Traditionally, this chapter of pediatrics has been unpopular with practicing pediatricians, and understandably so when it consisted of a catalogue of rare diseases with barbaric eponyms about which very little was known and which defied rational classification. Furthermore, these diseases could be expected to progress relentlessly and to kill the child after a usually prolonged period of total and degrading regression in all aspects of behavior, during which physician and parents could only stand by helplessly and try to deal with their own feelings of pity, impotence, guilt, and anger.
Much has been learned recently about these diseases, since many have become the focus of intensive research with the combined tools of electron microscopy, histochemistry, neurochemistry, enzymology, tissue culture, and genetics. For large groups of these disorders, new chemical and enzymologic knowledge has provided a rational classification that has brought with it a much better understanding of pathogenesis and the relationships between syndromes.
For some of them - Wilson's disease, for instance - chemical understanding has already provided rational and effective therapy. For others, the possibility of therapy with enzyme replacement (e.g., kidney grafts for Fabry's disease) is being explored actively and may become more than a dream in the decades ahead. Intrauterine diagnosis is a reality, and many parents can now be assured of having healthy children. This article will focus particularly on new developments that have dissipated some of the hopelessness and substituted a requirement for genetic understanding on the part of the pediatrician, who must be equipped to provide genetic counseling. He must protect patient and family from unnecessary investigation, from illadvised, redundant consultation, and from useless and exploitative treatments. He must supply careful long-term management in order to avoid some of the complications of these illnesses, which add unnecessarily to the child's handicaps. Finally, to minimize the devastating impact of such an illness on the entire family, he must provide counseling, education, and emotional support to the child's parents and siblings. As pointed out by Thomas,2 when basic science has not yet provided a magic bullet that can prevent or cure a disease with a simple therapy (such as polio vaccine, or penicillin for streptococcal infections), the art of medicine is paramount. There is no field of pediatrics where this is more true than the progressive geneticmetabolic diseases of the nervous system in children. These diseases challenge the pediatrician to practice his art with ultimate skill and compassion, providing him an opportunity for human and professional satisfaction that he would miss in a practice concerned primarily with acute disorders of childhood and well-baby care.
TIME OF ONSET AND EFFECTS ON COGNITIVE FUNCTION
In general, diseases that start early in life and profoundly affect neuronal metabolism preclude normal cell function and prevent or retard myelination or the extensive development of dendrites and synapses that takes place postnatally. Ultimately, many result in cell death and severe depletion of neuronal populations. Such diffuse disorders may result in a total lack of behavioral development or profound mental retardation (Table 1). Dysfunction of particular cell groups will be reflected by cortical blindness, spasncity, movement disorders, or seizures.
If the disorder is less profound, affecting metabolic processes that are occurring at a slower rate or systems whose function is not reflected behaviorally for some time postnatally (e.g., cerebellar neurons), signs of neuronal dysfunction may be delayed or even inapparent for a long time. One of the difficult tasks the clinician encounters is to decide whether a child who is making developmental progress, but at a slow pace, is suffering from a static encephalopathy or from a progressive disease whose rate of interference with brain function is slower than the normal rate of development (Figure 1). In the latter case, the child acquires new milestones even while his brain is degenerating. The clinical situation is complicated further by the fact that normal development often occurs in fits and starts, with some periods when no new milestones seem to be achieved and others when new accomplishments are noted daily. The pediatrician may require repeated developmental assessment and careful questioning of the mother before he can be sure that a prolonged plateau in fact reflects regression or, even more difficult, that development is proceeding, but so slowly as to leave the child further and further behind the normal curve of development ("progressive mental retardation"). The situation is much clearer when the disease process becomes apparent in childhood and the dementia is readily evident.
GENETIC-METABOLIC DISEASES CAUSING SEVERE OR PROFOUND DEMENTIA
Figure 1. Theoretical curves to show the possible effects of progressive brain dysfunction on behavior, depending on time of onset and rapidity of its course (A-F). The curve depicting observed behavior solid line with open circles ○-○-○-○-) is the result of the difference between the curves indicating expected development (-) and brain function ([black circle]-[black circle]-[black circle]-[black circle]-). A: Prenatal onset, with damage at birth so advanced that no development is observed, suggesting a severe static encephalopathy. B: Prenatal onset, with damage at birth somewhat less severe. Development is minimal and markedly delayed but does appear to be taking place initially. C and D: Onset at birth, with a less acute course. E: Onset in adulthood. Note that in B, C, and D, loss of milestones (R) may not appear until months or years after the onset of the illness, which will therefore not appear progressive unless it is realized that deceleration of development or developmental standstill implies deteriorating function. When a progressive disease starts after adolescence (E), loss of function should be less delayed and the disease recognized as progressive virtually from its start. A severe static lesion acquired postnatally (G) may produce total regression acutely, but development may be expected to resume until the time of puberty. (Reproduced with permission from Rapin, I. In Rudolph, A. M. [ed.]. Pediatrics, 16th Edition. New York: Appleton-Century-Crofts. [In press.])
DISEASES PRODUCING A HEARING LOSS
DISEASES ASSOCIATED WITH ORGANOMEGALY
DISEASES ASSOCIATED WITH CHANGES IN THE SKIN AND HAIR
Some disorders cause little or no intellectual impairment - for instance, many of the mucopolysaccharidoses (types I- Scheie, II- Hunter [mild variant], IV-Morquio, VIMaroteaux-Lamy, and VII), some of the juvenile sphingolipidoses (Fabry's disease, juvenile Gaucher's disease, etc.), abetalipoproteinemia, phytanic acid storage disease (Refsum's disease), most of the spinocerebellar degenerations, acute intermittent porphyria, Wilson's disease, other diseases of the basal ganglia (with the exception of Huntington's chorea and familial calcification of the basal ganglia), and ataxia telangiectasia. Some children function suboptimally because of hearing impairment (Table 2), visual loss (mucopolysaccharidoses, juvenile ceroid lipofuscinosis, some of the spinocerebellar degenerations), or other physical handicaps for which the child has not been provided with special schooling. Education should not be withheld because the child's ultimate prognosis is poor. Special education and rehabilitation are needed to keep the child functioning optimally as long as possible and will foster a more positive attitude in the family.
The correct diagnosis is often suggested by findings outside the central nervous system. Organomegaly (Table 3) suggests a storage disease. Bone and joint abnormalities point to a disorder affecting connective tissue, such as mucolipidoses and mucopolysaccharidoses.4 Scoliosis is characteristic of Friedreich's ataxia and other spinocerebellar degenerations, ataxia telangiectasia, abetalipoproteinemia, dystonia musculorum deformans, Hallervorden-Spatz syndrome, as well as the mucopolysaccharidoses and some of the mucolipidoses. Foot deformities are seen in Friedreich's ataxia (pes cavus, hammer toes) and dystonia musculorum deformans (semilunar foot). Diseases that produce distal neuropathies, such as some of the mucopolysaccharidoses, may also produce hollow feet, hammer toes, and claw hands.
Skin lesions (Table 4) may be diagnostic of the phakomatoses but are also present in ataxia telangiectasia, some sphingolipidoses, adrenoleukodystrophy, and other disorders. Ocular abnormalities5 (Table 5) often provide very useful hints towards diagnosis. Enlargement of the head is classically present in spongy degeneration, in Alexander's disease (leukodystrophy with hyaline inclusions), and late in the course of TaySachs disease. Hydrocephalus or increased pressure may develop in adrenoleukodystrophy, mucopolysaccharidoses types I, II, VI, and VII, Alexander's disease, and phakomatoses that present with intracranial neoplasms (neurofíbromatosis, more rarely tuberous sclerosis, von Hippel-Lindau disease, and neurocutaneous melanosis, which may also produce hydrocephalus). Microcephaly is present in very severe encephalopathies of early life, such as globoid cell leukodystrophy, infantile ceroid lipofuscinosis, glioneuronal dystrophy, incontinentia pigmenti, neuroaxonal dystrophy, etc. Patients may have a characteristic fades - for instance, in the mucopolysaccharidoses (except type III early in its course), mucolipidosis type II, infantile GMi gangliosidosis, the cerebrohepatorenal syndrome, trichopoliodystrophy, and phakomatoses involving the face. Abnormalities of the hair are listed in Table 4. The hair and eyebrows are twisted, stiff, wiry, and poorly pigmented in trichopoliodystrophy. Premature graying occurs in ataxia telangiectasia. Infants with GM1 gangliosidosis have facial hirsutism, as have children with mucopolysaccharidosis.
