The Metabolic &
`Molecular Bases of
`Inherited Disease
`
`eighth edition
`
`
`
`ASSOCIATE EDITORS
`
`Barton Childs, M.D.
`Kenneth W.Kinzler, Ph.D.
`Bert Vogelstein, M.D.
`
` \
`
`EDITORS
`
`‘
`
`Charles R. Scriver, M.D.C.M.
`Arthur L. Beaudet, M.D.
`William S. Sly, M.D.
`David Valle, M.D.
`
`.
`
`McGraw-Hit.
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`The Metabolic and Molecular Bases of Inherited Disease, 8th Edition
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`The metabolic and molecular bases of inherited disease / editors,
`Charles R. Scriver.., [et al.].—8th ed.
`ps
`em.
`Includes bibliographical references and index.
`ISBN 0-07-913035-6 (set)
`1. Metabolism, Inborn errors of
`Scriver, Charles R.
`[DNLM: 1. Hereditary Diseases. 2. Metabolic Diseases. 3. Metabolism, Inborn Errors.
`WD 200 M5865 2001]
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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 basolateral
`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 citrulline and the cationic amino
`acids do not share transport mechanisms in the tubules,
`part of the citrulline is converted to arginine and then to
`ornithine in the tubule cells during reabsorption. A
`basolateral transport defect prohibits antiluminal efflux 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 inerease 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 ofthe patients
`and the control subjects,
`The exact cause of hyperammonemia in LPI remains
`unknown, The enzymes of the urea cycle haye normal
`activities in the liver, and the brisk excretion of orotic acid
`during hyperammonemia supports the view that N-acet-
`ylglutamate and carbamyl phosphate are formed in
`sufficient quantities. Low plasma concentrationsof arginine
`and ornithine suggest that the malfunctioning of the cycle is
`caused by a deficiency of intramitochondrialornithine. 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 .
`aminoacid,it is well-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 hyperammonemia 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 explana-
`tions imply that the transport defect is expressed also in the
`organelle(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
`hyperammonemia, including enlargement of the liver and
`spleen, poor growth and delayed bone age, and osteoporosis.
`Oral lysine supplements are poorly tolerated by the patients
`
`Page 4 of 26
`
`7
`
`because of their poor intestinal absorption. e-N-acetyl-L-
`lysine, but not homocitrulline, efficiently increases plasma
`concentration of lysine in the patients, but acetyllysine or
`other neutral
`lysine analogues have not been used for
`supplementation.
`Recently, a 622-amino-acid retroviral receptor (murine
`leukemia viral receptor REC1) 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-1, mouse cationic amino
`acid transporter-1. The functional characteristics of the
`transporter are similar to those of system y*, a widely
`expressed Na*t-independent transport system for cationic
`amino acids. The human counterpart of the mouse REC1
`gene, encoding the retroviral receptor-transport protein,
`has been assigned to chromosome 13q12-q14 and named
`ATRCI1, MCAT-1 (and y*) 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-
`seq also in activated T and B lymphocytes) and MCAT-2 —
`are probably responsible for the low-affinity transport of
`cationic amino acids that is characteristic of (mouse) liver,
`Studies addressing the ATRC1 gene as well as the Tea and
`MCAF-2 genes as candidate genes for LPI are under way.
`8. Treatment
`in iysinuric protein intolerance consists of
`protein restriction 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,
`The clinical and biochemical findings in other cationic
`alninoacidurias 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
`lysinuria has severe growth failure, seizures, and mental
`retardation. Her transport defect is apparently limited to
`lysine, and hyperammonemiais not a feature of the disease.
`
`~
`
`Perheentupa and Visakorpi described the first three patients with
`“familial protein intolerance with deficient
`transport of basic
`amino acids” in 1965. The disease is now called lysinuric protein
`intolerance (LPI) (MIM 222700) or “hyperdibasic aminoaciduria
`type 2.°2-5 Over 100 patients with this autosomal recessive
`disease have been described or are known to me; 41 of them are
`Finns or Finnish Lapps.®~5? The incidence in Finland is
`1
`in
`60,000 births but varies considerably within the country.2°
`Patients of black and white 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, arginine, 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
`
`

`

` CHAPTER 192 / LYSINURIC PROTEIN INTOLERANCE AND OTHER CATIONIC AMINOACIDURIAS 4935-
`
`
`
`GENETIC DEFECT OF
`
`EPITHELIAL LYS, ARG & ORN TRANSPORT
`
`| INTESTINAL
`| TUBULAR RE-
`ABSORPTION
`ABSORPTION
`
`
`DEFICIENCY OF
`ORN, ARG &
`
`—————*|
`
`TRANSPORT INTO
`LIVER CELLS
`
`the diagnosis frequently has been delayed until the school age or
`even adulthood.*>47,5°
`Around the age of | 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 becameisoelectric when the
`IMPAIRED UREA CYCLE
`children were tube-fed with high-protein foods.?795404147 Enteral
`!
