Neurodevelopmental Disorders

MedGen Sec.2

Neurodevelopmental disorders

group of conditions that manifest as impairments in development and function early in life

Neurodevelopmental disorders include the following

• ID

• ASDs

• ADHD

• Communication disorders

• Motor Disorders (ex. cerebral palsy)

• Specific learning disorders

Neurodevelopmental disorders

group of conditions that manifest as impairments in development and function early in life

Neurodevelopmental disorders include the following

• ID

• ASDs

• ADHD

• Communication disorders

• Motor Disorders (ex. cerebral palsy)

• Specific learning disorders

What are the 2 types of deficits required to diagnose an ID?

• Deficit of intellectual functioning

  • measure by intelligence quotient (IQ)

• Deficit of adaptive behavior

  • conceptual, social, and practical

    • Ex. Handling money, being able to travel independently

Before what age must a disability manifest to be considered an intellectual disability?

18

Intellectual disabilities (IDs) are on a spectrum. Genetic causes are more likely to be identified in individuals with IDs that are considered

• More severe or profound IDs

Categories of IDs and presentations

• Mild (85%, IQ 50-70)

  • difficulty with learning and complex tasks, can attain 6th grade education level, able to work & live independently

• Moderate (10%, IQ 35-50)

  • elementary level education, somewhat independently living or group home, may travel to familiar places independently

• Severe (3-4%, IQ of 20-35)

  • extensive support w daily activities & self-care, use single words or phrases

• Profound (1%, IQ <20)

  • require 24/7 care, typically non-verbal

Developmental Delay (DD)

when a child does not attain developmental milestones in an expected time frame

• can impact one area (speech or gross motor milestones)

Global developmental delay (GDD)

diagnosed when a child has significant (2 SD below mean) delays in 2 or more domains

• Gross or fine motor

• Speech/language

• Cognitive

• Social/personal

• Activities of daily living

Why should genetic testing always be considered for someone with GDD?

Genetic factors are responsible for 40% of cases of GDD

Examples of gross motor skills

Involves using larger muscles

• Standing

• walking

• running

• Sitting up-right without back support

• jumping

• climbing

Examples of fine motor skills

Involves using smaller muscles

• writing

• buttoning up a shirt

• picking up small objects

• using scissors

• zipping a zipper

• tying shoelaces

• Using utensils (fork, spoons, knife, etc,)

Developmental milestones (definition)

physical or behavioral skills most children attain by a certain age

• note that every child is different (they may attain them later or earlier than normal)

Categories of developmental milestones include

• social interaction

• motor coordination

• adaptive skills

• cognition

Developmental regression

when a child loses a skill / skills they had previously attained

• (ex. loss of words or no longer able to walk)

A period of regression in a child may be normal under these circumstances

• infants / toddlers who have been hospitalized for extended periods

• children diagnosed with ASD

  • speech / interaction regression can occur around 18-24 months (not motor skills)

Unexplained regression can be a sign of

• neurodegeneration

• inborn error of metabolism

• neuromuscular disorder

  • other conditions

Examples of Interventions & Services for children with DD or disabilities

• Early Intervention (EI)

  • 0-3 yrs

  • via state

  • therapies: speech, occupational

• Committees on Special Education and Preschool Special Education (CSE/CPSE)

  • after 3 yrs old, transition therapies

• Individualized Education Plan (IEP)

  • until 12th grade

  • ensures appropriate learning opportunities, accommodations, & special services

    • Extra test time, therapies, smaller classroom

Autism Spectrum Disorders (ASDs)

group of conditions characterized by

• limitations in social communication and interactions

• restrictive interests

• repetitive behaviors

What is the typical age of onset for someone who may be on the ASD spectrum?

before 3 years old

Features / Signs of ASD

• decreased sharing of interest with others

• limited eye contact

• difficulties coping with change (need routines)

• fixations (niche subjects)

• sensory hypersensitivity (lights, loud noises, textures)

• repetitive movements (hand flapping, spinning, rocking)

• arranging objects in a particular manner (lines up toys)

True or False? Global Developmental Delay always leads to an intellectual disability

False

How many individuals with ASD have an ID?

