Neurocognitive Impairment in Inherited Metabolic Disorders due to Intoxication and Energy Defects: A Systematic Review

ABSTRACT

Inherited metabolic disorders (IMD) can disrupt brain development and functioning, leading to cognitive and behavioral abnormalities. This systematic review aims to provide a comprehensive synthesis of the evidence regarding neurocognitive impairments in intoxication IMD due to the accumulation of small molecule disorders and energy‐related IMD. A search was conducted in the PubMed database until August 2024, using the term “cognition” and up to 421 energy‐related IMD and 196 intoxication IMD. Reviews, animal models, studies with non‐standardized measures, and studies that focused on complex molecule disorders, small molecule deficiencies, and phenylketonuria were excluded. In total, 163 studies were included in the final analysis. The cognitive domains assessed were executive functions, attention, processing speed, language, speech, visual performance, fine motor dexterity, memory, behavioral and emotional regulation, and social cognition. Most available evidence focused on intoxication IMD (83%), which exhibited better global cognitive functioning than energy defects. The cognitive domains most frequently reported as impaired were fine motor dexterity (80.9%), behavioral and emotional regulation (80%), executive functions (73.3%), attention (72.4%), and social cognition (65.6%). After applying the chi‐square test with a 95% confidence level, no statistically significant differences were found between intoxication and energy‐related IMD. However, language impairments were slightly more pronounced in intoxication disorders, while visuospatial deficits were more common in energy disorders. Individuals with IMD are at a higher risk of neurodevelopmental disorders, which can persist despite early detection and treatment. Although the number of cognitive studies has increased in recent years, further research with standardized measures is necessary to understand the underlying pathophysiology of neurocognitive impairments.

1. Introduction

Inherited metabolic disorders (IMD) disrupt metabolic pathways, significantly affecting brain development and function. These disruptions increase the risk of a wide range of neurodevelopmental and psychiatric disorders [1]. Among them, phenylketonuria (PKU) and other well‐studied IMDs have become models for understanding cognitive dysfunction caused by abnormal brain chemistry and neuronal damage [2, 3]. However, beyond these classic disorders, the number of recognized IMDs has rapidly increased in recent years. Although IMDs are estimated to account for up to 5% of nonspecific intellectual disabilities [4], this figure requires constant revision as new diseases are identified.

Advances in medical care have improved long‐term survival rates for individuals with IMDs, making health‐related quality of life an increasingly important issue [5, 6]. Since cognitive and behavioral impairments significantly impact daily life [7, 8], understanding their neurocognitive consequences is essential for optimizing patient care and developing novel interventions. Accurate neuropsychological assessment and targeted interventions are crucial in addressing the long‐term needs of this population [9].

Over time, individuals with IMDs often experience slowed cognitive development, resulting in an increasing performance gap compared to their peers. The severity of neurocognitive deficits is influenced by several factors, including the number, severity, and duration of metabolic decompensation episodes, the age at symptom onset, or the extent of early intervention, even among those identified by newborn screening programs [10, 11]. Psychiatric disorders frequently contribute to misdiagnosis or delayed diagnosis of IMDs, further complicating early intervention [12, 13]. While many patients show cognitive improvement after treatment, studies on long‐term cognitive outcomes remain scarce, highlighting the need for further research [14, 15].

This review aims to synthesize the neurocognitive profiles of IMDs associated with intoxication due to the accumulation of small molecules and energy‐related metabolic defects [16]. Detailed neurocognitive assessments can be conducted in patients with normal intelligence (IQ) or mild intellectual impairment. However, in cases of moderate or severe intellectual disability, comprehensive neuropsychological evaluations are often unfeasible due to the complexity of cognitive impairment.

Disorders involving complex molecule defects, which are largely untreatable and tend to show a neurodegenerative progression with heterogeneous cognitive profiles, fall outside the scope of this review. Additionally, conditions related to small molecule deficiencies (such as amino acid, fatty acid, and metal deficiencies) are not included, as they usually present with severe encephalopathies, global psychomotor delay, and extensive neurological symptoms, making the assessment of higher cognitive functions challenging [17].

This systematic review provides a comprehensive synthesis of existing evidence on cognitive and behavioral impairments associated with intoxication‐type and energy‐related IMDs. Despite the variability in clinical manifestations, grouping these disorders into pathophysiological categories may help identify common neurocognitive features. Predicting cognitive trajectories in these patients can support the development of early detection strategies and therapeutic interventions; ultimately helping to prevent learning disabilities and neuropsychiatric disorders. By mitigating the cognitive and behavioral impact of IMDs, these efforts can significantly improve the quality of life for both patients and their families.

