Mitochondrial disease Flashcards
mitochondrial disease incidence (inc subtypes)
prevalence of all forms of childhood-onset (<16 years of age) mitochondrial diseases has been estimated to range from 5 to 15 cases per 100,000 individuals
recessive mutations in POLG (encoding DNA polymerase subunit γ1, which is the catalytic subunit of mtDNA polymerase) are one of the most common causes of childhood-onset mitochondrial diseases in many countries, due to the spread of two ancient European founder mutations
most common childhood presentation of a mitochondrial disease is Leigh syndrome, which comprises >75 monogenic disorders
populations with high consanguinity often show an increased prevalence of inherited diseases, for example, autosomal recessive childhood-onset mitochondrial diseases in the Australian Lebanese and Irish travelling communities
mit DNA (and how many mit-related protein nuclear genes?)
encodes 13 structural peptide subunits of the oxidative phosphorylation system and 24 RNA molecules that are required for intra-mitochondrial protein synthesis
mtDNA has a circular structure and lacks an intron–exon structure. In addition, replication, transcription and translation of mtDNA are all controlled by a single non-coding region, known as the displacement loop
multiple copies of mtDNA exist within each cell and the total amount can vary between a few hundred and many tens of thousands of copies, depending on the cell type. Many patients with a mitochondrial disease have a mixture of mutated and wild-type mtDNA (known as heteroplasmy); the proportion of mutated and wild-type mtDNA is a key factor that determines whether a cell expresses a biochemical defect
over ∼1,500 different nuclear genes encode mitochondrial proteins
clinical features of mit diseases (age, diversity of presentation, 28 general sx)
onset of mitochondrial diseases has been shown to have a bimodal distribution with a peak in the first 3 years of life followed by a second broader peak beginning towards the end of teenage years and into the fourth decade of life (adult-onset diseases), although mitochondrial diseases can present much later
single organ involvement is possible but it is normally multisystem
some mtDNA mutations can give rise to several different clinical syndromes; reverse is also true in that specific syndromes can have a diverse genetic aetiology
general sx: retinitis pigmentosa, ptosis, optic atrophy, prog external opthalmoplegia, sensorineural hearing loss, epilepsy, ataxia, migraine, parkinsonism, developmental delay/regression, myopathy, peripheral neuropathy
non neuro sx: cardiomyopathy or conduction defects, resp failure, liver failure, fanconi syndrome or RTA, FSGS, CKD, adrenal insuff, diabetes mellitus, pancreatitis, GI dysmotility, short stature, bone marrow failure, cataracts, kyphoscoliosis
childhood onset mit diseases
generally severe, although not always fatal
Common, nonspecific clinical features can present in childhood-onset mitochondrial diseases, including hypotonia, generalized weakness, failure to thrive, dysautonomia, fatigue, exercise intolerance, vomiting, seizures and encephalopathy. Limb spasticity with axial hypotonia is typical of central nervous system involvement, but is not specific for mitochondrial diseases.
The pattern of hypomyelination and leukodystrophy observed on cranial MRI scans can help to distinguish, for example, mitochondrial diseases from other causes of white matter disease
Renal involvement in young children with mitochondrial diseases can occur due to several different genetic defects and can be a cystic disorder or proximal tubulopathy
Hypertrophic cardiomyopathy is much more frequently observed than dilated cardiomyopathy in patients with mitochondrial diseases
Sensorineural hearing loss can occur
Leigh syndrome
most common syndrome associated with childhood-onset mitochondrial disease
usually begins between 3 months and 2 years of age and can be caused by mutations in at least 75 different genes; can have rapid onset from birth
In most children, the first noticeable sign is the loss of previously acquired motor skills. When there is early onset (i.e., 3 months), loss of head control and poor sucking ability may be the first noticeable symptoms. This may be accompanied by a profound loss of appetite, recurrent vomiting, irritability, continuous crying and possible seizure activity. Delays in reaching developmental milestones may also occur. Affected infants may fail to grow and gain weight at the expected rate (failure to thrive)
If the onset of Leigh syndrome is later in childhood (e.g., 24 months), a child may experience difficulty articulating words (dysarthria) and coordinating voluntary movements such as walking or running (ataxia)
Progressive neurological deterioration associated with Leigh syndrome is marked by a variety of symptoms including generalized weakness, lack of muscle tone (hypotonia), clumsiness, tremors, muscle spasms (spasticity) that result in slow, stiff movements of the legs, and/or the absence of tendon reflexes
Episodes of lactic acidosis may occur