1/3

Because NDDs are on a continuum, different NDDs might share a same

genetic pathogenic variant

• (Ex. 16p11.2 micro-deletion reported in persons with ASD, GDD, ID, and other neuropsychiatric conditions)

Comorbidities

medical conditions that coexist alongside a primary diagnosis

Common comorbidities of NDDs include

• epilepsy

• psychiatric disorders

  • may see in family hx.

• processing disorders

• ADD/ADHD

What are some of the purposes or utilities of genetic testing for NDDs?

• Improve care and medical management

  • aid in obtaining services, avoid unnecessary evaluations, recommend additional treatments -monitoring-or evaluations

• Provide more accurate recurrence risks for family planning

• Psychosocial benefits

  • families get an “answer”, specific support groups / resources, prepare for outcome/course of disease, alleviate guilt or blame

Approximate diagnostic yield for ASDs (old numbers)

• CMA (10%)

• Fragile X (1-5%)

• MECP2 (gene) (4% of females, affects males too)

• PTEN (gene) (5% of those with macrocephaly greater than 2,5 SDs)

• Karyotype (3%)

• Other (10%)

What should be the first-tier test for any patient with unexplained GDD, ID, and/or ASD?

Microarray (10% yield)

• if additional features (syndromic) then yield is 15-20%

After a microarray is performed on a patient with a suspected NDD, CNVs might reveal what about their family history?

Variable expressivity and/or decreased penetrance related to a genetic variant

• CNV might present as seizure, ADHD, ID, or psychiatric disorder in a relative

You have received the results of a chromosomal microarray. Your proband is 5 year old child with ASD and seizures. The results come back positive for a pathogenic copy number variant. The proband’s parents do not present with any hx or signs of NDDs. Should they be offered testing?

YES. Always offer the parent testing regardless of obvious concerns.

• remember CNV can have variable expressivity or decreased penetrance

When should Chromosome analysis (karyotyping) be considered as a first-tier test as opposed to CMA?

• Clinically suspected chromosome aneuploidy

  • Turner, Klinefelter, Downs

• Family or reproductive history suggestive of chromosomal rearrangements

  • recurrent miss-carriages

If CMA suggest an unbalanced translocation/rearrangement in your patient

chromosome analysis (karoytpe) and/or FISH should be sent to confirm structural rearrangement

If CMA suggest a balanced translocation

karyotype / FISH should be sent for a balanced translocation in unaffected parent

• reproductive implications

An unbalanced translocation in a proband (simultaneous loss of material and gain of material) might be indicative of what?

That one of their parents has a balanced translocation

Under what circumstances is FMR1 trinucleotide repeat expansion analysis considered first-tier testing?

Non-specific GDD, ID, and/or ASD (non-syndromic, no other signs)

What is the most common monogeneic cause of ASD?

Fragile X

What percentage of cases of ASD are due to fragile x syndrome?

2-3%

If a mother has had carrier screening for FMR1 premutation with negative results, would you need to test their child with ASD for fragile X?

No, the child wouldn’t have fragile X if their mother isn’t a premutation carrier

What are some signs in a person’s family history indicative of fragile x?

• Early menopause

• Fertility concerns

• Tremors, ataxia, or diagnosis of adult-onset neurological disorders (Parkinson’s)

How many individuals with fragile X also have ASD?

50-70%

Females and males who are heterozygous for FMR1 premutation are at risk for

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)

• Late on-set (60-65 yrs)

• cerebellar ataxia, intention tremor, cognitive decline, brain MRI abnormalities

• Risks of heterozygous premuation (55-200)

  • Males: over age 50, 40%

  • Females: over age 50, 16-20%

Females (only) who are heterozygous for FMR1 premutation are at risk for

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

• 20% premutation carriers at risk (22-200 CGG)

• hypergonadotropic hypogonadism before 40 (infertility)

MECP2 duplications impact ___ more frequently and severely than ___

males, females

What type of test is recommended as a second-tier test for female patients with ASD?