2. Methods

2.1. Inclusion and Exclusion Criteria

To ensure accuracy, this systematic review focused on specific subgroups of the International Classification of Inherited Metabolic Disorders (ICIMD) [18] related to the broad categories of “Intoxication IMD” and “Energy‐related IMD” of the simplified classification [16]. Figure 1 shows a graph that associates the different categories of the international classification with the categories of the simplified classification, in which intoxication defects and energy‐related disorders are found.

FIGURE 1.

Association between the different categories of the international classification with the categories of the simplified classification [16, 18].

The inclusion criteria encompassed all prospective and retrospective studies, as well as case reports, that utilized standardized cognitive measures, such as developmental scales and neuropsychological tests. Due to the limited number of cognitive studies available for this population, we included all research published up to August 2024 involving children and adult samples.

We excluded review reports and studies with animal models or non‐standardized cognitive measures. Additionally, complex molecule disorders and small molecule deficiencies were not included, as they fall outside the scope of this research. PKU was also excluded because its neuropsychological profiles have already been extensively documented.

2.2. Search Strategy

The systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines established in 2020 [19].

A comprehensive search was conducted in the Pubmed database for articles reporting neurocognitive impairment in patients with intoxication and energy‐related IMD. PubMed, including MEDLINE, was searched for its comprehensive biomedical coverage and precise MeSH indexing for rare disorders. Other databases yielded very few additional relevant studies. The search was complemented by manual screening of reference lists to identify further eligible articles.

Up to 617 IMD (n = 421 energy‐related IMD; n = 196 intoxication IMD) were searched using the terms “cognition” AND “the name of each IMD” until August 2024.

2.3. Selection of Publications

After searching the Pubmed database, a total of 416 records were identified. Abstracts and full texts were evaluated by one reviewer and verified by another, with any disagreements addressed through discussion. Following an initial screening of the titles and abstracts, 31 review studies were excluded from the analysis. From the remaining 385 records, a full‐text evaluation for eligibility was conducted, resulting in the removal of 222 studies due to the lack of standardized neuropsychological measures or the use of animal models. Ultimately, 163 records were included in this review (see Figure 2).

FIGURE 2.

Flow diagram summarizing the different steps of the review based on the PRISMA 2020 statement [19].

In cases where a study addressed more than one type of IMD, the analysis was separated for each disorder. Consequently, we identified 166 articles focusing on intoxication IMDs (83%) and 34 articles on energy‐related IMDs (17%).

2.4. Data Analysis

The variables reviewed in all studies included the year of publication, sample size, sample age, and the classification of each IMD. To assess intellectual disability (ID), the percentage of individuals with ID was included when available, along with the reported severity levels (moderate to severe ID, mild to borderline ID, and average intellectual quotient or IQ).

The cognitive domains assessed were executive functions, attention, processing speed, language, speech, visual performance, fine motor dexterity, memory, behavioral and emotional regulation, and social cognition. When available, performance in any cognitive domain was measured on a categorical scale of “impaired” or “preserved.” Only studies that described performance in each function were included in the analysis of cognitive domains.

Prior to the statistical analysis, we performed a normality test on the quantitative variables, using the Kolmogorov–Smirnov test. A significant p value (p < 0.05) indicated that the variables studied did not follow a normal distribution. Therefore, we used non‐parametric tests: Mann–Whitney U test for categorical variables with two categories and the Kruskal–Wallis test for those with three or more groups. Fisher's exact test was used for variables with fewer than five cases in any category. For qualitative variables, we applied Pearson's chi‐square test.

All statistical tests were conducted with a confidence level of 95% and were considered significant at p < 0.05. The IBM SPSS statistical software 29.0 was used to perform all analyses.

3. Results

A total of 163 studies about neurocognitive impairment in IMD, published between 1981 and 2024, were reviewed (see Table S1).

3.1. Year of Publication

Most of the studies were published from 2010 onwards (74%); see Supplementary Figure S1. The year with the most publications was 2020 (n = 21). Regarding the different cognitive domains, we found that speech was reported less impaired in recent years (p = 0.004; chi‐square test).

3.2. Age of the Sample

Most of the studies reviewed were focused on pediatric samples. Children accounted for 60.5% of the studies, whereas only 11% of the studies used an adult sample. About 28.5% of all studies used both children and adult participants. In order to clear this confusing variable, studies with mixed children and adult samples were excluded from the statistical analysis; only studies with children (84.6%) or adults (15.4%) were considered.

Among studies on intoxication IMD, 86% were on children and 14% were on adults. Energy‐related IMD studies also were more frequent on children (79.3%) than adult samples (20.7%). Among energy‐related IMD, we found that cytoplasmic defects had a higher percentage of studies with adults (37.5%) than mitochondrial defects (20%) and cell membrane disorders (9.1%).