DISEASES WITH OCULAR ABNORMALITIES
Cardiovascular abnormalities, most notably a cardiomyopathy, occur in Friedreich's ataxia and some of the other spinocerebelïar syndromes. The mucopolysaccharidoses frequently cause valvular disease, while patients with Fabry's disease may develop coronary artery disease. Strokes have been reported with Fabry's disease and trichopoliodystrophy. Endocrine disturbances include hypogonadism in ataxia telangiectasia, adrenal insufficiency in adrenoleukodystrophy, and diabetes in ataxia telangiectasia and Friedreich's ataxia. A strong tendency to neoplasia, especially Iymphomas, is seen in ataxia telangiectasia, and neoplasms are characteristic of many of the phakomatoses. Renal pathology is the hallmark of Fabry's disease and is the most common cause of death. Renal cysts occur in von Hippel- Lindau disease, tuberous sclerosis, and the cerebrohepatorenal syndrome. Cirrhosis of the liver characterizes the cerebrohepatorenal syndrome and Wilson's disease; a nonfunctioning gallbladder, metachromatic leukodystrophy; and jaundice, infantile Niemann-Pick disease. Patients with abetalipoproteinemia have intestinal malabsorption.
Failure to thrive occurs in all children during the terminal part of a severe neurologic illness. It is striking in children with infantile Gaucher's disease (who swallow poorly), infantile Niemann-Pick disease, the cerebrohepatorenal syndrome, trichopoliodystrophy, and abetalipoproteinemia. Dwarfing characterizes the mucopolysaccharidoses, except for types III-Sanfilippo and I-Scheie. It may also be notable in some of the mucolipidoses, the Lesch-Nyhan syndrome, and -ataxia telangiectasia.
DISEASES WITH PROMINENT SEIZURES OR MYOCLONUS
DISEASES ASSOCIATED WITH ABNORMAL INVOLUNTARY MOVEMENTS
The neurologic features of the illness also provide clues as to disease processes. Seizures (Table 6) and abnormal movements are most likely to be seen in patients with gray-matter diseases. Most of the sphingolipidoses and ceroid lipofuscinoses cause seizures, as do the cerebrohepatorenal syndrome, trichopoliodystrophy, and glioneuronal dystrophy. Of the mucopolysaccharidoses, only type III is likely to be associated with seizures. Huntington's chorea, which virtually never produces seizures in adults, often does so in children. Lafora's disease and syndromes that resemble it clinically, although not pathologically - namely, the Ramsay Hunt syndrome (dyssynergia cerebellaris myoclonica), Unverricht-Lundborg disease, and the cherry red spot myoclonus syndrome - are characterized by severe intention myoclonus. Acute intermittent porphyria and adrenoleukodystrophy may also precipitate seizures.
Abnormal movements (Table 7) and dystonic posture suggest disease processes affecting the basal ganglia. These diseases are more common in childhood and adolescence than in infancy - except for the LeschNyhan syndrome, which can be confused with athetoid cerebral palsy because the children do not mutilate themselves in early life. All children with abnormal movements or dystonic posture should be tested for Wilson's disease and hypoparathyroidism, since these disorders are treatable.
Illnesses that affect the white matter - such as the leukodystrophies, spongy degeneration, and the neuroaxonal degenerations - or lead to severe neuronal dropout, such as the infantile variants of the sphingolipidoses, will result in spasticity or rigidity. In the terminal stages of all diffuse cerebral degenerations, children tend to lie in a state of decorticate rigidity, essentially unresponsive to their environment. Hypotonia or floppiness should suggest involvement of the cerebellum, anterior horn cells, peripheral nerves, or muscles. The gangliosidoses affect anterior horn cells and produce a combination of floppiness and signs of upper motor neuron involvement (Babinski's sign, clonus, etc.). A spastic, unresponsive child with nystagmus, muscle wasting, and areflexia almost certainly does not have cerebral palsy: diseases that affect both central and peripheral myelin should be suspected, such as metachromatic leukodystrophy. (The nystagmus probably reflects the optic atrophy and poor vision.) Entrapment neuropathies (for instance, the carpal tunnel syndrome) are seen in many of the mucopolysaccharidoses (Table 8). Acute intermittent porphyria precipitates an acute neuropathy resembling the Guillain-Barré syndrome. Slowed conduction velocity is diagnostic of a neuropathy. Spinal fluid protein is usually elevated in diffuse neuropathies.
Compression of the spinal cord manifested by spastic paraparesis or quadriparesis is a feature of mucopolysaccharidoses type IVMorquio (due to instability of the odontoid peg and atlantooccipital dislocation) and type VI-MaroteauxLamy. Cerebellar dysfunction (Table 9) is difficult or impossible to diagnose in infants who do not sit, stand, ambulate, or use their hands. Consequently, cerebellar ataxia, like extrapyramidal disorders, is seen more often in childhood or adolescence than in early life.
DISEASES ASSOCIATED WITH A NEUROPATHY
DISEASES WITH PROMINENT CEREBELLAR SIGNS
Profound deficiency of one enzyme explains the chemical pathology of gene tic- metabolic diseases whose pathogenesis has been unraveled. This enzymatic block may have several consequences: the substrates of reactions proximal to the block in the metabolic pathway accumulate, those distal to the block are deficient, and alternative pathways may become activated, resulting in some cases in secondary enzymatic changes and in the production of abnormal and potentially toxic metabolites. (The latter mechanism appears to account for the severe destruction of oligodendroglia characteristic of globoid leukodystrophy.6,7) When the block results in the piling up of insoluble substrates in cells, the cells become distended and one speaks of a "storage disorder." This term is used most frequently when referring to the sphingolipidoses, mucopolysaccharidoses, glycogenoses, and ceroid lipofuscinoses. The accumulated substrate can disrupt the cell's economy in various ways, most of which are not understood. In Tay-Sachs disease, neurons do not accumulate GM2 ganglioside alone; they incorporate the excess GM2 ganglioside into abnormal membranous structures, the membranous cytoplasrnic bodies, which contain other sphingolipids and cholesterol in specific molar ratios.8,9 Purpura10 has recently shown that these membranes are dendritic, the only type that the cell is programmed to produce at the time. The axon torpedoes of neurons in Tay-Sachs disease, which enlarge progressively as more membranous cytoplasrnic bodies are stored, are enclosed not by an axonal membrane but by a dendritic membrane with dendritic spines on which other neurons synapse. As a consequence, the electrophysiology of these neurons may be altered profoundly, since these synapses short-circuit normal synapses on the cell's dendritic tree and soma.
In most of the storage diseases, the missing enzyme is a catabolic enzyme or acid hydrolase that is normally located in the lysosomes, membrane-bound intracellular organelles in which the breakdown of complex molecules takes place. These diseases are, therefore, frequently referred to as lysosomal diseases.11 The stored material can be shown by electron microscopy to be enclosed in greatly distended lysosomes.
The lack of enzymatic activity can be demonstrated in such peripheral tissues as serum, white blood cells, and skin fibroblasts, as well as in the central nervous system. The appreciation that enzyme deficiencies affect all tissues, even those where the microscope shows no pathology because the deficient pathway is unimportant to that tissue's economy, was a major step toward noninvasive diagnosis (i.e., it abolished the need for cerebral biopsy), amniocentesis and prenatal diagnosis, and genetic counseling.
Carrier detection. In most of the autosomal recessive diseases, it is possible to differentiate hétérozygote carriers from normals and from affected homozygotes because their enzyme levels are intermediate between those of normals and homozygotes. The situation is somewhat different for the heterozygote female carriers of sex-linked recessive traits. The tissues of these women are made up of a mosaic of cells, some with normal enzyme complement and some with drastically reduced enzyme complement, in accordance with the Lyon hypothesis, which indicates that in each cell one or the other X chromosome is inactivated randomly in early life. In at least some of these X-linked conditions - for instance, mucopolysaccharidosis type ?-Hunter - the cells with normal enzyme level "correct" the cells with deficient enzyme. To show that a female is a heterozygote carrier, it is necessary to grow her cells (for instance, skin fibroblast) in tissue culture, separate individual cells, and grow the clones (descendants of a single cell) separately.12 One can then demonstrate that the female is a mosaic and, therefore, a carrier, since two types of clones, normal and deficient, will grow out.
