The Metabolic &
`
`Molecular Bases of
`Inherited Disease
`
`eighth edition
`
`
`
`\
`
`EDITORS
`“.
`
`
`ASSOCIATE EDiTone
`
`Charles R. Scriver, M.D.C.M.
`
`a
`
`Barton Childs. MD.
`
`Arthur L. Beaudet, MD.
`
`Kenneth W. Kinzler, Ph.D.
`
`William S. Sly, MD.
`David Valle, MD.
`
`Bert Vogelstein, MD.
`
`McGRm-v-Hiu.
`
`Medical Publishing Division
`
`San Francisco Auckland Bogota Caracas Lisbon London Madrid Mexico City
`St. Louis
`New York
`Milan Montreal New Delhi
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`Mchw-Hi ll
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`32
`
`The Metabolic and Molecular Bases of Inherited Disease, 8th Edition
`
`Copyright © 2001, 1995, 1989, 1983, 1978, 1972, 1966, 1960 by The McGraw-Hill Companies. Inc. Formerly published as
`The Metabolic Basis of Inherited Disease. All rights reserved. Printed in the United States of America. Except as
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`The metabolic and molecular bases of inherited disease I editors,
`Charles R. Scriver ... [et aI.].—8th ed.
`p.;
`cm.
`
`includes bibliographical references and index.
`ISBN 0—07—913035-6 (set)
`1. Metabolism, Inborn errors of
`Scriver, Charles R.
`
`2. Medical genetics.
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`3. Pathology, Molecular, I.
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`[DNLM: 1. Hereditary Diseases. 2. Metabolic Diseases. 3. Metabolism, Inborn Errors.
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`

`
`4934 PART 21 / MEMBRANE TRANSPORT DISORDERS
`
`lysine in intestinal biopsy specimens have
`fluxes of
`confirmed that the defect indeed localizes to the hasolateral
`cell surface. Similar cellular localization of the defect in the
`kidney tubules is suggested by infusions of citrulline, which
`cause not only citrullinuria but also significant argininuria
`and ornithinuria. Because citrullinc and the cationic amino
`acids do not share transport mechanisms in the tubules,
`part of the citrnllinc is converted to arginine and then to
`ornithine in the tubule cells during reabsorption. A
`hanilateral transport detect prohibits antiluminal either of
`arginine and ornithine, which accumulate and escape
`through the luminal membrane into the urine. The genetic
`mutations in LPI and possibly in all cationic aminoacid-
`urias apparently lead to kinetic abnormalities in the
`transport protein[s} of the cationic amino acids. This is
`suggested by the fact that increasing the tubular load of a
`single cationic amino acid by intravenous infusion increases
`its tubular reabsorption, but reabsorption remains sub-
`normal even at high loads. he other cationic amino acids are
`able to compete for the same transport site{s] also in LPI.
`but an increase in the load of one cationic amino acid
`frequently leads to net secretion of the others.
`The plasma membrane of cultured fibroblasts shows a
`defect in the trans-stimulated efflux of the cationic amino
`acids; i.e., their flux out of the cell is not stimulated by
`cationic amino acids present on the outside of the cell as
`efficiently as it is in the control fibroblasts. The percent of
`trans-stimulation of homoarginine efflux in the fibroblasts
`of the heterozygotes is midway between that of the patients
`and the control subjects.
`rl‘he exact cause of hyperamnlonemia in LPI remains
`unknown. The enzymes of the urea cycle have normal
`activities in the liver, and the brisk excretion of orotic acid
`during hypel'alnmonemia supports the view that N-acet-
`ylglutamate and carbamyl phosphate are formed in
`sufficient iluantities. Low plasma concentrations of al'ginine
`and ornithine suggest that the malfunctioning ol’ the cycle is
`caused by a deficiency of intramitochondrial ornithine. This
`hypothesis is supported by experiments in which hyper-
`ammonemia after protein or amino nitrogen loading is
`prevented by intravenous infusion of arginine or ornithine.
