How do genetic and metabolic disorders differ from traumatic brain injury? - Chapter 5

Metabolic and endocrine disorders are challenging for clinical neuropsychologists. They are encountered less frequently in routine clinical practice and have received less attention in research than more frequently encountered conditions, such as traumatic brain injury. Hence, the knowledge base to guide clinical assessment is less complete. Genetic and metabolic disorders differ from traumatic brain injury (TBI) in the sense that they involve a potential for ongoing CNS insult across neurodevelopment. In addition, whereas the timing of TBI is easily known, the timing of putative insults is often unknown. Genetic and metabolic disorders are life-long conditions, although treatment demands vary across the conditions. The potential impact of an insult varies depending on the stage of neurodevelopmental at which it occurs. Some disorders, like galactasaemia, invariably demonstrate symptoms from birth onward, whereas for example individuals with Wilson's disease usually become symptomatic in the second and third decades of life.  In this chapter, common genetic and metabolic disorders (Klinefelter syndrome, galactasaemia, Wilson's disease, and type 1 diabetes) will be discussed.

What are the characteristics of Klinefelter syndrome?

Epidemiology

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in humans with an incidence of 1 in every 400-500 male births. It is characterised by an extra X chromosome in one or more cells resulting in a 47, XXY karyotype. Physical symptoms of KS are: tall stature, reduced endogenous testosterone production, hypogonadism, and fertility problems. During puberty, the following characteristics manifest themselves: small testes, breast enlargement, reduce body and facial hair, heavier and less muscular bodies. The clinical phenotype of KS is highly variable and it is estimated that approximately two-thirds of those with KS are never diagnoses, despite evidence that early identification affects physiological, reproductive and possibly neurodevelopmental outcomes.

Neuropsychological findings

Various neuroanatomical correlates of KS have been documented: reduced total grey matter (GM) and white matter (WM) volumes, compensatory increase in ventricular size, regional changes (reduced GM volumes in bilateral amygdala, hippocampus, insula and temporal lobes, inferior frontal lobes and cerebellum, while other regions are increased, such as sensorimotor and parietal-occipatal GM). 

Functional outcomes

Although there is a lot of variability, IQ is on average lower in individuals with KS with verbal IQ typically lower than performance IQ. A common finding in research is elevated rates of language deficits in individuals with KS. Further, delays in fine and gross motor skills are found, including problems with dexterity, speed, coordination and strength, as well as impaired visuo-graphic skills. Between 60 and 80% of individuals with a clinical diagnosis of KS function below grade level and require special educational resources, usually for a language-based learning difficulty. 

It is expected that the clinical phenotype of KS (how it manifests itself) is influenced by environmental, genetic, and hormonal factors. For example, researchers showed that there is a strong, positive effect of environmental advantage showing an above average score on IQ (110) in a high SES sample, despite the usual motor and language delays and physical features of KS. 

Treatment

The standard treatment (currently the only available medical treatment) for KS is testosterone replacement, which is associated with reduced fatigue, increased libido, and improved mood and concentration. Yet, it has little effect on fertility. 

What are the characteristics of galactasaemia?

Epidemiology

Galactasaemia (GAL) is an autosomal recessive disorder of carbohydrate metabolism that is caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT) which converts galactose-1-phosphate to glucose-1-phosphate. In the absence of GALT, galactose metabolites accumulate in tissues, causing direct damage to vulnerable neurons and/or white matter in utero, prior to or even while following treatment. Although GAL has a low incidence (between 1 in every 35,000 - 60,000 children), it is one of the most common inherited metabolic disorders. 

Symptoms and manifestations of GAL are:

• Delayed early expressive language and speech milestones.
• Increased risk for attention deficit without hyperactivity in primary school.
• Deterioration in academic performance in transition from primary to high school.
• Arithmetic difficulties at all ages.
• Left-handedness.
• Difficulties with complex language processing, such as understanding oral language.
• Decreased gross motor skills and strength.
• Communication diagnosis.
• Pubertal delay.
• Anxiety, depression, psychosis.
• Adherence to medical treatments. 

Interventions

Some interventions to consider are: early speech and language evaluation, classroom accommodations, avoiding distractions at home during homework, medication, retesting academic performance prior to detect areas requiring extra attention (promoting educational continuity), writing and sports accommodations, physical and occupational therapy, emotional support, addressing isolations and shame through peer support (group psychotherapy), psychological treatment and teaching compliance strategies.

Neuropathology

Cerebral and cerebellar atrophy and white matter abnormalities have been identified in patients with GAL. Due to GAL, early development is delayed and IQ is affected. Studies have consistently identified borderline / low average IQ. In addition, speech and language deficits are common in individuals with GAL, as well as motor deficits (including ataxia, tremor, reduced hand strength and impaired manual dexterity and balance). Moreover, visuo-motor and visuo-perceptual skills are impaired. Not surprisingly, academic difficulties are identified in individuals with GAL and there is some evidence that learning difficulties increase with age. 