usually develop respiratory problems including the temporary cessation of spontaneous breathing (apnea), difficulty breathing (dyspnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns (Cheyne-Stokes). Some infants may also experience difficulty swallowing (dysphagia). Visual problems may include abnormally rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves of the eyes (optic atrophy)
asymmetric septal hypertrophy
most common treatment for Leigh syndrome is the administration of thiamine (Vitamin B1) or thiamine derivatives. Some people with this disorder may experience a temporary symptomatic improvement and a slight slowing of the progression of the disease. In those patients with Leigh syndrome who also have a deficiency of pyruvate dehydrogenase enzyme complex, a high fat, low carbohydrate diet may be recommended
alpers-huttenlocher syndrome
also a childhood-onset mitochondrial disease that is characterized by intractable epilepsy, psychomotor regression and liver disease
majority of cases are a consequence of mutations in POLG, whereas an Alpers-like syndrome has also been reported in individuals with mutations in genes encoding mitochondrial tRNA synthetase
almost universally fatal in childhood
MELAS syndrome
characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
80% of all cases of MELAS syndrome harbour an m.3243A>G mutation in MT-TL1
Children with MELAS often have normal early psychomotor development until the onset of symptoms between 2 and 10 years old. Though less common, infantile onset may occur and may present as failure to thrive, growth retardation and progressive deafness. Onset in older children typically presents as recurrent attacks of a migraine-like headache, anorexia, vomiting, and seizures
Most people with MELAS have a buildup of lactic acid
NARP syndrome
Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) is a progressive neurodegenerative disorder that often presents in early childhood, but might remain quiescent or stable into adult life, and forms a clinical continuum with maternally inherited Leigh syndrome
individuals with heteroplasmy levels of <70% of the m.8993T>G mutation are often asymptomatic, those with heteroplasmy levels of 70–90% manifest clinically with a NARP phenotype, whereas those with heteroplasmy levels of >90% manifest clinically as Leigh syndrome
general diagnostic algorithm for mit disease
In young children with common phenotypes, targeted gene sequencing for the commonly affected genes in both nDNA and mtDNA that cause the phenotype is both sensible and efficient
If no diagnosis is made, then either further genetic studies, including exome sequencing to detect nDNA mutations, or the testing of clinically relevant or affected tissue should be performed. Performing exome sequencing might avoid the need for an invasive skeletal muscle biopsy, but some cases will still require biopsy for biochemical confirmation of the consequences of mutations of unknown importance. Skeletal muscle biopsy can be extremely helpful and can be used for histochemical and biochemical analysis
further genetic investigations will involve sequencing of specific genes, analysis of a panel of genes (for example, complex I gene panel), exome sequencing or whole-genome sequencing. A skin biopsy to isolate fibroblasts should be considered when taking a muscle sample. Cultured skin fibroblasts can sometimes recapitulate the deficiency in oxidative phosphorylation identified in skeletal muscle and can be a vital resource in assigning pathogenicity to new mutations. Once a diagnosis has been established in an index case, testing of relatives might proceed (with consent) in a much less invasive manner using buccal, urine and blood DNA samples
mit disease biomarkers
mostly metabolic intermediates, specific enzymes or the end products of anaerobic glucose metabolism, resulting from impairment of oxidative phosphorylation
these include lactate, pyruvate, creatine kinase, alanine, thymidine and deoxyuridine, acylcarnitines and organic acids. In practice, these biomarkers are often not mitochondrial disease-specific, exhibit poor sensitivity and specificity, and the interpretation is not always straightforward
general mx of mitochondrial disease
Dietary supplements that are frequently used by patients with mitochondrial diseases include antioxidants (inc vit C/E), agents to modulate mitochondrial electron transfer flux (such as vitamin B2 (also known as riboflavin), nitric acid precursors (such as L-arginine and L-citrulline), energy buffers (such as creatine), drugs involved in fatty acid uptake (such as L-carnitine) and mitochondrial biogenesis (such as vitamin B3)
organ-specific guidelines are important in the daily care of patients, including advice on the management of diabetes, ptosis, stroke-like episodes and cardiac, respiratory, gastrointestinal and renal involvement. Other advice to guide clinical decision making in patients with mitochondrial diseases and other health issues that can affect their underlying mitochondrial disease (such as pregnancy, anaesthesia, surgery and vaccination) are now increasingly recognized as paramount
seizures can be managed with AEDs but valproate is not recommended, because mitochondrial dysfunction is a risk factor for valproate-induced liver failure; Nasogastric tube or gastrostomy tube feedings are ways to treat the feeding difficulties and failure to thrive.
