When to think about metabolic disorders in adulthood?

Wouter MeerssemanGeneral Internal Medicine

Adult Metabolic ClinicWouter Meersseman, Leuven, Belgium

Man, 25 year-old

Normal developmentFrom 15 months to adulthoodRecurrent episodes of hypotonia/weakness/Ataxia/lethargy during fever episodes (about once a year).

In between episodes: polyneuropathy, scoliosisDiagnosis: 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 fever2) Acute optic neuropathy3) 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(N<67µM)

173 µM 250 µM

L/P (N<20) 9 11

Amino acids chromatographyHyperalaninemia (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 neurologistsE.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

Intoxications

1. Urea cycle defects2. Homocysteine remethylation defects3. Acute porphyrias4. Non ketotic hyperglycinemia5. MSUD

Energy metabolism defects (Leigh syndrome or pseudo-strokes)

Normal MRI Abnormal MRI

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%

Mitochondrial diseases: diversity of clinical expressions (organs relying on OXPHOS !!!)

Any symptom in any combinations at any ageThink “mitochondrial” when lactic acidosis is present with any of the above

features

Think mitochondrial if new “strange” symptoms arise following metabolic

stressWhat 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 inheritanceMaternally transmitted, girls and boys can be affected, only girls

pass it through on to their childrenClinical variability within one family: heteroplasmyVariability in time

Mitotic segregation

HOMOPLASMY

HOMOPLASMY

HETEROPLASMY

Importance of muscle biopsy

ragged red fibers, Showed by a Gomori stain

Accumulation of abnormal mitochondria at the periphery of the muscle fibreElectron-transport chain assays: defect in complex I

DNA sequencing: G13513A missense mutation, MELAS syndrome

Gomori stain COX mosacism

Primary mitochondrial diseases

Mendelian mode of inheritance

4q34-35 →ANT1adenine nucleotide translocator

Autosomal dominant external ophthalmoplegiaLarge-scale mtDNA deletions

Kaukonen Science 2000

Adult medicine: presenting with ptosis, myopathy and/or encephalopathy

What is relevant for the internalmedicine 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, lacticacidosis, liver failure: think “mitochondrial” and talk to a metabolic physician

Woman, 71 yrs

Past history :– Hysterectomy– Progressive spasticity (legs) since 5 yearsExamination: Spastic paraparesisTetrapyramidal 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

Metabolic leukoencephalopathy!

Patient

Krabbe’s disease (galactocerebrosidase deficiency)

What pattern did you recognize?

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 leukodystrophy2) Krabbe’s disease3) Adrenoleukodystrophy4) Refum’s disease5) Cerebrotendinous xanthomatosis

Intoxications (amino and organic acids)

- normal EMG- Superficial white matter (U

fibres)

1. Organic acidurias2. 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

Energy requirement on the short-term

Creatine kinase 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 exercise-related 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%

Polyneuropathy 24%

Parkinsonian syndrome <10%

Atherosclerosis 10%

95%

MOGHADASIAN, 2004; VERRIPS et al., 2000. BARKHOF et al.,2000

20-50 years

•Pyramidal signs (90%)•Cataract (90%)•Cerebellar signs (70%)•Dementia (70%)•Polyneuropathy (70%)•Xanthomata (40%)•Psychiatric signs (30%)•Atheroma (30%?)•Epilepsy (20%)

• Learning difficulties (>70%) • Juvenile cataract (50%)•Chronic Diarrhoea (40%)•Tendon xanthomata (10%)• Neonatal Cholestasis (?)

Childhood

Adulthood

Clinical spectrum of cerebrotendinous xanthomatosisEstimated from 124 published cases

Cerebellar ataxia

Energy metabolism disordersPDH deficiencyRespiratory chain disorders

IntoxicationsUrea cycle disordersHartnup’s disease

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..

Acute Chronic

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…

Question 1: Could it be an inborn error of metabolism?

In general, think to an IEM when..

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)

5) Metal storage disorders (copper, iron, manganese)

Question 2: What kind of metabolic pathway could be

involved?