46040ourmal ofNeurology, Neurosurgery, and Psychiatry 1995;59:460-470 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from NEUROLOGICAL INVESTIGATIONS Diagnosis of inherited metabolic disorders affecting the nervous system Phillip D Swanson The number of metabolic disorders that can dominant neurodegenerative diseases. The produce neurological symptoms is daunting. pace of new discoveries in medical genetics is The clinician cannot simply send off to the incredibly rapid. Many of the new discoveries laboratory a blood sample and ask for a meta- have led to diagnostic methods that were bolic "screen" that will detect a hypothetical unanticipated only a few years ago. metabolic abnormality. The range of possible Certain terms used by medical geneticists conditions must be narrowed to the most should be familiar to neurological practition- likely before deciding which investigative ers. Anticipation refers to a disease beginning approach should be taken. Most biochemical earlier and often being more severe in disorders encountered by neurologists are succeeding generations. In some autosomal genetically determined. Thus one of the most dominant disorders, such as myotonic important elements of the history is the family dystrophy and spinocerebellar ataxia 1, this history. It is not sufficient to ask "has anyone phenomenon seems to be related to the in your family had a neurological problem?". length of an expanded trinucleotide repeat in The clinician must be aware of the different the abnormal gene.4 Penetrance refers to the forms of inheritance patterns (autosomal proportion of subjects with the abnormal dominant, autosomal recessive, X linked, gene who will develop symptoms if they live mitochondrial) and must obtain enough long enough. The degree of expression of a information to construct a meaningful family genetic disease refers to the variation of sever- tree. Directed questions must be asked about ity of the phenotype that is seen in a patient siblings as well as parents, grandparents, population. Mosaicism refers to variation uncles, aunts, cousins, and children. Table 1 among different cells and tissues in the chro- lists features that characterise single gene mosome complement. This occurs normally inheritance patterns.1'3 in women due to lyonisation, in which one of Most of the clear cut genetic diseases are each cell's two X chromosomes is randomly due to single gene abnormalities.There are inactivated. Mitochondrial disorders (see http://jnnp.bmj.com/ several different mechanisms, however, that later) are associated with heteroplasmy, a term produce abnormal genes. A point mutation of that refers to variation in the proportion of a single DNA nucleotide can result in a normal or genetically abnormal mitochondria different amino acid being coded for in the in different tissues. resulting polypeptide or protein. There can In autosomal dominant disorders, multiple Department of be deletion of a segment of a gene or insertion generations are usually affected, although this Box one Neurology, of or more nucleotides. Duplication of a might not have occurred if the affected on September 27, 2021 by guest. Protected copyright. 356427, University of gene has been reported in Charcot-Marie- Washington School of patient represents a new mutation. Male to Medicine, Seattle, WA Tooth disease type IA. Unstable expansions male transmission only occurs with au'toso- 98195, USA of portions of a gene (trinucleotide repeats) mal dominant transmission. Each child of an P D Swanson are being increasingly found in autosomal affected parent will have a 50% chance of having or not having the abnormal gene. Autosomal recessive disorders occur when Table 1 Some characteristics ofsingle gene inheritance expression of the disease requires the abnor- Type ofinheritance Charactenrstics mal gene to be inherited from both parents, so Autosomal dominant Multiple generations affected that the affected person's cells have two Father to son transmission (rules out X linked and abnormal alleles. Many autosomal recessive mitochondrial inheritance patterns) Males and females equally affected disorders are associated with defective Autosomal recessive Only siblings affected enzymes. The low level of enzyme activity Parental consanguinity common often leads to accumulation of the enzyme Males and females equally affected substrate with resultant toxicity to susceptible X Linked Never father to son transmission Transmission through unaffected mothers cells. The carrier parents seldom manifest Only males affected (rare exceptions) symptoms because the normal gene codes 50% risk to sons of carrier women All daughters of affected men are carriers for normal enzyme that is active enough to