Category Archives: Genetics

Cobalamin related metabolic disorders

Amino acid homocysteine is converted to methionine (“remethylated”) – cobalamin is involved in some of these processes, folate metabolism also important.

Various disorders.

Variety of presentations, at different ages:

  • Neurological (central and peripheral)
    • Feeding difficulties, apnoea in babies
    • Seizures
    • Subacute combined degeneration of spinal cord (peripheral neuropathy, ataxia, incontinence)
    • Acute and/or chronic encephalopathy – hypotonia, regression
    • Neuropsychiatric problems
  • vascular problems (stroke/embolism)
  • bone marrow (megaloblastic anaemia, cytopenia) – folate related
  • Atypical HUS
  • Glomerulopathy


  • High homocysteine, usually
  • Vitamin B12 and folate, for differential
  • Methylmalonic acid (in urine)
  • Acylcarnitine
  • Methionine (usually goes low)


Start intramuscular B12 (hydroxocobalamin) as soon as samples collected, to prevent end organ damage.

Betaine should be started if high homocysteine with low methionine found, helps push conversion to methionine.


Autosomal recessive condition of high homocysteine in blood and urine, causing similar neurological problems, thrombosis, Marfanoid appearance, downward subluxing lenses.

Needs low methionine diet. Betaine supplements help.

Cystic Fibrosis


  • family history
  • congenital intestinal atresia
  • meconium ileus
  • distal intestinal obstruction syndrome
  • faltering growth (in infants and young children)
  • undernutrition
  • recurrent and chronic pulmonary disease, such as:
    • recurrent lower respiratory tract infections
    • clinical or radiological evidence of lung disease (in particular bronchiectasis)
    • persistent chest X-ray changes
    • chronic wet or productive cough
  • chronic sinus disease
  • obstructive azoospermia (in young people and adults)
  • acute or chronic pancreatitis
  • malabsorption
  • rectal prolapse (in children)
  • pseudo-Bartter syndrome.

Angelman syndrome

Caused (mostly) by absence of maternal contribution to a region of the 15q chromosome.  Paternal uniparental disomy is one way this can happen, although mostly there is de novo maternal deletion.  The same region is also responsible for Beckwith-Wiedemann syndrome, but this syndrome is the result of a paternal deletion.

Characteristically “happy puppet” –

  • severe speech and language delay
  • learning disability and epilepsy
  • Movement disorder esp ataxia, also tremor, hyperreflexia
  • open mouthed expression, large mandible
  • Excitability, paroxysmal laughter


Hereditary spherocytosis

One of the genetic red blood cell abnormalities that protects against malaria (cf sickle cell), as haemolysis shortens life span and potential for parasite reproduction.

Phenotype (severity) consistent within family, but very different between families. FH may be vague eg splenectomy, jaundice rather than awareness of underlying diagnosis…


Anaemia, jaundice and splenomegaly classically. Splenomegaly is usually mild and there is no increased risk of rupture. Neonatal jaundice can be severe but does not predict severe disease! Severe cases (assessed when well, not during crises, only about 5%) can be transfusion dependent in first years of life (erythropoietin helpful) but not usually afterwards.

May present with parvovirus aplastic crisis (not just red cells; white cells and platelets often drop too) – only happens once.

Diagnosis by spherocytes on film, reduced MCV, high reticulocytes (but retics do not go up during aplastic crisis), unconj hyperbilirubinaemia, splenomegaly. There are other causes of spherocytes, and they can be seen in normal neonatal blood films.

Differential is autoimmune haemolytic anaemia, which is associated with acute viral infection (direct Coombs test usually positive). Osmotic fragility test does not distinguish, can be false negative in iron deficiency, and is unreliable in the first few months of life. New EMA dye binding test takes 2 hours and is 92% sensitive. Gene tests don’t add much.

Other problem is gallstones. High reticulocyte count predicts.

Folate probably only necessary for severe cases.