Regarding the cognitive impairment related to the age of the sample, no significant differences between children and adults were found on the Pearson chi‐square test regarding severe/moderate ID, mild/borderline ID, average IQ, executive functions, attention, processing speed, visual performance, motor dexterity, memory, behavioral and emotional regulation, and social cognition. However, the studies reviewed reported significantly more language and speech problems in children than in adults (p = 0.007, chi‐square test; p = 0.042, Fisher's exact test).

3.3. Sample Size and Most Reported IMD

Taking into account all the studies reviewed, the number of subjects added up to 4.313 patients with IMD; more than 1.717 children and 527 adults. We found that the mean number of subjects per article was 21.57 (SD = 40.97). Studies with intoxication IMD had a mean number of 24.54 subjects per study (SD = 44.21); whereas studies with energy‐related IMD had a mean of 7.03 subjects per study (SD = 9.47).

Considering the simplified classification, intoxication IMD were the most reported in the literature (83%), energy‐related IMD represented only 17% of all studies. Accordingly, amino acid metabolism disorders encompassed 58% of the evidence, being urea cycle disorders and organic acidurias the most frequently studied among them (26.5% and 13%, respectively). Disorders of carbohydrate metabolism were the second most reported category (20%); being disorders of galactose metabolism (12%) the most studied diseases within this category. Among energy‐related IMD, cell membrane carriers (41.2%) were the most frequently studied, followed by mitochondrial defects (32.3%) and cytoplasmic defects (26.5%).

Considering each disease alone, the most reported in the literature was galactose‐1‐phosphate uridylyltransferase deficiency (11.5%), followed by ornithine transcarbamylase deficiency (8%), GLUT1 deficiency (7%) and glutaryl‐CoA dehydrogenase deficiency (6%).

3.4. Neurocognitive Impairment

3.4.1. IMD Global Cognitive Functioning

Regarding neurocognitive outcomes, the most commonly studied impairment was intellectual disability (ID), encompassing 88% of the articles. However, about 66.5% of the studies reported mild/borderline ID (n = 177) and 53.4% an average IQ (n = 94). Only 32.2% of the records reported severe or moderate ID (n = 57); see Figure 3.

FIGURE 3.

Percentage of studies reporting impairment of each cognitive domain.

The mean percentage of ID reported in the studies was 49.44 (SD 39.15). Higher percentages of ID were related to more language and social cognition impairment (p = 0.001 and p = 0.022, respectively; Mann–Whitney U test). However, no other cognitive domains were related to the percentage of ID.

Considering all the studies reviewed, the domains most frequently reported as impaired were fine motor dexterity (80.9%), behavioral and emotional regulation (80%), executive functions (73.3%), attention (72.4%) and social cognition (65.6%). On the opposite, the less reported as being impaired was processing speed (36.4%).

3.4.2. Intoxication and Energy‐Related IMD

When the data were analyzed according to each IMD type, we found that intoxication IMD presented a significantly higher percentage of studies than energy‐related IMD with average IQ (57.3%, p = 0.029; chi‐square test). Although there was also a difference in mild/borderline ID percentages, it was not statistically significant (p = 0.107, chi‐square). Accordingly, energy‐related IMD had a higher percentage of cases with severe–moderate ID (51.5%) than intoxication IMD (27.8%); the differences were statistically significant (p = 0.008; chi‐square test).

The percentage of ID was higher among energy‐related IMD (mean 60.95, SD 42.46) than intoxication IMD (mean 46.91, SD 38.08). When the variable energy‐related IMD were decomposed, the mean percentage of ID among cytoplasmic defects (mean 80.38, SD 27.89; p = 0.025, Kruskal‐Wallis test) was significantly higher than that of cell membrane carriers (mean 68.35, SD 40.41) and mitochondrial defects (mean 35.80, SD 45.94). In cytoplasmic defects, severe–moderate ID (66.7%) was more common than in cell membrane carriers (57.1%) and mitochondrial defects (30%), with the differences being statistically significant (p = 0.017; chi‐square test). Likewise, average IQ was more frequently reported among mitochondrial defects (60%) than cell membrane carriers (35.7%) and cytoplasmic defects (11.1%), with significant differences as well (p = 0.026; chi‐square test). No differences were found regarding mild/borderline ID.