`alimentation and total parenteral nutrition may cause symptomsin
`POSTPRANDIAL HYPER-
`patients who have remained undiagnosed, because the protein or
`AMMONEMIA
`amino acid loads often exceed patient’s tolerance. Prolonged,
`‘
`
`moderately increased protein intake may lead to dizziness,
`NAUSEA, PROTEIN
`
`AVERSION
`psychotic periods, chronic abdominal pains, or suspicion of
`SEIZURES, STUPOR
`abdominal emergencies.
`COMA
`
`Bone fractures occur
`frequently, often after minor
`trau-
`ma,*!+30,35,63-66 Ty 4 Finnish series, 20 of 29 patients (69 percent)
`
`GROWTHFAILURE[osteororosis | HEPATOMEGALY ]
`had suffered from fractures of the long bones or of compression
`fractures of the lumbar spine; 10 (34 percent) had had more than 2
`Fig. 192-1 The suggested pathogenesis of lysine, arginine, land
`fractures during the 18-year
`follow-up.°?-° Most
`fractures
`ornithine deficiency, hyperammonemia, and aversion to protein in
`LPI.
`occurred before the age of 5 years, Symptoms of osteoarthrosis
`- often 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 citrulline 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 glomerulotubular disease with or without renal
`insufficiency as thefirst clinical finding (see “Complications and
`Autopsy Findings” below).
`
`PROTEIN MAL-
`NUTRITION
`
`édefi-
`saying that hyperammonemia is caused by “functional
`ciency” ofthe urea cycle intermediates arginine and ornithine in
`the urea cycle*!!:1454 (Big, 192-1), LPI 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 basolateral,
`(antiluminal) membraneof the epithelial cells.°°-°’ Further, in LPI
`the parenchymal cells show a defectin the trans-stimulated efflux
`of the cationic amino acids, suggesting that
`the basolateral
`membraneof the epithelial cells and the plasma membraneofthe
`parenchymalcells have analogous functions.**
`Recently, the first candidate gene for LPI, ATRC1, encoding a
`human cationic amino acid transporter, has been mapped to the
`long arm of chromosome 13 (13q12-q14).© Without further proof,
`it is intriguing to hypothesize how a mutation in this or in a
`functionally similar gene or in genes encoding regulatory proteins
`of these transporters might lead to the membr’ne-selective cationic
`amino acid transport defect of LPI and to the complicated clinical
`features of the disease.
`'
`Several patients with variant forms of cationic amingaciduria
`have been described in which the protein tolerance often is better
`than in LPI andthe selectivity and severity of cationic amino-
`aciduria differs,23:25.33.61.62 Ty the report by Whelan and Scriver®!
`only the history of the index case suggested hyperammonemia, but
`other members of the pedigree have been symptom-free. The
`inheritance ofthis hyperdibasic aminoaciduria type 1 is autosomal
`dominant, implying that the patients are heterozygous for LPI or
`another type of hyperdibasic aminoaciduria.
