X-Linked Recessive Diseases

Question 1

Lesch-Nyhan Syndrome

Answer 1

= Hypoxanthine-guanine phosphoriboysl transferase (HGPRTase) deficiency

X-linked recessive so only seen in boys

Features:

• Gout
• Renal F
• Neurological Deficits
• Learning difficulties
• ? Self mutilation

Mx = Allopurinol for life!

Question 2

Fabry’s Disease

Answer 2

Fabrys disease is an X-linked lysosomal storage disorder which causes a painful peripheral neuropathy, due to deposition of glycosphingolipids (a type of fat) within small sensory fibres. Nerve conduction studies are typically normal as large fibres are unaffected.

Example Question:
An 18-year-old migrant from Syria presents to you after recent successful application for asylum. He has no family with him in the country. Since he can remember he gets severe burning pain and tingling in the hands and feet, particularly after exertion or when weather temperatures are extremely hot or cold. He remembers once having a transient episode of slurred speech and right facial droop that lasted less than 24 hours. He has never had the opportunity to consult about his problems. Physical examination reveals a rash of blue-black telangiectasia across his trunk and a mid-systolic murmur heard loudest in the apex and radiating into the axilla. The examination is otherwise unremarkable. He recalls that his younger brother, who died some years ago, had similar problems and his sister, who he is no longer in touch with, seems to have not had any problems. Which of the following findings is consistent with the underlying diagnosis?

Positive anticentromere antibodies
> Deficiency in plasma levels of alpha-galactosidase
Aortic coarctation visualised by aortic angiography
Raised HBA1C
Excessive excretion of mucopolysaccharides in urine

The diagnosis is Fabry disease.

This is an X-linked recessive lipid storage disorder in which there a deficiency in the fat enzyme alpha-galactosidase. This results in the accumulation of alpha-galactosyl-lactosyl-ceramide in various tissues, including kidney, liver, blood vessels and nerve ganglion cells. It often presents with severe features in childhood/adolescence but can also less typically present in the 5th or 6th decade with milder features. The clinical features of Fabry disease include:

acroparaesthesia: tingling, burning pain in the hands and feet triggered by stress such as emotion, extreme temperatures, or exercise
Angiokeratoma corporis diffusum: lightly verrucous, deep-red to blue-black papules on the trunk (in the bathing trunk distribution)
Cardiac: mitral valve prolapse or regurgitation usually, but any valvular heart defect can occur
Strokes: including young strokes/TIAs
Chronic Kidney Disease: proteinuria usually, can present late in fulminant renal failure

Classically death occurred in the 4th decade but this has improved since the availability of dialysis. It would be important to organise urgent renal investigations in this young man amongst your workup.

Another lipid storage disorders that may come up:

Gaucher’s disease: autosomal recessive disorder characterised by a deficiency of glucocerebrosidase, resulting in glucocerebroside accumulating in the phagocytic cells of the body and hence you get massive (painless) splenomegaly (can be a typical otherwise well, young PACES patient and the condition is found principally in Jews of European stock). You expect the pancytopenia picture on blood tests; typical of hypersplenism. Life span is shortened but not markedly.

Question 3

Kallman’s Syndrome

Answer 3

Kallman’s syndrome

Kallman’s syndrome is a recognised cause of delayed puberty secondary to hypogonadotrophic hypogonadism. It is usually inherited as an X-linked recessive trait. Kallman’s syndrome is thought to be caused by failure of GnRH-secreting neurons to migrate to the hypothalamus.

The clue given in many questions is lack of smell (ANOSMIA) in a boy with delayed puberty

Features
‘delayed puberty’
hypogonadism, cryptorchidism
anosmia
sex hormone levels are low
LH, FSH levels are inappropriately low/normal
patients are typically of normal or above average height

Cleft lip/palate and visual/hearing defects are also seen in some patients

NB Klinefelter’s vs Kallmans
Klinefelter’s = LH and FSH RAISED
Kallman’s = LH and FSH LOW/NORMAL

Example Question:
A 22-year-old woman with a history of partial Kallmann syndrome comes to the fertility clinic for review. She got married some 6 months earlier and wants to start a family. She has normal external genitalia and sparse pubic and axillary hair and has a normal body mass index of 23kg/m². Which of the following is the most appropriate intervention?

	Clomiphene
	> HCG and FSH then IVF
	Metformin
	Oestrogen
	Referral for adoption

The correct answer is HCG and FSH then IVF. Restoration of ovulation in females with Kallmann syndrome is complex and often requires HCG to drive production of gonadal steroid hormones, FSH to drive ovulation, harvesting of eggs, and IVF. This process is most effective in achieving successful pregnancy.

Clomiphene does induce ovulation and is useful in patients with other conditions such as polycystic ovarian syndrome. It is however very unlikely to be effective in patients with gonadotrophin failure like Kallmann syndrome. Metformin has previously been used in the management of PCOS. Oestrogen doesn’t restore ovulation in patients with Kallmann syndrome but may be considered for patients who don’t want to get pregnant. In the event that fertility treatment isn’t successful, adoption can be considered.

Question 4

X-Linked Recessive

Answer 4

= ONLY MALES ARE AFFECTED

Exception = Female patients with Turners Syndrome affected as they only have one X!

