WELLNESS AND AGE

CHAPTER V

1Medical Unversity of Lublin, University Children's Hospital,

Pediatric Neurology Department

Uniwersytet Medyczny w Lublinie, Klinika Neurologii Dziecięcej

2Medical University of Lublin, I Clinic of Psychiatry,

Department of Psychiatry for Children and Youth

PAULINA HOŁOWICKA-KŁAPEĆ1, RENATA KONCEWICZ1,

AGATA MAKAREWICZ2, EWA DWORZAŃSKA1,

KRYSTYNA MITOSEK-SZEWCZYK1

The global developmental delay and intellectual disability -

diagnostic difficulties

Globalne zaburzenia rozwojowe i niesprawność intelektualna –

trudności diagnostyczne

Key words: global developmental delay, intellectual disability

Słowa kluczowe: niesprawność intelektualna, globalne opóźnienie rozwoju

The estimated incidence of delayed psychomotor and mental retardation varies

between 1% and 10%. There is no determined etiology of these disorders in 50% to

80% of all cases. Intellectual disability (ID) is a condition defined as a reduction of

neurocognitive function (IQ below 70), and a significant reduction in the adaptabili-

ty of social life, communication, work, rest, daily life, occurring throughout life,

with the onset before the age of 18 years. For children under 5 years of use the term

“global developmental delay” is adapted.. This delay refers to two or more domains

of development (deficits in motor skills or so called small motor skills, speech /

language, cognitive, social interaction / personal, dysfunction of everyday activities,

benign dysmorphic disturbances, the abnormalities in neurological examination -

hypotonia, spasticity, apraxia, microcephaly, macrocephaly). Intellectual disability

affects between 1% to 3% of the population of children and adults worldwide. Peo-

ple with ID have a large number of co-morbidities, including neurological disorders,

systemic problems, and behavioral disorders. Approximately 25-50% of cases is

associated with genetic disorders. Diagnosis is putted usually before the age of 5

years old. More frequent affects boys and it may indicate a disorder linked to chro-

mosome X [13].

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58

The causes of intellectual disability are very heterogeneous and include envi-

ronmental causes (eg, infection, exposure to teratogenic factors), genetic causes and

multifactorial. In developed countries, more than 50% of the cases of intellectual

disability genetic factor is considered as main cause due to chromosomal abnormali-

ties or individual genes.

Currently cytogenetic studies play a major role in the evaluation of children with

intellectual disability. These studies have a high diagnostic value. Availability and

dissemination of this study encounter some limitations, technical and financial. This

may lead to failures in the assessment of metabolism disturbances in newborns,

identifiable genetic disease, for which curative treatment is available.

Learning disabilities are defined as a restrictions on intellectual (reasoning /

solving / learning / problem) and adaptive behavior (conceptual / social / practical

skills) and relate to children over the age of five and adults with onset before the age

of eighteen years. The degree of disturbance and global learning difficulties can be

divided into mild, moderate and severe. Diagnosis is to explain the etiology, to term

prognosis, to discuss genetic mechanisms and the risk of intellectual disability, to

evaluate treatment options and to avoid unnecessary diagnostic tests and provide

support for the family.

In order to clarify these disorders, the algorithms of the study were elaborated.

These include genetic testing, metabolic and radiological examinations in cases of

disorder of unknown etiology.

The first step is to take the history and physical examination. A comprehensive

medical history is to be extended to medical history spanning three generations.

Gather family history of genetic disorders /intellectual disability, neurocognitive

dysfunction, cerebral palsy, encephalopathy, hypotonia, seizure disorders, birth

defects (such as heart defects, cleft palate), growth failure, other than a family inhe-

ritance dysmorphic features. The family history of recurrent miscarriages is also

important [7, 14].

The age of the occurrence of developmental disorders, problems with learning,

presence / absence of recourse to distinguish between congenital and acquired de-

fects, a history of recurrent miscarriages, stillbirths, deaths are very important. Intel-

lectual disability in boys, male relatives of mothers family with learning difficulties

or developmental delay, can indicate a disorder associated with the X chromosome

diseases. Phakomatosis such as neurofibromatosis type 1, tuberous sclerosis and

Sturge-Weber syndrome, dysrafia core can often be associated with developmental

disorders. Hepatosplenomegaly or cardiomyopathy can indicate inborn error of me-

tabolism.

