My Clinical Notes

• Inherited inborn disorders may affect any protein or peptide but most commonly there is an enzyme abnormality

 

Deficiency of X may cause;

• Deficiency of product B e.g. cortisol deficiency in congenital adrenal hyperplasia
• Accumulation of substance A acted in by the enzyme e.g. phenylalanine in PKU
• Diversion through an alternative pathway; other products may accumulated and produce effects e.g. in CAH, accumulation of androgens causes virilisation

 

Patterns of inheritance

Autosomal dominant inheritance

• Dominant abnormal genes affect both heterozygotes and homozygotes (homozygotes perhaps more severely)
• Classically;
  • Every individual has at least one affected parent
  • Offspring in successive generations are affected
  • Clinically normal offspring are not carriers of the abnormal gene
  • Statistically 3 in 4 children are affected in both parents are heterozygotes
• An example is familial hypercholesterolaemia

 

Autosomal recessive

• Only affects homozygotes
• Heterozygotes are not usually clinically affected
• Clinical consequences may miss offspring in succeeding generations
• Clinically normal children may be homozygous and therefore be carriers of the abnormal gene
• 1 in 4 children of heterozygous parents with be affected
• Autosomal recessive disorders have a lower expression frequency in an effected family but are more likely to be severe compared with autosomal dominant disorders
• An example is CF

 

Sex linked inheritance

X-linked recessive inheritance

• Disorder carried on the X chromosome, the abnormal chromosome is latent when combined with a normal chromosome but active when combined with a Y chromosome
• If a woman carries an abnormal X chromosome, she will appear normal but ½ of her sons with be affected and half of her daughters will be carriers
• If the father is affected but the mother has two normal X chromosomes, none of the sons will be affected but all of the daughters will be carriers
• Disease is manifest in males and carried by females
• Female will only be clinically affected if she inherits the abnormal genes from an effected father and a carrier mother
• An example is haemophilia

 

X-linked dominant inheritance

• Both women and men are affected – very rare

• An example is familial hypophosphataemia

 

Genetic diagnosis

Cystic fibrosis

• Often caused due to a 3 base pair deletion in codon 508 of the CFTR – the mutation can be detected via PCR, the products of which are run on a polyacrylamide gel
• Used to screen for carriers and affected pregnancies using CVS

 

α1-antitrypsin deficiency

• Gene is polymorphic with more than 50 variants
• PCR is used to detect clinically important alleles

 

PKU

• Can be detected by measuring phenylalanine on neonatal blood spots
• PCR can also be used to identify affected pregnancies via CVS

 

Sickle cell anaemia

• Due to an A to T substitution in the 6^th codon of the β-globin gene
• Can be detected during amniocentesis by allele-specific hybridisation

 

Thalassaemia

• Characterised by the absence of size alteration of the globin mRNA
• Can be detected using Northern blot techniques

 

Screening

• Criteria for screening newborn infants (based on Wilson criteria);
  • Disease should be well defined with a known incidence
  • The disease should not be clinically apparent at the time of screening and should have a relatively high incidence in the population
  • The disease should be treatable or early treatment should improve outcome
  • The screening test should be simple and reliable  and cost effective

 

• In East Anglia between days 5 and 8 babies are screened for;
  • PKU
  • Congenital hypothyroidism
  • CF
  • Sickle cell
• By taking a small capillary blood sample from a heel prick stab, blood is placed on a paper card which can be posted to the regional laboratory for assay
• From June will test for MCADD – medium chain acyl CoA dehydrogenase deficiency

 

Prenatal screening

• High risk groups only
• Done to aid planning e.g. mode of delivery or termination
• Involves demonstrating the metabolic defect in cultured fetal fibroblasts obtained by amniocentesis early in the 2^nd trimester or by CVS during the 1^st trimester
• Done in women with a previously affected infant on in ethnic groups with a relatively high incidence e.g. Ashkenazi jews (high incidence of  the lipid storage disorder, Tay-Sachs disease)

 

When to suspect an inborn error of metabolism

• Classically the infant is term and deteriorates after a symptom free interval
• Early clinical findings may be;
  • Hypoglycaemia
  • Metabolic acidosis (hyperventilation due to lactate acidosis)
  • Failure to thrive
  • Vomiting
  • Fits/spasticity
  • Hepatosplenomegaly
  • Prolonged jaundice
  • A funny smell or staining of nappies
  • Death of a child in the family and a positive family history – male deaths think X-liked condition
  • Cataracts (galactosaemia)
• Late clinical findings may be;
  • Retarded mental development
  • Refractory rickets
  • Renal calculi
  • Neuropathy
  • Short stature
  • Dysmorphic features