X-linked recessive disorders are transmitted by HETEROZYGOTE FEMALES (Carriers)
Male-male transmission is not seen

Each male child of a heterozygote female carrier has a 50% chance of being affected
Each female child of a heterozygote female carrier has a 50% chance of being a carrier

NB The possibility of an affected father having children with heterozygous female carrier is generally speaking extremely rare however in certain Afro-caribbean communities G6PD deficiency is common and homozygous females with clinical manifestations of enzyme defect are seen!

Examples:

• Fabry’s disease
• Duchenne/Becker muscular dystrophy
• Androgen insensitivity syndrome
• Retinitis pigmentosa
• Haemophilia A,B
• G6PD deficiency
• Colour blindness
• Primary immunodeficiency disorders e.g. WAS (Wiskott-Aldrich)
• Lesch-Nyhan Syndrome
• Ocular albinism
• Kallman’s Syndrome

Question 5

Androgen Insensitivity Syndrome

Answer 5

= X-linked recessive condition due to end-organ resistance to testosterone

> Genotypical MALE children (46XY) but have a female phenotype

Features:

• ‘Primary amenorrhoea’
• Undescended testes causing groin swellings
• Breast development may occur as result of conversion of testosterone to estradiol

Diagnosis:
- Buccal smear or Chromosomal analysis to reveal 46XY genotype

Mx:
- Counselling - raise child as female
- Bilateral orchidectomy 
- Oestrogen therapy 
NB - Increased risk of testicular cancer due to undescended testes

Question 6

G6PD Deficiency

Answer 6

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red blood cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in a X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad (fava) beans

Pathophysiology
↓ G6PD → ↓ glutathione → increased red cell susceptibility to oxidative stress

Features
neonatal jaundice is often seen
intravascular haemolysis
gallstones are common
splenomegaly may be present
Heinz bodies on blood films

Diagnosis is made by using a G6PD enzyme assay

Some drugs causing haemolysis
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas

G6PD vs Hereditary Spherocytosis
Gender
G6PD = Male (X-linked recessive)
HS = Male + female (autosomal dominant)

Ethnicity
G6PD = African + Mediterranean descent
HS = Northern European descent

Typical history	
G6PD: 
• Neonatal jaundice 
• Infection/drugs precipitate haemolysis 
• Gallstones

HS: 
• Neonatal jaundice 
• Chronic symptoms although haemolytic crises may be precipitated by infection 
• Gallstones 
• Splenomegaly is common

Blood film
G6PD = Heinz bodies
HS = Spherocytes (round, lack of central pallor)

Diagnostic test
G6PD = Measure enzyme activity of G6PD HS = Osmotic fragility test

Question 7

B-Cell Primary Immunodeficiency Disorder - Bruton’s (x-linked) congenital agammaglobulinaemia

Answer 7

Bruton’s (x-linked) congenital agammaglobulinaemia:
Underlying defect = Defect in Bruton’s tyrosine kinase (BTK) gene that leads to a severe block in B cell development
X-linked recessive. Recurrent bacterial infections are seen
Absence of B-cells with reduced immunoglogulins of all classes

Question 8

Combined B and T Cell Primary Immunodeficiency Disorder - Wiskott-Aldrich Syndrome

Answer 8

Wiskott-Aldrich syndrome
Underlying Defect = Defect in WAS gene
X-linked recessive.
Features include recurrent bacterial infections, eczema, thrombocytopaenia.
Low IgM levels
Increased risk of autoimmune disorders and malignancy

Question 9

Combined B and T Cell Primary Immunodeficiency Disorder - Severe Combined Immunodeficiency

Answer 9

Severe combined immunodeficiency
Underlying Defect = Many varying causes.
Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency
Recurrent infections due to viruses, bacteria and fungi.
Reduced T-cell receptor excision circles
Stem cell transplantation may be successful

Question 10

Duchenne and Becker Muscular Dystrophy

Answer 10

Dystrophinopathies

Overview

• X-linked recessive
• due to mutation in the gene encoding dystrophin, dystrophin gene on Xp21
• dystrophin is part of a large membrane associated protein in muscle which connects the muscle membrane to actin, part of the muscle cytoskeleton
• in Duchenne muscular dystrophy there is a frameshift mutation resulting in one or both of the binding sites are lost leading to a severe form
• in Becker muscular dystrophy there is a non-frameshift insertion in the dystrophin gene resulting in both binding sites being preserved leading to a milder form

Duchenne muscular dystrophy

• progressive proximal muscle weakness from 5 years
• calf pseudohypertrophe
• Gower’s sign: child uses arms to stand up from a squatted position
• 30% of patients have intellectual impairment

Becker muscular dystrophy
develops after the age of 10 years
intellectual impairment much less common
Affects the limb girdles in males who carry the X affected gene

BMD is a X-linked disorder of dystrophin, a component of skeletal muscle that reinforces the sarcolemma-glycoprotein complex and prevents degradation. Respiratory, cardiac and bulbar manifestations are common. Diagnosis is made on clinical suspicion, raised CK, EMG suggestive of small polyphasic potentials, a muscle biopsy suggestive of dystrophinopathy and subsequent genetic testing.

Becker’s muscular dystrophy causes a proximal myopathy, average age of presentation and diagnosis is at 11 with severe disability at 40.