Disorders of energy substrate metabolism, disorders of peptide and amine metabolism, neurotransmitter disorders, and disorders of mitochondrial gene expression were the most common showing severe–moderate ID (p = 0.001; chi‐square test). For mild/borderline ID, the most frequent categories were nuclear‐encoded disorders of oxidative phosphorylation, disorders of mitochondrial DNA maintenance and replication, disorders of amino acid metabolism, and disorders of carbohydrate metabolism (p = 0.049; chi‐square test). Lastly, the categories with higher percentages of average IQ were disorders of tetrapyrrole metabolism and disorders of fatty acid and ketone body metabolism (p = 0.019; chi‐square test). No differences were found for other cognitive domains among the more specific categories.

Both types of IMD showed a similar pattern of impairment in specific cognitive domains; see Figure 4. After applying the chi‐square test, with 95% confidence, no statistically significant differences were found. However, qualitatively, intoxication IMD showed more frequent attentional and language deficits, while energy‐related IMD showed more frequent visuospatial deficits, specifically cell membrane carriers (p = 0.024; chi‐square test).

FIGURE 4.

Percentage of studies reporting impairment on each cognitive function among Intoxication and Energy‐related IMD.

3.4.3. Neurocognitive Impairment in Particular Disorders

Due to the significant diversity and complexity of the diseases involved, conducting statistical analysis on larger groups was not feasible. However, qualitative descriptions can still be drawn from the data, highlighting patterns of impairment associated with each specific IMD. Figures 5 and 6, serving as visual aids, offer a guided summary of the cognitive impairments reported for each group and individual disease. As previously mentioned, many IMD exhibit similar patterns of impairment, with motor dexterity, executive functions, and attention being the most frequently reported issues. However, some groups of IMD lack detailed descriptions of cognitive functioning. For instance, biotin metabolism disorders have mainly been associated with motor dexterity and visuospatial deficits. Disorders related to pyruvate carboxylase deficiency have shown a greater prevalence of language disorders. In contrast, disorders such as those related to heme synthesis and porphyrias have primarily been characterized by psychiatric symptoms, along with difficulties in behavioral and emotional regulation.

FIGURE 5.

A visual guide illustrating the specific neurocognitive impairments associated with each group of IMD.

FIGURE 6.

A visual guide illustrating the specific neurocognitive impairments associated with each IMD.

3.5. Risk of Bias

Due to the heterogeneity of study designs and case reports, it was not possible to employ standardized tools for the thorough assessment of quality or the evaluation of potential bias within the included studies.

4. Discussion

To the best of our knowledge, this review summarizes most of the evidence available about cognitive and behavioral functioning in a large number of IMD.

Over the past decade, there have been an increasing number of studies focused on the neurocognitive outcomes of IMD. Previously, the core of the research was based on genetic, metabolic, and neurological studies since most survivors presented moderate to severe developmental disabilities [9]. Recently, areas such as executive functions and social cognition have gained increased attention in the literature on IMD. While much work still needs to be done, the scientific community is becoming more aware of the neuropsychological impairments associated with these rare diseases, enhancing research in this field.

In recent years, the frequency of studies highlighting speech difficulties has declined; partially pointing towards positive effects of early detection and improved interventions.

Among the records reviewed, the vast majority focused on intoxication IMD. The most commonly reported conditions included urea cycle disorders, organic acidurias, and galactose metabolism disorders. Among energy‐related IMD, cell membrane carriers, such as GLUT1 deficiency, were the most frequently studied.

Overall, the specific disorders that received the most research attention were galactosemia, ornithine transcarbamylase (OTC) deficiency, GLUT1 deficiency, and glutaric aciduria type I (GA‐1). Given that IMDs are rare diseases, the average number of subjects in studies was relatively small. For intoxication IMDs, the mean was 24 subjects, while for energy‐related IMDs, it dropped significantly to 7 subjects per study. This disparity may result from the limited availability and variability of patient samples, as well as a high percentage of severe encephalopathies in pediatric energy‐related disorders, which makes the study of detailed neuropsychological profiles unfeasible. Finally, these limitations force studies to concentrate on specific diseases or individual case reports, underscore the inherent challenges of researching rare diseases, and complicate efforts to draw comprehensive conclusions.

Systematic reviews that focus on specific IMD also face similar limitations, such as heterogeneous or small sample sizes, lack of control groups, and incomplete neuropsychological evaluations. Furthermore, the absence of standardized protocols in psychometric assessments across different centers complicates comparative analysis and makes it difficult to draw clear conclusions [11, 12, 20].

4.1. Intellectual Disability (ID)

More than half of the subjects exhibited average IQ levels. Among those studies reporting on ID, a significant majority identified cases of mild ID or borderline IQ, whereas severe to moderate ID was the least represented in the literature.