Corrective factors. The "correction" of deficient cells by normal cells in tissue culture, indicating that the cells secrete their enzymes into the culture medium and that these enzymes can be taken up by other cells, has been exploited to unravel the enzymatic abnormalities of the mucopolysaccharidoses. Cells of patients with Hurler's syndrome (i.e., homozygotically deficient for U-Liduronidase, the missing enzyme in that syndrome), grown in tissue culture with cells from patients with Hunter's syndrome (i.e., homozygotically deficient for sulfoiduronidosulfatase, the missing enzyme in Hunter's syndrome), do not accumulate mucopolysaccharides, while each one grown alone does so and shows an accumulation of metachromatic stored material under the microscope.13 The Hunter cells have normal activity for the missing Hurler enzyme and vice versa; therefore they can cross-correct each other. These observations have raised the prospect of grafting tissues with normal enzyme activity onto patients with metabolic deficiencies or injecting them with purified enzyme preparations. Several experimental attempts have been made.14 The only one so far with any success was the grafting of normal kidneys into patients with Fabry's disease and renal failure.15 Some of the patients have improved because of improved renal function. It is not yet clear, however, whether the enzyme replacement provided by the graft has affected other manifestations of the disease.
Cross-correction experiments in fibroblast tissue culture have revealed that what appeared to be one syndrome clinically - mucopolysaccharidosis IÏ, or Sanfilippo's syndrome - is two or maybe three different diseases with distinct enzyme deficiencies.16·17 It was shown by the fact that some patients with Sanfilippo's disease do not crosscorrect each other (i.e., presumably have the same enzymatic defect), while others, with an apparently identical clinical condition, do (i.e., must be suffering from different enzymatic defects). Conversely, what were thought to be totally different diseases clinically, mucopolysaccharidosis I-Hurler and Scheie's disease, do not cross-correct each other, and both have been shown to have a deficiency of a-L-iduronidase. (Scheie's disease is, therefore, classified as mucopolysaccharidosis I-Scheie and no longer as mucopolysaccharidosis V.18·19) Since these syndromes are clearly distinct clinically and genetically (i.e., are not found in the same family) despite apparently identical enzymatic defects, it is supposed that the Hurler gene and Scheie gene are allelic and that the Hurler and Scheie a-iduronidase enzyme proteins differ (in ways yet unknown) in their chemical structure, much as the various hemoglobins differ by various amino acids.
Isoenzymes. There are other situations where apparently identical enzymatic deficiencies result in different clinical diseases. Hexosaminidase A deficiency characterizes Tay-Sachs disease. A number of other syndromes with partial deficiency of hexosaminidase A are now known: late infantile, juvenile, and adult chronic GM3 gangliosidoses.20,21 The activity of hexosaminidase A (Hex A) is studied routinely in the laboratory with artificial chromogenic substrates - i.e., substrates that are chemically simpler than the natural substrate and whose reaction products can be demonstrated conveniently by their staining properties on Chromatographie plates. It has been shown recently, in a case of juvenile GM2 gangliosidosis where the activity of Hex A was only partly deficient with artificial substrates (in the same range as the activity in healthy hétérozygotes for the Tay-Sachs gene), that it was profoundly deficient towards the natural substrate GM2 ganglioside.22 It is now possible to separate several components of Hex A and other hydrolases with special methods. These components or isoenzymes differ in their enzymatic properties at different pHs or temperatures. Genetically distinct forms of diseases are being demonstrated with increasing frequency in what was presumed to be one illness. One can expect that when these genetically distinct forms are separated enzymatically, they will account for atypical syndromes or clinical variants occurring ai different ages - infantile, late infantile, and juvenile forms of a disease, for instance.
The foregoing discussion should have made clear that accumulation of one particular substrate - for instance, GM2 ganglioside, GM1 ganglioside, sulfatide, or glucocerebroside - is no longer an adequate criterion to define a nosologie entity; nor is the demonstration of the deficiency in the activity of an enzyme against artificial substrates or even against the natural substrate (e.g., Hurler's and Scheie's diseases). One must expect that clinically and genetically distinct syndromes reflect genetically distinct enzyme deficiencies, which will need to be defined.
In diseases for which an enzymatic deficit has been discovered, one can make a definite diagnosis by demonstrating the absence of that enzyme in appropriate peripheral tissues, especially leukocyte and fibroblast cultures. In those diseases, intrauterine diagnosis on cultured amniotic cells is available, and the detection of heterozygotes is possible or theoretically possible if not yet achieved. Diseases that fall into this category include the sphingolipidoses, mucopolysaccharidoses, Lesch-Nyhan syndrome, Refsum's disease, acute intermittent porphyria, the glycogenoses, galactosemia, and some of the mucolipidoses. The risks of amniocentesis at the end of the first trimester of pregnancy are minimal for the mother and the fetus.23 Most diagnoses based on enzymatic assays require four to six weeks, so amniocentesis should be carried out at 12 to 14 weeks in order not to delay the date of abortion, should it be required, beyond 18 to 20 weeks. So far, errors in diagnosis have been extremely rare. Women willing to consider a therapeutic abortion for genetic reasons appear to tolerate the procedure with minimal emotional turmoil. Every pediatrician should know where he can refer mothers who have borne a child with a genetic illness for prenatal diagnosis, as well as for which diseases prenatal diagnosis is available. Their number is increasing rapidly, and published lists are never up to date; genetic centers should be consulted before a pregnant woman is told that prenatal diagnosis is not yet available.
In diseases for which the enzymatic deficiency is not yet clear, the stored material can often be identified (e.g., copper in Wilson's disease), or the lack of a material distal to an enzymatic block can be demonstrated (e.g., copper deficiency in trichopoliodystrophy, abetalipoproteinemia in BassenKornzweig disease). In some of the diseases about which chemical knowledge is even less advanced, a firm diagnosis can be made on clinical grounds when signs and symptoms are distinctive (for instance, ataxia telangiectasia, dysautonomia, adrenoleukody s trophy, Huntington's chorea, the cerebrohepatorenal syndrome, the phakomatoses, etc.). There is a residue of cases where it is possible to suspect a diagnosis but not to prove it without a biopsy (for instance, muscle or liver biopsy in Lafora's disease, skin and muscle biopsy in ceroid lipofuscinosis, nerve and muscle biopsy in neu roa xo nal dystrophy, cerebral biopsy in spongy degeneration, glioneuronal dystrophy, atypical variants of ceroid lipofuscinosis, Alexander's disease). Finally, there are diseases that will remain very difficult or impossible to diagnose in life because of a lack of pathology in accessible tissues. These include the spinocerebellar degenerations, some diseases affecting the basal ganglia (e.g., HallervordenSpatz disease, which may be confused with dystonia musculorum deformans early in its course), and variants of Leigh's syndrome in which there is no inhibitor of thiamine triphosphate in the urine.
In general, it is crucial to educate the families of children with genetic-metabolic diseases concerning the need for an autopsy long before the child becomes terminally ill. Having considered this and had a chance to discuss it at leisure when emotional stress was not at its peak, the parents are more likely to consent to an autopsy than if first confronted with this request at the time of the child's demise. Early discussion of the need for an autopsy will often make postmortem examination available to the interested physician, even if the child dies in a nursing home away from the medical center where the diagnosis was made. The physician must explain to the parents that a necropsy will not only confirm the clinical diagnosis, or be likely to yield a diagnosis in cases where no definite diagnosis was made during life, but also provide tissue for further investigation of the disease process. Not all visceral and cerebral tissue obtained at autopsy should be fixed; some should be stored in the deep freeze for later chemical work. For instance, enzymatic studies were performed in Germany five years after death in a patient with juvenile GM2 gangliosidosis who had been cared for by me in New York22; Golgi stains on fixed brain tissue of patients autopsied many years ago have provided critical data on the morphologic changes in Tay-Sachs disease, the mucopolysaccharidoses, and other profound dementias of infancy10*24 - data that are shedding new light on the pathophysiology of these disease processes.
