When to think about metabolic disorders in adulthood? Wouter Meersseman General Internal Medicine Adult Metabolic Clinic Wouter Meersseman, Leuven, Belgium
Man, 25 year-old Normal development From 15 months to adulthood Recurrent episodes of hypotonia/weakness/ataxia/lethargy during fever episodes (about once a year). In between episodes: polyneuropathy, scoliosis Diagnosis: Charcot Marie Tooth type II (axonal polyneuropathy)
What features suggest an inborn error of metabolism? 1. Acute relapsing episodes triggered by fever 2. Chronic polyneuropathy
19 yo: left acute visual loss (left optic neuropathy) 24 yo: right acute visual loss ( right optic neuropathy) What kind of inborn error of metabolism do you suspect and why? Energy metabolism disorder because: 1) Episodes triggered by fever 2) Acute optic neuropathy 3) Axonal polyneuropathy
Mitochondria: the tiniest rotatory motor DiMauro. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656-68
alanine PDH
What investigations will you ask for?
fast Post prandial Lactates (N<1.8mM) 1.6 mm 2.8 mm Pyruvate 173 µm 250 µm (N<67µM) L/P (N<20) 9 11 Amino acids chromatography Hyperalaninemia (789 mm)
Treatment with thiamine (500 mg/d) Visual acuity before treatment Right =4/10,Left =1/10 Visual acuity one year later: Right eye=8/10, Left eye=6/10.
Primary mitochondrial disease: frequently overlooked!!!! Important for internists and neurologists E.g. - Diabetes-deafness syndrome - Classic MELAS phenotype - Hypertrophic cardiomyopathy, renal failure and diabetes - Kearns-Sayre syndrome (3th degree AV block, deafness, retinitis and diabetes) - Myopathy (PEO) - Alpers syndrome: liver brain valproic acid
Leigh Syndrome
Leigh syndrome Biotin responsive basal ganglia disease Pyruvate dehydrogenase deficiency Complex 3 deficiency
Acquired causes of «Leigh Syndrome» Acquired metabolic disorders -Gayet Wernicke s encephalopathy -Hypoglycemia Toxic causes -Carbon monoxide poisoning -Cyanide poisoning -Intoxication with Methylbromide -Intoxication with Methanol.. Anoxia -Drowning, hanging, etc
Acute encephalopathies/comas Normal MRI Abnormal MRI Intoxications 1. Urea cycle defects 2. Homocysteine remethylation defects 3. Acute porphyrias 4. Non ketotic hyperglycinemia 5. MSUD Energy metabolism defects (Leigh syndrome or pseudo-strokes)
Mitochondrial diseases: diversity of clinical expressions (organs relying on OXPHOS!!!) Central nervous system Myopathy 36% Encephalopathy 20% CVA 18% Spasticity 12% Cerebellar syndrome 8% Growth retardation Neonatal distress 31% Failure to thrive 20% Cardiac system Cardiomyopathy 24% Hepatic system Acute liver failure 20% Eye system Retinitis pigmentosa 8% Renal system Tubulopathy 8% Ear system Deafness 8% Endocrine system Diabetes 7% Any symptom in any combinations at any age Think mitochondrial when lactic acidosis is present with any of the above features
Think mitochondrial if new strange symptoms arise following metabolic stress What is in the diagnostic armamentarium? -Organic acid analysis in the urine (krebs cycle intermediates: lactate, fumarate, methylglutaconic acid) -Mutation analysis -Muscle biopsy
Mitochondrial mode of inheritance Maternally transmitted, girls and boys can be affected, only girls pass it through on to their children Clinical variability within one family: heteroplasmy Variability in time Mitotic segregation HOMOPLASMY HETEROPLASMY HOMOPLASMY
Importance of muscle biopsy Gomori stain COX mosacism ragged red fibers, Showed by a Gomori stain Accumulation of abnormal mitochondria at the periphery of the muscle fibre Electron-transport chain assays: defect in complex I DNA sequencing: G13513A missense mutation, MELAS syndrome
Primary mitochondrial diseases
Mendelian mode of inheritance Autosomal dominant external ophthalmoplegia Large-scale mtdna deletions 4q34-35 ANT1 adenine nucleotide translocator Adult medicine: presenting with ptosis, myopathy and/or encephalopathy Kaukonen Science 2000
What is relevant for the internal medicine doctor? In case of a known mitochondrial disease: avoid valproate, biguanides, linezolid and barbiturates Speak to the relatives: ethical dilemmas In case of a rare unexplained diagnostic conundrum: e.g. unexplained encephalopathy, opthalmoplegia, neuropathy, myopathy, lactic acidosis, liver failure: think mitochondrial and talk to a metabolic physician
Woman, 71 yrs Past history : Hysterectomy Progressive spasticity (legs) since 5 years Examination: Spastic paraparesis Tetrapyramidal syndrome
What features suggest an inborn error of metabolism?