Intoxication IMD presented overall better cognitive functioning than energy‐related IMD, with a significantly higher number of subjects with average IQ and mild ID. Accordingly, energy‐related IMD had more subjects with moderate to severe ID, especially among cytoplasmic defects such as creatine disorders. Mitochondrial beta‐oxidation defects such as MCAD had the best cognitive outcome among energy‐related IMD.

A wide range of genetic and epigenetic factors are involved in the heterogeneity of global cognitive functioning [21]. Following the implementation of newborn screening and improved detection methods, some IMD can now be identified at an earlier stage. This advancement has helped prevent many life‐threatening symptoms and severe neurological damage. Consequently, there is an increasing number of asymptomatic patients and individuals exhibiting milder phenotypes when diagnosed before symptoms appear [11, 22, 23].

Disorders related to energy substrate metabolism, such as defects in creatine, are associated with more severe outcomes, in particular creatine transporter deficiency, since creatine supplementation and other dietetic strategies may not affect brain creatine concentrations or cognitive outcomes [24, 25]. Therefore, new treatment strategies are still needed to prevent this population's most severe cognitive impairments.

It is important to note that measuring severe to moderate ID using psychometric standardized tests can also be challenging. Developmental tests may struggle to differentiate among lower ability levels accurately due to the floor effect. As a result, some studies excluded may have used qualitative measures for individuals with more severe ID, potentially leading to their underrepresentation in the literature.

This review found that a higher percentage of ID is associated with increased language and social cognition. It is known that vocabulary levels and language development are essential in bolstering overall cognitive functioning.

On the other hand, the complex processes involved in social cognition engage advanced cognitive skills. Understanding social functioning is essential to conceptualizing intellectual disabilities, as it constitutes one of the primary components of overall adaptive functioning, alongside traditional intelligence quotient (IQ) measures. Furthermore, it is important to note that autism spectrum disorder frequently co‐occurs with intellectual disabilities; in fact, over 40% of genetic syndromes associated with ID tend to score relatively poorly on established social‐cognitive assessments.

Additionally, performance on social‐cognitive tasks in individuals with ID is related to difficulties in executive function and language. This connection underscores the challenge of separating social‐cognitive abilities from language and general cognitive difficulties central to ID when using traditional assessment methods. The nature of these difficulties and the degree to which they emerge varies greatly among different disorders.

While most studies reported average or milder phenotypes, neurocognitive impairment can still be present in patients with higher overall cognitive abilities.

The neuropsychological domains commonly reported as impaired in the literature include fine motor dexterity, behavioral and emotional regulation, executive functions, attention, and social cognition. In contrast, processing speed, aside from severe ID as previously mentioned, is less frequently addressed.

4.2. Motor Dexterity Impairment

Motor disturbances are the most commonly observed impairments in individuals with IMD. Since motor disorders may negatively impact many psychometric tests, lower scores often do not accurately reflect the individual's cognitive abilities. The interaction between motor difficulties and cognitive testing emphasizes the need for a careful assessment approach to provide a more comprehensive understanding of the individual's capabilities.

Among intoxication IMD, organic acidurias such as glutaric aciduria type I typically show acute‐onset dystonia and dyskinesia. Following an acute encephalopathic crisis, these children may suffer from motor and language impairment, and severe dystonia can affect their long‐term outcomes. Neuroimaging findings in this population often include frontotemporal atrophy, delayed myelination patterns, subdural hygromas, ventriculomegaly, and acute striatal necrosis of the basal ganglia. These factors contribute to movement disorders and motor delays [26, 27].

Among energy‐related IMD, GLUT1 deficiency syndrome is commonly associated with dysarthria and various movement disorders [28, 29]. Movement disorders in this condition have been associated with pyramidal, extrapyramidal, and cerebellar systems [30], and epilepsy is also common among this population. Early intervention in GLUT‐1 deficiency syndrome has been associated with improved motor outcomes and better control of epileptic seizures. However, the connection to cognitive outcomes still requires further research. Mild improvements in processing speed have been reported, and research shows that beginning treatment at an earlier stage may lead to more favorable cognitive IQ scores [14, 31, 32, 33].

4.3. Executive Functions and Attention Deficits

Executive functions are often reported to be affected in intoxication and energy‐related IMD. Research on this topic has used advanced neuroimaging techniques, including diffusion tensor imaging (DTI), magnetic resonance spectroscopy, functional MRI (fMRI), functional near‐infrared spectroscopy (fNIRS), or positron emission tomography (PET) [34]. These impairments are likely the most important consequences affecting individuals with neurodevelopmental disorders, influencing their ability to plan, focus, and regulate their behavior effectively. The impact of these impairments extends beyond cognitive challenges, profoundly affecting individuals' overall functioning and quality of life.

