galactose exposure i. It houses one of the world's largest and most accessible agricultural information collections and serves as the nexus for a national network of state land-grant and U.

Department of Agriculture field libraries. In fiscal year Oct through Sept NAL delivered more than million direct customer service transactions. Data provider:. National Agricultural Library. Active Data provider submitted metadata in the last calendar year. Journal Article. Two studies additionally used control subjects [ 19 , 20 ]. Both these studies matched their controls on age and gender, and one of them added parental educational coding as a matching variable [ 20 ].

Three studies were of low quality, with a high risk of bias [ 20 , 26 , 28 ]. All other studies were found to be of moderate quality.

The results of the risk of bias assessment can be found in Additional file 4. The most frequent issue was the recruitment process of the patients in the eight studies investigating multiple patients.

Two studies had a high risk for selection bias due to nonconsecutive- and incomplete inclusion [ 25 ], or unclear exclusion criteria for controls and cases [ 20 ]. In all five cross-sectional studies the recruitment process was unclear [ 15 , 21 , 22 , 23 , 24 ].

Only one study described the recruitment process in sufficient detail [ 19 ]. Moreover, three studies applied exclusion criteria containing neurological or psychiatric disorders [ 21 ] and mental retardation [ 19 , 22 ]. The presence of psychiatric symptoms was mentioned in three studies but possible effects for, or associations with cognitive outcomes were not tested [ 15 , 19 , 21 ].

Moreover, in the majority of the included studies the association between IQ and performance on the neuropsychological tests was not tested nor accounted for. Finally, there was a large variability between studies in utilized neuropsychological tests.

One study used a test of unclear psychometric quality [ 22 ]. Due to this variability and the moderate to low quality of the included studies, a quantitative meta-analytic approach was not possible.

A systematic, narrative approach was utilized for the current review. All results of the neuropsychological tests can be found in Table 2. Two studies examined information processing speed [ 21 , 23 ].

A cross-sectional study reporting a total score of two subtests measuring information processing speed and cognitive inhibition, demonstrated an impaired performance averaged across a sample of 24 patients adults and children , but did not report what process caused the impairment [ 21 ]. Thirty percent of the individual patients performed on an impaired level i.

Two cross-sectional studies addressed attention and found no impairment [ 21 , 23 ]. However, in both studies the range of performances exceeded the level of impairment, indicating that a proportion of the patients i. Two studies addressed verbal memory [ 21 , 23 ]. A cross-sectional study of children and adults found no impairments in verbal information encoding and retrieval [ 21 ]. However, The same was found in another cross-sectional study [ 23 ].

Three studies examined visual memory [ 19 , 21 , 24 ]. A small cross-sectional study reported an impaired overall immediate recall of the same complex figure but did not differentiate the results of the different elements or report the delayed recall-results [ 24 ].

Six studies examined expressive language [ 19 , 20 , 22 , 23 , 25 , 27 ]. A cross-sectional study found expressive vocabulary impairment in adults, but not in children [ 23 ]. However, the range of performances was large indicating that a proportion of the patients functioned on an impaired level.

A case-series reported expressive vocabulary impairment in two out of four children [ 25 ]. A poorly designed case-control study found no impairment in another five-year old patient [ 20 ].

One cross-sectional study of 32 children and adults found impairments on another aspect of expressive language, namely repetition, measured by a German test of unclear psychometric quality [ 22 ]. Lastly, two case studies assessed multiple aspects of expressive language by means of a language scale [ 20 , 27 ]. Both found an impairment in expressive language. Seven studies addressed receptive language [ 15 , 20 , 23 , 25 , 26 , 27 , 28 ].

No receptive vocabulary impairment was found in a cross-sectional study concerning 27 early-treated adults [ 15 ]. In contrast, another cross-sectional study concerning both adults and children found impairment in adults, but not in children [ 23 ].

However, the scores of patients in both studies showed a large variation indicating that a proportion of the patients performed on an impaired level. A case-series found receptive vocabulary impairment in three children and no impairment in one child [ 25 ].

Three case reports, of which one was controlled, found no impairment [ 20 , 26 , 28 ]. A group study reported no impairments in phonological awareness, another basic aspect of receptive language [ 23 ]. Lastly, two case studies assessed multiple aspects of receptive language by means of a language scale [ 20 , 27 ].

Both found an impairment in receptive language. Two studies addressed visuoconstruction [ 19 , 23 ]. They also showed no impairment on another copying test, a result also found in another cross-sectional study [ 23 ]. Two studies addressed visual perception [ 21 , 23 ]. Averaged across all 23 patients, impairment in space perception, but not in object perception was found in a cross-sectional study [ 21 ].

Only 4. Another cross-sectional study found no impairment in object perception, but scores differed extensively between individual patients [ 23 ]. Three studies examined executive functioning [ 19 , 21 , 23 ], which is an umbrella term for several higher-order functions of which four were investigated in patients with CG i. A pediatric case-control study assessed abstract thinking together with cognitive flexibility [ 19 ].

