New Autosomal-Recessive Syndrome of LeberCongenital Amaurosis, Short Stature, GrowthHormone Insufficiency, Mental Retardation,Hepatic Dysfunction, and Metabolic Acidosis

Hiroaki Ehara,1* Chizuko Nakano,3 Kousaku Ohno,2 Yu-Ichi Goto,4 and Kenzo Takeshita1

1Division of Child Neurology, Institute of Neurological Sciences, Tottori University School of Medicine,Yonago, Japan

2Department of Neurobiology, School of Life Sciences, Tottori University School of Medicine, Yonago, Japan3Department of Pediatrics, National Suzuka Hospital, Suzuka, Japan4Division of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology andPsychiatry, Kodaira, Japan

We report on a new autosomal-recessivesyndrome in 4 Japanese children in 2 fami-lies. The key manifestations are Leber con-genital amaurosis, short stature, growthhormone insufficiency, mental retardation,hepatic dysfunction, metabolic acidosis,and autosomal-recessive inheritance. Therewere no consanguineous marriages. Abnor-mal eye movements were noticed neona-tally, and ophthalmological examinationsshowed no visual acuity, pigmentary retinaldegeneration, and nonrecordable electro-retinograms in all cases. Inadequate weightgain and short stature gradually became ap-parent after birth, and at present the heightrange is −4.6– −7.2 SD (standard deviations).Developmental delay was noted at age 4months, and the developmental quotient is50–70 at present. Deterioration of develop-ment and convulsions were not recognized.Elevated serum aminotransferase levelsand metabolic acidosis were also found atage 4 months. Proximal renal tubular acido-sis was clarified by bicarbonate tolerancetests in 1 case, and may have caused meta-bolic acidosis. Growth hormone secretionwas insufficient by insulin tolerance testin 3 cases. One year of growth hormonetherapy in 2 cases did not affect growth ve-locity. Hepatic dysfunction and metabolicacidosis ameliorated later. No renal cystswere found. A cranial computed tomo-graphic scan and magnetic resonance imag-

ing showed normal findings. Amino acids,organic acids, and very long chain fatty acidlevels in plasma were all normal in the 3cases examined. Histopathological and mi-tochondrial DNA analyses showed no evi-dence of mitochondrial disorders. Am. J.Med. Genet. 71:258–266, 1997.© 1997 Wiley-Liss, Inc.

KEY WORDS: Leber congenital amaurosis;poor weight gain; short stat-ure; growth hormone insuffi-ciency; mental retardation;hepatic dysfunction; meta-bolic acidosis; hyperurice-mia; hyperchloremia; autoso-mal-recessive inheritance

INTRODUCTION

Leber congenital amaurosis (LCA) is an autosomal-recessive trait marked by blindness before age 6months, variable fundus changes, and an absent ormarkedly reduced electroretinogram (ERG) [de Laey,1991]. It is a heterogenous disorder often associatedwith anomalies of the central nervous system [Deka-ban, 1972; Steinberg et al., 1992], renal system [Godelet al., 1980], and other abnormalities [de Laey, 1991].LCA also occurs in various syndromes (Senior-Lokensyndrome [LCA and nephronophthisis], Saldino-Mainzer syndrome [LCA, nephronophthisis, cerebellarataxia, and skeletal anomalies], LCA with cerebellarhypoplasia, and LCA with cardiomyopathy [de Laey,1991]) and in some peroxisomal disorders [Wanders etal., 1988; Ek et al., 1986]. In this paper we present 2pairs of unrelated sibs in 2 families with LCA, shortstature, growth hormone (GH) insufficiency, mental re-tardation, hepatic dysfunction, and metabolic acidosis,

*Correspondence to: Hiroaki Ehara, M.D., Ph.D., Division ofChild Neurology, Institute of Neurological Sciences, Tottori Uni-versity School of Medicine, Nishi-machi 86, Yonago 683, Japan.

Received 5 September 1995; Accepted 25 December 1996

American Journal of Medical Genetics 71:258–266 (1997)

© 1997 Wiley-Liss, Inc.

which we consider a new autosomal-recessive syn-drome, not suggestive of mitochondrial disorders fromhistopathological and mitochondrial DNA analyses.

CLINICAL REPORTS

The affected cases are 4 Japanese children in 2 fami-lies. Their relatives are healthy and have no retinopa-thy and no signs suggestive of mitochondrial disorders.The clinical and laboratory findings are summarized inTable I.

Patient 1 ([3949)

The parents (mother is age 23 years, father 29 years)of patients 1 and 2 are healthy and not consanguine-ous. He was the product of a primagravid woman, bornin 1979 at 41 weeks of gestation. His birth length was46.5 cm (−1.7 SD), weight 2,880 g (−0.8 SD), and headcircumference (OFC) 37.0 cm (+ 2.2 SD). As the Apgarscore was 3 at 1 minute, oxygen was administered.Tachypnea (80–100 times/min) persisted for 3 days af-ter birth. At age 7 days, cerebrospinal fluid was exam-ined and antibiotics were administered under a diag-nosis of bacterial meningitis, which resolved. Results ofGuthrie tests were normal. The parents noticed abnor-mal eye movements neonatally.

