Elevated lactate is a feature of a number of inborn errors including organic acidaemias (A), fat oxidation defects (B), respiratory chain disorders, pyruvate disorders, disorders of gluconeogenesis, hereditary fructose intolerance, biotinidase deficiency, and glycogen storage disorders (I, III, VI and IX). In practice, hypoperfusion and hypoxia need to be excluded because secondary causes of lactic acidaemia are more common. Spurious elevations of lactate commonly arise due to a squeezed blood sample. An arterial sample should be taken if a free-flowing venous sample cannot be obtained.
The diagnosis of congenital adrenal hyperplasia depends upon the demonstration of inadequate production of cortisol, aldosterone, or both in the presence of accumulation of excess concentrations of precursor hormones. For example, the distinguishing characteristic of 21-hydroxylase deficiency is a very high serum concentration of 17-hydroxyprogesterone (usually >1000 ng/dL) in the presence of clinical features suggestive of the disease (e.g. ambiguous genitalia, evidence of salt wasting with a low sodium level and high potassium level). 21-hydroxylase acts to convert progesterone to deoxycortisterone. Salt-wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone concentrations, hyponatremia, hyperkalemia, and elevated plasma renin activity (PRA) indicating hypovolemia.
The key features of Refsum’s disease are cerebellar ataxia, mixed polyneuropathy and retinitis pigmentosa; the onset is slowly progressive, with 40% of cases presenting before 10 years of age. The sensorimotor polyneuropathy often begins in the distal lower extremities and becomes central with time. Other features include sensorineural hearing loss, cardiac conduction defects and cardiomyopathy, the latter being the commonest cause of death in untreated patients. The metabolic cause is phytanol coenyzme A hydroxylase deficiency, which leads to an increase in phytanic acid level. The treatment is a dietary restriction of phytanic acid, and plasmapheresis has been used in individuals with very high levels.
Dicarboxylic acids are formed when fatty acids undergo omega-oxidation in the microsomes.
Barth syndrome is an X-linked condition affecting cardiolipin metabolism, an essential component of the inner mitochondrial membrane in which the respiratory chain in embedded. Secondary mitochondrial dysfunction is common, and lactates are variable. The diagnosis is suggested by dilated cardiomyopathy in a male infant with associated neutropenia. The latter can be cyclical and therefore the blood count should be checked on more than one occasion if suspected as it can be missed. Methylglutaconic aciduria is associated but not present in every case. Management consists of nutritional and immune support (prophylactic antibiotics, aggressive management of infections, with or without granulocyte colony-stimulating factor or GCSF).
Patients with classic galactosaemia have Galactose-1-phosphate uridyl transferase deficiency. Postprandial hypoglycaemia seems to be due to an inhibition of phosphoglucomutase by galactose-1-phosphate, thereby causing inhibition of glycogenolysis.. Protein hydrolysate formulas are only used if there is severe liver disease as these do contain some lactose.
mtDNA depletion syndrome is a nDNA encoded respiratory chain disorder that is associated with severe liver disease in some cases. The mtDNA is qualitatively normal, but reduced in amount.
Mitochondrial DNA large-segment duplications and deletions as seen in Kearns–Sayre syndrome (pigmentary retinopathy, progressive external ophthalmoplegia, heart block, ataxia, raised cerebrospinal fluid protein) tend to be sporadic occurrences and therefore the risk of inheritance in other siblings is negligible.
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