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Investigation of Mitochondrial Disease on September 23, 2021 by Guest 94 Hutchison Commentary poor communication - yours'). The weaknesses of this Health care professionals, for long accustomed to thinking 'social model' of disability are all too obvious to the parent Arch Dis Child: first published as 10.1136/adc.73.2.94-a on 1 August 1995. Downloaded from in terms of pathological entities rather than functional or carer whose life is devoted to providing the total care significance, have had difficulty in grasping the full impli- needed by their profoundly multiply disabled adult off- cations of the distinctions between impairment, disability spring. Hutchison is right to try and bridge the gap and handicap, as defined by the WHO. Even now, nearly between these differing perspectives. 20 years after this classification was introduced, the terms Secondly, better classification, definition, and registra- are still frequently misused. It could be argued that we tion of impairments would have many scientific and should aim for better understanding and more appropriate practical benefits. Although the terminology used in the usage of the existing terms, rather than redefining them; OPCS survey probably came closer to the ideal than any but there are several reasons why change is needed. other attempt so far, its application in routine service has Firstly, the international disability movements have proved difficult. Ways ofmeasuring quality oflife would be generally rejected the WHO definitions in favour of two helpful2 and might make registration more acceptable. At basic concepts related to the social model of disability: present, some people actively avoid being registered, 'impairment' meaning the loss or abnormality plus the because they do not feel disabled and do not wish to be effect on function; and 'disability/handicap', the dis- defined as such - whatever the professionals might think. advantage or restriction of activity caused by social factors Thirdly, a change in terminology might facilitate provi- which take little or no account of people who have impair- sion of services for people with disabilities, without having ments and thus exclude them from the mainstream ofsocial to apply the dreadful 1948 definitions of disability. The activities.' This simpler classification has the additional dilemma is a real one. A person has an impairment which, advantage of being easier to translate for non-English without equipment and resources for better living condi- speakers, as few other languages recognise the subtle dis- tions, will render him disabled. In order to minimise his tinction between disability and handicap. Furthermore, we disability, he must first submit to being classified as should refer to 'disabled people', not to 'the disabled', or disabled. Surely we can do better than this. 'the handicapped'. The latter terms are offensive because We should accept the challenge to re-think our attitudes they classify people on the basis of a single characteristic and our terminology, but we must learn the lessons of the and do not acknowledge their individuality. past 20 years and make sure the new terms are acceptable Is this another example of 'political correctness'? and understandable. Change must be driven by the real Perhaps - but being PC is no bad thing. By adopting PC needs of disabled people. Complex human problems must terminology we not only acknowledge that there may be not be forced into the crude and often arbitrary categories some justification for the new terms, we also help to bring demanded by our still primitive computer software. about change. Phrases which our generation regards as D M B HALL 'PC' and uses tongue in cheek could become the accepted Department ofPaediatrics, language and attitude of the next generation. Sheffield Children's Hospital, Articulate people with physical disabilities rightly point Sheffield SJ0 2TH out that they are disadvantaged by the attitudes of society 1 Coleridge P. Disability, liberation and development. Oxford: Oxfam more than by their loss of function - a view elegantly Publications, 1993: 100-1. 