A word must be said here about cerebral biopsy. Except under very exceptional circumstances, this investigation should be offered only when a firm clinical or chemical diagnosis cannot be made on peripheral tissues. The grounds for biopsy should be diagnosis for the purpose of genetic counseling and prognosis. In well-equipped medical centers, cerebral biopsy in infancy and early childhood carries minimal morbidity and only the mortality associated with general anesthesia. Among children biopsied at our center, postoperative seizures have occurred only in those who had seizures preoperatively. In my opinion, brain biopsies should be carried out only in centers that are equipped to use all the modern tools of investigation. These include not only light microscopy, histochemistry, and electron microscopy but also neurochemistry and, in some cases, tissue culture. All these studies can be carried out on 1 gm. of tissue, usually removed from the right frontal lobe. The goals of the biopsy should be explained to parents in detail and their informed consent obtained. A planning conference including the clinicians and neurosdentists who will study the tissue should be called before the biopsy; another conference is arranged after the studies are completed so that the full benefit of interdisciplinary discussion can take place. Under these conditions, the biopsy may not only provide a diagnosis but also allow significant progress towards unraveling the disease process.
REVIEW OF PARTICULAR DISEASES
The Mucopolysaccharidoses (MPS)
Table 10 summarizes known variants of the mucopolysaccharidoses and current knowledge concerning their enzymatic deficits, as well as the salient clinical features of each variant. These diseases are due to a catabolic block in the breakdown of sul fa ted carbohydrates from glycoprotein polymers, called mucopolysaccharides, found in connective tissue and, in at least some types of mucopolysaccharidoses, a block in the cleavage of similar carbohydrate moieties from gangliosides (glycolipids) that accumulate in the brain. Various clinical pictures will evolve, depending on the particular mucopolysaccharide that cannot be broken down and its concentration in various tissues. The mucopolysaccharidoses affect joints and bones, and connective tissue in many organs, including blood vessel walls, heart valves, the cornea, middle ear, leptomeninges, liver and spleen parenchyma, bone marrow, and skin. In such variants as Hurler's and Sanfilippo's diseases, where neuronal storage of ganglioside takes place, the child will become progressively demented.
The diagnosis can usually be suspected on clinical grounds and confirmed by demonstration of excessive excretion of mucopolysaccharide in the urine.* Definitive diagnosis based on quantitative chemical determination of the exact mucopolysaccharide excreted in the urine is more difficult and is available only in specialized laboratories, as are enzymatic determinations based on cross-correction experiments in tissue culture.
Severity and rate of progression vary greatly among these syndromes (Table 10). It is important to provide follow-up for the patients in order to be able to treat correctable complications of the illness; this will significantly ameliorate the quality of the patient's life and that of his family. For instance, hearing loss should be detected and treated with special education and hearing aids, cord compression and entrapment neuropathies relieved surgically, and consideration given to shunting in patients with Hurler's syndrome who develop hydrocephalus early in their course, before profound dementia from neuronal storage has had time to occur. Finally, the family pediatrician can play a crucial role in providing supportive care for these children and their families, and in directing traffic among the many specialists who will see the child at one time or another.
The Mucolipidoses (ML)
These lysosomal storage disorders are less well understood than the mucopolysaccharidoses and include disorders in which there is storage of both glycoproteins and glycolipids, without excessive excretion of mucopolysaccharide in the urine.29 Clinically, some of these disorders have features reminiscent of the mucopolysaccharidoses - for instance, cloudy corneas in mucolipidosis IV, severe bony changes in mucolipidoses II and ??, and organomegaly in mucolipidosis II, mannosidosis, infantile fucosidosis, and GM1 gangliosidosis. Infantile GM1 gangliosidosis is usually classified among the sphingolipidoses, since the storage of GM1 ganglioside and the deficiency of j8-galactosidase, which cleaves the terminal galactose from GM1 ganglioside, are viewed as the principal chemical abnormalities, although it does have the same characteristics of polysaccharide storage in the viscera as the other mucolipidoses.
Table 11 provides a summary of these disorders and their principal clinical features. Enzymatic and chemical elucidation is less advanced than for the mucopolysaccharidoses and the sphingolipidoses. Intrauterine diagnosis based on enzymatic criteria is available in the diseases for which enzymatic defects have been described. It may be available on ultrastructural criteria in mucolipidosis IV, where the enzymatic deficit is unknown, because of distinctive inclusions in amniotic cells,40 as well as in skin fibroblasts.
Mucolipidosis II (I -cell disease or cell disease) is particularly from an enzymatic standSeveral acid hydrolases (e.g., a- and /3-galactosidases, 0-gIuhexosaminidase, aand arylsulfatase A) be found in marked excess in serum and in the media of cultured skin fibroblasts, while the same enare deficient intracellularly (e.g., in skin fibroblasts or liver) though not necessarily in all tissues (for instance, arylsulfatase A and hexosaminidase levels are normal in leukocytes). Other hydrolases (e.g., acid phosphatase and /3-glucosidase) appear to be unaffected. Neufeld32 has proposed that the hydrolases, synthesized in the endoplasmic reticulum of the cell, are secreted into the extracellular space, then taken up by the cell to be incorporated into lysosomes. She postulates a deficit in the recognition of the enzymes by the cell or in their transport back into the cell, perhaps because of a common structural deficit in the enzyme protein of several hydrolases. This theory needs to be confirmed, but the existence of I-cell disease suggests that mechanisms quite different from inactivity of the hydrolytically active site of enzymes account for their deficient activity in the patient.
Considerable progress has been made towards elucidating the biochemistry of this group of disorders, although, as noted earlier, multiple isoenzymes have been discovered for what was thought to be a single enzyme - for instance, arylsulfatase, hexosaminidase A, and j8-galactosidase - and many details remain to be worked out. Figure 2 shows the main pathway for the catabolism of gangliosides and globoside and the storage diseases associated with the various enzymatic defects. Table 12 summarizes clinical features and course of the principal sphingolipidoses.
Figure 2. Simplified diagram of the catabolism of the sphingolipids. The trivial names of the compounds are indicated in capital tetters. The name of the hydrolase involved at each step is indicated in the box, and the arrow points to its site of action. The pathways for the removal of NANA (Nacetyl-neuramintc acid) to form the asialo derivatives of the gangliosides are omitted for the sake of clarity. Hexosaminidase A and /3-galactosidase are also active against these asialo derivatives. The numbers refer to the disease that results from a catabolic block at the indicated site:
1. GMi gangliosidosis
2. Tay-Sachs disease
2 + 3. Sandhoff's disease
4. Fabry's disease
5. Metachromatic leukodystrophy
6. Krabbe's disease
7. Gaucher's disease
8. Niemann-Pick disease
9. Farber's disease
Reproduced with permission from Rapin, I. In Rudolph, A. M.[ed.].Ped/afncs, 16th Edition. New York: Appteton-Century-Crofts. [In press.])
Intrauterine diagnosis is available or theoretically possible for all these disorders.28 Efforts are being made to screen whole populations of Ashkenazic Jews for heterozygosiry for Hex A, in an effort to prevent the birth of even a first child affected with Tay-Sachs disease to couples in which both parents are hétérozygotes. Unfortunately, such population screening is impractical for very rare diseases, even if they have an ethnic predilection, and for diseases that have no ethnic predilection.
The outlook for treatment by enzymatic replacement in diseases that affect infants is dismal, since examination of affected fetuses aborted at 20 weeks of gestation has already shown histologie evidence of storage in the brain and spinal cord. In any case, means of delivering adequate enzyme levels across the blood-brain barrier have not been devised. The outlook is better, as discussed earlier, for sphingolipidoses with predominantly visceral involvement, such as juvenile Gaucher's disease14 and Fabry's disease, for which kidney transplants are no longer considered experimental therapy by some investigators.15
Classic Tay-Sachs disease was thought for a long time to be the only GM2 gangliosi dosis. The discovery of its enzymatic deficit goes back only to 1969, because previous investigators who suspected a deficit in hexosaminidase found its activity to be normal or increased in Tay-Sachs disease. It finally became clear that hexosaminidase activity could be separated into two fractions on the basis of temperature, pH, and other physical chemical characteristics.20,49 While Hex A was virtually inactive in Tay-Sachs disease, Hex B was higher than normal, explaining the lack of total hexosaminidase deficiency. Classic Tay-Sachs disease has been called GMi variant B (because Hex B is present). In Sandhoff's disease, or GM2 gangliosidosis variant O, there is a deficiency of both Hex A and Hex B. The children store GM2 ganglioside in the brain and have a clinical course essentially identical to that of children with classic Tay-Sachs disease; but they also store globoside in their viscera because, owing to the lack of Hex B, they cannot cleave the terminal N -acetylgalacto samine of globoside. Recently, three nonJewish children in two families have been found to have a clinical illness very similar to Tay-Sachs disease, but with normal activity of Hex A and Hex B when tested against artificial substrates (GM2 AB variant). Since only a small subfraction of Hex A is active against the natural substrate GM2 ganglioside, a deficit of this small fraction may remain undetected when total Hex A activity is tested against artificial substrates. Conversely, a few healthy parents of children with Tay-Sachs disease who were found not to have Hex A activity may be genetic compounds (double heterozygotes) who are heterozygous for total Hex A and heterozygous for the part of Hex A active against artificial substrates with the small fraction against natural substrates present. When these enzyme complexities are understood better, it will no doubt be possible to unravel the enzymatic genotype of other, clinically distinct syndromes exhibiting a partial deficiency of Hex A that occur after infancy.
Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (Krabbe'e disease) are storage diseases in which destruction of the white matter appears to be primary - as opposed to the gangliosidoses, in which devastation of the white matter, severe late in the course of the illness, is viewed as secondary to wallerian degeneration following destruction of neuronal cell bodies. In MLD and Krabbe's disease, oligodendrocytes and Schwann cells, whose greatly elongated processes wrapped around axons constitute myelin, bear the brunt of the metabolic derangement. Whereas in MLD metachromatic storage of sulfatide is readily demonstrable histologjcally and chemically, in globoid cell leukodystrophy all myelin constituents, including cerebroside, are depleted. Storage is evident only in globoid and perivascular scavenger cells, and in a relatively less marked decrease of cerebroside compared with sulfatide. The mechanism of this drastic loss of oligos, and therefore of myelin, in globoid cell leukodystrophy may be the toxic effect of psychosine, an intermediary compound in an alternative pathway for cerebroside catabolism, whose degradation is also blocked by the enzyme deficiency.6·7 Globoid cell leukodystrophy represents an interesting example of a disease with a catabolic block where pile-up proximal to the block is all but inexistent and overshadowed by a secondary consequence of the block.
Gaucher's disease (glucocerebroside lipidosis) produces devastating damage to the central nervous system in infants without histologie evidence for storage in the brain. As in globoid cell leukodystrophy, psychosine accumulation in the brain may play a role in the pathology.50 In both infantile and juvenile Gaucher's disease, there is massive storage of glucocerebroside in the viscera. The main source of glucocerebroside is the breakdown of red and white blood cell membranes in the spleen. Normal myelin contains galactocerebroside, while glucocerebroside is found only in small amounts in immature myelin. Consequently, the lack of cerebroside glucosidase has no effect on the brain of mature persons whose central nervous system is spared completely, but it does affect fetuses and infants with immature myelin who develop a neurologic illness.
Niemann-Pick disease (sphingomyelin lipidosis) of infants affects both the brain and the viscera. A variety of syndromes have been described in older persons - some of them without any neurologic involvement, some with. Details concerning sphingomyelinase activity have been less well worked out than those concerning hexosaminidase, because artificial substrates to study this enzyme have only very recently become available.51
Other Disorders of Lipid Metabolism
The sudanophilic leukodystrophies are diseases in which myelin appears to break down along the pathways of normal myelin catabolism to cholesterol esters, which stain with Sudan black. The pathogenesis of Pelizaeus-Merzbacher disease and its variants is unclear.52 The classic variant is inherited as a sex-linked recessive trait. Infants become symptomatic soon after birth and show dramatic nystagmus, spasticity, and variable intellectual impairment. Signs of the disease coincide with the period of most rapid myelination of the nervous system. Perhaps the disorder is due to the deposition of an abnormal myelin that is unstable and breaks down. This explanation has received support from several studies of mutant mice, in which a deficit in fatty acid elongation (i.e., a synthetic deficit rather than a catabolic one) has been found. There is no understanding yet of sudanophilic leukodystrophy in older children and adults.
Adrenoleukodystrophy,53 a sexlinked recessive trait, is characterized clinically by a subacute progressive breakdown of myelin of the cerebral white matter, progressing from the occipital region frontally, associated with chemical and/or clinical evidence for deficient secretion of cortisol. In some boys, adrenal insufficiency may be the only evidence of the disorder. The ultrastructural hallmark of the illness is biréfringent lipid leaflets found in macrophages of the white matter, especially at the active border of the demyelinating lesion, in parenchyma! cells of the zona fasciculata and zona reticularis of the adrenal, in the testes, and in Schwärm cells. There is no clinical evidence of neuropathy or testicular involvement. While a disorder of sterol metabolism has been suspected, the most recent evidence indicates that myelin lipids contain an excess of very-long-chain fatty acids.54 The pathogenesis of myelin breakdown and sterol deficiency remains to be worked out. It appears that most cases of Schilder' s disease described in the literature - at least, those occurring in males - probably represent examples of adrenoleukodystrophy without clinically evident adrenal insufficiency. Schilder's disease in females may represent transitional sclerosis, an acute variant of multiple sclerosis.
Refsum's disease (phytanic acid lipidosis)55 is a disorder of C20 fatty acid catabolism. The patients lack the enzyme to cleave the terminal carboxyl group from phytanic acid, which is derived from chlorophyll. The clinical manifestations resemble those of spinocerebellar degenerations, with the addition of ichthyosis, a peripheral neuropathy, pigmentary degeneration of the retina presenting as night blindness, and hearing loss. Like patients with Friedreich's ataxia, those with Refsum's disease often die suddenly from cardiac involvement, usually dysrhythmia. The disease is treatable with a diet containing no green vegetables or fat derived from animals that feed on leafy vegetables containing chlorophyll.
Cholestanol tipi dosis (cerebrotendinous xanthomatosis)56 involves storage of cholestanol (dehydrocholesterol). The patients develop nodules around tendons, especially the Achilles' tendon, and later in life a picture of ataxia and neuropathy, with cataract formation.
In Tangier disease,57 cholesterol esters are stored in the various tissues, including enlarged orange tonsils. The patients may develop mild corneal opacity. Damage to the central nervous system is absent or limited to a neuropathy. In abetalipoproteinemia,57 the deficit in low-density lipoprotein is associated with intestinal malabsorption, diarrhea and failure to thrive in infancy, night blindness, and a clinical picture again reminiscent of a severe spinocerebellar degeneration with a neuropathy in older subjects. Details of enzymatic deficiency remain to be worked out in both these diseases. It is hoped that their clarification will provide a key to the unraveling of the classic spinocerebellar degenerations, whose pathogenesis remains totally obscure. Patients with SjOgren-Larsson syndrome58 have mental retardation, spastic paraparesis, and, like at least some of the patients with Refsum's disease, ichthyosis. Perhaps a disorder of fatty acid metabolism may also be at fault, although there is still no chemical evidence for this suggestion. It has been proposed very recently that the infantile variant of ceroid lipofuscinosis (see below) may also involve a disorder of tatty acid metabolism.
This group of autosomal recessive disorders (Table 13) produces a cerebromacular degeneration in infants and children; in adults and in some families with atypical syndromes, however, only the brain appears to be involved, while the retina is spared. The hallmark of this group of illnesses is storage of insoluble, autofluorescent ïipopigment in neurons, associated with neuronal dropout and brain atrophy. This lipopigment, ceroid, resembles the aging pigment lipofuscin, with some differences in wavelength of emission spectrum and heavy-metal content.61 Ul tra structurally, inclusions in neurons tend to be granular in the infantile variant, to have the shape of short curvilinear membranes in the late infantile variant, and to be pleomorphic with more inclusions resembling classic lipofuscin in juvenile and adult cases. Correlation between ulrrastructural appearance and clinical course is far from perfect, so that ultrastructural features cannot be used for nosologie classification.
THE CEROID UPOFUSCINOSES
Classification based on clinical criteria is somewhat better, the best evidence for genetic heterogeneity among these syndromes being that affected siblings tend to run quite similar clinical courses and that no family has been found in which infantile, late infantile, and juvenile variants occur together.