Metabolic leukoencephalopathies -Symetrical -Fascicular -Weak signal intensity Symetrical Fascicular Weak signal intensity
Inflammatory leukoencephalopathies Leukoencephalopathies in vascular diseases
Patient Metabolic leukoencephalopathy!
What pattern did you recognize? Krabbe s disease (galactocerebrosidase deficiency)
Defects in a single metabolic pathway lead to different lysosomal storage diseases
When faced with leukodystrophy, think metabolic If symmetric lesions are present If there is a constellation of neurlogical signs and psychiatric signs (such as psychosis, pyramidal tract signs and polyneuropathy signs) If there is positive family history (X-linked ALD, autosomal recessive Krabbe s disease, metachromatic leukodystrophy)
Leukoencephalopathies Lipid storage disorders - Polyneuropathy - Deep white matter 1) Metachromatic leukodystrophy 2) Krabbe s disease 3) Adrenoleukodystrophy 4) Refum s disease 5) Cerebrotendinous xanthomatosis Intoxications (amino and organic acids) - normal EMG - Superficial white matter (U fibres) 1. Organic acidurias 2. Aminoacidopathies (homocysteine, phenylananine)
Adrenoleukodystrophy
What about raised CK levels? Woman, age 40 years Acute rhabdomyolysis following long distance walk in the mountains, dark urine, pain, oliguria In childhood, muscular pains frequently when doing sport activitity 3 sibs, with one sister with same complaints CK-level of 40,000 U/ml
Energy requirement: long-term
Exercise-related rhabdomyolysis: think metabolic!!! Carnitine-palmitoyltransferase II deficiëntie Very long chain fatty acid dehydrogenase deficiency You need oxydation of fatty acids for long term physical exercise
Creatine kinase Energy requirement on the shortterm Glycolysis
Glycogenoses: with exercise related complaints GSD V: McArdle disease (myofosforylase, 11q, AR) Onset: 15-25 years Symptoms At the beginning of exercise peak capacity Pain upon start exercise Rhabdomyolysis, swelling Second wind in 1/3 >40 jaar paresis
Glycogenosis with exerciserelated complaints GSD V: McArdle disease Diagnosis Permanent CK rise EMG: myogenic Fore armtest DNA
Man, 38 yo At the age of 15: cataract Normal education until the age of 13 Abnormal behavior from the age of 25, regular falls Brisk reflexes, ataxic gait, xanthomata
STATINES Ac CDCA
Dosage of Cholestanol/Cholestérol: 1/100 (N <1/1000) Accumulation of biliairy sterols in serum and urine Cerebrotendinous xanthomas
Tendon xanthomata
Juvenile bilateral cataract 90% Tendom xanthomata 70% Chronic diarrhea 33% Pyramidal syndrome 67% Cerebellar ataxia 60 Cognitive decline 57% Epilepsy 24% 95% Polyneuropathy 24% Parkinsonian syndrome <10% Atherosclerosis 10% MOGHADASIAN, 2004; VERRIPS et al., 2000. BARKHOF et al.,2000
Clinical spectrum of cerebrotendinous xanthomatosis Estimated from 124 published cases Childhood Learning difficulties (>70%) Juvenile cataract (50%) Chronic Diarrhoea (40%) Tendon xanthomata (10%) Neonatal Cholestasis (?) 20-50 years Adulthood Pyramidal signs (90%) Cataract (90%) Cerebellar signs (70%) Dementia (70%) Polyneuropathy (70%) Xanthomata (40%) Psychiatric signs (30%) Atheroma (30%?) Epilepsy (20%)
Cerebellar ataxia Energy metabolism disorders PDH deficiency Respiratory chain disorders Intoxications Urea cycle disorders Hartnup s disease Acute Chronic Lipid metabolism disorders and some lysosomal diseases - GM2 gangliosidosis - Niemann Pick C - Cerebrotendinous xanthomatosis - Adrenomyeloneuropathy - Refsum s disease α mannosidosis - Sialidosis type 1 - Vitamin E deficiency, - Abetalipoproteinemia Energy metabolism disorders - NARP syndrome - Kearns-Sayre syndrome - Others..
Question 1: Could it be an inborn error of metabolism? In general, think to an IEM when.. 1) Symptoms unexplained by «classical causes» 2) «Incongruous» association of symptoms 3) Acute episodes triggered by fever, exercise, surgery, drugs etc.. 4) Young age at onset 5) Exercise-related rhabdomyolysis 6) Familial history
5) Metal storage disorders (copper, iron, manganese) Question 2: What kind of metabolic pathway could be involved? 1) Energy metabolism disorders (respiratory chain, PDH, ETF, biotine) 2) Lipid storage disorders (sphingolipidoses, peroxisomal disorders, cerberotendinous xanthomatosis, Tangier disease) 3) Intermediary metabolism disorders (intoxications) 4) Neurotransmitter metabolism diseases (dopamine, serotonine)