He was admitted at age 4 months because he couldnot fix or follow objects, and showed poor weight gainjust after birth. On admission, his length was 54.7 cm(−3.9 SD), weight 4,100 g (−3.1 SD), and OFC 40.0 cm(−1.4 SD). He did not have jaundice, hepatosplenomeg-aly, or minor anomalies. Abnormal eye movements andnystagmus persisted but optic atrophy was not noted.

His development was at a 2-month level. Peripheralblood cell counts, urinalysis, and cerebrospinal fluidwere normal. The serum aspartate aminotransferase(AST) level was 53 units (normal, <34), alanine amino-transferase (ALT) 31 (normal, <29), uric acid 7.8 mg/dl(normal, <6), and chloride 116 mEq/l (normal, 98–108).The other electrolytes, total and direct bilirubins, bloodurea nitrogen, creatinine, albumin, g-globulin, alkalinephosphatase, lactate dehydrogenase, leucine amino-peptidase, g-glutamyl transpeptidase, and cholinester-ase levels were normal. Base excess was not examined.Toxoplasma, others, rubella, cytomegalovirus, and her-pes simplex (TORCH) antibodies were not present. En-docrinological assessment of the hypothalamus, pitu-itary, thyroid gland, and adrenal cortex was not per-formed. Electroencephalogram (EEG), motor nerveconduction velocity (MCV), and auditory brain stem re-sponses (ABR) were normal. Visual evoked potentials(VEP) were low-voltage. Ophthalmological examina-tion demonstrated blindness, retinal pigmentary de-generation, and a nonrecordable ERG in both eyes. Adiagnosis of LCA was made. A cranial computed tomo-graphic (CT) scan was normal. Amino acid and organicacid analyses of serum and urine, and very long chainfatty acid analysis of serum, were not performed. Thekaryotype was not analyzed.

Deterioration of development and convulsions werenot observed. He died unexpectedly at age 9 months.An autopsy was not permitted.

Patient 2 ([5101)

She was born in 1981 as the sister of patient 1 at 42weeks of gestation in breech delivery. Her birth weight

TABLE I. Summary of Clinical and Laboratory Findings*

Case 1 2 3 4

Birth year 1979 1981 1984 1984Age (years) (7 M) 12 9 9Sex Male Female Female Female

Family history + + + +Prenatal history Term Term Breech Term C/S Term C/S

2,880 g, Apgar 3 2,960 g, Apgar 10 2,360 g, Apgar 6 2,230 g, Apgar 6Neonatal history Tachypnea meningitis np Phototherapy Phototherapy

Congenital amaurosis + + + +Retinal pigmentary degeneration + + + +Electroretinogram No response No response No response No responseAbnormal eye movements + + + +Short stature + + + +

−3.9 SD −4.6 SD −5.8 SD −7.2 SDDevelopmental delay + DQ 4 70 DQ 4 45–50 DQ 4 55–60Hepatomegaly − − + +Kidney Cyst (−) Cyst (−) RTA Cyst (−) Cyst (−)

GOT/GPT 50–100 50–100 50–100 50–100GH secretion NT Decreased Decreased Decreased17-OHCS/17-KS NT 40% 50%, TT; WNL 50%, TT; WNLBase excess NT −4–7 −2–4 WNLAmino acids NT WNL WNL WNLOrganic acids NT WNL WNL WNLVery long chain fatty acids NT WNL WNL WNLLysosomal enzymes WNL WNL WNL WNLBrain CT/MRI WNL WNL WNL WNLKaryotype NT 46,XX 46,XX 46,XX

*Plus sign (+) indicates presence of clinical finding; minus sign (−) indicates absence of clinical finding. M, months; C/S, cesarean section; np, nothingparticular; RTA, renal tubular acidosis; NT, not tested; WNL, within normal limits; TT, tolerance test.

New Syndrome in Japan 259

was 2,960 g and the Apgar score was 10 at 1 minute.Poor weight gain and abnormal eye movements werenoted just after birth. She smiled at age 4 months,when her length was 56.4 cm (−2.2 SD), weight 4,320 g(−3.0 SD), and OFC 38.5 cm (−1.3 SD).

