Mitochondrial Diseases Flashcards
Mitochondrial Disease
Whilst most DNA is found in the cell nucleus, a small amount of double-stranded DNA is present in the mitochondria. It encodes protein components of the respiratory chain and some special types of RNA
Inheritance:
Mitochondrial inheritance has the following characteristics:
inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote
all children of affected males will not inherit the disease
all children of affected females will inherit it
generally encode rare neurological diseases
poor genotype:phenotype correlation - within a tissue or cell there can be different mitochondrial populations - this is known as heteroplasty)
Histology:
Muscle biopsy classically shows ‘red, ragged fibres’ due to increased number of mitochondria
Examples include:
Leber’s optic atrophy
MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
MERRF syndrome: myoclonus epilepsy with ragged-red fibres
Kearns-Sayre syndrome
Sensorineural hearing loss
MIDD - Maternally inherited Diabetes and Deafness
MELAS (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke)
MELAS is a rare mitochondrially inherited condition characterised by short stature, recurrent migraines, vomiting, muscle weakness, seizures and then development of multiple strokes at an early age (normally before 40 for diagnosis to be considered) along with a progressive dementia. There is also a raised lactic acid level in the blood and skeletal muscle biopsy will show ragged red fibres.
Example Question:
A 29 year old man presents to the stroke ward following a right sided middle cerebral artery territory infarct. You are reviewing him 4 weeks after as an outpatient. Whilst taking a history from him and his father you find out that he had a normal delivery and early development and initially performed well in school. However from about the age of 12 he started developing complex partial seizures with secondary generalisation that were difficult to control with medications and started to struggle in school.
Since adulthood, he has suffered from frequent migraines that have again been difficult to treat with medications. He also suffers from recurrent vomiting although a thorough gastroenterological assessment including OGD with biopsies could not find any cause for the vomiting.
When aged 26 whilst out walking, he suddenly became very dizzy and unable to walk properly. These symptoms resolved in a day and he never sought medical attention. Since that incident he has been left with a tremor that now makes his work as a painter almost impossible to do. He has also noticed that he is becoming more fatigued by walking. He goes to the gym regularly and is able to lift less and less weights as time has progressed. His mother died suddenly aged 37
Medications included: carbemazepine, clopidogrel and atorvastatin.
Examination
Height 4ft 11inches (150 cm)
Generalised muscle weakness with some atrophy
Left upper limb power 3/5 right upper limb power 5/5
Right upper limb power 5/5 left upper limb power 5/5
Lateral nystagmus 5 beats
Dysdiadochokinesia
Moderate intention tremor
MMSE 25/30
Hb 14.7 g/dl
Platelets 256 * 109/l
WBC 8.6 * 109/l
Na+ 140 mmol/l
K+ 4.5 mmol/l
Urea 4.6 mmol/l
Creatinine 54 µmol/l
Bilirubin 6 µmol/l ALP 89 u/l ALT 21 u/l Total cholesterol 5.7 mmol/l Albumin 40 g/l
CT Brain : right sided MCA territory infarct. Generalised atrophy
ABGs on air
pH 7.38 CO2 3.7 kPa O2 15.6 kPa Bicarb 49 mmol/l Lactate 8.4 mmol/l
What is the most likely diagnosis?
Familial hypercholesterolaemia > MELAS syndrome Carbemazepine poisoning CADASIL Pyruvate carboxylase deficiency
The answer is B MELAS (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke).
MELAS is a rare mitochondrially inherited condition characterised by short stature, recurrent migraines, vomiting, muscle weakness, seizures and then development of multiple strokes at an early age (normally before 40 for diagnosis to be considered) along with a progressive dementia. There is also a raised lactic acid level in the blood and skeletal muscle biopsy will show ragged red fibres.
Regarding the vignette, it is possible that his mother had the same condition which is typical of mitochondrial inheritance. It also sounds like he may have had a posterior stroke that was not treated as he had sudden onset of cerebellar symptoms and is left with an intention tremor and has nystagmus. Cerebellar infarcts do not always show up on CT and MRI is the best modality for viewing the posterior fossa. Although is MMSE score is normal, for a young man a score of 25/30 is a potential worry in the clinical context.
Although CADASIL would also present with migraines and stroke at an early age, lactic acidosis is not a feature and subcortical infarct would be more typical. Although this gentleman has a high cholesterol it is not high enough for a diagnosis of familial hypercholesterolaemia and would not explain the muscle weakness, vomiting and lactic acidosis.
Carbemazepine poisoning could explain the cerebellar symptoms but not the other symptoms. Pyruvate carboxylase deficiency would cause muscle weakness, vomiting and lactic acidosis but would not explain the early onset of stroke
Kearns-Sayre Syndrome
Kearns-Sayre syndrome is a mitochondrial disorder. Individuals usually present <20 years-of-age with progressive external ophthalmoplegia. Ptosis usually develops first, followed by difficulties with horizontal gaze. Patients don’t usually complain of diplopia as the extraocular muscle weakness is symmetrical.