`Citrulline, a third urea cycle intermediate, also abolishes
`hyperammonemia if given orally, because, as a neutral _
`amino acid, it is welt-absorbed from the intestine. Ornithine
`deficiency in LPI has recently been questioned because
`cationic amino acids and their nonmetabolized analogues
`accumulate in higher-than-normal amounts in intestinal
`biopsy specimens and cultured fibroblasts
`from LPI
`patients in vitro and the concentrations of the cationic
`amino acids in liver biopsy samples are similar or higher in
`the patients when compared to these concentrations in the
`control subjects. If hyperammonelnia is not due to simple
`deficiency of ornithine, it could be caused by inhibition of
`the urea cycle enzymes by the intracellularly accumulated
`lysine; by a coexisting defect in the mitochondrial ornithine
`transport necessary for the function of the urea cycle; or by
`actual deficiency of ornithine in the cytoplasm caused by
`abnormal pooling of the cationic amino acids into some cell
`organelle(s), most likely lysosomes. The latter two exploita-
`tions imply that the tramport defect is expressed also in the
`organellc(s).
`including
`in practically all proteins,
`. Lysine is present
`collagen. Lysine deficiency may cause many of the features
`of the disease that are not corrected by prevention of
`hyperanlmonemiu, including enlargement of the liver and
`spleen, poor growth and delayed bone age, and osteoporosis.
`Oral lysine supplements are poorly tolerated by the patients
`
`s—N—aeetyl-L—
`because of their poor intestinal absorption.
`lysine, but not homoeitrullinc, efficiently increases plasma
`concentration of lysine in the patients, but acctyllysinc or
`other neutral
`lysine analogues have not been used for
`supplementation.
`7. Recently, a fiZZ-amino-acid retroviral receptor (murinc
`leukemia viral receptor RECI) with 12 to 14 potential
`membrane-spanning domains has been cloned. The physio-
`logical role of the receptor was soon found to be that of a
`cationic amino acid transporter at the cell membrane; the
`protein was hence renamed MCAT—l. mouse cationic amino
`acid transporter-'1. The functional characteristics of the
`transporter are similar to those of system y”, a widely
`expressed Nat-independent transport system for cationic
`amino acids. The human counterpart of the mouse RECl
`gene, encoding the retroviral receptor-transport protein,
`has been assigned to chromosome 13q12—q14 and named
`ATRCI. MCAT-l (and 3"”) activity is not expressed in
`rodent liver, but two other related cationic amino acid
`transport proteins, formed presumably as a result of
`alternative splicing—Tea (T cell early activation; expres-
`sed also lll activated Tand B lymphocytes) and MCAT—Z—
`are probably responsible for the low-affinity transport of
`cationic amino acids that is characteristic of (mouse) liver.
`Studies addressing the A'l‘RCl gene as well as the Tea and
`MCA'BZ genes as candidate genes for LPI are under way.
`8. Treatment
`in lyfiiinuric protein intolerance consists of
`protein restrictio and supplementation with oral citrulline,
`3 to 8 g daily during meals. Patients are encouraged to
`increase their protein intake modestly during citrulline
`supplementation, but aversion to protein in most patients
`effectively inhibits them from accepting more than the
`minimal
`requirement. The treatment clearly improves
`the growth and well-being of the patients. Pulmonary
`complications (interstitial pneumonia, pulmonary alveolar
`proteinosis, cholesterol granulomas, and respiratory insuf-
`ficiency} have occasionally responded to early treatment
`‘ with high-dose prednisolone, or to bronchoalveolar lavages.
`No therapy is known for the associated renal disease and
`renal failure.
`9. The clinical and biochemical findings in other cationic
`alninoacitlurias differ slightly from those in lysinuric
`protein intolerance. The symptoms of the index case with
`hyperdibasic aminoaciduria type 1 resemble those of LPI,
`but
`the other affected members of
`the pedigree are
`clinically healthy. The Japanese patient with isolated
`lysinurla has severe growth failure. seizures, and mental
`retardation. Her transport defect is apparently limited to
`lysine, and hyperammonemia is not a feature of the disease.