As in other progressive genetic diseases of the central nervous system, the earlier the defect becomes clinically apparent, the more rapidly devastating its consequences. An infantile variant of ceroid lipofuscinosis was isolated in Scandinavia less than five years ago, but similar cases had previously been described in other countries as examples of the late infantile variant.59,60 The hallmark of the infantile variant is virtually total dropout of neurons in the cortex, reflected by an isoelectric EEG and unresponsive vegetative clinical state. In the late infantile variant, a vegetative state is reached after two to four years, as opposed to one to two years for the infantile variant, and the EEG does not become isoeiectric. Visceral storage in the late infantile variant has recently been shown to be reflected by the excretion in the urine of desquamated renal epithelial cells containing curvilinear profiles.65 This may provide a rather easy confirmatory laboratory test. The juvenile variant starts as pigmentary degeneration of the retina in school-age children. Neurologic manifestations - such as seizures, a slowly progressive dementia, ataxia, dystonic features, and a severe motor apraxia - may be delayed for several years. The course of the illness extends over 10 to 20 years. It appears to be most common in Scandinavia.
Zeman and Siakotos61 have championed the idea that ceroid storage reflects peroxidation of fatty acids with the formation of insoluble polymerized residues. A defect of a short-acting myeloperoxidase, described by Armstrong and colleagues,66 remains to be confirmed. In the infantile variant, Svennerholm and his colleagues60 have found a defect in fatty acid metabolism. Primary enzymatic defects remain unknown, so detection of heterozygotes and intrauterine diagnosis are not yet possible.
Atypical variants with movement disorders63 have been described. These variants enter into the differential diagnosis of dystonia musculorum deformane, HallervordenSpatz disease, and Huntington's chorea. An adult variant with dominant inheritance, resembling a spinocerebellar degeneration, is also known.67
Disorders Presumed to Involve intermediary Carbohydrate Metabolism
Diabetes mellitus, hypoglycemic syndromes, galactosemia, and glycogen storage disorders, some of which afîect the nervous system in children, will not be discussed here. Leigh's syndrome68 refers to a group of chemically and clinically heterogeneous illnesses whose pathology is reminiscent of that seen in thiamine deficiency (Wernicke's encephalopathy). There is capillary proliferation with microhemorrhages and areas of infarction not only in the brain stem but, in some cases, also in the basal ganglia, hypothalamus, and spinal cord. The mamillary bodies are usually spared, unlike those in Korsakoff's syndrome, and lesions in the cortex have been described. The children present with subacute ataxia, involvement of extraocular muscles, nystagmus, respiratory difficulty, long-tract signs, and, in some cases, intellectual impairment. The disease is usually rather rapidly fatal. In most infantile and late infantile cases, an inhibitor of the enzyme responsible for the synthesis of thiamine triphosphate in the brain is found in the urine. This syndrome is characterized chemically by a disorder of energy metabolism reflected by the accumulation of alanine, lactate, and pyruvate, with a metabolic acidosis of variable severity. In some cases there is a deficit of the liver enzyme pyruvate carboxylase, which is biotin and Upoic acid dependent; in others there is a deficit in pyruvate decarboxylase, part of the pyruvate dehydrogenase complex, which is thiamine dependent. More chronic cases in older children have been associated with a neuropathy or with a lipid myopathy, suggesting a defect in utilization of fatly acids, a major source of energy for mitochondria in muscle. It is possible that glioneuronal dystrophy, or Alper's disease,69 also represents a disorder of energy metabolism in the brain, resulting in a profound encephalopathy with seizures.
Clearly, this group of illnesses is only starting to be unraveled, and the chemical pathology of the different syndromes tentatively classified as Leigh's disease remains to be worked out. The importance of diagnosing this disorder is that it may be treatable. Patients who have an inhibitor of thiamine triphosphate and those who have a deficit in the pyruvate decarboxylase should be treated with pharmacologie doses of thiamine. Perhaps those with a deficit of pyruvate carboxylase will benefit from therapy with biotin and lipoic acid.
Lafora's disease70 is discussed here because of the evidence that the Lafora bodies, which are the pathologic hallmark of the illness, are constituted by glucose polymers. Lafora bodies are present not only in neurons of the cerebellum, brain stem, and some areas of the brain but also in the myocardium, hepatocytes, and striated muscle. Nothing is known of the disease's chemical pathology. Clinically, it must be distinguished from other syndromes with intention myoclonus but with a less rapidly progressive course, in which the dementia may be much less severe or absent. These include the Ramsay Hunt syndrome,71 in which there are more severe signs of cerebellar dysfunction, and Unverricht-Lundborg syndrome. Light precipitates myoclonus in all these patients. The cherry red spot myoclonus syndrome" (Table 13) is easily distinguished by the characteristic fund us appearance (although the cherry red spot may fade in adult life), by the evidence of storage of mucopolysaccharidelike material in the liver, and by the preserved intellect. The diagnosis of Lafora's disease can be made by the characteristic findings on muscle or liver biopsy. None of the disorders can be diagnosed biochemically, and intrauterine diagnosis is therefore unavailable.
Disorders Affecting Nucleic Acids and Purine Metabolism
Xeroderma pigmentosum72 is a cutaneous disorder due to a defect in the repair of DNA, resulting in severe actinic cutaneous changes and a high incidence of cutaneous carcinomas and melanomas. It is mentioned here because some patients have developed a syndrome reminiscent of a spinocerebellar degeneration. In some families, presumably genetically distinct, xerodenna pigmentosum is associated with considerable endocrine dysfunction, and these children tend to be mentally retarded and may become psychotic.
The Lesch-Nyhan syndrome,72 an X-linked recessive trait, affects purine metabolism and is characterized by a deficiency of the enzyme hypoxanthine-xanthine phosphoribosyl-transferase. Most boys with the disease have an unmistakable syndrome of self-mutilation and rage attacks, as well as a movement disorder of early life resembling choreoathetosis. They later develop uric acid stones and gout. The disease may remain undiagnosed in boys who do not mutilate themselves (the reason for this is unknown) or start to do so later in childhood. These boys are not severely retarded and, if prevented from selfmutilation, will usually become less irritable and educable. Allopurinol prevents gout from developing but does not affect the CNS manifestations, whose pathogenesis remains to be unraveled.
Disorders of Porphyrin Metabolism
Acute intermittent porphyria (hepatic porphyria) may have its onset in childhood or adolescence, although it is most frequent in young women.74 Episodic severe abdominal pain, transient psychosis, seizures, an acute polyneuropathy resembling the Guillain-Barré syndrome, and inappropriate ADH secretion, in various combinations, are the hallmarks of this illness. It is frequently precipitated by ingestion of drugs, especially barbiturates, and will be made worse if barbiturates are used in an attempt to calm the patient or treat her seizures. Attacks are self-limited, and complete recovery may be expected in a few weeks. Death has occurred because of inadequate ventilation in patients with severe neuropathy, and worsening of seizures occurs because of the development of inappropriate ADH secretion and brain edema or continued therapy with barbiturates. Other anticonvulsants, such as diphenylhydantoin and diazepam, may be used, and chlorpromazine is recommended for psychotic patients. Prevention of further attacks by avoidance of precipitating factors is very important.
The diagnosis can be made by showing an increase in d-aminolevulinic acid and porphobilinogen in the urine with the WatsonSchwartz test. Freshly voided urine is normal in color and takes on the characteristic Burgundy red color only upon exposure to light, when the colorless prophyrin precursors are transformed into pigmented porphyrins.
The disorder is inherited as an autosomal dominant trait, but with a marked predilection for postpubertal females. It is due to the partial deficiency of the enzyme uroporphyrinogen I synthetase, which catalyzes one step in the biosynthesis of heme from porphobilinogen. This partial deficiency, consonant with a dominant mode of inheritance, can be demonstrated in skin fibroblasts and other tissues. Most males and children and some females do not manifest the trait because they use a different pathway for steroid catabolism from that of affected females.75 The latter pathway is capable of activating the porphyrin-· heme pathway in the liver a.nd swamping it in patients with a deficiency of uroporphyrinogen synthetase. Other factors that demand increased heme or heme-containing enzyme synthesis - for instance, barbiturates - will also precipitate attacks. Glucose administration ameliorates attacks by inhibiting the synthesis of d-aminolevulinic acid, while fasting may precipitate attacks by releasing the feedback inhibition of its synthesis.
Thus, this disease illustrates a situation whereby the fundamental genetic deficit becomes manifest in patients only when environmental factors or a secondary enzymatic deficit, harmless in itself, stresses the partly deficient pathway io the point of symptom production.