Another cross-sectional study also utilized a test measuring both abstract thinking and cognitive flexibility [ 21 ]. They found an impaired performance averaged across all patients, and a proportion of However, separate scores for abstract thinking and cognitive flexibility were not reported, leaving it unclear whether the low performance was due to cognitive flexibility impairment alone. A cross-sectional study found scores within normal limits on an abstract thinking test which does not involve cognitive flexibility, however large differences between patients were present [ 23 ].

One cross-sectional study reported impairments on a test measuring cognitive inhibition [ 21 ]. However, this result was based on two tests measuring information processing speed and cognitive inhibition. Therefore, it is unclear which process underlies the impaired performance. Since none of the included studies examined social cognition with standardized neuropsychological tests, it remains unclear whether patients with CG are impaired in social cognition. The current systematic review examined the incidence of cognitive impairment in patients with CG and reviewed the impairment in specific cognitive domains.

Eleven studies were identified, including three case reports and one case-series. Of the eight studies investigating multiple patients, the quality was in seven studies moderate to low. Moreover, the number of studies per cognitive domain was low. The review revealed that large differences exist amongst patients with CG. The averaged performance of the patients reported in each group study was often on a below average to low level, while a proportion of the patients performed on an impaired level.

The range of vocabulary performances of the individual patients also exceeded the level of impairment, however specific percentages of the proportion of patients performing on an impaired level remained unknown.

Evidence for impairments in other aspects of language functioning was mainly limited to case studies. The average level of performance did reach an impaired level for information processing speed, space perception, cognitive flexibility and cognitive inhibition, but the evidence was based on only a small number of studies.

There is some indication that abstract thinking and visuoconstruction are relatively spared. Social cognition was not investigated at all. These results suggest that specific cognitive impairments indeed underlie the lower level of intellectual functioning.

However, a specific cognitive profile cannot be determined due to individual differences between patients and limited number of merely small studies. A large number of studies investigating cognition in CG was excluded in this review since they only utilized developmental screening- or intelligence batteries. This represents the initial main focus on clinically assessing developmental delay and intelligence only in patients with CG.

To improve the knowledge concerning cognitive functioning in CG, well-designed and well-reported studies covering multiple cognitive domains should be performed.

The risk of selection bias needs to be lowered for example by describing the recruitment process in more detail and by refraining from the exclusion of patients with other long-term complications of CG i.

Excluding these patients will lead to an underestimation of cognitive impairments that patients with CG may encounter. However, the inclusion of these patients will also add confounding factors which will need to be taken into account in the statistical analysis. Moreover, the influence of late treatment on cognitive development [ 11 , 12 ] needs to be acknowledged by either solely including early-treated patients i. Possible confounders such as anxiety and depression [ 15 ] should be considered in the analysis of cognitive results, since they can influence cognitive performance [ 14 ] just as the level of intelligence [ 8 ].

Future neuropsychological assessments need to cover several cognitive domains with preferably multiple tests per domain. Important domains include information processing speed, attention, memory, language, visuospatial perception, executive functioning and social cognition.

Information processing speed and executive functioning are especially important to be investigated in light of brain imaging findings in patients with CG. First, white matter abnormalities were found [ 29 , 30 ] which are associated with lower information processing speed in both healthy- and patient populations [ 31 ]. Second, grey matter abnormalities were found within areas involved in executive functioning i. Finally, the report of cognitive results needs to involve the quantitative results of tests, including subtests.

The mean raw score plus standard deviation and interquartile range, and normative score need to be reported as well as the proportion of patients performing on an impaired level to acknowledge the large individual differences between patients. Unfortunately, an important limitation of studying rare diseases is the absence of large sample sizes. In order to understand these differences in cognitive functioning between CG-patients, large patient cohorts are necessary.

Initiatives in which data of multiple patient cohorts are combined e. This will also make it possible to examine the association of cognition and other long-term complications of classical galactosemia such as movement disorders e. Lower intellectual functioning has been found to be more frequent in patients with motor dysfunction [ 35 ], raising the question whether cognitive impairment in patients with CG is associated with other long-term complications of CG.

Therefore, cognitive functioning should be part of this registry as well. The recent international clinical guideline for the management of classical galactosemia [ 3 ] acknowledges that certain cognitive domains i. This review supports this recommendation, but also highlights that neuropsychological assessment of CG-patients should not be limited to these three cognitive domains. Preferably all cognitive domains should be assessed by means of a neuropsychological assessment.

This will result in a better understanding by the patient, caregivers, teachers and coworkers and consequently a more suitable guidance plan can be made and access to appropriate interventions e. Ultimately, this could improve the health-related quality of life which is affected by the lower level of cognitive functioning [ 5 ].