The development disturbances appear in mitochondrial cytopathies. Neurologic

manifestation in infancy is associated with seizures (infantile spasms, myoclonic

epilepsy), visual impairment, deafness, central dysphagia, apnoea and respiratory

failure, diffuse muscular hypotonia, global developmental delay. In older children

and young adults dystonia, cerebellar deficits, spastic diplegia, memory loss, cogni-

tive deficits, progressive, hearing loss, dementia, autism, peripheral neuropathy,

hypotonia and weakness, external ophtalmoplegia of all six muscle occur. Respirato-

Paulina Hołowicka-Kłapeć, Renata Koncewicz, Agata Makarewicz,

Ewa Dworzańska, Krystyna Mitosek-Szewczyk

The global developmental delay and intellectual disability - diagnostic difficulties

59

ry insufficiency may result from myopathic involvement or from central respiratory

failure or combination.

The second step is to study metabolic, genetic and neurological tests.

The literature review conducted in 2012, identified 81 treatable inborn errors of

metabolism that cause intellectual disability. Fifty-two factors (65%) are detectable

by biochemical blood and urine tests, and the rest of the metabolic disturbances were

establish by clinical symptoms and appropriate genetic tests, biochemical tests.

Early diagnosis of a treatable form of intellectual disability is necessary, because the

diet, vitamin supplementations, inhibitors, stem cell transplantation, gene therapy

and other methods of treatment may prevent permanent damage to the brain and

optimize the developmental effects.

Next steps in the diagnosis of a child with unexplained cause of intellectual disa-

bility requires consideration of current diagnostic guidelines, which recommend

testing, such as testing eyesight and hearing, microarray chromosomes test and in

some cases, the test for fragile X and neuroimaging.

Borderline Intellectual Functioning: Consensus and good practise guidelines

(process proposed by the CONFIL 2007 consensus group to detect and diagnose

Bordeline Intellectual Functioning –BIF):

1. Clinical history – aspect of diveleopment, examination and clinical observa-

tion, biomedical investigation.

2. Establiching IQ – verbal and/or manipulative tests

3. Cognitive assessment – Language, attention, memory, visual-spatial function,

behavioural and emotional aspects

4. Bordeline intellectual functioning BIF?

5. Specific developmental disorders

6. Generalised neurodevelopmental disorders

7. Comorbidity: disorders of behaviour, anxiety, depression, psychosis

Definition of BIF by the CONFIL 2007:

BIF is not a syndrom, nor a disorder, nor a disease. It is a heterogenous grou-

ping of specific neurodevelopmental syndromes, disorders or disease and po-

ssibly of extreme variations of normality.

BIF can be defined as a “health meta-condition that requires specific public

attention”.

The cognitive deficits that undrlie overall IQ assessment are heterogeneous,

so cognitive assessment of the individuals with BIF should not to be limited

to IQ measurement.

Not all the individuals with an IQ between 71 and 85 have limitations in ac-

tivity and restrictions inparticipation. Consequently, a specific assessment of

capacities and functioning is needed to make a diagnosis of BIF.

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The diagnosis of a treatable form of intellectual disability is especially important

for pediatricians, whose first objective is to provide early and effective treatment.

Interdisciplinary collaboration in the field of metabolic diseases, genetics, pediatrics,

neurology, psychiatry enable faster diagnosis.

Indications for study of intellectual disability: dysmorfizm, congenital defects,

unexplained seizures, psychomotor retardation or regression of development, hypo-

tonia, abnormal growth, autism spectrum disorders (ASD). Autism is a heteroge-

neous group of neurodevelopmental disorders with onset in early childhood, charac-

terized by different levels of functioning. The main areas of disorders are social

relations, stereotypical behavior and interests. Many studies have shown abnormali-

ties in the brain neurotransmission in people with autism. There is a possibility of

coexistence of other disorders: mental retardation, epilepsy, attention deficit hyper-

kinetic disorder, sleep disturbances, anxiety. Epilepsy is a common co-morbidities

of autism. These disorders lead to dysfunction of the anatomical structures of the

brain that are responsible for stimulating specific cognitive functions. There is a

need of the complex multidisciplinary care.

All patients should be considered the primary screening, eye and hearing test,

test for intoxication with lead, consult a genetic.

Genetic tests: Array CGH, Fragile X Syndrome, chromosomal G-banding. Meta-

bolic tests: Plasma AA, Urine OA / Gags, Haematology, Biochemistry. Radiological

test: MRI brain.