2 Lindstr6m B. Quality of life for children and disabled children based on presented in the advertising campaigns of the Spastics health as a resource concept. J Epidemiol Community Health 1994; 48: http://adc.bmj.com/ Society, now known as Scope ('our biggest handicap is 529-30. Investigation of mitochondrial disease on September 23, 2021 by guest. Protected copyright. Mitochondrial diseases are now recognised as a significant Which patients warrant investigation? group of neurometabolic disorders in childhood' and may Patients may present with a recognised clinical syndrome be caused by mutations in mitochondrial DNA (mtDNA). or a suggestive constellation of symptoms. Mitochondrial The major energy generating reactions in a cell are con- studies are clearly indicated in patients with Leber's centrated in the mitochondrion where the pathways of hereditary optic neuropathy (LHON) (in which patients carbohydrate, fatty acid, and amino acid oxidation con- present in adolescence with acute loss of vision),24 verge and feed into the tricarboxylic acid cycle and thence Keams-Sayre syndrome (in which patients present the electron transport chain. This review will use the term with proximal myopathy, chronic progressive external 'mitochondrial disorder' to refer to diseases of the electron ophthalmoplegia, and retinopathy), mitochondrial transport chain and associated central pathways, many of encephalomyopathy, lactic acidosis and stroke-like which are associated with lactic acidosis and/or caused by episodes (MELAS)5 6 and myoclonic epilepsy and ragged mtDNA mutations. red fibres (MERRF)7 (table 2). Because mtDNA diseases Diagnosis of mitochondrial diseases is frequently diffi- cult because of the wide variety of clinical presentations Table 1 Mode ofinheritance ofmtDNA disease which are possible particularly in the paediatric age range. While there have been major advances in recent years, a 1. Sporadic Major rearrangements (Kearns-Sayre syndrome, CPEO, Pearson's) molecular diagnosis is considerably less likely in paediatric 2. Mitochondrial Point mutations (MELAS, MERRF, NARP, than in adult practice. In this review we will first discuss LHON, aminoglycoside induced deafness) Familial duplications the general investigation of these patients. We will then 3. Autosomal dominant Variable deletions introduce the basic biology of mtDNA in order to classify 4. Autosomal recessive Depletion Chaperonin deficiency mtDNA diseases by mode of inheritance (table 1) and the 5. X linked ?Susceptibility in LHON specific investigation of some of the commoner clinical syndromes (table 2). CPEO=chronic progressive external ophthalmoplegia. Investigation ofmitochondrial disease 95 may mimic so many unrelated disorders, the pickup rate is complex array of multimeric proteins are encoded in the much lower in patients with multisystem disease. nucleus and have to be imported into the mitochondrion, Suggestive features include primary lactic acidosis, muscle as are many other essential mitochondrial proteins (such as Arch Dis Child: first published as 10.1136/adc.73.2.94-a on 1 August 1995. Downloaded from weakness particularly with progressive external ophthal- chaperonins for protein assembly). Thus while mtDNA moplegia and cytochrome oxidase deficiency, cardiomy- diseases might be maternally inherited, they can also have opathy, etc, as in table 3. a mendelian pattern ofinheritance or be sporadic. mtDNA A raised blood lactate concentration may be due to poor also has genes for 22 transfer RNAs and two ribosomal sampling or be secondary to a wide variety of conditions RNAs because the mitochondrion has its own genetic code including hypoperfusion, liver dysfunction, sepsis, and and protein assembly system. Unlike nuclear DNA where other genetic metabolic diseases.8 Lactic acidaemia is there are usually only two copies of each gene per cell, present as a primary biochemical abnormality in patients mtDNA is a multicopy gene. In normal individuals all of with defects in pyruvate metabolism, the tricarboxylic acid the thousands of mtDNAs are identical (that is homo- cycle, gluconeogenesis, and glycogen metabolism. A plasmy). In disease, there may be more than one distinct normal blood lactate does not exclude a mitochondrial dis- population of mtDNA in each cell (heteroplasmy), one order, and some patients have episodes of severe lactic aci- being normal and the other(s) mutant. The proportion of dosis punctuated by periods when blood lactate is within mutant mtDNA in any cell or tissue may vary from the normal range.8 A raised cerebrospinal fluid lactate is a 0-100% and this may change with timeI0 11 and have pro- more sensitive and specific finding, but even this is not found effects on respiratory function. always helpful in the early stages of MELAS or Leigh's Heteroplasmy probably explains some of the variation syndrome. Furthermore, cerebrospinal fluid lactate may in phenotype found in patients with the same mutation remain above the normal range for several days after an and makes it essential to choose an appropriate tissue episode of meningitis or prolonged seizures. such as muscle for mtDNA analysis (table 4). Varying Muscle biopsy is extremely helpful in many mito- levels of heteroplasmy may also make antenatal diagnosis chondrial disorders as both cytochrome oxidase deficiency difficult. and ragged red fibres are commonly seen. However, a normal biopsy is the rule in conditions such as LHON where there are no clinical features of muscle disease. Specific
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