Most children are asymptomatic, but severe cases can have growth failure, lethargy, heart failure and leg ulcers. Should be delayed until at least 5 yrs, potentially laparascopic and/or partial. Do cholecystectomy at same time if symptomatic. Platelets rise to abnormally high levels after splenectomy, but no apparent increase in thrombosis.

[Arch Dis Child PMID 15321852]

Autosomal dominant polycystic kidney disease

ADPKD – previously Adult PCKD but now recognized as having manifestations in childhood.  Cf Autosomal recessive disease, severe, renal failure in infancy.

1 in 400 to 1,000 live births, making it the most common monogenic cause of renal failure. The typical age of onset is in middle life, but the range is from infancy to 80 years.  Associated with liver cysts (asymptomatic) and intracranial aneurysms. 10-25% do not have family history (de novo mutations, missing records or mosaicism).

Possible presenting symptoms of renal disease in children with ADPKD are frequency, nocturia and/or, hematuria, urinary tract infection(s) and back, flank or abdominal pain. Often, the earliest symptoms are polyuria and polydipsia, from decreased urinary concentrating ability.

Extrarenal manifestations seen esp hypertension (renin angiotensin system, sodium retention, endothelial dysfunction), also liver cysts (asymptomatic), intracranial cysts and valvular defects but these are only seen in adults. 25% of children are hypertensive by the time they reach adolescence.  (GFR stays stable until around 40yrs, then rapid decline, about 50% have ESRF by 60yrs).

Importantly, children who were diagnosed in utero or within their first 18 months of life, the so-called VEO group, represent a particularly high-risk group of ADPKD patients and should be managed accordingly.  Diagnostic imaging criteria not validated under 15yrs, genetic testing also challenging.

Recommendation from Kidney Disease Improving Global Outcomes (KDIGO) Consortium against screening children for APCKD.  [Also highlight variety of different cystic disorders in children, so recommend thorough clinical assessment for extrarenal manifestations in case syndrome eg Von Hippel Lindau, USS of parents and/or grandparents if negative family history, and USS to look for dysplastic kidneys, glomerulocystic disease, and tuberous sclerosis complex].[Kidney international 2015]

Increasing evidence that hypertension, left ventricular hypertrophy (even between 75th and 95th centile for BP) and increased kidney volume predates symptoms in affected children.  A study of early use of ACE inhibitor halted progression of LVH and fall in renal function.  Adding pravastatin reduced progression of structural kidney disease.  Disease modifying drugs in development.  [BMJ 2016;353:i2957 Editorial, GOS, Birmingham, Evelina].  “We propose an urgent national debate on an improved inclusive approach involving patients and their families and a range of clinicians, ethicists, and commissioners. A few pounds spent now on screening and early intervention could save many thousands later by delaying hypertensive complications and chronic kidney disease.”

Potential for pre-implantation genetic diagnosis.  See Ethics.

Only one drug known to have moderate effect on disease progression in adult ADPKD patients, vasopressin V2 receptor antagonist tolvaptan (recent Cochrane review).  But timing of use unclear.

Psychological impact of having genetic disease that can be passed on to children very common in adult patients.  But a benefit of diagnosis is potential to target modifiable risk factors  – children with normal BP have slower cyst growth.  And knowledge can give sense of control over life decisions, esp reproductive decisions.

Multiple sclerosis

Not considered a paediatric disease, but has been described.  Consider differential however:

  • lysosomal storage disorders,
  • various mitochondrial diseases,
  • other neurometabolic disorders,
  • Krabbe, Metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Fabry, Niemann-Pick C, Chidak-Higashi.  [Clue is in the name, leukodystrophy]

Since these are genetic conditions, essential for management and genetic counselling.

J Weisfeld-Adams

Mitochondrial inheritance

A mother with a mitochondrial DNA gene mutation will pass this abnormal gene to all of her children. The children will all be affected, but with different degrees of severity.

As it is not possible to predict how the children will be affected, this is immensely difficult for planning a family.