Category Archives: Metabolic

Galactosaemia

General paediatrics, Metabolic, Neonatology, Nutrition

Actually 3 different gene defects possible, most commonly Galactose-1-Phosphate uridyl transferase deficiency (GALT, or Gal-1-PUT). The others have different phenotypes.

Presents in the newborn period after initiation of milk feeding, most commonly with jaundice, which can be unconjugated in first week but becomes conjugated thereafter. The other features listed below are seen in only a minority:

  • Vomiting,
  • poor feeding
  • Hypotonia
  • Hepatomegaly
  • Encephalopathy
  • Cataract – can be present at birth, but more usually after a week or two.
  • Sepsis – esp E coli septicaemia

Lab findings include hypoglycaemia, deranged LFTs, coagulopathy, metabolic acidosis, abnormal urine aminoacid excretion. Urine for reducing substances is not sensitive or specific. The definitive test is RBC Gal-1-PUT activity, but if a transfusion has been given alternatives are genotyping or testing the parents for carrier status.

Management is by diet. Nonetheless, neuropsych problems usually develop in adolescence and ovarian failure often occurs. Some debate about whether galactose can be tolerated from age 2-3yr.

Urate

Community, General paediatrics, Genetics, Metabolic, Neurology

Product of amino acid metabolism.

In developmental delay, an abnormally high or low result is significant viz:

  • Glycogen Storage disorder
  • Purine disorders eg Lesch Nyhan
  • Molybdenum Cofactor deficiency – other features are microcephaly, hyperekplexia

High urate levels can also be risk factor for urolithiasis (stones in urinary tract)

Niemann Pick disease

General paediatrics, Metabolic, Neurology, Respiratory

Sphingomyelinase (lysosome) disorder.  Type B has only visceral involvement, can survive into adulthood.  More common in Ashkenazi Jews.

Typically develop symptoms at around 6 months.  Can be prolonged jaundice as baby, else abdominal distension (hepatosplenomegaly), growth failure, hypotonia, failure to meet milestones.

Death usually around 3yrs, recurrent lung infections, interstitial lung disease.  Spasticity develops later.

Cherry red spot seen on fundoscopy in macula, possibly not in early stages.

Beckwith Wiedemann Syndrome

Genetics, Metabolic, Neonatology

Chromosome 11p problem, where IGF2 gene lies. Hemihypertrophy, macroglossia, ear creases/pits, exomphalos, umbilical hernia, visceromegaly, macrosomy, hyperinsulinism.

Focal disease is associated with uniparental disomy in chromosome 11 (“upd(11)pat”), whereas diffuse disease can be familial or sporadic.

Focal disease can be managed by limited surgery, whereas diffuse disease needs near total pancreatectomy for any benefit. DOPA-PET scans can differentiate focal disease with a sensitivity of 88-94%, and are 100% accurate in localizing the focal lesion (Aberdeen does).

At increased risk of tumours esp nephroblastoma, adrenal carcinoma, hepatoblastoma. Screening recommendations depend on mutation viz IC2 LOM, IC1 GOM, upd(11)pat etc. For all but the first, every 3 months until age 7yrs.

OMIM link.

Support group https://www.bwssupport.com/

Congenital Hyperinsulinism

Congenital, Genetics, Metabolic, Neonatology

Hyperinsulinaemic hypoglycaemia is a common cause of persistent severe hypoglycaemia, and is associated with long term neurodisability and epilepsy. Can be congenital, due to unregulated beta cell function (used to be called nesidioblastosis), else secondary to various other conditions eg:

  • Maternal diabetes mellitus
  • Birth asphyxia
  • IUGR
  • Beckwith Wiedemann Syndrome – about 50% are affected, usually transiently
  • Inborn error of metabolism eg glycosylation disorder

Can present with severe hypoglycaemia in the newborn period despite good oral intakes, else more insidiously in infancy and childhood. No ketones of course – cf ketotic hypoglycaemia.  Macrosomia (+/- hypertrophic cardiomyopathy and hepatomegaly) is a feature of fetal hyperinsulinism but is not always present, otherwise typical features of hypoglycaemia may be seen, including seizures.

Cases secondary to IUGR/asphyxia tend to be transient, settling within a few days, but some have persistent symptoms for months before suddenly resolving!

Recessive defects in sulphonylurea receptor probably most common cause.  Fasting or exertion are the usual triggers, but postprandial symptoms may reflect dumping syndrome (usually secondary to gastro-oesophageal surgery) or else hyperammonaemic hyperinsulinism (glutamate dehydrogenase disorder – the high ammonia of 100-200 is persistent but asymptomatic). A form of exercise induced hyperinsulinism exists that requires exercise testing to diagnose.

Insulinoma is more likely in later childhood. Can be part of a multiple endocrine neoplasia syndrome type 1 (ask family history).

Raised plasma hydroxybutyrylcarnitine and urinary 3-hydroxyglutarate are diagnostic of Hydroxy AcylCoA Dehydrogenase (HADH) deficiency.

Management aims to achieve normal glucose levels, using Carbohydrate supplemented oral feeds plus IV fluids. A central line may be needed to give concentrated dextrose solutions, esp if chubby. Glucagon can be given IM in an emergency but may lead to paradoxical insulin release. Glucagon and/or octreotide can be given as infusions in resistant cases.

For ongoing treatment, diazoxide acts on K-ATP channels in beta cells. Chlorthiazide is synergistic in the neonatal period. Hypertrichosis is the main side effect of diazoxide. Some rare gene defects are resistant to Diazoxide! Feeding probs esp GORD common, partly due to all the NG/IV feeding.