 

Phenylketouria

• Autosomal recessive disorder
• Caused by an abnormality of the phenylalanine hydroxylase system
• Incidence in the UK is 1 in 10,000
• Phenylalanine cannot be converted to tyrosine and accumulates in plasma and is excreted in the urine alone with its metabolites
• Clinical features are;
  • Mental retardation developing between 4 and 6 months of age and psychomotor irritability
  • A tendency to reduced melanin formation because of reduced production of tyrosine – patients are pale skinned, blond and blue eyed
  • Irritability, feeding problems, vomiting and fits during the first few weeks of life
  • Generalised eczema
• Diagnosis may involve measuring phenylalanine concentration in blood from the heel prick test – used to be done by the microbiological Guthrie test but now done by chromatography or tandem mass spectroscopy
• Don’t do this too early in the newborn as you need to wait for the enzyme system to develop or you get false positives
• Treatment
  • Low phenylalanine diets – should be maintained throughout life
  • Strict control is required when a women becomes pregnant since maternal hyperphenylalaninaemia has been shown to affect the foetus in utero even if it doesn’t have PKU itself

 

Congenital Hypothyroidism

• Incidence of 1 in 3000
• If diagnosis is confirmed start treatment immediately and then after 1 year stop and reassess as neonatal hypothyroidism may be transient
• Thyroid hormones are essential for the general growth and development of the child and are particularly important for the CNS
• Clinical features;
  • Decreased activity
  • Poor feeding
  • Jaundice
  • Constipations
  • Hoarse cry
  • A ‘good’ baby – rarely cries and sleeps a lot
• Physical signs;
  • May not be present at birth
  • Coarse facial features
  • Macroglossia
  • Umbilical hernia
  • Mottled cool dry skin
  • Developmental delay
  • Pallor
  • Goitre
  • Other birth defects
• Treatment – give thyroxine, early treatment can prevent brain damage and optimise outcome
• Without treatment, mental retardation, stunted growth and spasticity

 

Cystic fibrosis

• Incidence is 1 in 2500 births with a carrier rate of 1 in 25
• Defect in the cystic fibrosis transmembrane conductance regulator – results in impaired chloride transport and the production of thick viscous exocrine secretions, leading to chronic lung infections and poor digestion
• Intestinal obstruction may occur in the neonate, called a meconium ileus due to increased viscosity of faecal maternal
• Neonatal screening involves detection of high levels of immunoreactive trypsin in the neonatal plasma – raised in 98% of infants with CF. Unrelable after 8 weeks of ge
• If positive molecular genetic analysis for the common mutations in the CFTR gene can be performed to confirm diagnosis
• Management is directed towards prevention of respiratory infections by regular physiotherapy and prolonged antibiotic therapy and maintainance of nutrition by a good diet and addition of pancreatic enzymes

 

Medium chain acyl CoA dehydrogenase deficiency

• A disorder affecting mitochondrial fatty acid metabolism
• Defect in fasting adaptation – unable to use fatty acids as fuel in prolonged fasting
• Presentation usually is preceded by a minor illness – reduced food intake and increased energy expenditure speeds up need for fatty acid oxidation
• Symptoms are related to the rapid onset of hypoglycaemia and the toxic effects of raised fatty acids and intermediates
• Clinical features of an acute attack;
  • Drowsiness, lethargy
  • Hepatomegaly and liver dysfunction
  • Hypotonia
  • Hyperglycaemia and perhaps hypoketotic
  • Stupor/coma
  • Sudden death
• Of those presenting clinically 25% will die and 33% of survivors will have brain damage

 

Congenital adrenal hyperplasia

• 95% are due to 21-hydroxylase deficiency
• The majority of the remaining 5% are due to deficiency on 11β-hydroxylase
• 21-hydroxylase deficiency;
  • Results in decreased cortisol production and because of the block the substrate accumulates and there is increases formation of adrenal androgens
  • Due to the decreased cortisol there is decreased negative feedback to the pituitary and thus increased secretion of ACTH which stimulates the synthesis of adrenal androgens
  • Female infants may be born with ambiguous genitalia or if the deficiency is only partial it may not present until early adulthood with hirsutism, amenorrheoa or infertility
  • Males may present with a pseudoprecocious puberty
  • In complete 21-hydroxylase deficiency, the infant may present with salt wasting, vomiting, dehydration, failure to thrive and shock
  • Treat with a glucocorticoid e.g. hydrocortisone and if necessary a mineralocorticoid e.g. fludrocortisone – not only does this replace the deficient hormones but by negative feedback suppresses ACTH production and androgen production