On admission at age 7 months for further examina-tion of poor weight gain and abnormal eye movements,growth failure (length, 56.7 cm [−4.3 SD]; weight, 4,630g [−3.7 SD]; and OFC, 41.2 cm [−1.6 SD]) was promi-nent. She did not have jaundice, hepatosplenomegaly,minor anomalies, or the oculodigital sign. Her dailyenergy intake was 120 kcal/kg body weight. She couldnot fix or follow objects and showed floating eye move-ments. Nystagmus was observed at lateral gaze. Herdirect and indirect light reflexes were extremely slug-gish. Fundoscopic examination showed no optic atro-phy. Other cranial nerves were apparently normal. Shesmiled and held objects, but had no head control, herdevelopment being at a 3-month level (developmentalquotient (DQ), about 40). Muscle consistency was de-creased but muscle strength was normal. Deep-tendonreflexes were normal except for the Achilles tendon re-flex and triceps reflex, which were absent. Grimace andwithdrawal responses to painful stimuli were present.

On laboratory examination, blood cell counts and uri-nalysis were normal. The serum aminotransferase lev-els were elevated (AST 90 units [normal, <34] and ALT45 [normal, <34]), but the total and direct bilirubin,blood urea nitrogen, creatinine, uric acid, albumin,g-globulin, alkaline phosphatase, lactate dehydroge-nase, leucine aminopeptidase, g-glutamyl transpepti-dase, cholinesterase, total cholesterol, triglyceride, andammonium levels were all normal. TORCH antibodieswere absent. Total cell counts and protein and glucoselevels were normal in cerebrospinal fluid. Arterialblood gas analysis showed metabolic acidosis (base ex-cess, −6.6 mmol/l). The serum amino acid and organicacid analyses were normal. The pyruvate and lactatelevels in blood and cerebrospinal fluid were normal.The maximum tubular reabsorption of HCO−

3 was cal-culated to be 13.5 mmol/l [normal, 28.0] from the bicar-bonate tolerance tests, which was thought to be thecause of the acidosis. Results of the ammonium chlo-ride tolerance test was normal. The serum triiodothy-ronine (T3), thyroxine (T4), and thyroid-stimulatinghormone (TSH) levels, and urinary excretion of 17-hydroxy-corticoid (17-OHCS) and 17-ketosteroids (17-KS), were normal. The insulin tolerance test did notprovoke GH secretion (0.4 ng/ml at 45 min). Ophthal-mological examination documented blindness, pigmen-tary retinal degeneration, narrowing of retinal vessels,depigmentation of the iris, and nonrecordable ERG inboth eyes, and so she was diagnosed as having LCA.EEG, ABR, somatosensory evoked potentials (SEP),MCV, electrocardiogram (ECG), a caloric test, chestroentogenogram, and a cranial CT scan were normal.The karyotype was 46, XX (G-banding).

She attained head control at age 8 months, rolledover at 15 months, spoke several words at 19 months,and stood with support at 2 years.

She was readmitted at age 23⁄12 years for furtherexamination of short stature, when her height was 66.5cm (−5.5 SD), weight 6,620 g (−4.0 SD), and OFC 43.5

cm (−2.5 SD). She exhibited eye-pressing and hand-flapping mannerisms (the oculodigital sign). Abnormaleye movements continued as before. She stood withsupport but did not walk. She spoke about 20 words butdid not speak two-word sentences. Her DQ was 45. Onlaboratory examination, elevation of serum amino-transferase levels (AST 104 units [normal, <34], ALT57 [normal, <29]) and metabolic acidosis (base excess,−5.2 mmol/l) persisted. Serum amino acids were nor-mal. Serum and urinary organic acid levels were alsonormal as analyzed by gas chromatography. The otherlaboratory findings were essentially the same as thoseat age 7 months. The GH response following insulinadministration was low (maximum level, 5.3 ng/ml at90 min). Hexosaminidases A and B and b -galactosi-dase activities in white blood cells were normal. Thepyruvate dehydrogenase complex, pyruvate carboxyl-ase, and phosphoenolpyruvate carboxykinase activitiesin fibroblasts were normal. The serum T3, T4, and TSHlevels, and urinary excretion of 17-OHCS and 17-KS,were normal.

At age 58⁄12 years (Fig. 1A), her height and weightwere 80.4 cm (−6.7 SD) and 8.3 kg (−4.0 SD), respec-tively.

At age 13 years, her height, weight, and OFC were127.2 cm (−4.6 SD), 26.6 kg (−2.5 SD), and 50.5 cm(−2.0 SD), respectively. Serum AST, ALT, uric acid,chloride, T3, T4, and TSH levels were normal. Arterialblood gas analysis was not performed. DQ was about70. A fundus photograph is shown in Figure 2A. Dete-rioration of development and convulsions have notbeen noticed.

Patients 3 ([6699) and 4 ([6701)

Patients 3 and 4 are monozygotic twins and haveessentially the same history and physical, neurological,ophthalmological, and laboratory findings. Growthcurves of both patients are shown in Figure 3.

