Mitochondrial Disease

Mitochondria

• Produce energy

• Support growth and functioning

• Store calcium for cell signalling

• Mediate cell growth and death

Dysfunction causes

• Cell deprived of ATP

• Cell accumulates energy precursors and oxygen

• Mechanism ineffective and produces lactic acid and reactive oxygen species

Mitochondria DNA variation

• 1 in 200 to 250 people

Case studies

• John 26

  • Clear vision loss and mild dystonia

  • Leber Hereditary Optic Neuropathy (LHON)

• Stacy 33

  • Bilateral ptosis and impaired eye movements

  • Chronic Progressive External Ophthalmoplegia (CPEO)

• Shelby 13

  • Hearing impairment

  • Kearns-Sayre Syndrome (KSS)

• Milo 18/12

  • Difficulty walking, balance, coordination and speech

  • Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)

• Beth 47

  • Migraines and tripping over with loss of balance

  • Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS)

• Dad 19

  • Epilepsy diagnosis

  • Myoclonic Epilepsy and Ragged-Red Fibres (MERRF)

When to consider

• Common disease with atypical features

• Three or more systems involved and/or red flags

Organ systems

• Brain and Nerves - Developmental delay, intellectual disability/regression, stroke-like episodes, seizures, coma, neuro-psychiatric disturbances, atypical cerebal palsy, myoclonus, movement disorders, ataxia, migraines, strokes, weakness (which may be intermittent), neuropathy, absent or excessive sweating resulting from temperature regulation problems, dementia.

• Eyes - Visual loss/blindness, optic atrophy disorders of extra-ocular muscles, ptosis, retinal degeneration with signs of night blindness, colour vision deficits, pigmentary retinal changes such as retinitis pigmentosa, or 'salt and pepper' retinopahy

• Ears - Aminoglycoside-induced hearing loss.

• Heart - Conduction defects (e.g. heart blocks, WPW), cardiomyopathy.

• Liver - Hypoglycaemia, unexplained liver failure, valproate-induced liver failure.

• Pancreas - Diabetes and exocrine pancreatic failure (inability to make digestive enzymes).

• Digestive - Gastro-oesophageal reflux, delayed gastric emptying, constipation, pseudo-obstruction, chronic or recurrent vomiting.

• Kidneys - Proximal renal tubular wasting causing the loss of protein, magnesium, phosphorous, calcium and other electrolytes, aminoaciduria, nephrotic syndrome, renal failure.

• Muscles - Weakness, hypotonia, cramping, muscle pain, recurrent rhabdomyolysis.

• Systemic - Whole body - Exercise intolerance which is not proportional to weakness, fatigue, short stature, respiratory problems including dyspnoea, hypersensitive to general anaesthetics.

• Skin - Symmetrical lipomatosis.

• Blood - Sideroblastic anaemia.

Red Flags

• Seizure

• Coma

• Ptosis

• Salt and pepper retinopathy

• Aminoglycoside-induced hearing loss.

• Diabetes

MELAS

• Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes

• 2 years and 20 years

• Lactic acidosis, stroke like episodes with seizures, dementia, muscle weakness, SNHL, blindness, migraines, myopathy, cardiomyopathy, diabetes, ataxia, short stature

• Maternal inheritance

MERRF

• Myoclonic Epilepsy and Ragged-Red Fibres (MERRF)

• Usually late adolescence to adulthood

• Stimulus sensitive myoclonus, seizures, cardiomyopathy, SNHL, ataxis, dementia, weakness, short stature

• Maternal inheritance

KSS

• Kearns-Sayre Syndrome (KSS)

• Before age 20

• Progressive external ophthalmoplegia, ptosis, pigmentary retinopathy, heart block, cardiomyopathy, SNHL, ataxia, dementia, DM, other endo abnormalities

• Sporadic inheritance

MILS

• Maternally inherited leigh syndrome subacute necrotising encephalomyopathy

• Infancy

• Motor and intellectual regression with ataxia, dystonia, seizures, visual loss and cardiomyopathy

• Maternal or nuclear

NARP

• Neurogenic weakness with Ataxia and Retinitis Pigmentosa

• Infancy or childhood

• Impaired eye movements with ptosis and msucle weakness

• Maternal or nuclear

CPEO

• Chronic Progressive External Ophthalmoplegia

• Any age but more severe with younger onset

• Impaired eye movements with ptosis and muscle weakness

• Maternal or Nuclear

LHON

• Leber Hereditary Optic Neuropathy

• More predominance, medial age of onset is 24 years

• Bilateral vision loss and sometimes pre-excitation cardiac syndrome and dystonia

• Maternal inheritance

Testing

• Challenging as symptoms vary

• Australian Medicare funds genetic testing from November 2023

• However even when genetic testing is negative - this does not rule out mitochondrial disease

Diagnosis

• Early diagnosis is key

• Suspect

• History

• Exam

• Consider specific syndromes

• Imaging and testing

• Biomarker testing FGF21 + GDF15

• Genetic referral

• Genetic testing

• Muscle biopsy if unclear

History

• Thorough history of patient and family members (this can sometimes help you identify an inheritance pattern by noting ‘soft signs’ in unaffected relatives, such as deafness, diabetes, short stature, migraines, and PEO)

Exam

Neurological tests, including muscle power, reflexes, vision, hearing and speech assessments

• Developmental and cognitive assessment

• Tests of strength and endurance

• Mood and anxiety screen

• Growth and anthropometric parameters

Investigations

Depending on the individual presentation, request:

• Hearing tests to detect sensorineural hearing loss

• ECG/Holter/Echo to detect any cardiac abnormalities

• Renal dysfunction tests: blood pressure, comprehensive metabolic panel with magnesium and phosphate, albumin/creatine, urine

• Endocrinology screen: including gonadotropins, parathyroid hormone, thyroid-stimulating hormone, free thyroxine

• Blood biochemistry: FBC with differential, calcium, magnesium, phosphate, vitamin D, transaminases, liver dysfunction, glucose (including HbA1C), vitamin B12, blood film; quantitative immunoglobulin levels, vaccine-specific immunoglobulin G (IgG) titres and lymphocyte subset level

• GI transit studies: to detect gut dysmotility, reflux and/or cyclical vomiting

• Electrophysiology studies (e.g., EEG, NCS, EMG) to monitor or detect seizure activity

• Ophthalmological examination: to detect ptosis, eye muscle dysfunction, retinal changes of degeneration, pigmentation abnormalities, visual acuity, visual fields, and optic atrophy

• Respiratory studies: muscle weakness and additional comorbidities including obstructive sleep apnoea, bulbar weakness, risks for aspiration, gastroesophageal reflux, asthma and chronic obstructive pulmonary disease

• Serum creatine kinase: may be slightly elevated in mitochondrial disease but usually only high in cases of mitochondrial DNA depletion

• Allied health team assessments (occupational therapist, speech pathologist, physiotherapist): to identify abnormalities and establish baselines for future reviews

Referral

• When suspicious and initially testing is complete up until FGF21 + GDF15

Standard of Care for GPs

• Recommendations for what tests to do for suspected or proven mitochondrial disease by body system

• Patient Care Standards for Primary Mitochondrial Disease in Australia - Mito Society Recommendations

Resources

• Mitochondrial Disease Guide for Health Professionals - Mito Foundation

• Maybe it’s Mito - Arterial Education CPD for GPs

• Mito Foundation - Newly Diagnosed

• Mito Foundation - Registry

• Mito Foundation For Health Professionals

• Mito Foundation Facebook - https://www.facebook.com/groups/44299119727/