Specific Gene Conditions

Fragile X syndrome

This is a condition which is caused by a trinucleotide repeat in the FMR1 gene.

– FMR1 gene encodes the FMRP protein found in highest concentration in brain and testes which is responsible for selective binding mRNA in brains and transporting it to nucleus and neural synapses.

Inheritance:

X-linked dominant, meaning it is seen much more in males

– The condition shows variable expressivity and reduced penetrance but genetic anticipation

– It affects males more severely as women have random X-chromosome inactivation

In unaffected people, the FMR1 gene contains 5-44 repeats of the sequence CGG

– Between 45-54 repeats this is a “grey zone”

– Repeats 55-200 is considered premutation

– If person has >200 repeats, this causes a full mutation in the FMR1 gene

N.B. women with a premutation have higher risk of having a fully affected child

Symptoms:

– Intellectual –> Learning difficulties and autism spectrum disorder

– Facial –> Big protruding ears, long face, high arched palate

– Behaviour –> Social anxiety, hypersensitive to stimuli and hand flapping/biting, poor eye contact

– Complications –> Macroorchidism, hypotonia and mitral valve prolapse

Diagnosis:

– This can be made antenatally by CVS or amniocentesis

– PCR and Southern blot shows number of CGG repeats

Management:

– No cure, managed by MDT team for behavioural therapy, speech, education etc.

Prader-Willi Syndrome (PWS)

A genetic condition due to loss of function of genes in the PWS region of chromosome 15 (15q11-13)

– It classically leads to hyperphagia, meaning that the children and always hungry

Inheritance:

This is an example of genetic imprinting (as certain genes expressed according to parental origin)

– In the absence of a functioning paternal copy of the PWS region, the child develops PWS

– In the absence of a functioning maternal copy, the child will develop Angelman syndrome

Symptoms:

– CNS –> Developmental delay, learning difficulties, behavioural problems in teens

– Appetite –> Hyperphagia which leads to obesity and type 2 diabetes

– Short stature with hypotonia

– Dysmorphic facial features

– Hypogonadism and infertility

Management:

– No cure available, treatment focussed on managing symptoms

– important to restrict access to food to prevent risk of morbid obesity

Pierre-Robin

This is a genetic condition caused by a mutation near the SOX 9 gene, which leads to facial abnormalities.

– it gives a similar phenotype to Treacher-Collins syndrome, yet this is more commonly due to de novo mutations so there is less likely to be a positive family history

Inheritance:

Most cases are the result of de novo mutations

Symptoms:

Classic set of craniofacial abnormalities:

– Jaw –> Micrognathia (small jaw with receding chin)

– Posterior tongue displacement (can cause upper airway obstruction)

– Cleft palate

– May also cause hearing loss and speech difficulty 

Management:

Assistance/corrective procedures to aide breathing and feeding

Williams syndrome

This is a genetic condition which is caused by a microdeletion on chromosome 7

Inheritance:

– Autosomal dominant condition (most cases are de novo mutations)

Phenylketonuria

This is an amino acid disorder which affects phenylalanine metabolism causing it to build up in the blood

– There is a mutation in phenylalanine hydroxylase, an enzyme which converts phenylalanine to tyrosine.

– High levels of phenylalanine lead to problems such as learning difficulties and seizures

Inheritance:

– Autosomal recessive condition due to mutation in phenylalanine hydroxylase on Chromosome 12

Symptoms:

– Developmental delay

– CNS –> learning difficulties, seizures

– Face –> Fair hair and blue eyes

– Physical –> Heart problems, small head, low birth weight

– Skin –> Lighter skin

– “Musty” odour in urine and sweat (due to phenylacetate)

Diagnosis:

– Guthrie screening test –> the ‘heel-prick’ test done at 5-9 days of life

– Blood test shows raised phenylalanine levels in the blood

Management:

– Dietary restriction of phenylalanine (especially for pregnant mothers with the condition)

– Amino acid supplements to replace the missing phenylalanine in the diet

DiGeorge Syndrome (Velocardiofacial syndrome)

This is a condition which is caused by a deletion to the small part of Chromosome 22 (22q11.2)

– It leads to specific facial deformities with congenital heart problems and learning difficulties

Inheritance:

Usually due to a sporadic mutation, but can be inherited in autosomal dominant fashion

Symptoms:

These can be summarised using the mnemonic CATCH-22

Cardiac –> Tetralogy of Fallot, aortic arch anomalies, truncus arteriosus

Abnormal facies –> Small palpebral fissures with epicanthic folds

– Smooth philtrum, low nasal bright and small head

Thymus Abnormality –> Gives immunodeficiency

Cleft Palate

Hypoparathyroidism –> leads to hypocalcaemia giving seizures

Diagnosis:

Genetic analysis using FISH studies

Management:

No cure available, manage the complications 

Rett Syndrome

This is a rare genetic disorder which produces a phenotype like autism, with additional neurological features

– It is usually diagnosed in females around the ages of 6-18 months

Inheritance:

Due to a genetic mutation in the MECP2 gene which is expressed in the locus coeruleus

Symptoms:

– Autistic features –> Impaired language and communication, repetitive movements

– General –> slower growth, small head size

– Neurological –> seizures, sleeping problems

Management:

No cure possible, treatment aimed at managing the symptoms (e.g., seizures)