`
`Perhccntupa and Visakorpi described the first three patients with
`“familial protein intolerance with deficient
`transport of basic
`amino acids" in 1965.1 The disease is now called lysinuric protein
`intolerance (LPI) (MJM 222700} or “hyperclibasic aminoaciduria
`type 23‘2—5 Over 100 patients with this autosomal recessive
`disease have been described or are known to me; 4] of them are
`Finns or Finnish Lappsfi‘52 The incidence in Finland is
`1
`in
`60,000 births but varies considerably within the couiitry.2-5-°’
`Patients of black and while American,
`Japanese, Turkish,
`Moroccan, Arab, Jewish. Italian, French. Dutch. Irish, Norwegian,
`Swedish, and Russian origin have also been described. The
`fascinating combination in the disease of urea cycle failure,
`expressed as postprandial hyperammonemia, and a defect in the
`transport of the cationic amino acids lysine, argininc, and ornithine
`in the intestine and kidney tubules has led to extensive studies of
`the mechanisms that link these two phenomena. The mechanisms
`are still partly unresolved, and the sequence of events leading to
`hyperammonemia is unclear. We can simplify our knowledge by
`
`Page 4 of 26
`
`Page 4 of 26
`
`

`

` CHAPTER T92 f LYSINURIC PROTEIN INTOLERANCE AND OTHER CATIONIC AMINOACIDURIAS ' I
`
`GENETIC DEFECT 0F
`
`EPITHELIAL LYS. ARG Br ORN TRANSPORT
`/ I
`\
`I INTESTINAL
`I TUBULAR FIE—
`TRANSPORT INTO
`ABSORPTION
`ABSORPTION
`LIVER CELLS
`
`DEFICIENCY OF
`
`BEEN. ARE. 3.
`PROTEIN MAL-
`NUTRITION
`
`—“‘-—‘—"'
`
`7.- ’77
`[MPAIRED UREA CYCLE I
`POST PRANDIAL HYPER-
`AI'II'I MONEMIA
`I
`
`NAUSEA, PROTEIN
`AVERSION
`
`SEIZURES, STUPOR
`COMA
`
`
`
`GROWTH FAILURE I LOSTEOPDROSISI
`I HEPATOMEGALY I
`Fig. 192-1 The suggested pathogenesis of Iyslne, arginine, [and
`ornlthlne deflelency, hyperammonemia, and aversion to protein in
`LPI.
`
`saying that. hyperammonemia is caused by “functional defi—
`ciency” of the urea cycle intermediates arginine and ornithlne in
`the urea cyclc“'”"‘1*Sal (Fig. 192-1). LPl has also been a productive
`model for studies of cellular transport: It is the first human disease
`where the transport defect has been localized to the basolatcral‘t
`(antiluminal) membrane of the epithelial cells.55—57 Further, in LPI
`the parcnchymal cells show a defect in the trans-stimulated efliux
`of the cationic amino acids, suggesting that
`the hasolateral
`membrane of the epithelial cells and the plasma membrane of the
`parenchynral cells have analogous functionssstas‘
`Recently, the first candidate gene for LP], ATRCI, encoding a
`human cationic amino acid transporter, has been mapped to the
`long arm of chromosome 13 (l’.iqu—ql4).“’O Without further proof,
`it is intriguing to hypothesize how a mutation in this or in a
`functionally similar gene or in genes encodi g regulatory proteins
`of these transporters might lead to the membr nc—selcctive cationic
`amino acid transport defect of IPI and to the complicated clinical
`features of the disease.
`.
`Several patients with variant forms of cationic aminpaeiduria
`have been described in which the protein tolerance often is better
`than in LPI and the selectivity and severity of cationic amino—
`aciduria differs.23‘25-33mm In the report by Whelan and Scriver‘51
`only the history of the index case suggested hyperammoncmia, but
`other members of the pedigree have been symptom—free. The
`inheritance of this hyperdibasic aminoaeidurla type 1 is autosomal
`dominant, implying that the patients are heterozygous for LP] or
`another type of hypcrdihasic aminoaciduria.