Treatment

Based on the hypothesis that defective galactosylation of complex macro-molecules such as myelin is due to a deficiency of uridine diphosphate galactose, pharmacological interventions have included trials of uridine supplementation. However, they failed to demonstrate a beneficial effect of cognition. Currently, medical interventions are focused on manipulations regarding the severity and timing of dietary restrictions. Cognitive interventions nowadays focus on language, yet demonstrating inconsistent findings. Some studies found beneficial effects of early speech therapy, whereas others found that the language difficulties are often treatment resistant. Gubbels and colleagues suggested that social skill training in combination with speech therapy may yield positive outcomes, but the efficiency of this approach has not been tested empirically yet. A broader focus on all areas of deficit based on individualised and comprehensive neuropsychological assessment may inform more targeted and effective interventions in the future.

What are the characteristics of Wilson's disease?

Epidemiology

Wilson's disease (WD) is an autosomal recessive disorder characterised by a defective biliary excretion of copper. Copper accumulates in body organs, in particular in the liver, kidney, eyes, and brain, causing oxidative stress, damaging mitochondria, and apoptotic cell death in the affected organs. Accumulation usually starts in the basal ganglia, but as the disease progresses, widespread neuronal loss can be observed in the brainstem, cerebellum, midbrain corpus callosum, and sometimes the cortex. WD is caused by a mutation in the copper-transporting ATP7B gene, which is located on chromosome 13q14.3. WD is more common in Sicily, southern Italy, and eastern Europe than in other countries. WD is a rare disorder affecting approximately 1 in every 30,000- 40,000 individuals although there are many more carriers (estimated to be as high as 1 in 90). Although WD is already present at birth, the diagnosis is commonly made later, when copper toxicity has built up to a degree that causes symptoms, usually between 15 and 21 years. Initial symptoms are liver disease and non-specific neurological or non-specific physiological symptoms, which makes accurate and timely identification of WD a challenging task.

Treatment and prognosis

WD is fatal, if it is not treated. The commonly recommended therapy is a diet, restricting copper-rich foods such as chocolate, nuts, shellfish, and liver. Untreated WD may cause subcortical dementia with prominent features of slowness, executive dysfunction, apathy, and depression. The most compromised area of cognitive functioning in WD is executive functions. Many studies have shown significantly impaired scores on tests of, for instance, digit span, verbal fluency, and encoding memory. Further, psychiatric symptoms are common in WD.

To date, there are no published reports of academic outcomes in WD. This may be due to the fact that, until recently, diagnosis has only occurred towards the end of or after formal schooling has been completed. Nowadays, earlier diagnosis is becoming increasingly common due to the availability of molecular testing, neonatal screening programmes in high-risk populations, and increasing clinical awareness of the symptoms and clinical manifestations of WD.  

What are the characteristics of type 1 diabetes?

Epidemiology

Type 1 diabetes (T1D) is a chronic disorder of glucose metabolism, which commonly begins in childhood. It s one of the most common chronic diseases in childhood with the highest incidence in people of European descent at around 1.7 in every 1,000. The beta cells of the pancreas are destroyed in an autoimmune process, leading to an absolute and lifelong loss of insulin production. Insulin is a hormone required for the synthesis of glucose. A constant supply of glucose to the brain is crucial for normal cerebral metabolism. Insulin deficiency, which occurs in T1D, has downstream effects on carbohydrate, lipid, and amino acid metabolism. The brain is one of the major organ systems that is affected by T1D. 

Treatment

Treatment of T1D is complex, involving the administration of exogenous insulin by injection or subcutaneous pump, in combination with careful daily monitoring of dietary intake and exercise in an attempt to maintain blood glucose levels within an acceptable euglycaemic range. Although medical treatments are still in its infancy, there is a large body of studies showing that psychological interventions in T1D yield significant reduction in psychological distress as well as a marginally positive effect on metabolic control. Further, standardised interventions with a theoretical basis were more effective than a-theoretical ad hoc programmes. In addition, there is no evidence of a positive benefit in adults with T1D, which suggests that intervention in childhood is crucial. A case study that is described in this book resulted in the following intervention recommendations: improved metabolic control (primary focus of the intervention), proactive mental health support, educational support (such as a quiet and distraction-free working environment, as well as reduced demands on working memory), and strengthening peer relationships. 

Neuropsychological findings and functional outcomes

There is a slight decrease in IQ found in T1D patients. That is, IQ scores are consistently within the average range, but lower than those of age-matched healthy controls. Studies demonstrate inconsistent findings regarding the influence of sex, as well as the association between disease variables and neurodevelopmental variables. In summary, studies found many functional implications of T1D regarding cognition, academic achievement, adaptive functions, and psychopathology, depression, eating and other affective disorders.