Affected patients also usually suffer from pigmentary retinopathy, which causes atrophy of the retinal pigment with bony spicule formation typical of retinitis pigmentosa. As the changes progress, patients often complain of funnel-vision and night blindness.
Cardiac conduction defects usually develop after the onset of ophthalmoplegia and sudden death may occur as a result. Regular cardiac follow-up is essential. Other abnormalities include cerebellar ataxia, sensorineural deafness, muscle weakness and diabetes mellitus.
Features:
- night blindness
- onset < 20 years
- external ophthalmoplegia
- retinitis pigmentosa
- ptosis
- diplopia
Example Question:
A 19-year-old university student is reviewed in the general medical clinic with bilateral ptosis. It has developed gradually over the last few months and has now progressed to the extent that he has to tilt his head upwards during lectures. He denies diurnal variation in his symptoms.
His past medical history is unremarkable and he takes no regular medications. He tells you that his mother had a pacemaker fitted due to frequent ‘blackouts’.
On examination, you note the presence of bilateral ptosis. He also has impaired abduction and adduction of both eyes. Direct fundoscopy shows black spicules in the periphery of both eyes. An ECG is taken and shows sinus rhythm with first-degree heart block.
Given the likely diagnosis, which additional symptom is he most likely to describe?
> Night blindness Syncope Tremor Flank pain Diplopia
The most likely diagnosis is Kearns-Sayre syndrome.
Kearns-Sayer Syndrome - Muscle Biopsy: Example Question
A 19 year old woman presents to the general medical clinic for review. She has been referred due to drooping of her eyelids, first on the right and now bilaterally. On further questioning she reveals that she has been struggling to read in dim light and recalls that two family members have required insertion of cardiac pacemakers. Examination reveals partial bilateral ptosis and a generalised ophthalmoplegia in all directions of gaze. Fundoscopy demonstrates central areas of dark pigmentation on a pale fundus.
From the options given which investigation is most likely to reveal the diagnosis?
Serum for anti-acetylcholine receptor antibodies Serum for anti-voltage gated calcium channel receptor antibodies > Muscle biopsy Karotyping Thyroid function tests
A triad of chronic progressive external ophthalmoplegia, pigmentary retinopathy and cardiac conduction defects makes Kearns-Sayer syndrome likely.
Kearns-Sayer syndrome is an example of a mitochondrial disease, a group of rare conditions which many find confusing. Despite their rarity, those candidates who do a rotation in neurology are likely to encounter mitochondrial disease in one form or another and so a basic knowledge is useful.
Kearns-Sayer syndrome is characterised by ptosis and external ophthalmoplegia occurring in the first or second decades of life. Cardiac conduction defects usually occur later and are usually in the form of atrio-ventricular nodal block, often requiring cardiac pacing. Multiple endocrinopathies may be associated and a proximal myopathy may be evident. Serum elevation of lactate and pyruvate is frequently seen, as is the case with many mitochondrial conditions.
The diagnosis should be suspected from the history and clinical features as listed above and diagnosis is confirmed by muscle biopsy which demonstrates characteristic ‘ragged red fibres’, this is often supplemented by polymerase chain reaction analysis of mitochondrial DNA for mutation detection.
Anti-acetylcholine receptor antibodies are seen in myasthenia gravis, and would be involved in the work-up of any patient with an unexplained bilateral ptosis, but this wouldn’t explain the pigmented retinopathy or the family history of pacemaker insertion. This is also the case for anti-voltage gated calcium channel antibodies, found in the Lambert-Eaton myasthenic syndrome.
Ptosis - Diagnosis: Kearns-Sayers Syndrome: Example Question
A 22-year-old male is referred to clinic by his GP. His initial complaint had been that his friends have been increasingly remarking on how his eyelids look increasing ‘droopy’ over the past 9 months. He denies any diplopia or muscle weakness. He has no past medical history, is a non-smoker and non-drinker. On examination, you note bilateral inability to abduct or adduct his eyes. Vertical gaze is also inconsistently impaired. His upper and lower limb neurological investigation was unremarkable except very mild finger-nose dysmetria, his bloods tests show no abnormalities. His ECG demonstrates sinus rhythm with a PR interval of 260ms. Fundoscopy reveals a pigmented retina. What is the diagnosis?
Myasthenia gravis Thyroid eye disease Oculopharyngeal musculodystrophy Extraocular muscle fibrosis > Kearns-Sayre syndrome
This young patient demonstrates a combination of retinitis pigmentosa, chronic progressive external ophthalmoplegia, bilateral ptosis, mild cerebellar signs and a cardiac conductive defect (first degree heart block). These features are consistent with a mitochondrial disorder, in particular Kearns-Sayre syndrome. Some patient may also display proximal myopathy, cognitive impairment or short stature. The underlying cause is a genetic mitochondrial disorder. Patients rarely live beyond their 40s and there are no therapeutics currently available.
Maternally Inherited Diabetes and Deafness (MIDD)
Maternally inherited diabetes and deafness (MIDD)
MIDD is a mitochondrial disease most commonly caused by the m.3243A>G mutation. The classical features are of sensorineural hearing loss and diabetes but a number of other systems can also be involved. It affects up to 1% of all patients with diabetes.