`
`CLINICAL ASPECTS
`
`Lysinuric Protein Intolerance
`Natural Course of the Disease. The gestation and delivery of
`infants with LPI has been i.ineventful."'—“’-9—''v35 Breast—fed infants
`usually thrive because of the low protein concentration in human
`milk, but symptoms of hyperammonemia may appear during the
`neonatal period and reflect exceptionally low protein tolerance or a
`high protein content in the breast milk, Nausea, vomiting, and. mild
`diarrhea appear usually within 1 week of Weaning or another
`increase in the protein content of the meals. Soy-based formulas
`are perhaps slightly better tolerated than cow’s milk. The infants
`are poor feeders, cease to thrive, and have marked muscular
`' hypotonia. The patient's liver and spleen are enlarged from the
`neonatal period-onward. The association of episodes of vomiting
`with high protein feeds is not always apparent to the parents and
`may remain unnoticed even by trained physicians for years. Thus,
`n
`
`Page 5 of 26
`
`the diagnosis frequently has been delayed until the school age or
`even adultlrood.35'47'63
`Around the age of 1 year, most patients begin to reject cow’s
`milk, meat, fish, and eggs. The diet then mainly contains cereals
`cooked in water, potatoes, rice and vegetables, fruits and juices,
`bread, butter, and candies. The frequency of vomiting decreases on
`this diet, but accidental
`increases in protein intake lead to
`dizziness, nausea, and vomiting. A few patients have lapsed into
`coma, to the point where the EEG became isoelectr'rc when the
`children were tube—fed with high—protein foodsFT‘E-‘m-“A? Enteral
`alimentation and total parenteral nutrition may cause symptoms in
`patients who have remained undiagnosed, because the protein or
`amino acid loads often exceed patient‘s tolerance. Prolonged,
`moderately increased protein intake may lead to dizziness,
`psychotic periods. chronic abdominal pains, or suspicion of
`abdominal emergencies.
`trau—
`frequently, often after minor
`Bone fractures occur
`1113.4‘14'30'35'63 ‘65 In a Finnish series, 20 of 29 patients (69 percent)
`had suffered from fractures of the long bones or of compression
`fractures of the lumbar spine; 10 (34 percent) had had more than 2
`fractures during the
`18—year
`follow—up.“*55 Most
`fractures
`occurred before the age of 5 years. Symptoms of osteoarthrosis
`soften begin at the age of 30 to 40 years. The radiologic signs of
`osteoporosis are usually severe before puberty but decrease with
`advancing age. The effect. of citrullinc therapy on osteoporosis is
`minimal.
`Our accumulating experience with the late complications
`associated with the disease,
`together with recent
`reports of
`patients from outside Finland, suggest that in a sizable. proportion
`of the patients the classic symptoms of protein intolerance may
`remain unnoticed.
`Instead,
`the patients may present with
`interstitial lung disease or respiratory insufficiency! or have renal
`glomerular' or glometulotubular disease with or without renal
`insufficiency as the first clinical finding (see “Complications and
`Autopsy Findings" below).
`
`Physical Findings. Muscular hypotonia and hypotrophy are
`usually noticeable from early infancy but improve with advancing
`age.35 Most patients are unable to perform prolonged physical
`exercises, but acute performance is relatively good. The body
`proportions of patients after the first couple of years of life are
`characteristic: the extremities are thin, but the front view of the
`body is squarelikc with abundant centripetal subcutaneous fat. The
`hair is thin and sparse, the skin may be slightly hyperelastic, and
`the nails are normal. The liver is variably enlarged, and the spleen
`is often palpable and is large by ultrasound.
`the age of
`Patients who have remained undiagnosed until
`several years have had characteristics typical of protein-calorie
`malnutrition and frequently resemble patients with advanced
`celiac disease. The subcutaneous fat may be reduced and the skin
`“loose” and “too large for the body" (Fig. 192-2}.