 

Investigation of prolonged neonatal jaundice

• Physiological jaundice occurs shortly after birth and is due to;
  • Immaturity of hepatic conjugating enzymes
  • Normal postnatal haemolysis
  • Enterohepatic circulation of bilirubin (conversion to urobilinogen cannot occur until the gut becomes colonised with bacteria)
• The bilirubin is primarily unconjugated and rarely exceeds 100μmol/L
• Jaundice is never present at birth and does not persist beyond 14 days
• Physiological unconjugated bilirubin levels may be very high in premature infants because of hepatic immaturity
• If the bilirubin concentration exceeds the albumin binding capacity, the unbound fat soluble unconjugated bilirubin may cross cell membranes and be deposited in the brain causing kernicterus – may cause brain damage or death
• Neonatal jaundice should be investigated if;
• It is present at birth or appears during the first 24hours of life
• Persists beyond 14 days of life
• Total plasma bilirubin concentration is >250μmol/L
• There is conjugated hyperbilirubinaemia – always pathological
• Jaundice is associated with other symptoms or signs

 

Causes of unconjugated hyperbilirubinaemia in the newborn;

• Increased haemolysis e.g. ABO or rhesus incompatibility or red cell defects e.g. glucose-6-phosphate or pyruvate kinase deficiency
• Decreased conjugation e.g. Crigler-Najjar syndrome, hypothyroidism or breast milk jaundice (benign condition seen in some breast fed infants thought to be due to interference with bilirubin conjugation due to free fatty acids)

 

Causes of conjugated hyperbilirubinaemia in the newborn;

• Haemolytic conditions
• Hepatic dysfunction due to;
  • Infections
  • Congenitial – rubella, CMV, syphilis
  • Acquired – UTI, septicaemia, hepatitis
  • Metabolic disorders;
  • α1- antitrysin deficiency
  • Galactosaemia
  • Tyrosinaemia
  • CF
• Congenital abnormality e.g. bilary atresia

 

Some IEM can present in adults;

 

Haemochromatosis

• Autosomal recessive – defect in the haemochromatosis gene (HFE)
• 1 in 10 carriers and 1 in 1000 are homozygous
• more likely to manifest in males as menstruation in females lowers iron stores
• Increased iron absorption results in large iron stores in the liver, pancreas, joints, heart and gonads
• It presents in middle age with;
  • Liver cirrhosis
  • Diabetes mellitus
  • Joint pains
  • Cardiomyopathy
  • Hypogonadism
  • Greyish skin pigmentation due to melanin not iron
• There is an association with hepatocellular carcinoma
• Diagnosed by high saturation of transferrin in the blood and high serum iron and ferritin levels. Confirmed by liver biopsy showing heavy iron deposition and hepatic fibrosis
• Management;
  • Venesection
  • Therapy for cirrhosis and DM
  • Investigation of first degree relatives by blood testing and genetic screening

 

Wilson’s disease

• Autosomal recessive disorder of copper metabolism results in chronic destructive liver disease
• Due to a mutation in the copper transport ATPase gene resulting in the failure of the liver to secrete the copper-ceruloplasmin complex into the plasma
• Characterized by;
  • Decreased biliary excretion of copper
  • Decreased incorporation of copper onto ceruloplasmin (a copper binding protein)
  • Copper is deposited in the liver, basal ganglia of the brain and the cornea of the eye
• Diagnosis is by low levels of serum ceruloplasmin and high free copper levels in the blood. Liver effects are confirmed by biopsy
• Managed by copper chelators e.g. penicillamine

 

Familial hypercholesterolaemia

• Autosomal dominant trait – prevalence of 1 in 500
• Different mutations can affect LDL synthesis, ligand binding, clustering in coated pits and recycling
• In all cases there is a defect in the uptake and catabolism of LDL
• Plasma concentration of LDL and total cholesterol are increased
• In the rare homozygotes, there are no LDL receptors present, plasma cholesterol levels are very high and untreated patients develop coronary artery disease in childhood
• Heterozygotes tend to develop coronary artery disease 20 years before the rest of the population

 