Chest physiotherapy, artificial ventilation, tracheostomy or ventilators can be used to treat respiratory insufficiency. Other treatments include the surgical treatment of scoliosis, kyphosis, or ptosis and cochlear implantation in the cases of hearing loss
special diets eg continuous feeding to prevent hypoglyc or ketogenic diet to stimulate beta-oxidation
Supplementation with key compounds of the ETC is a widely used treatment for
MDDS
POLG mutations
encodes the catalytic subunit of
DNA polymerase gamma, the enzyme responsible for mitochondrial DNA replication and repair
majority of patients have relatively diffuse
clinical features with hypotonia, developmental delay, failure to thrive, and seizures. These nonspecific clinical features overlap with the manifestations of other mitochondrial disorders presenting during early childhood
associated with a wide range of overlapping clinical phenotypes, including (i) Alpers syndrome; (ii) myocerebrohepatopathy spectrum (MCHS); (iii) myoclonic epilepsy, myopathy, sensory ataxia—including disorders previously described as spinocerebellar ataxia with epilepsy; (iv) ataxia neuropathy spectrum, including phenotypes previously described as sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia
and mitochondrial recessive ataxia syndrome; (v) autosomal dominant progressive external ophthalmoplegia; and (vi) autosomal recessive progressive external ophthalmoplegia
Diagnostic criteria for MCHS include absence of hepatic histopathological features of classical Alpers and at least two
of the following: neuropathy; seizures; elevated blood or cerebrospinal fluid lactate; dicarboxylic aciduria; renal tubular
dysfunction with aminoaciduria, glycosuria, or bicarbonaturia; hearing loss; abnormal magnetic resonance image (MRI), with either cerebral volume loss, delayed myelination,
or white matter disease; and either isolated deficiency of complex IV (cytochrome c oxidase) or a combined defect of
two or more oxidative phosphorylation complexes in skeletal muscle or liver biopsy
mitochondrial DNA depletion syndromes
some mitochondrial diseases caused
by mutations in nuclear genes affect proteins needed for mtDNA replication and maintenance. When the proteins encoded by these genes do not work properly, dysfunctional mtDNA replication results in quantitative alterations (reduction in mtDNA copy number, i.e., mtDNA depletion) and/or qualitative alterations (multiple deletions in mtDNA and, in some cases, point mutations). For this reason, this specific group of disorders is known as mitochondrial DNA depletion and multiple deletions syndromes (MDDS)
genes linked to MDDS inc POLG, POLG2, TWNK, TFAM, thymidine phosphorylase, thymidine kinase 2, deoxyguanosine kinase (DGUOK) and many more
nucleoside metabolism for mit
two anabolic pathways to obtain dNTPs in cells: the de novo pathway that is
fully active in dividing cells only, and the salvage pathway that recycles deoxyribonucleosides from endogenous turnover and from the diet and takes place in both dividing and non-dividing cells. In addition, catabolism (consecutive dNTP dephosphorylation and further
degradation of the resulting deoxyribonucleosides) also contributes to dNTP homeostasis; all 3 areas can be mutated in mito diseases
salvage pathway first phosphorylation (from dN to dNMP) is the rate-limiting
step; in the cytosol, it is catalysed by thymidine kinase 1 (TK1), which phosphorylates thymidine, dThd (and also deoxyuridine, dUrd), and deoxycytidine kinase (dCK) that phosphorylates deoxycytidine (dCtd), deoxyadenosine (dAdo) and deoxyguanosine (dGuo).
The equivalent enzymes in mitochondria are thymidine kinase 2 (TK2), which phosphorylates the pyrimidine dNs (dThd, dCtd and dUrd), and deoxyguanosine kinase (dGK), which phosphorylates the purine dNs (dAdo and dGuo). dNMPs produced in these first steps are further phosphorylated by nucleoside monophosphate kinases (NMPKs) and nucleoside diphosphate kinases (NDPKs), before finally obtaining dNTPs; thus mutations in TK2 and DGUOK (encoding TK2 and dGK) are associated with severe
MDDS