Diseases Affecting Cations
These disorders are quite rare. Trichopoliodystrophy70,77 is presumably due to a defect in resorption of copper from the gut, with a resultant deficiency of all copper-containing enzymes, such as cytochrome oxidase, which is crucial to energy metabolism; monoamine oxidase, intermediate in catecholamine and biogenic amine metabolism; and tyrosinase, instrumental in melanin metabolism. This is a sex-linked recessive disorder of male infants, who have a characteristic fades with pale skin and hair, wiry or bushy hair and eyebrows, and a profound encephalopathy of the neonatal period with seizures. Death usually occurs during the first year. Attempts at parenteral copper replacement therapy have not been successful yet, but this approach is obviously worth pursuing.
Wilson's disease78 should be very familiar to pediatricians because it is one of the fatal metabolic diseases for which successful treatment is available, and appropriate measures in asymptomatic homozygotes can prevent the appearance of the disease. It should be considered in the differential diagnosis of all children with subacute hepatitis and all those with a movement disorder. The disease reflects positive copper balance with deposition of copper in the liver and brain, most notably the corpus striatum of the basal ganglia. The primary enzymatic defect is unknown, but it appears to involve the secretion of copper by the hepatocytes into the bile. The diagnosis may be missed at autopsy in children who die of hepatic failure before they develop signs of neurologic involvement, because the histologie findings in the liver are not pathognomonic of the illness.
In children, the disorder is much more likely to appear as subacute liver failure, often mistaken for prolonged hepatitis. Cirrhosis of the liver develops in more chronic cases. In adolescence, the disease may occur as a movement disorder with clumsiness and prominent dystonic features, in some cases with psychiatric symptoms and, rarely, seizures. Tremor and cerebellar signs are characteristic of the more chronic adult variant of the disorder. Patients with neurologic signs invariably have a Kayser-Fleischer ring, a brownish ring at the limbus of the cornea that can usually be seen with a flashlight held tangentially but cannot be ruled out without a slit-lamp examination.
A high index of suspicion for this diagnosis must be maintained. The finding of a serum level of ceruloplasmin (a copper-containing serum globulin) below 20 mg./100 ml. should lead to the measurement of urinary copper excretion (usually more than 100 /Ag. of copper in 24 hours), decreased fecal copper, and increased copper content in the liver (more than 250 ju.g./gm. dry weight).
The detection of heterozygotes and prenatal diagnosis have not yet become possible.
Treatment consists of a low-copper diet (avoiding in particular chocolate, nuts, broccoli, mushrooms, liver, shellfish, and molasses), binding of copper in the gut by the administration of potassium sulfide (40 mg. with each meal), and, most important, chelating body stores of copper by the use of D-penicillamine (1-4 gm./day in divided doses). With this treatment, marked improvement in liver function and disappearance of all but the most severe neurologic symptoms can be expected. The same regimen is prescribed for asymptomatic patients. All siblings of a child with Wilson's disease must be tested, since each has a one-infour chance of being affected. Early treatment provides virtually normal life for patients with Wilson's disease. Unfortunately, the diagnosis is often missed until a second child develops liver disease in a family that has already lost a child with alleged hepatitis. The responsibility of family physicians, internists, and pediatricians in thinking of the diagnosis is high, since this disorder is not excessively rare.
Familial calcification of the basal ganglia79 is a poorly understood syndrome that may produce a movement disorder. Its relationship to pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism is unclear.
The cerebrohepatorenal syndrome80 is another autosomal recessive encephalopathy of early life, characterized by excessive stores of iron in the body, cirrhosis of the liver, deposit of neutral fat in astrocytes, seizures, floppiness, retardation, and early death. As in trichopoliodystrophy, the encephalopathy may reflect a profound derangement of energy metabolism due to a block, in this case in the electron transport chain prior to the cytochromes. Abnormal mitochondria and a lack of peroxisomes are probably histologie reflections of abnormal cellular respiration. No treatment has been devised, but intrauterine diagnosis, based on the study of mitochondria! respiration of amniotic cells, has been attempted, although no affected fetus has yet been detected.
Diseases Presumed to Involve Biogenic Amine Metabolism
Familial dysautonomia (Riley-Day syndrome)81 is an autosomal recessive disease seen only in children of Ashkenazic Jewish ancestry. It affects sensory and autonomie function in many organ systems. Its pathogenesis is not understood. Diagnosis rests on the characteristic clinical features and confirmatory tests of autonomie dysfunction. No consistent pathologic findings have been described. Intrauterine diagnosis and detection of heterozygote carriers are not yet possible.
Infants are often symptomatic from birth with poor sucking and swallowing difficulty. Generally of lower birth weight than their siblings, these infants show a deficiency of weight gain and growth. Aspiration pneumonia is often a life-threatening problem that may eventually lead to chronic lung disease. The children are labile temperamentally and cry frequently, but without overflow tears - one of the most characteristic findings in this illness. Lack of tears and corneal anesthesia frequently result in corneal ulceration, which requires vigorous treatment to avoid serious corneal scarring. Taste is impaired, and the fungiform papillae (small rounded taste buds on the anterior portion of the tongue) are missing, so the tip of the tongue is abnormally smooth. The children are insensitive to pain and have hypoactive or absent tendon stretch reflexes. Fractures or trauma to joints may go unnoticed and result in limb deformities. By adolescence, many of these children develop scoliosi^, which may require splinting in a Milwaukee brace. Development is slow: walking is delayed, presumably because of hypoactive vestibular function. Speech is also slow to appear, even though hearing is normal. Cognitive function appears to be somewhat lower than that of their siblings, although several affected persons have been able to attend college.
Evidence of parasympathetic dysfunction, in addition to the lack of tears and abnormal esophageal motility, includes severe episodic vomiting, at times with hematemesis, and poor control of the bladder. Sympathetic dysfunction is reflected by hypertensive crises and postural hypotension. The children tend to sweat excessively and develop skin blotching when feeding or when excited. Urinary excretion of vanillylmandelic acid, a metabolite of epinephrine and norepinephrine, tends to be decreased; that of homovanillic acid, a metabolite of dopamine, may be increased.
Instillation of a 2.5 per cent solution of metacholine in the conjunctival sac of one eye will result in constriction of the pupil compared with that of the untreated side, a reaction that does not occur in normals. Intradermal injection of 1:10,000 solution of histamine produces a wheal but no pain or axon flare around it.
These children have decreased sensitivity to hypercapnia and to hypoxia. They are able to hold their breath longer than other children and may develop breath-holding spells with seizures. Several accidental drownings and anesthetic accidents are attributable to this manifestation of the disease. Convulsions do not occur, except in response to hyperpyrexia or hypoxia. In some patients, decreased insulin release in response to a glucose load has led to frank diabetes mellitus. Puberty is delayed, and no patient is known to have reproduced.
The life expectancy of these children is reduced because many die of acute or chronic pulmonary infection; some die of unexplained hyperpyrexia. Others survive into adulthood with aggressive management of the many complications of the illness, in particular the respiratory problems. Chronic administration of bethanechol (Urecholine®) may restore the flow of tears and the tendon stretch reflexes and improve gastrointestinal motility and bladder control. Chlorpromazine appears to be the most useful drug to treat vomiting.
Dystonia musculorum deformane82,83 is an uncommon but not rare syndrome that may be inherited as an autosomal recessive trait in children, especially those of Ashkenazic Jewish ethnic origin, or as an autosomal dominant trait without racial predilection. It may become manifest at any age, from childhood to middle age. Dominant cases tend to be somewhat less severe than recessive cases; they may involve the axial musculature more than the limbs, and may present with torticollis or dystonic scoliosis. The recessive variant is said to be linked with high intellectual ability.
The course of this illness is highly variable. It may progress rapidly over a few months and result in severe abnormalities of movement and posture that render the children helpless, or it may be much more insidious. Arrest of the disease or even spontaneous improvement of symptoms is common and may last for years, but there is no understanding of why it occurs or what triggers further progression of the illness. While some young children die of the illness because of severe cachexia, scoliosis, and limb deformity, most patients remain ambulatory despite their often grotesque posture. Muscles of the face and of phonation tend to be relatively less severely affected, reflex changes do not occur, and there is no intellectual deterioration or seizure activity.