For children aged over 2 to 3 years with isolated global delay development

/intellectual disability, with or without ASD, in the absence of progress in deve-

lopmental disorders, it is recommended basic blood tests (including the muscle en-

zymes boys to identify cases of Duchenne muscular dystrophy), homocysteine test,

thyroid hormones. In children aged 2 to 3 years with expect progression comprehen-

sive neurometabolic study are indicated.

Genetic studies, including high-resolution karyotype and the fragile-X should be

performed in every case of a global developmental delay or intellectual disability.

Intellectual disability (ID) is characterized by genetic diversity. Several hundred

genes are associated with monogenic form of ID and that complicates molecular

diagnostics.

If convulsions or hypotonia are present metabolic consultation is recommended.

Metabolic testings to perform:

plasma amino acidsurine organic acids

acyl plasma

glycosaminoglycans

carnitine profile

oligosaccharides

purine

pyrimidine

metabolites GAA / creatinine

aCGH test if ID or dysmorfism are present

Paulina Hołowicka-Kłapeć, Renata Koncewicz, Agata Makarewicz,

Ewa Dworzańska, Krystyna Mitosek-Szewczyk

The global developmental delay and intellectual disability - diagnostic difficulties

61

Imaging CT / MRI with / without spectroscopy – must be consider if focal neu-

rological symptoms, microcephaly, convulsions, hypotonia, or macrocephaly are

present. Differential diagnosis: environmental factors (severe prematurity, malnutri-

tion, prenatal exposure, eg, ethanol, antiepileptics, lead poisoning, meningitis, ne-

glect / abuse, metabolic disorders, hearing or vision problems, thyroid disease.

Radiologic testings to perform:

MRI brain is recommended when the GDD / LD are one of the following:

severe / profound learning difficulties or

with early onset seizures or

moderate or severe motor delay or

spasticity, ataxia and movement disorders or

features asymmetrical motor or

abnormal head size.

Compared to computed tomography (CT), MRI is more sensitive in the detection

of specific disorders of the brain. CT contributes to the etiological diagnosis of GDD

of about 30% of cases and may have advantages compared to MRI in certain

circumstances, such as congenital infections [14].

Algorytm of Developmental Delay (DD) or Intellectual Disability (ID) Testing

(by ARUP Laboratories) [1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 15]:

1. Risk factors:

Family history of genetic disorders / ID

Neurocognitive dysfunction

Cerebral palsy and static encephalopathy

Hypotonia

seizure disorder

Birth defects (eg, cardiac defect, cleft palate, club feet)

Growth abnormalities

Nonfamilial dysmorphic features

Family history of recurrent miscarriages

2. Evaluation for DD / ID, identify family history of risk factors:

Sufficient minor or major dysmorphic (atypical) features

- if yes, refer for genetics consultation

- if no, estimate of presence of microcephaly, macrocephaly, focal findings

on neurologic exam, cerebral palsy, hypotonia, seizures, autism / ASD:

– if yes, order MRI / CT, then may want to consider cytogenetic and /

or molecular testing based on clinical presentation and genetics

consultation

– if no, may want to consider cytogenetic and / or molecular testing

based on clinical presentation and genetics consultation

Episodic deterioration

- Metabolic testing, refer for metabolic consul

Family history of metabolic disorder

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62

- if yes, metabolic testing refer for metabolic consul

IF male with neurocognitive dysfunction order Fragile X (FMR1) With a Reflex

Methylation Analysis. Note: test more likely to be positive in the following

cases:

- Physical features characteristic of Fragile X

- Family history supportive of X-linked ID

- Maternal family history of premature ovarian failure, ataxia and / or tumor

3. Negative metabolic testing and family history of metabolic disorder:

Cytogenomic SNP Microarray or Cytogenomic SNP Microarray Buccal Swab -

first line testing for most developmental delay syndromes or

Cytogenomic SNP Microarray with Five-Cell Chromosome Study, Peripheral

Blood - useful if chromosome and array tests would otherwise have been

ordered concurrently

Other available testing :

X Chromosome Ultra-High Density Microarray (Consider this test if FMR1

testing is negative)

