Mitochondrial Disorders

Clinical features of mitochondrial disease: High lactate concentrations Multisystem disease – organs with high energy needs most affected e.g. heart, kidneys Progressive myopathy or neurological disease Typical feature is: Progressive external ophthalmoplegia (weakness of the eye muscles – ptosis and reduced eye movement) mtDNA genetics: mtDNA encodes subunits of the respiratory chain It is maternally inherited A mutation can exist in all the mtDNA (homoplasmy) or some (heteroplasmy) Most pathogenic mutations are heteroplasmic For heteroplasmic mutations, pathogenic when proportion of mutated DNA reaches a threshold (e.g. 70%) Above the threshold, the higher the level of mutation, the more severe the phenotype Level of mutation can vary in different tissues (generally lower in blood)   How to tell if the mtDNA mutation is pathogenic: Previous reports Conservation in evolution Homoplasmy (most are benign polymorphisms) vs Heteroplasmy Segregation with clinical problems   Inheritance: Can be sporadic most are maternally inherited mtDNA Can be recessive or X-linked Level of mutation can vary from mother to child - rapid segregation (mtDNA bottleneck when forming oocytes) Options for pregnancy: Prenatal testing (can be complicated – is it over the threshold? Also, the mutational load may not be the same in all tissues) PGD Pronuclear transfer (in development)  

Clinical features:Typically childhood onset Myopathy Encephalopathy Lactic Acidosis Stroke-like episodes Migraine Diabetes Deafness Cardiomyopathy     Inheritance:mitochondrial (maternal) - woman transmits to all her offspringor could be de novo somatic mitochondrial mutation

Leigh Syndrome Usual onset by age 2 years Clinical features: Failure to thrive Hypotonia Difficulty swallowing Abnormal breathing pattern Eye movement disorder Dystonia Children tend to show improvements in development and then quickly decline again, losing abilities Inheritance Mitochondrial inheritance Mother usually has lower mutational load so may not get symptoms, however, some mothers do get symptoms later in life

general

melas

leigh syndrome