Drug treatment is still primitive and controversial. While some patients appear to improve with levodopa or other antiparkinsonian drugs, others appear not to benefit or even to be made worse. Recently, carbamazepine (Tegretol®) has been tried and found to be beneficial for some patients. Surgical treatment with cryothalamotomy has dramatically reversed the symptoms of some patients and restored them to a fully functional state. Others have had further progression of the illness and have required repeated bilateral interventions. The dangers of hemiparesis and, most notably after bilateral interventions, pseudobulbar palsy, accompanied in some patients by severe dysarthria or even anarthria, should be taken into account when recommending surgery, especially repeated intervention. The course of the illness is so unpredictable that the evaluation of any therapy is difficult.
Lack of knowledge concerning the pathology and chemical derangements responsible for the disorder has prevented the development of effective drug therapy and genetic counseling.
Huntington's chorea84 is a common autosomai dominant disorder with complete penetrance affecting the cortex and neostriatum that is manifested by a dementia and movement disorder. While it is most likely to become clinically evident in adult life, children can develop the disorder, especially if their father is affected. Children tend to be rigid and pseudoparkinsonian rather than choreic; they often have seizures, and may appear psychotic as well as demented. The course of the illness is about 10 years.
The pathogenesis of the disorder is unknown. There is a loss of cortical neurons and small interneurons in the striatum. Decreased levels of γ-aminobutyric acid, an inhibitory neurotransmitter, seem to be present in the striatum, perhaps associated with an increase in dopamine. No effective treatment is available. Levodopa worsens the patient's symptoms and may precipitate choreic movements in an asymptomatic carrier of the gene. Genetic counseling is essential, since persons at risk often have children before they are aware that they are affected.
Genetic Disorders with Undetermined Pathophysiology
Spongy degeneration85 is an autosomai recessive disorder that is usually manifested in infancy or early childhood by a progressive dementia and floppiness, leading to total behavioral regression and a decorticated state with optic atrophy. The diagnosis can be suspected because the head is usually enlarged. The disease is more common among Ashkenazic Jews than other ethnic groups. Death usually supervenes in a few years but may be delayed for 10 years. A more chronic juvenile variant with pigmentary degeneration of the retina may be mistaken for ceroid lipofuscinosis.
The characteristic pathology is a chronic edema with vacuolation of the deep layers of the cortex and white matter. The pathogenesis is unknown but may involve transport of water or electrolytes into protoplasmic astrocytes. No treatment is available, and intrauterine diagnosis is not yet possible.
Alexander's disease96 is rarer than spongy degeneration but resembles it because it also produces behavioral regression with an enlarged head. The head enlargement may be due to obstructive hydrocephalus or to brain enlargement. The pathologic hallmark of the illness is eosinophilic hyalin inclusions in astrocytic footplates along blood vessels and in the subpial and subependymal regions of the brain, where they may obstruct the aqueduct and thus produce the hydrocephalus. The diagnosis cannot be made except pathologically, and neither treatment nor intrauterine diagnosis is possible.
Neuroaxonal dystrophy87,88 is another autosomal recessive encephalopathy of infancy characterized by profound floppiness due to a neuropathy, progressive loss of pain sensation starting in the legs, nystagmus, dementia, and, late in the course, seizures and optic atrophy. The children usually die before 10 years of age, often in the preschool years. The cause of the illness is unknown. The characteristic pathologic feature is the appearance of spheroids in axons, especially in their presynaptic terminals in the vicinity of neuronal cell bodies or at the myoneural junction in muscle. These segmentai distentions of axons have a tubular and filamentous core and an accumulation of mitochondria. They are not pathognomonic of this disease, and their pathogenesis is still unknown.
Hallervorden-Spatz disease87,89 shares with neuroaxonal dystrophy the occurrence of spheroids, but in this disorder they are more prevalent in the basal ganglia, where deposition of iron-containing lipopigment in large concretions is also present.
Clinically, the chronic form of the disease presents in school-age children as a movement disorder that may be mistaken for dystonia musculorum deformans. In some cases, pigmentary degeneration of the retina suggests the diagnosis. The illness is slowly progressive, and the patients eventually become dysarthric, rigid or spastic, and demented. Atypical cases may appear in early childhood and raise the question of the relationship of HallervordenSpatz disease and neuroaxonal dystrophy. Death usually occurs in the late teens or early 20s. No treatment is available, and the diagnosis rests on the demonstration of the typical pathologic findings. Efforts at demonstrating a disorder of iron metabolism have been unsuccessful.
Ataxia telangiectasia90 is a complex autosomal recessive disorder affecting the nervous system, the immune system, endocrine glands, and blood vessels. Its pathogenesis is still unknown.
The children develop ataxia in early childhood, a dystonic-athetotic syndrome, and signs suggesting a spinocerebellar degeneration in adolescence. They are usually wheelchair bound before the teens. Intelligence and vision are unaffected, but ocular movements may be impaired.
Most of these children are very susceptible to sinopulmonary infections because they have hypogamma globulin ernia A and E. Their thymus is hypoplastic, and they have lymphopenia and impaired cellular immunity as well. They have a tendency to neoplasia, especially lymphoreticular tumors, and an increased incidence of chromosome breakage and aneuploid cells. They develop signs of premature aging (gray hair, atrophie skin) and of endocrine dysfunction (hypogonadism, diabetes mellitus, and growth failure).
The diagnosis is suggested by the classic clinical signs (especially the ataxia and respiratory infections) and the appearance of tortuous telangiectasias on the bulbar conjunctiva and on the pinnas, neck, and elsewhere. The course of the illness is slow. Survival into the third decade depends on aggressive care of the infectious manifestations and on the age at occurrence of the neoplasms, which kill almost half of the patients. These children respond so poorly to radiation therapy and to radiomimetic drugs that these are contraindicated.
The complexities of this illness provide a challenge to investigators, since no common pathogenetic mechanism has yet been discovered and no effective treatment is available beyond management of its multifarious clinical signs. Detection of heterozygote carriers and intrauterine diagnosis have not been achieved.
The spinocerebellar degenerations91 are a heterogeneous group of illnesses affecting the distal portion of axons in long fiber tracts in the spinal cord and, in some syndromes, in the peripheral nerves. Friedreich's ataxia is an autosomal recessive syndrome of unknown cause that appears in childhood and is characterized by ataxia, nystagmus, absent reflexes, loss of position and vibration sense, Babinski toe responses, scoliosis, high arched feet, and heart disease, which reduces the life expectancy of these children drastically.
A number of other syndromes with features reminiscent of the spinocerebellar degenerations but clearly distinct genetically are known. These include the Roussy-Lévy syndrome (spinocerebellar syndrome with a peripheral neuropathy), Marie's syndrome (spastic ataxia), Behr's syndrome (spastic ataxia with optic atrophy), familial spastic paraplegia (which is usually dominant), Charcot-Marie-Tooth disease (peroneal muscular atrophy, both dominant and recessive types), olivopontocerebellar atrophy, MarinescoSjögren syndrome (ataxia with cataracts and oligophrenia), SjögrenLarsson syndrome (spastic ataxia with ichthyosis and oligophrenia), and many others, all of which have totally obscure biochemical pathology.
A number of known metabolic derangements may present with a neurologic syndrome suggestive of a spinocerebellar degeneration - among them vitamin B12 deficiency, abetalipoproteinemia, phytanic acid lipidosis (Refsum's disease), cerebrotendinous xanthomatosis, Leigh's syndrome, and some of the juvenile variants of the neuronal storage disorders. These diseases must be sought in patients with a spinocerebellar syndrome because some of them are treatable. Progress in unraveling these disorders depends on defining specific genetic syndromes as precisely as possible, examining as many members of each family as are available, and investigating each patient for known metabolic disorders as well as seeking to discover new ones.
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GENETIC-METABOLIC DISEASES CAUSING SEVERE OR PROFOUND DEMENTIA
DISEASES PRODUCING A HEARING LOSS
DISEASES ASSOCIATED WITH ORGANOMEGALY
DISEASES ASSOCIATED WITH CHANGES IN THE SKIN AND HAIR
DISEASES WITH OCULAR ABNORMALITIES
DISEASES WITH PROMINENT SEIZURES OR MYOCLONUS
DISEASES ASSOCIATED WITH ABNORMAL INVOLUNTARY MOVEMENTS
DISEASES ASSOCIATED WITH A NEUROPATHY
DISEASES WITH PROMINENT CEREBELLAR SIGNS
THE CEROID UPOFUSCINOSES