α1 – antitryspin deficiency

• Homozygotes for the normal protein are termed Pi (protease inhibitor) MM
• Over 30 alleles of the gene have been described
• Disease is most commonly caused by homozygosity of the Z allele – genotype frequency of 1 in 3000
• Plasma concentration of α1 – antitryspin is 10-15% of normal
• Defect is due to a single amino acid substitution which causes the protein to form aggregates that cannot be secreted from the liver and cause liver damage
• Patients have a high risk of developing emphysema due to a lack of inhibition of neutrophil elastase

 

Multiple endocrine neoplasias

• Autosomal dominant disorders in which tumours (benign or malignant) develop in two or more endocrine glands
  • MEN I Werner’s syndrome
    • Parathyroids
    • Pancreatic islets – tumours producing gastrin and insulin
    • Anterior pituitary adenomas
    • Rarely thyroid tumours and adrenal cortical adenomas
    • Caused by a germline mutation in the MEN-1 tumour suppressor gene
  • MENIIa – Sipple’s syndrome
    • Phaechromocytoma
    • Medullary carcinoma of the thyroid
    • Parathyroid hyperplasia
  • MENIIb – MEN III syndrome
    • Associated with the same clinical features as MEN Iia but with additional somatic symptoms
    • Neuromas and ganglioneuromas in the dermis and submucosal regions throughout the body
    • Mafanoid body habitus
    • Skeletal abnormalities e.g. kyphosis, high arch palate, pas cavus
    • MEN II is linked to mutations in the RET proto-oncogene

 

Cystinuria

• Autosomal recessive disorder of tubular reabsorption resulting in excessive urinary excretion of the dibasic amino acids, cystine, ornithine, arginine and lysine
• Cystine is relative insoluble and high levels in the urine in homozygotes can result in calculi formation
• Otherwise it is relative harmless and management is to increase fluid consumption, possible alkalosis of the urine and to consider penicillamine which forms a chelate which increases the solubility of cystine

 

Inherited homocystinuria differs from acquired hyperhomocystinaemia

• Inherited homocystinuria is an autosomal recessive disorder due to a deficiency in cystathionine synthase
• Patients develop progressive CNS dysfunction, thrombotic disease, cataracts and CVS problems
• Acquired hyperhomocystinaemia can be caused by;
  • Deficiency in folate, Vit B6 and VitB12
  • Age
  • Impaired renal function
  • Hypothyroidism
  • Psoriasis
  • Drugs such as methotrxate, theophylline and L-dopa

 

Porphyrias

• Group of inherited diseases in which a partial deficiency of one of the enzymes of porphyrin synthesis leads to decreased formation of haem and thus by releasing ALA synthase from inhibition leads to the excessive formation of porphyrin precursors e.g ALA and PBG or porphyrins
• When precursors are produced in excess they produce primarily neurological manifestations (precursors are neurotoxins)
• When porphyrins are produced in excess the predominant feature is photosensitivity as porphyrins absorb light and become excited inducing the formation of toxic free radicals
• Apart from a couple of exceptions most mutations are autosomal dominant

 

 

Acute porphyries

• Acute intermittent porphyria is the commonest
• Clinical features
  • Acute attacks separated by periods of complete remission
  • Abdominal pain and psychiatric disturbances are common. Patients can also present with peripheral neuropathy
  • Can also present with cardiovascular symptoms, sinus tachycardia and systemic hypertension
• They can be precipitated by a number of factors including;
  • Alcohol
  • Drugs such as barbiturates and OCP
  • Pregnancy
  • Premenstrual
  • Infections
  • Stress
  • Starvation
• These factors are thought to increase the activity of ALA synthase
• Diagnosis of acute porphyrias
  • ALA and PBG are excreted in the urine during an attack
  • Be suspicious with unexplained acute abdominal pain, peripheral neuropathy and psychosis
  • Once diagnosis is confirmed screen relatives so precipitating factors can be avoided

 

Nonacute porphyries

• Cutaneous hepatic porphyria presents with photosensitivity
• The initial lesion is erythema but this progresses to the formation of vesicles and bullae and eventually to scarring and pigmentation
• Patients with hereditary coproporphyria and variegate porphyria can have acute manifestations as well as photosensitivity

 

Other causes of porphyria;

• Liver disease particularly cholestasis – normal biliary excretion of porphyrins is impaired resulting in increased urinary excretion
• Lead poisoning
• Bleeding lesions in the upper GI tract
• Iron deficiency and sideroblastic anaemia

 

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