`
`CLINICAL ASPECTS
`
`Lysinuric Protein Intolerance
`Natural Course of the Disease, The gestation and delivery of
`infants with LPI has been uneventful.4~%°-!!5 Breast-fed infants
`usually thrive because of the low protein concentration in human
`milk, but symptoms of hyperammonemia may appear during the
`neonatal period andreflect 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 fo the parents and
`may remain unnoticed evenby trained physicians for years. Thus,
`ee
`
`Page 5 of 26
`
`Physical Findings. Muscular hypotonia and hypotrophy are
`usually noticeable from early infancy but improve with advancing
`age."° Most patients are unable to perform prolonged physical
`exercises, but acute performance is relatively good. The body
`proportions ofpatients after the first couple of years of life are
`characteristic: the extremities are thin, but the front view of the
`body is squarelike 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 reducedand the skin
`“loose” and “too large for the body” (Fig, 192-2),
`The ocular fundi have been normal by ophthalmoscopy.®> Of
`20 patients studied, 14 had minuteopacities 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 underlyingthe 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 Jengths 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
`maturationis considerably delayed.**4 The bones usually mature
`
`Page 5 of 26
`
`

`

`4936 PART 21 / MEMBRANE TRANSPORT DISORDERS \\
`
`Fig. 192-2 Two children with LPI. The pictures were taken atthe time—thorax of the child in A is deformed and her trunk shortened because
`of diagnosis. A, Child 12 years old. B, Child 6 years old. Note the
`of osteoporosis and pathologic fractures of the vertebrae.
`prominent abdomen, hypotrophic muscles, and “loose” skin. The
`\
`
`slowly and linearly without a pubertal catch-up spurt, and most
`patients have not reached skeletal maturity by the age of 20 years,
`The final height of the patients has almost invariably been closerto
`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 forage.
`The body ,ptoportions 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 LPI2°?-° Two-thirds 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 turcica have been normal in roentgenograms.
`Over 70 percent of the patients have some skeletal abnor-
`malities, either osteoporosis, deformations, or early osteoarthro-
`sis,3-In radiographs of 29 Finnish patients, osteoporosis was
`present in 13; 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
`7.4 Morphometric analyses of bone biopsy samples showed
`moderate to severe osteoporosis in eight of nine patients studied;
`trabecular bone and osteoid volume were markedly reduced.®
`After double-labeling of bones with tetracycline in vivo, barely
`identifiable single lines were detected, suggesting poor bone
`deposition;
`the findings resembled those in severe malnutri-
`tion.°*-"* The numberof osteoblasts and osteoclasts was low, and
`the extent of osteoid along the bone surfaces was low or normal in
`all specimens studied.
`Laboratory tests for evaluation of calcium and phosphate
`metabolism have given unremarkable results.2°~° Serum
`calcium and phosphate concentration, urinary excretion of calcium
`and phosphate, serum magnesium, estradiol, testosterone, thyroid-
`stimulating hormone, cortisol, vitamin D metabolites [25-(OH)2-
`D, 1,25-(OH)2-D and 24,25-(OH)2-D], parathyroid hormone,
`calcitonin, and osteocalcin concentrations have all been within
`the reference range,
`
`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 + 103 pmol/m?; adult reference range, 60 to 180 umol/
`m?),6 The serum hydroxyproline concentration is increased in
`almostall patients irrespective of age. Serum concentrations of the
`C-terminal propeptide of type I procollagen and of the N-terminal
`propeptide of type III procollagen have been normal
`in all
`pediatric patients, but the concentration of the latter increases
`Pd
`‘during puberty and remains elevated in adult patients.
`The incorporation of labeled hydroxyproline into collagen was
`significantly decreased in cultured LPI fibroblasts as compared
`with age-matched controls at the ages of 5, 14, and 30 years, but
`therk was no difference at the age of 44 years.Morphometry of
`the collagenfibrils 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 hepatocytes,**>-*.7> In olderpatients, delimited
`areas in periportal or central parts of the liver lobules contained
`hepatocytes with ample pale cytoplasm and small pyknotic nuclei.
`In these cells, the glycogen content is decreased, 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 acid-Schiff. 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, apolipoprotein synthesis is decreased, and lipoprotein
`lipases are inhibited.?* Similar liver changes have also been
`induced in rats by lysine and arginine deprivation.”’
`
`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 percentof 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 psychomotorseizures,'® Four patients have had
`psychotic periods, which have clearly been precipitated by
`prolonged moderate hyperammonemia,?5
`Neuropsychologic evaluation of the patients suggests that
`mathematical and other abstract skills are particularly vulnerable
`to hyperammonemia. Treatment with a low-protein diet and
`citrulline supplementation!''*+6 (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 40at the age of 12 years, lives
`now at the age of 40 in the custody of another family apd is
`capable of taking care of herdaily activities; she also works in a
`protected environmentoutside the home fora 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 ak an
`internist, is married, and is a mother of one. Several otherpatients
`have also graduated from high school or other secondary schools
`and are permanently employed. The physicalfitness of the patients
`is fair, but their capacity for prolonged heavy work and physicah
`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 yéars 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.!®!.29 One male and seven
`female patients are married.