Chromosome Analysis, Peripheral Blood

Chromosome FISH Metaphase Fragile X (FMR1 ) With Reflex is Methylation

Analysis

Rett Syndrome (MECP2) Sequencing and Deletion / Duplication

Rett Syndrome (MECP2) Full Gene Sequencing

Rett Syndrome (MECP2) Deletion and Duplication

Angelman Syndrome and Prader-Willi Syndrome by Methylation-Sensitive

PCR

Angelman Syndrome (UBE3A) Sequencing

Angelman Syndrome and Prader-Willi Syndrome by Methylation-Sensitive

PCR Fetal

CDKL5 -Related Disorders (CDKL5 ) Sequencing and Deletion / Duplication

CDKL5 -Related Disorders (CDKL5) Sequencing

CDKL5 -Related Disorders (CDKL5 ) Deletion / Duplication

PTEN -Related Disorders (PTEN) Sequencing and Deletion / Duplication

X-Linked Intellectual Disability Panel, Sequencing, 76 Genes

1. Genetic consultation and treat symptomatically

The etiology of symptomatic or unexplained global developmental disorders and

learning disabilities remains a challenge for pediatricians and physicians adults. The

precise diagnosis on the basis of the specific etiology may have implications for the

treatment, prognosis. Many cases of global developmental delay and learning diffi-

culties can be attributed to genetic disorders (25-50%) and metabolic disorders (1-

5%).

Paulina Hołowicka-Kłapeć, Renata Koncewicz, Agata Makarewicz,

Ewa Dworzańska, Krystyna Mitosek-Szewczyk

The global developmental delay and intellectual disability - diagnostic difficulties

63

Metabolic disorders may result in developmental problems and it is important to

quickly identify those that are susceptible to treatment. Neuroimaging study can

identify the specific cause of the disorders associated with the process of learning

disability in a few cases in the absence of abnormalities such as head size, epilepsy

and disorders of motor. However, the efficiency of these tests is low. Therefore,

genetic, metabolic and radiological examinations have become routine in the dia-

gnosis of developmental disorders and intellectual.

The diseases with associated global developmental delay and intellectual disabi-

lity:

Prenatal encephalopathies of disruptive origin

Congenital infections

Teratogen – related encephalopathies

Genetic encephalopathies

Down syndrome

Fragile-X syndrome

Subtelomeric deletions

Patau syndrome

Chromosomal defects diagnosed by CGH array

Tuberous sclerosis

Congenital myotonic dystrophy

Rett syndrome

Dravet spectrum disorder

Prader-Willi syndrome

Angelman syndrome

Neurofibrimatosis type 1

Inborn errors of metabolism

Mitochondrial disease

Lysosomal disease

Perinatal and postnatal encephalopathies

Brain tumor

SUMMARY

If any of these are present, they should be included detailed clinical accompany

the application for metabolic studies:

1. Global development delay / Learning desability (public domain and degree of

delay)

2. family history of metabolic disease

3. relationship

4. belonging to an ethnic group

5. dysmorphic features

6. hypoglycemia (glucose state requirements)

7. seizures

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8. microcephaly / macrocephaly

9. hypotonia

10. hepatomegaly

11. eye Disorders

12. the hearing disorders

13. vomiting

14. sepsis

15. mechanical ventilation

16. intravenous (IV) fluids such as glucose

17. medications (IV / oral) such as dopamine antiepileptics

18. failure to develop (as if in feed containing medium-chain triglycerides

(MCT), oil, or carnitine)

19. the sampling time from the last meal

20. lethargy

21. metabolic acidosis

22. raised plasma lactate

23. raised plasma ammonia

24. raised CPK levels

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ABSTRACT

Developmental disorders are a group of chronic diseases, which can be attributed

to physical or mental disability. Global developmental delay and intellectual disabil-

ity are the most common reasons for consultation in pediatric neurology. The rea-

sons for these disorders may be different, genetic or metabolic. Diagnosis is easy

when they are associated with cerebral palsy, epilepsy, blindness, profound hearing

loss. It is more difficult in the case of coexistence of autism spectrum disorders.

Genetic studies provide assistance in cases of disorders of unknown etiology.

STRESZCZENIE

Zaburzenia rozwojowe to grupa przewlekłych chorób, którym można przypisać

upośledzenie fizyczne lub psychiczne. Globalne opóźnienie rozwoju i niepełno-

sprawność intelektualna są to najczęstsze powody konsultacji w neurologii dziecię-

cej. Przyczyny tych zaburzeń mogą być różne, m. in. genetyczne, metaboliczne.

Postawienie rozpoznania jest łatwe gdy są związane z porażeniem mózgowym,

WELLNESS AND AGE

66

padaczką, ślepotą, głębokim niedosłuchem. Trudniejsze w przypadku współistnienia

zaburzeń ze spektrum autyzmu. Badania genetyczne służą pomocą w przypadkach

zaburzeń o niewyjaśnionej etiologii.

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