A hallmark of any mitochondrial disease is the maternal inheritance of the condition.
The same m.3243A>G mutation causes the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like symptoms) highlighting the variable presentation of different patients with the same mutation.
Clinical features include: Diabetes Sensorineural hearing loss Stroke-like symptoms Retinal dystrophy Proximal myopathy Cardiomyopathy, arrhythmias End stage renal failure - most often FSGS pattern on biopsy Short stature, low BMI
Example Question:
A 45-year-old teacher is reviewed in a routine nephrology clinic. She has end stage renal failure with focal segmental glomerular sclerosis (FSGS) on biopsy and is receiving renal replacement via haemodialysis. She requires hearing aids for bilateral sensorineural hearing loss and is of short stature. She mentions that she has been feeling more tired and lethargic in the last few months. A fasting blood sugar taken by her GP is 8.0mmol/l. She has a family history of diabetes in her mother and maternal grandmother, both of whom also required hearing aids at an early age. Given the above features, what is the most likely cause of her end stage renal failure?
Autosomal dominant polycystic kidney disease Alport syndrome Liddle syndrome > Maternally inherited diabetes and deafness (MIDD) Granulomatosis with polyangiitis (Wegener granulomatosis)
Alport syndrome and GPA could also cause end stage renal failure and deafness. However, diabetes is not a feature of Alport syndrome and GPA is not a directly heritable disease.
ADPKD causes end stage renal failure with an autosomal dominant pattern of inheritance but would not explain the other features.
Liddle syndrome is a genetic cause of hypertension due to mutations in the epithelial sodium channel in the distal convoluted tubule.
MELAS - Example Question
A 32-year-old male presents with a sudden onset left sided weakness with new onset expressive dysphasia and dress apraxia. He has a seven year history of progressive cognitive impairment and seizures, lives in sheltered accommodation and was brought in after his relatives, who visit him on a weekly basis, noted a change from his baseline. The patient is a poor historian and could not remember the duration of symptoms. He reports a recent history of burning sensation when passing urine associated with increased frequency and reduced oral intake for the past four days. An MRI head demonstrates multiple areas of ischaemia within left and right cortex inconsistent with one single vascular territory. A urine dip is positive for leucocytes and nitrites, negative for ketones. A venous blood gas is taken:
pH 7.15 PaCO2 2.4 kPa Bicarbonate 6 mmol/l Lactate 18 mmol/l Anion gap 16 mmol/l
What is the unifying diagnosis?
> MELAS Diabetic ketoacidosis Ingestion of antifreeze Severe dehydration secondary to urosepsis Metformin induced lactic acidosis
Young patients with significant cognitive impairment should raise suspicion. This patient presents with a significant lactic acidosis, with low bicarbonate likely secondary to chronic neutralisation in the presence of systemic acidosis. Multiple ischaemic infarcts inconsistent with vascular territories are suspicious of a metabolic disorder within the brain parenchyma. In this case, a mitochondrial genetic condition, mitochondrial encephalopathy with lactic acidosis and stroke like episodes (MELAS), is most likely. Focal and generalised seizures are common for MELAS patients, as is early onset dementia, focal weakness and cortical blindness from multiple ischaemic stroke episodes. Symptoms normally present at late childhood and early adulthood, with patients develop normally until then. Diagnosis is made through lactic acidosis, a progressive neurological and dementing clinical course and muscle biopsy for ragged red fibres. The majority of patients have been linked to an underlying mutation in transfer RNA1.
In this case, the UTI is a red herring. While the patient may have a UTI, it does not produce a unifying diagnosis of cerebral and metabolic abnormalities. A normal anion gap rules out ingestion of inorganic acids or DKA. The patient is negative for urinary ketones. There is no suggestion he takes metformin.
- Montagna P, Gallassi R, Medori R, Govoni E, Zeviani M, Di Mauro S, Lugaresi E, Andermann F. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology. 1988;38(5):751
MERRF Syndrome
MERRF syndrome: myoclonus epilepsy with ragged-red fibres
= a mitochondrial DNA disorder diagnosed by ragged red fibres on muscle biopsy.
Presentation:
Cognitive impairment developing after a period of normal development, seizures, myoclonic jerks, Wolff-Parkinson White syndrome and worsening vision (consistent with optic atrophy).
Example:
A 14 year old boy presents his third generalised seizure over the past 72 hours, despite recently being started on sodium valproate by a neurologist for recurrent seizures 6 weeks ago, with worsening vision at night and hearing loss bilaterally. The patient has a number of myoclonic jerks as you arrive. On examination, his heart sounds are unremarkable but you notice a tachycardia at 140 and regular. The ECG shows WPW.
The patient is uncooperative to further neurological examination but you notice sluggishly reactive pupils of equal size. His mother reports that he has been educated in a special needs school for the past 5 years but had been attending the local primary school until aged 9, when he dropped further behind than his peers. Which investigation produces the underlying diagnosis?