`The ocular fundi have been normal by ophthalmoscopy.35 0f
`20 patients studied, l4 had minute opacities in the anterior fetal Y
`suture of both lenses. In 10 patients, the opacities were surrounded
`by minute satellites. The opacities were never large enough to
`cause visual
`impairment and have remained stable,
`in some
`patients now for over 25 years. The mechanism underlying the lens
`abnormalities is unknown.“
`The dentition of the patients has been normal, and the patients
`do not appear to be especially prone to caries, despite the high
`carbohydrate content of the diet._
`
`for
`and lengths have been normal
`Growth. Birth weights
`gestational age, and postnatal growth is normal before weaning.
`The growth curves then begin to deviate progressively from the
`normal mean, and, at the time of diagnosis, 16 of 20 Finnish
`patients were more than 2 SD below the mean height, 12 patients
`were more than 3 SD. 6 patients more than 4 SD, 2 patients more
`than 5 SD, and 1 patient 6 SD below the mean.” Skeletal
`maturation is considerably delayed?!“ The bones usually mature
`
`Page 5 of 26
`
`

`

`
`4936 PART 21 I MEMBRANE TRANSPORT DISORDERS
`
`
`
`Fig. 192~2 Two children with LPI. The pictures were taken at the time
`of diagnosis. A, Child 12 years old. 8, Child 6 years old. Note the
`prominent abdomen, hypotrophlc muscles, and “loose” skin. The
`
`slowly and linearly without a pubertal catch-up spurt, and most
`patients have not reached skeletal maturity by the agc of 20 years.
`The final height of the patients has almost invariably been closer to
`the normal
`than the height measured at the time of diagnosis,
`because of therapy and the late cessation of growth. The head
`circumferences have been normal for age.
`The body ifiroportions are normal, but with advancing age the
`moderate centripetal obesity, which is present from early child
`hood, becomes more obvious.
`
`Skeletal Manifestations and Bone Metabolism. Osteoporosis is
`often recognizable in skeletal radiographs and has occasionally
`been the leading Sign of 1.1590553"65 Two—diirds of the patients
`have had fractures, half of which have occurred after insignificant
`trauma. All fractures have healed properly within a normal time. _
`The skull and sella lurcica have been normal in roentgenograms.
`Over 70 percent of the patients have some skeletal abnor—
`malities. either osteoporosis, deformations, or early osteoartin'o—
`snob-3’55 In radiographs of 29 Finnish patients. osteoporosis was
`present in l3; the cortices of the long bones were abnormally thin
`in 5; the vertebrae had endplate impressions in 8; metaphyses were
`rickets—like in 2'. and cartilage showed early destruction in 3. The
`cortex of the metacarpal bones was characteristically thickened in
`7.6"“ Morphometric analyses of bone biopsy samples showed
`moderate to severe osteoporosis in eight of nine patients studied;
`trabecular bone and osteoid volume were markedly l'ozlut‘,ed_E'5
`After (ioublcalabcling of bones with tetracycline in viva, barely
`identifiable single lines were detected, suggesting poor bone
`deposition;
`the findings resembled those in severe malnutri-
`tion.68 ’74 The number of osteoblasts and osteoclasts was low, and
`the extent of ostcoid along the bone surfaces was low or normal in
`all specimens studied.
`Laboratory tests for evaluation of calcium and phosphate
`metabolism have given unremarkable ICSUltS.35‘63"65 Serum
`calcium and phosphate concentration, urinary excretion ol’calcitlln
`and phosphate, serum magnesium, estradiol, testosterone, thyroid-
`slimuiating hormone, cortisol, vitamin D metabolites [25~(OI—l)2-
`D,
`l,25-(Ol[)2—D and 24.25—(011h-D'], parathyroid hormone,
`calcitonin, and ostcocalein concentrations have all been within
`the reference range.
`
`‘l:
`thorax of the child In A Is deformed and her trunk shortened because
`of osteopoiosla and pathologic fractures of the vertebrae.