Intoxication IMD have been particularly associated with attentional deficits and dysexecutive functioning. As reported by Waisbren et al. [9] in a review of 678 patients with urea cycle disorders, OTCD patients showed a higher dorsolateral prefrontal cortex (DLPFC) activity, suggesting a pattern of prefrontal inefficiency, and decreased white matter integrity in the frontal lobe, cingulum, and supplemental motor. These findings correlated with an altered cognitive profile in working memory, executive functioning, and attention. Similarly, in a twin case study with OTCD, Anderson et al. [35] analyzed the hemodynamics of the prefrontal cortex with fNIRS during an N‐back working memory task. The sibling with OTCD, compared to the control sibling, showed a higher hemodynamic variation, especially in the left prefrontal cortex, during a higher working memory demand and a reduced interhemispheric functional connectivity as the task load increased. These findings correlated with inefficient autoregulation and executive functioning in OTCD.

In a study with children with MSUD, Bouchereau et al. [36] found that almost all patients had attentional and executive dysfunction. They speculate that the chronic accumulation of BCAA could provoke white matter abnormalities with consequent executive dysfunction. Also, amino acid depletion leads to neurotransmitter deficits like dopamine, crucial in the prefrontal circuit and executive functions.

4.4. Behavioral and Emotional Dysregulation

This is often associated with the psychiatric symptoms related to intoxication and energy‐related IMD. During episodes of acute decompensation, individuals may experience a range of psychiatric symptoms, including mental confusion, delirium, anxiety, aggression, and agitation, bizarre behavior, delusions, and psychosis. These manifestations have been observed in conditions such as porphyrias, homocystinurias, or urea cycle disorders, among others. In cases of subacute or chronic psychiatric manifestations, mood and anxiety disorders are often seen as clinical manifestations related to the underlying disease and treatment management. In contrast, symptoms like schizophrenic‐spectrum disorders, catatonia, eating disorders, and aggressive and self‐injurious behaviors can indicate specific features of different IMD [12, 20, 37].

Approximately 6% of cases of secondary psychosis are associated with neurometabolic disorders. However, the prevalence of IMD within the mental health population is often underestimated, as psychiatric symptoms may overshadow neurological signs for years before becoming evident [12, 20]. Understanding the underlying causes of these psychiatric manifestations is essential for effective patient management. Since simple dietary modifications can lead to improvements in treatment outcomes, IMD should be considered a potentially treatable cause of acute psychosis [38, 39].

Furthermore, clinicians should be alert to the possibility of an IMD if patients with intellectual disabilities and epilepsy show resistance to antipsychotic medications or experience adverse side effects that complicate their treatment [13]. A family history of consanguinity, signs of multisystem involvement, and unexplained infant deaths can all provide significant clues pointing toward the diagnosis of IMD [4].

Therefore, systematic assessments for metabolic disorders should be conducted when atypical signs are observed in the psychiatric population. This approach can facilitate earlier diagnosis and treatment, ultimately enhancing the quality of mental health care [13, 20, 40].

4.5. Social Cognition Deficits

They have gained interest in the literature on IMD in recent years. Even though the prevalence of IMD in non‐syndromic autism spectrum disorder (ASD) might be similar to the general population, the incidence is higher in countries with elevated consanguinity rates [41, 42].

In a series of 179 patients diagnosed with ASD, 3.3% had an IMD, and the disorders identified in these patients included undiagnosed phenylketonuria (PKU), homocystinuria, Sanfilippo syndrome, and 3‐methylcrotonyl‐CoA carboxylase deficiency [43]. Other organic acidurias, such as propionic academia, have also been associated with ASD [44] as well as cerebral creatine deficiency, succinic semialdehyde dehydrogenase deficiency (SSADHD), glycogen storage disease type IXa, pyrimidine metabolism disorders, and hypobetalipoproteinemia [45]. PKU remains a significant health concern in patients from countries that lack newborn screening programs, especially among those who immigrated as refugees [45].

Although the association between ASD and IMD has not been extensively documented in the literature, an underlying IMD could potentially be a treatable cause of ASD. While metabolic screenings in the ASD population may not seem cost‐effective [41], it is essential to gather a thorough personal and family medical history of the patient. Additionally, metabolic and genetic studies should be conducted when atypical findings are present, such as epilepsy, intellectual disabilities (ID), dysmorphic features, motor disturbances, and other neurological or psychiatric disorders [43, 46]. However, further research is necessary to enhance our understanding of the association between ASD and IMD, as well as how these conditions may interact and inform treatment opportunities.