Mitochondrial Maternally inherited prevent substrate accumulation. Consan- Never father to child transmission guineous marriages between cousins are more Both sons and daughters can be affected common in families with autosomal recessive Adapted from table 9-1.3 diseases. Diagnosis ofinherited metabolic disorders affecting the nervous system 461 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from X Linked disorders are due to abnormal encountered by neurologists. The second genes located on the X chromosome. Clinical section contains a discussion of differential disease characteristically occurs in males who diagnoses of metabolic conditions that might have inherited the abnormal gene from a produce particular complexes of neurological carrier mother. Occasionally the mother or symptoms, including mental retardation, daughter with one normal and one abnormal dementia, ataxias, motor neuron disease, gene will manifest symptoms, which almost movement disorders, and stroke. always are milder than in the affected son or father, who has only one X chromosome. Male to male transmission cannot occur Categories of metabolic disorders because a son receives the X chromosome AMINOACIDURIAS AND ORGANIC ACIDAEMIAS from his mother. These are the classic disorders of infancy and Mitochondrial disorders are due to abnor- childhood associated with mental retardation malities in genes (deletions, point mutations) and seizures. The aminoacidurias include located in mitochondrial DNA. Both male phenylketonuria, maple syrup urine disease, and female mitochondria are derived from the homocystinuria, and other disorders listed in ovum rather than the sperm. Both males and table 2.5 Screening the urine for amino acids females can be affected by mitochondrial is routinely done in clinical chemistry labora- disorders, but father to child transmission tories. Although it would be very unusual for does not occur. Because tissues and cells vary first symptoms to occur in adult life, patients in the proportion of normal and abnormal with treated phenylketonuria eventually will mitochondria they carry (heteroplasmy), the be seen as adults by neurologists. expression of the disorder in different tissues Organic acidaemias, including methyl- and in different subjects can be extremely malonic acidaemia and propionic acidaemia, variable. usually have their onset in infancy. Symptoms This contribution will not include much of dehydration are associated with ketoacido- discussion of diseases that primarily affect sis, hypoglycaemia, and hyperammonaemia. muscle or nerve, as these have been the Diagnosis is made by urinalysis for organic subjects of previous articles in this series. acids, and can be confirmed by measuring Some metabolic conditions, however, includ- activity of the abnormal enzyme in cultured ing metachromatic leukodystrophy and fibroblasts. certain mitochondrial disorders that affect These disorders are becoming better both central and peripheral structures, will be understood since the advent of modem mole- included. Non-genetic metabolic conditions cular investigative techniques. For example, it such as hypoglycaemia, hepatic encephalo- is now known that there are three genes pathy, deficiency diseases, and electrolyte located on three different chromosomes (1, 6, disorders will not be discussed. Emphasis will 19) that code for the structural proteins be on conditions that are seen in adults by unique to the deficient enzyme (branched neurologists but many of these disorders will chain ketoacid dehydrogenase complex be variants of diseases that usually have their [BCKAD]) in maple syrup urine disease. first manifestations in infancy or childhood. Mutations in different components of the The first section contains brief discussions of complex can lead to variable clinical mani- categories of metabolic disease likely to be festations.6 http://jnnp.bmj.com/ Table 2 Aminoacidurias and organic acidaemias Disease Clinicalfeatures Increased substances Enzymne defect Phenylketonuria Mental retardation Phenylalanine Phenylalanine Phenylpyruvic acid hydroxylase on September 27, 2021 by guest. Protected copyright. Maple syrup urine disease Ketoacidosis Branched chain aminoacids Branched chain ketoacid Infantile seizures (leucine, isoleucine, valine) dehydrogenase complex Characteristic odour (urine: branched chain Progressive encephalopathy ketoacids) Milder variants Homocystinuria Ectopia lentis, stroke Homocystine Cystathionine,B-Synthase Non-ketotic Coma, progressive Glycine Glycine clearance system hyperglycinaemia encephalopathy (4 proteins) Methylmalonic acidaemia Ketoacidosis Methylmalonic acid Methyl-malonyl CoA mutase Hyperammonaemia Propionic acidaemia Ketoacidosis 3-hydroxypropionic