`\
`
`The daily urinary excretion of hydroxyproline is significantly
`increased during pubertal growth, but half of the adult patients also
`have
`supranormal
`excretion
`rates
`(mean
`of
`all
`adults
`212 :L- [03 ttmoilmg; adult reference range, 60 to 180 pmol!
`1112).“ The seruni hytlroxyproline concentration is increased in
`almost all patients irrespective of age. Scrum concentrations of the
`C~terminal propeptide of type [ precoilagen and of the Niterminal
`propcptide of type III procollagen have been normal
`in all
`pediatric patients, but the concentration of the latter increases
`1‘during puberty and remains elevated in adult patients.
`The incorporation of labeled hydl‘oxyprolinc into collagen was
`significantly decreased in cultured LP] fibroblasts as compared
`with age-matched controls at the ages of 5, 14, and 30 years, but
`ther was no difference at the age of 44 years.‘55 Morphometry of
`the collagen fibrils in electron microscopy showed no differences
`between patients and controls.
`
`Liver Pathology. In the youngest patients. the histologic findings
`in liver biopsy specimens have been normal, with only occasional
`fat droplets in the hepatocytesfismlfi In older patients, delimited
`areas in periportal or central parts of the liver lobules contained
`liepatocytes with ample pale cytoplasm and small pyknotic nuclei
`In these cells, the glycogen content is dcc1cascd, and glycogen
`appears in coarse particles. At the borders of the abnormal areas.
`many nuclei are ghostlike and have central
`inclusion bodies
`staining positively with periodic acidischiff. Cytoplasmic fat
`droplets occur especially in the periportal areas. Children who died
`of alveolar proteinosis with multiple organ dysfunction syndrome
`have mostly shown extensive fatty degeneration of the liver but
`minimal or moderate cirrhosis. Inflammatory cells have always
`been absent in the liver biopsy samples.
`Liver changes
`in LPI may reflect generalized protein
`malnutrition, because in kwashiorkor
`liver
`fat
`synthesis
`is
`increased, apolipoprotcin synthesis is decreased. and lipoprotcin
`lipascs are inhibited.76 Similar liver changes have also been
`induced in rats by lysine and arginine deprivation.W
`
`in
`Performance in Adult Life. Mental development is normal
`most subjects. Performance is decreased, particularly in patients
`with known histories of prolonged hyperammonemia. Altogether,
`
`Page 6 of 26
`
`Page 6 of 26
`
`

`

`
`CHAPTER 192 / LYSINURIC PROTEIN iNTOLERANCE AND OTHER CATIONIC AMINOACIDURIAS 4937
`
`about 20 percent of the patients with LPI reported in the literature
`or otherwise known to me are mentally retarded. Convulsions are
`uncommon, but periods of
`stupor have occasionally been
`misinterpreted as psychomotor seizures.15 Four patients have had
`psychotic periods, which have clearly been precipitated by
`prolonged moderate 11ypcrarnrnonemia.35
`Neuropsychologic evaluation of the patients suggests that
`mathematical and other abstract skills are particularly vulnerable
`to hyperammonernia. Treatment with a low—protein diet and
`citrullinc supplementation' “453 (see “Treatment” below) has
`significantly improved the life quality of the patients. Episodes of
`vomiting and other signs of hyperammonemia have become a rare
`exception. The patients who underwent prolonged periods of
`hyperammonemia in early infancy and childhood and who
`appeared severely retarded at the first presentation have consider-
`ably and continuously improved their performance during therapy.