[Kapoor, Arch Dis Child 2009 PMID 19193661]

Hypoglycaemia

Endocrinology, General paediatrics, Metabolic, Neonatology

Glucose levels are maintained after a meal by release from glycogen stores in liver (glycogenolysis), driven by Glucagon. When glycogen stores are low, then glucose can be produced from fat stores by fatty acid oxidation (via ketones) and from protein by gluconeogenesis. The switching over is moderated by cortisol, and growth hormone (reduces insulin resistance) also important.  Insulin is the only hormone that lowers blood sugar levels.

Cortisol increases gluconeogenesis, adrenaline increases lipolysis. Hypoglycaemia makes you grumpy, sweaty, pale. You can feel sick with it, and it can give you palpitations.  It can cause a wide range of acute, transient neurological symptoms including tremor, confusion, ataxia, weakness, visual disturbance.  If severe, it causes seizures, which causes release of glucose from muscles. Some cases of sudden unexpected death are thought to be due to inborn errors of metabolism causing hypoglycaemia.

Recurrent severe episodes in infancy can lead to permanent neurodisability.

There is debate about what level of blood sugar is abnormal, or whether it is only symptomatic low blood sugar that is important.  What the level in the blood is, is not the same as levels in the brain, of course.  Less than 2.6mmol/l is uncontroversial (note that near patient tests are not very accurate at low levels, which they are not really designed for, so lab confirmation is always required).  Generally <3.3 used in practice, but clinical signs important.

Usual cause is acute viral illness with reduced oral intake and vomiting.  But this can also be a trigger that reveals an underlying metabolic disorder…

  • Neonate? If big liver, remember Galactosaemia and Fructosaemia (reducing sugars in urine). Else Beckwith Wiedemann Syndrome.
  • High glucose requirement (see below)? =Hyperinsulinism
  • High ammonia? If encephalopathic, metabolic. Else Hyperammonaemia hyperinsulinaemia –  second most common congenital cause of hyperinsulinism. Gain of function mutations in the mitochondrial enzyme glutamate dehydrogenase (GDH). Can treat with diazoxide.
  • Signs of adrenal insufficiency? Abdominal/back pain, low Na, high K/Ca! Hyperpigmentation.
  • Signs of hypopituitarism? Growth failure, midline defects, micropenis.
  • Encephalopathy (esp vomiting)? Consider organic aciduria
  • Odour? Consider Maple syrup urine disease etc
  • Ketones should be present. If not then Fatty acid oxidation disorder eg MCAD.
  • Hepatomegaly? Glycogen storage disorders, also galactosaemia, acute liver failure eg Reyes syndrome (this may also be the mechanism in respiratory chain disorders).
  • With sepsis and shock consider galactosaemia – usually big liver too
  • Overdose? Propranolol, alcohol, salicylates in particular.
  • Consanguinity?
  • Time of last meal? Endocrine problems can cause symptoms at any time, as can hyperinsulinism. Glycogen storage/synthase problems cause early hypoglycaemia (ie within 3-8 hours).

Investigations

Get 1 ml lactate & 6 ml lithium heparin, bloodspots on neonatal screening card during hypo, and first urine (freeze).

Glucose requirement (mg/kg/minute) can be calculated from the following formula:

  • from IV fluids = Infusion rate (ml/hr) x % of glucose infusion x 0.1677/weight.
  • from oral feed: glucose content of standard infant formula is 7.2g/ 100ml, and of LBW formula is 8.6g/ 100ml.

Normal is 4-6 mg/kg/min, over 8 is suspicious of hyperinsulinism.

  • Insulin and C-peptide. Insulin should be undetectable, C-peptide 0.3-1.12 if hypoglycaemic with appropriate insulin response. Else hyperinsulinism (exogenous, or congenital)
  • Blood Glucose – below 2.6 considered true hypoglycaemia.  Note that BM sticks are not really designed for low sugars, and are not reliable.
  • Lactate – should be normal, otherwise high (with ketones) suggests glycogen storage disorder (with notable exception of Glycogen synthase defect)
  • TFTs – hypopituitarism
  • Cortisol – hypoadrenalism (cortisol should be high as part of stress response – else consider hypoadrenalism (Addison’s). Infants under 6 months should go over 800, older should be over 500. If low cortisol but GH >15 unlikely to be pituitary problem.
  • LFTs – beware primary liver problem
  • U&Es, Calcium – Low sodium, high potassium/Ca seen in hypoadrenalism
  • Ammonia – for organic acidaemias etc, or primary liver problem
  • Amino acids – for Maple Syrup Urine Disease etc
  • Carnitine, hydroxybutyrate – for Fatty Acid Oxidation (FAO) disorders
  • Acylcarnitines (blood spot) – for FAO disorders
  • Free Fatty acids – for FAO disorders, esp FFA/3OH-butyrate ratio (ketones are made from FFA so should be higher or not much lower, else block)
  • Blood gas – ?Acidosis
  • Urine for reducing sugars (Galactosaemia etc),
  • Urine/blood for organic acids

Prognosis

Mostly ketotic hypoglycaemia, due to starvation/vomiting. Adequate history?  Beware encephalopathy, raised ammonia, hepatomegaly.

75 LGA newborns with hypoglycaemia followed up to age 4 – no late effects. [Archives of Disease in Childhood 2005;90]