(faces) of inherited metabolic diseases Dr. Abdulmateen Abdulrahman Shukri Pediatrician Univeristy of Duhok/ College of medicine Introduction: The cause of signs and symptoms of IMD?
Why diagnosis is delayed in
patients with IMD? Inherited metabolic disease (IMD) may present at any age and the signs and symptoms may result from: • Accumulation of substrate that leads to a toxic effect. • Accumulation of a minor metabolite that in excess is toxic. • Deficiency of a product of a specific reaction. • Secondary metabolic phenomena. The commonest error in managing infants and children with IMD is a delay in diagnosis, and therefore a delay in starting treatment. Failure to recognize an IMD may occur because its clinical features are confusing because of: • Genetic heterogeneity. • A presenting inter-current illness. • similarity with other common, acquired conditions where the differential diagnosis has not been fully explored. A. Neurological presentations: 1- Chronic encephalopathy: A. Grey matter .. Developmental delay, psychomotor retardation. B. White matter … Gross motor delay, weakness and incoordination. C. Encephalopathy with problems outside the CNS. Developmental delay is a common problem, but the features that warrant investigation for IMD include: • Global delay affecting all areas of development. • Progressive course with loss of developmental milestones. • Objective evidence of neurological dysfunction (e.g. special senses,pyramidal tract, extrapyramidal, cranial nerves). • Severe behaviours including irritability, impulsiveness, aggressiveness, and hyperactivity. • Seizures (complex partial or myoclonic) originating early in life that are resistant to usual therapy. 45-day-old boy presents with recurrent myoclonic seizures that were not responding to multiple anti- epileptic medications ( phenobarbital, levetiracetam, and phenytoin). Seizures immediately respond to pyridoxine ( vitamin B6) injection. When has been inadvertently stopped by parents after discharge, seizures recurred and then terminated upon on given injection again confirming the diagnosis of pyridoxine-dependent seizure. 6-week-old boy had multiple daily seizures that partially responded to sodium valproate. In addition he had marked developmental delay and features of encephalopathy. Examination revealed severe extensive seborrheic dermatitis on his scalp, back and perineal region. Biotinidase deficiency … dramatic response to biotin. X-linked ALD … MRI white matter changes Investigations for chronic encephalopathy • Clinical: developmental assessment and neurological examination • Imaging: MRI of head; X-rays of hands, chest, lateral spine • Blood: plasma amino acids; ammonia; lactate • Urine: amino acids, organic acids, and mucopolysaccharide and oligosaccharide screen • Electrophysiology: auditory brainstem refl exes; visual-evoked potentials; somatosensory-evoked potentials; nerve conduction;EMG; EEG 2- Acute encephalopathy The likely causes are: hypoglycaemia; hyperammonaemia; amino acidopathy; organic aciduria ; fatty acid oxidation defect ; mitochondrial defect. 3- stroke or stroke-like episodes. Fabry disease 4-year-old girl with right-sided stroke with her 11-year-old tall brother who underwent lens surgery before. Homocystinuria Cranial MRI … acute infarct Coagulation screening … normal Screening for autoimmune diseases … negative Metabolic … elevated homocysteine, methionine and normal vitamin B12 Rx: Anti-coagulation, vitamin B6, later on betaine if no response. 4- Movement disorders. 5- Myopathy. 6- Autonomic dysfunction. 7- Psychiatric disturbances. B. Metabolic acidosis. Either from abnormal bicarbonate loss or accumulation of organic anion. Anion gap, serum chloride, urine anion gap for the first category ( GI vs renal causes). Causes of the second category are: lactic acidosis, ketoacidosis or organic aciduria. C. Storage or dysmorphism. D. Hepatic: These include: 1- Jaundice. 2- Hepatomegaly. 3- Hypoglycemia. 4- Hepatocellular dysfunction. Glycogen storage disease type IV in a 5-year-old girl with marked abdominal distension with hepatosplenomegaly. E. Cardiac: These include: cardiomyopathy, arrhythmias and coronary artery disease. Glycogen metabolism (hypertrophic cardiomyopathy) Pompe disease (GSD II)—presents in early infancy with marked skeletal myopathy, massive cardiomegaly (large QRS, left axis deviation, shortened PR, T-wave inversion). Fatty acid metabolism (dilated cardiomyopathy) Systemic carnitine defi ciency: presents with skeletal myopathy, hypotonia encephalopathy, hepatic syndrome (hepatomegaly, hypoglycaemia, hepatocellular dysfunction).