`All Finnish patients are now able to take care of the activities of
`daily life, and none of them is institutionalized The most severely
`retarded patient, who had an IQ of 40 at the age of 12 years, lives
`now at the age of 40 in the custody of another fatnin apt] is
`capable of taking care of her daily activities; she also works in a
`protected environment outside the home for a few hours a day and
`helps routinely in the household. She is talkative, happy, and
`socially active. At the other end of the spectrum, one patient has
`graduated from a medical School, works successfully air an
`internist, is married, and is a mother of one. Several other patients
`have also graduated from high school or other secondary schools
`and are permanently employed. The physical fiurcss of the patients
`is fair, but their capacity for prolonged heavy work and physicali
`endurance is clearly limited. One patient worked as a construction
`Worker in a building company for a few years, but found the job
`too heavy; another has been an active jogger for years and is
`capable of running 15 km without problems. The oldest patient in
`Finland is now 49 years of age and retired '7 ydhrs ago because of
`back problems. He is mentally and physically active and takes care
`of the household duties of a small farmhouse. A Finnish—born
`patient in Sweden is now 58 years old.'6'2"29 One male and seven
`female patients are married.
`
`Pregnancies of the Patients. The seven mahied women have had
`fifteen pregnancies. One of the mothers was treated 'during the
`pregnancy only with protein restriction;
`the other t’received
`citmllinc supplementation (8 to 14 pills containing lit-414 g I.-
`citi‘ulline daily during meals). Anemia (hemoglobin < 8.5 g/dl)
`occurred in all, and the platelet count decreased to less than
`50 x 1031mm3. A severe hemorrhage complicated two deliveries
`in one patient. Another patient had severe toxemia in her second
`pregnancy. The blood pressure increased to crisis values and she
`had prolonged convulsions and unconsciousness, but she recov-
`ered totally. In a third patient, an ultrasound-guided amniotic fluid
`puncture led to a bleed and loss of the fetus at 35 gestational
`weeks. Despite the mothers’ anemia and severely decreased
`platelet count, other pregnancies and deliveries have been”
`uneventful.
`Of the 14 living children born to the patients, l3 are well at the
`age of 0.5 to 14 years. One child, whose delivery was complicated
`by a severe maternal hemorrhage, has hemiplegia and slightly
`delayed mental development, and another one was late in learning
`to speak but has later developed well.
`One male patient has a healthy son.
`
`Complications and Autopsy Findings. Since the first description
`of LPI in 1965,1 4 children and 1 adult of the 39 known Finnish
`patients have died. and a few pediatric LP] patients have died in
`other countries. A Moroccan patient died with pulmonary
`symptoms and autopsy findings similar to those of the four
`Finnish children (see below),37 and a Japanese patient has had
`long~lasting, slowly progressive interstitial changes in the lungs.36
`An American child with I P}! presented with interstitial pneumonia
`at the age of 27 months and later died of pulmonary alveolar
`»;
`
`three Italian patients with severe
`proteinosis.38 More recently,
`interstitial lung disease have been described.5i One of them died at
`the age of 18 months;
`two others had an accompanying renal
`glomcrular or glomerulotubluar disease. One Arab child had
`Severe respiratory insufficiency as the presenting sign at the age of
`11 years, and had had clubbing of the fingers for 5 years.52 An
`open lung biopsy showed cholesterol casts surrounded by a
`granulomatous process and giant cells; there was a small amount
`of interstitial inflammation and a moderate degree of scarring.
`Electron microscopy demonstrated cholesterol casts around and
`within macrophages and within alveolar cells in the alveolar
`spaces, but no hemorrhage.
`Two of the four Finnish children who died had another
`systemic disease in addition to LP] (SLR; hypothyreosis). In all
`four,
`the fatal courses began as acute or subaeute respiratory
`insufficiency, which progressed to multiorgan failm‘efafls'lm‘” the
`symptoms fulfilled the criteria of the multiple organ dysfunction
`syndromem-i32 Progressive fatigue, cough, and mild to high fever
`were typical. and some children had blood in the splttttlrt.73'80
`Dyspnea with marked air hunger during minimal exercise
`developed. Hemoglobin and platelet values fell, and the values
`of serum ferritin and lactate dehydrogenase, which are high in
`‘ normal circumstances in these patients, increased even further. The
`sedimentation rate was elevated. Arterial oxygen tension was
`decreased, and the children had a severe bleeding tendency. The
`severity of
`liver, kidney,
`and pancreas
`involvement
`in the
`multiorgan failure varied. The pulmonary symptoms lasted from
`2 weeks to 6 months before death.