`Pregnancies of the Patients. The seven mavied women have had
`fifteen pregnancies. One of the mothers was treated during the
`pregnancy only with protein restriction;
`the other yreceived
`citrulline supplementation (8 to 14 pills containing O\4l4 g L-
`citrulline daily during meals). Anemia (hemoglobin < 8.5 g/dl)
`occurred in all, and the platelet count decreased to less than
`50 x 107/mm*. 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.
`Ofthe 14 living children born to the patients, 13 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 waslate in learning
`to speak but has later developed well.
`One male patient has a healthy son.
`
`Complications and Autopsy Findings. Since thefirst description
`of LPI in 1965,! 4 children and 1 adult of the 39 known Finnish
`patients have died, and a few pediatric LPI 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),?’ and a Japanese patient has had
`long-lasting, slowly progressive interstitial changes in the lungs.*®
`An American child with LPI presented with interstitial pneumonia
`vat the age of 27 months and later died of pulmonary alveolar
`oo
`
`three Italian patients with severe
`proteinosis.** More recently,
`interstitial lung disease have been described.>! One of them died at
`the age of 18 months;
`two others had an accompanying renal
`glomerular 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.°* 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 LPI (SLE; hypothyreosis). In all
`four,
`the fatal courses began as acute or subacute respiratory
`insufficiency, which progressed to multiorgan failure;®*7578-®°the
`symptoms fulfilled the criteria of the multiple organ dysfunction
`syndrome.®!8? Progressive fatigue, cough, and mild to high fever
`were typical, and some children had blood in the sputum.7®-®°
`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 circumstancesin 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.”® Diffuse, reticulonodulardensities
`and, later, signs of rapidly progressing airspace disease appeared
`in the chest radiographs at the mean age of 5 year's (range 1.2 to
`10.2 years) (Fig. 192-3). Two children developed acute respiratory
`insufficiency 2 months after the first radiologic signs of lung
`involvement, but 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, 192-4).7? Samples from the patient
`with pulmonary cholesterol granulomas containedinterstitial and
`intra-alveolar cholesterol crystals and some multilamellar struc-
`tures.
`It
`is
`interesting that
`similar pulmonary cholesterol
`granulomas were described in the lung biopsy sample of the
`Saudi Arabian child from Israel.54
`One adult patient developed acute respiratory insufficiency
`with cough, fever, dyspnea, and hemoptysis at
`the age of 23
`years.’®-89 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 ofinterstitial 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 vasculitis nor full-blown alveolar proteinosis
`were found. The cytocentrifuge 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 prednisolone treatment. Eight months
`later, the patient relapsed with hemoptysis, but he responded well
`again to an increased corticosteroid dose. Now, 5 years later,
`he is symptom-free;
`the results of pulmonary function tests,
`
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`Page 7 of 26
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`4938 PART 21 / MEMBRANE TRANSPORT DISORDERS
`
`tory insufficiency after a mild respiratory infection. A, Chest
`radiograph at the time of the first respiratory symptoms showed
`reticulonodular interstitial densities. B, Chest radiograph taken two .
`weeks later showsinterstitial and alveolar densities. C, Pulmonary
`biopsy specimen showssignsofalveolar proteinosis (hematoxylin-
`eosin, original magnification 115). (From Parto et al.” Used by
`permission.)
`
` Fig. 192-3 A 13-year-old girl with LP! who developed fatal respira-
`
`ct
`
`Fig. 192-4 Pulmonary macrophages of patients with LPI. A, An
`electron micrograph shows macrophage containing multilamellar
`structures and electron-dense bodies that contain iron (magnifica-
`tion x3100). B, The same cell at a greater magnification shows
`characteristic electron-dense areas which, according to the x-ray
`spectrum, contained mainly iron (x4600). C. Another pulmonary
`macrophage containing a numberof black-staining, iron-containing
`precipitations (x 27,200). (From Parto etal.”° Used by permission.)
`
`(8 of 14).78 Most of the symptom-free patients (9 of 12) also
`showed mild abnormalities in perfusion imaging or in pulmonary
`function tests (8 of 12),
`Thetotal cell count in the bronchoalveolarlavage fluid of three
`adult LPI patients was normal, but