4.6. Differences Between Intoxication and Energy‐Related Disorders

In our review, we found similar cognitive and behavioral patterns between intoxication and energy‐related IMD despite differences in global intelligence. No significant differences were observed in any cognitive functions; however, slight tendencies were noted. Specifically, language skills were slightly more impaired in cases of intoxication IMD, particularly in disorders related to carbohydrate metabolism, such as galactosemia.

Timmers et al. [47] studied the brain connectivity responsible for language production deficits in 13 patients with galactosaemia and 13 age‐ and gender‐matched controls. They found more extensive connectivity in frontal and motor regions and restricted and weaker connectivity in superior temporal regions. Also, higher baseline blood flow was shown in the inferior frontal gyrus, superior temporal regions, insula, and supplementary motor area. These changes within the language network could be associated with impairment in syntactic and speech‐motor planning in patients with galactosaemia. Similarly, Potter et al. [48] described the risk factors associated with language impairment in 33 patients aged 4–16, with classical galactosaemia and a history of sound speech disorders. Participants with typical cognitive development showed more often expressive language disorders, while those with borderline‐low cognitive development had both receptive and expressive language disorders. They concluded that children with galactosaemia and speech disorders have a 4–6 times greater risk of developing language impairment than patients with speech disorders of unknown origin.

Among energy‐related IMD, visuoperception was the only domain that showed a significant impairment in patients with cell membrane carrier defects. In a retrospective study with 25 patients with GLUT1 deficiency syndrome, aged 3 to 40 years, De Giorgis et al. [31] concluded that difficulties in visuospatial and visuomotor skills were particularly pronounced among this population. However, they suggested that these deficits could be influenced by prominent extrapyramidal symptoms, including movement disorders.

4.7. Age‐Related Manifestations

A wide range of IMD usually presents in the newborn period or childhood. As children transition into the school environment, a cognitively challenging environment, these disabilities can exacerbate and lead to increasingly dysfunctional outcomes.

As a result, much of the existing research on neurocognitive impairment has primarily focused on pediatric populations. Interestingly, while both types of IMD are reported more frequently in children compared to adults, those related to intoxication show a notably higher concentration of studies involving children. In contrast, IMD associated with energy deficiency tends to have a greater proportion of research on adults, highlighting a significant difference in how these disorders manifest and are studied across different age groups.

Cytoplasmic defects like creatine metabolism disorders were the most described in adults, particularly in males due to the X‐linked character of creatine transporter deficiency. Female patients with creatine deficiency tend to have a more attenuated phenotype or be completely asymptomatic, which allows a more detailed evaluation in adulthood [4].

UCD were the intoxication IMD more represented on adult samples, primarily asymptomatic OTCD. However, studies on children or both children and adult series were more frequent among these disorders. It is important to note that PKU probably represents much of the literature about adult intoxication type IMD and was not included in this review.

When examining neurocognitive outcomes related to age, both children and adults displayed a similar pattern of dysfunction. However, language and speech disorders were found more frequently in children than in adults. Given that language and speech are cognitive functions that develop during infancy and childhood, it is not surprising that a substantial proportion of the literature concentrates on these developmental stages, highlighting the impact of cognitive disruptions during this period.

Currently, the emergence of new genetic and metabolic treatments offers potential, but their efficacy and long‐term impact on cognitive outcomes require further exploration through longitudinal studies and clinical trials. The available treatments can prevent neurocognitive impairment by avoiding most metabolic decompensations that cause additional neurological damage and stabilizing premorbid functioning. The new interventions have shown a notable effect on motor disorders. For instance, in a review article with 270 patients with GLUT1 deficiency syndrome, Schwantje et al. [49] found that the ketogenic diet improved epilepsy for 83% of the sample within days or weeks, and movement disorders improved by 82% within months. However, cognition only improved in 59% of the patients and remained stable for 40%.

The direct effect of treatments on specific cognitive deficits remains uncertain; revealing a need for systematic neuropsychological assessments and interventions in this population [11, 50, 51].

Although the evidence points towards a large variability in cognitive functioning among IMD, we progress towards a vision of IMD as a continuous spectrum of symptoms in which the particular defect and the individual idiosyncrasy determine the predominance of one symptom over another [16, 52]. Providing an overview of the clinical manifestations reported in the literature can help identify a spectrum of neuropsychological deficits and ultimately guide the individual neuropsychological assessments and interventions to improve IMD's quality of life.

4.8. Conclusions

This systematic review summarizes the existing literature on neurocognitive functioning in a wide range of IMD. Various neurocognitive impairments, including intellectual disabilities, motor disturbances, executive dysfunction, attention deficits, behavioral and emotional deregulation, as well as deficits in social cognition, are frequently reported among individuals with these disorders. These impairments significantly affect both the daily functioning and quality of life for patients and their families.