`The radiologic findings during the acute phase were similar in
`all patients with a fatal course.TH Diffuse, l'cticttlonodular densities
`and, later, signs of rapidly progressing airspace disease appeared
`in the chest radiographs at the mean age of 5 ycafs (range 1.2 to
`10.2 years) (Fig. [92-3]. Two children developed acute respiratory
`insufficiency 2 months after the first radiolog'ic signs of lung
`involvement, bttt one patient had densities for over 2 years and
`another for 12 years before acute exacerbation.
`In one patient, a lung biopsy specimen taken at the time of
`appearance of the reticulonodular densities showed pulmonary
`alveolar proteinosis (Fig. 192—3C). At autopsy, three of the patients
`showed pulmonary alveolar proteinosis, and one had pulmonary
`hemorrhage with cholesterol granulomas. The specimens showed
`accumulations of myelin~like multilamellar structures, simple
`vesicles, granules, amorphous material, and crystals in transmis—
`sion electron microscopy (Fig. l9'2—4t).7'9 Samples from the patient
`with pulmonary cholesterol granulomas contained interstitial and
`intro-alveolar cholesterol crystals and some multilamellar struc-
`tures.
`lt
`is
`interesting that
`similar pulmonary cholesterol
`granul'omas vvene described in the lung biopsy sample of the
`Saudi Arabian child from Israel.52
`
`One adult patient developed acute respiratory insufficiency
`with cough, fever, dyspnea, and hemoptysis at
`the age of 23
`yew-5.7840 Chest radiographs showed interstitial densities and
`airspace disease. Pulmonary function tests
`showed minimal
`obstruction of the distal airways but normal diffusing capacity.
`Extensive microbiologic investigations showed no evidence of
`infection. An open lung biopsy specimen showed bronchiolitis
`obliterans with signs of interstitial pneumonia. Granulation tissue
`polyps obstructed bronchiolar
`lumina,
`alveolar
`septa were
`thickened, and the sample contained a number of infiltrating
`lymphocytes and macrophages as well as signs of alveolar
`hemorrhages; no vaSeulitis nor full—blown alveolar proteinosis
`were found. The cytoccntrifuge preparation made from the lung
`biopsy specimen showed 57 percent macrophages, 15 percent
`neutrophils, and 26 percent lymphocytes of the total cell count.
`The T—helper
`to T—suppressor cell
`ratio was 0.81. Symptoms
`disappeared rapidly and radiologic findings normalized within two
`months during high-dose prcdnisolone treatment. Eight months
`later, the patient relapsed with hemoptysis, but he responded well
`again to an increased corticosteroid dose. New, 5 years later,
`he is symptom—free;
`the results of pulmonary function tests,
`
`Page 7 of 26
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`Page 7 of 26
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`4938 PART 21 / MEMBRANE TRANSPORT DISORDERS
`
`Fig. 192-3 A 13-year-old girl with LPI who developed fatal respira-
`tory Insufficiency after a mild respiratory infection. A, Chest
`radiograph at the time 01 the first respiratory symptoms showed
`reticulonodular interstitial densities. 3, Chest radiograph taken two .
`weeks later shows interstitial and alveolar densities. C, Pulmonary
`biopsy specimen shows signs of alveolar proteinosis (hemaioxylin-
`eosin, original magnification x115). (From Farm at 3L7 Used by
`permission.)
`
`high—resolution computed tomography, and radionuclide imaging
`are normal, but the proportion of erythrocytes in the bronchoal—
`veolar lavage fluid is increased.
`Another patient developed chronic, slowly progressive pul-
`monary insufficiency with dyspnea, cough. chest pain. and
`hypoxia at the age of 42 yeal‘s.73’m A bronchoalvcolar lavage
`cuned clinical symptoms in hours. and the response has been as
`good in all of the six relapses that have occurred during the 7 years
`of followup. His chest radiographs show increasing interstitial
`linear and nodular densities. Six years afte