MECP2 single-gene testing

Pathogenic mutations in what gene can result in Rett Syndrome? On what chromosome is the gene located?

MECP2, X-chromosome

Classic Rett Syndrome overview

• period of developmental regression b/w age 1-4, followed by recovery of stabilization

• partial or complete loss of hand skills

• hand movements (wringing, squeezing, “washing”, rubbing)

• loss of speech/language skill

• gait abnormalities

• breathing disturbances

• teeth grinding / clenching (buxism)

• inappropriate laughing/screaming

• diminished response to pain

• sleep disturbances

• growth restriction, microcephaly

• seizures

MECP2 Duplication Syndrome overview

• complete penetrance in males

  • variable expressivity in females

    • mild ID - severe

• early-onset hypotonia

• poor/absent speech

• recurrent respiratory infections

• seizures

• GI manifestations (GERD, constipation)

• Autistic features in some

10-10% of individuals with ASD and macrocephaly have pathogenic variants in

PTEN

• single gene testing reccomended

You suspect someone of having a PTEN related disorder. What might increase your suspicion when taking a family hx?

• Benign or malignant tumors of the breast, thyroid, endometrium, and kidney

Clinical manifestations of PTEN related disorders

• DD and/or ASD

• macrocephaly

• cutaneous features (tumors): lipomas, trichilemmomas, oral papillomas

• Freckling of the glans penis (BRRS)

• GI polyps

What screening would you recommend for a child found to have a PTEN related disorder. Why?

Annual thyroid ultrasound in childhood (increased risk for cancer, earliest reported case of thyroid cancer for PTEN patient was 7 yrs old)

What are some of the red flags of inborn errors of metabolism?

• Developmental regression

• organomegaly

• cyclic vomiting

• decompensations

• failure to thrive

• dietary triggers / restrictions

• concerning lab/biochemical findings

Why is diagnosis high-impact for inborn errors of metabolism?

There may be targeted treatment available

What is the diagnostic yield for WES/WGS for NDDs?

~40%

What is the diagnostic yield for WES/WGS for isolated (non-syndromic)ASD?

~3%

When might you considered utilizing mitochondrial genome sequencing?

If a patient presents with

• seizures

• multiple organ systems affected (especial organs that utilize a lot of energy)

• elevated plasma lactate concentration

What is the recurrence risk for full siblings of a child with ASD? What is the risk if there are more than one affected sibling?

• ~3-10%

• 30-50%

If parents have an affected daughter with ASD, does their recurrence risk of having another child with ASD increase or decrease?

It increases because ASD is less common in females

Is targeted testing with IVF/PGT or with CVS/amnio possible for NDDs?

No, you can test for genetic conditions that might lead to an NDD or NDD(s), however, you cannot test just for an NDD as some do not have a genetic basis (or known genetic basis)

Important milestones by 15 months

• Claps when excited (social / emotional)

• Hugs stuffed doll or other toy (social / emotional)

• shows you affection: hugs, cuddles, kisses (social / emotional)

• Tries to say one or two words besides “mama” or “dada” (language / communication)

• Looks at a familiar object when you name it (language / communication)

• Follows directions: gesture and words. ex. “Give me the toy” and they give it to you (language / communication)

• Tries to use objects correctly: phone, cup, book (Cognitive)

• Stacks at least 2 objects, like blocks (cognitive)

• Takes a few independent steps (movement / physical dev.)

• Uses fingers to feed themselves (movement / physical dev.)

For ASD, list the 1st and 2nd tiered approach

First Tier

• CMA

• Fragile X (methylation analysis or PCR targeted analysis)

Second Tier

• WES

• Single Gene Testing

  • Females: MECP2

  • Microcephaly 2.5 SDs below normal: PTEN

• X-linked intellectual disability gene panel

What is the diagnostic yield of WES for syndromic NDDs (NDDs alongside associated medical and neurological problems)?

53%

If a child has a combination of hypotonia & microcephaly, what type of additional testing might be ordered?

Mitochondrial genome sequencing