A similar pattern of neurocognitive impairment was observed between intoxication and energy‐related IMD. However, slight differences, such as in language and visuoperception, were noted. Overall, the intoxication type IMD demonstrated better global cognitive performance, with higher IQ scores.

Despite the recent increase in cognitive studies, there is still a significant need for more research to establish guidelines for early detection and treatment, as well as to enhance the neuropsychological outcomes of IMD. This discussion includes important risk factors and indicators that can aid in early differential diagnosis.

4.9. Limitations

The main limitation of this review is the scarcity of papers on neurocognitive impairment. It is important to remark that IMDs often cause very severe encephalopathies, and patients are not suitable for detailed neuropsychological assessments. Consequently, the current body of literature may fall short of fully representing IMD's wide‐ranging complexity and diversity. This gap underscores the need for more comprehensive research to understand better the neurocognitive consequences associated with these conditions.

Moreover, the significant variability in the methodologies employed across the studies presents a complex challenge to drawing broad conclusions. Each research effort often utilizes different standardized measures, and the sizes of the samples vary considerably, further complicating the reliability of the results. The symptoms associated with each IMD also exhibit considerable heterogeneity, adding another layer of difficulty to generalization. These intricate factors underscore the need to interpret the data carefully. Additionally, it emphasizes the necessity of shifting the way cognitive functions are recorded and analyzed in the literature to more accurate representations and a deeper understanding of cognitive processes.

The classification of IMD and cognitive‐behavioral disorders may have changed over time as our understanding of these conditions has evolved. As a result, many studies utilize different classifications, which complicate the review process in terms of searching, organizing, and synthesizing information.

Many studies fail to clarify key clinical features relevant to neurocognitive outcomes. Important aspects to consider in future studies include the timing of diagnosis and treatment (whether early neonatal or late onset), the frequency of metabolic crises, neuroimaging data, and the biochemical profile of toxic metabolite accumulation associated with each disease‐specific profile. Addressing these factors would enhance our understanding of how treatments influence the development of cognitive deficits. As a consequence, the findings should only guide future research and personalized assessments based on the patient's history and daily functioning.

4.10. Future Directions and Neuropsychological Recommendations

Further neuropsychological studies are needed to understand better the underlying mechanisms of cognitive‐behavioral impairment in this population.

International protocols for neuropsychological assessment and treatment are also needed to standardize methodology, facilitate the comparison of studies, and establish guidelines for evidence‐based interventions addressing the frequent neurocognitive impairments associated with IMD.

Comprehensive, multicenter, and longitudinal studies are essential to evaluate treatment effects on neurodevelopmental endpoints. Given the wide‐ranging neurocognitive impairments observed in individuals with IMD, we recommend establishing standardized neuropsychological protocols to be used both at the time of diagnosis and during annual follow‐ups. These protocols should assess key cognitive areas, including global intelligence (using tools such as the Wechsler scales), fine motor skills (e.g., the Purdue Pegboard), attention and executive functions (e.g., the CPT‐3 or BRIEF), and social cognition (e.g., Theory of Mind or Affect Recognition tasks). By conducting thorough and repeated evaluations, we can facilitate the early detection of cognitive strengths and weaknesses, allowing for timely personalized interventions. This proactive approach can help prevent negative impacts on academic performance and daily functioning, enhancing the quality of life for individuals with IMDs and their families.

Author Contributions

Conceptualization and methodology: M.G.‐G., R.C.‐R., and A.G.‐C. Study selection, data extraction, formal analysis: M.G.‐G. Writing – original draft: M.G.‐G. Writing – review and editing: R.C.‐R., A.G.‐C., C.A., and J.‐M.S. Supervision: R.C.‐R. and A.G.‐C. All authors approved the final version of the manuscript as submitted and agreed to be accountable for all aspects of the work. All authors confirm the absence of previous similar or simultaneous publications.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

Ángeles García‐Cazorla has received honoraria for research support and lectures from PTC Therapeutics, Immedica and Nutricia, honoraria for lectures from Biomarin and Recordati Rare Diseases Foundation, and is a co‐founder of the Hospital Sant Joan de Déu start‐up “Neuroprotect Life Sciences.” The other authors declare no conflicts of interest.

Supporting information

Table S1: Data reviewed for each specific IMD and its classification.

Figure S1: Number of reports published each year from 1981 to 2024.

Gil‐González M., Arias C., Saudubray J.‐M., Colomé‐Roura R., and García‐Cazorla Á., “Neurocognitive Impairment in Inherited Metabolic Disorders due to Intoxication and Energy Defects: A Systematic Review,” Journal of Inherited Metabolic Disease 48, no. 5 (2025): e70084, 10.1002/jimd.70084.

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article.