The parents are not consanguineous. The patients’elder sister was delivered by cesarean section (themother did not remember the reason) at 41 weeks ofgestation with a birth weight of 3,200 g in 1978 and isa healthy senior high school student at present. Thefather, age 44 years, is healthy. The mother had a spon-taneous abortion at 3 months of gestation in 1981.

The mother, a gravida 3, para 1 healthy woman, age38 years, had glucosuria (at 18–31 weeks of gestation)and transient edema. The patients were delivered bycesarean section (the mother did not remember the rea-son) at 38 weeks of gestation in 1984. Birth weightswere 2,360 g (−2.3 SD) and 2,230 g (−2.3 SD) in pa-tients 3 and 4, respectively, but body length and OFCwere not recorded. As their Apgar scores were 6 at 1minute, oxygen was administered. Phototherapy for 10hr was carried out in patient 3, but the serum bilirubinlevel was not recorded. Poor feeding was noticed neo-natally in both patients, but they did not have vomit-ing, weak cry, or convulsions. At age 1 month, theirabnormal eye movements were noticed, when theywere diagnosed as having LCA (microphthalmos, novisual acuity, pigmentary retinal degeneration, nar-rowing of retinal vessels, optic atrophy, depigmenta-tion of the iris, and nonrecordable ERG). Because of

260 Ehara et al.

poor weight gain and short stature, they were admittedat age 4 months. Their weights were 3,540 g (−4.7 SD)and 3,250 g (−5.1 SD), body lengths, 53.2 cm (−4.4 SD)and 53.3 cm (−4.4 SD), and OFC, 36.2 cm (−3.3 SD) and

37.2 cm (−2.4 SD) in patients 3 and 4, respectively. Theliver was palpable at 5 cm and 3 cm in patients 3 and4, respectively, on the right mammary line. Jaundice,splenomegaly (in patient 4), and minor anomalies were

Fig. 1. Patient 2, age 5 years (A), patient 3, age 9 years (B), and patient4, age 9 years (C).

New Syndrome in Japan 261

not found. On neurological examination, they had float-ing eye movements, nystagmus, and optic atrophy.Their development was at a 2-month level. Muscletone, muscle strength, and deep-tendon reflexes werenormal. Grimace and withdrawal responses to painfulstimuli were present.

On laboratory examination, peripheral blood cell

counts and urinalysis were normal. The serum chlo-ride, aminotransferases, total bile acids (in patient 4),and blood ammonium (in patient 3) levels were el-evated (Cl, 114 and 113 mEq/l) [normal, 98–110]; AST,101 and 79 U/l [normal, <29]; ALT, 74 and 69 U/l [nor-mal, <34] in patients 3 and 4, respectively; total bileacids (in patient 4), 22.2 m mol/l [normal, <14.4]; and

Fig. 2

262 Ehara et al.

ammonium (in patient 3), 132 mg/dl [normal, 30–86]).But the other electrolytes, total and direct bilirubins,uric acid, blood urea nitrogen, creatinine, albumin,g-globulin, alkaline phosphatase, lactate dehydroge-nase, leucine aminopeptidase, g-glutamyl transpepti-dase, cholinesterase, total cholesterol, triglyceride, to-tal bile acids (in patient 3), ceruloplasmin, copper, anda1-antitrypsin levels were normal. The blood ammo-nium level in patient 4 was normal. The TORCH anti-bodies, Epstein-Barr (EB) virus antibodies (viral capsidantigen and Epstein-Barr nuclear antigen), hepatitis Aantibody, hepatitis B surface (HBs) antigen, and HBsantibody were negative. The hepaplastin test was nor-mal. The serum T3, T4, adrenocorticotropic hormone(ACTH), and cortisol levels were normal. Total cellcounts, and protein, glucose, lactate, and pyruvate lev-els in cerebrospinal fluid, were normal. Arterial bloodgas analysis demonstrated metabolic acidosis (base ex-cess, −4.4 mmol/l) in patient 3 (patient 4, within nor-mal limits). Serum amino acid was normal. The serumand urinary organic acids were also normal as ana-lyzed by gas chromatography. Hepatomegaly, spleno-megaly (in case 3), and normal kidneys and heart wereobserved on ultrasound examinations. The ophthalmo-logical findings were the same as those at 1 month ofage. EEG, ABR, SEP, MCV, ECG, a caloric test, and acranial CT scan were normal. Their karyotype was 46,XX (G-banding).

At age 22 months, they were evaluated further forpoor weight gain. The daily energy intake was about400–450 kcal in patient 3. Patient 4 had almost thesame intake energy intake as patient 3. Their heightswere 61.5 cm (−7.6 SD) and 59.7 cm (−8.2 SD), weights,

4,510 g (−5.0 SD) and 4,140 g (−5.3 SD), and OFC, 42.3cm (−3.1 SD) and 42.3 cm (−3.1 SD) in patients 3 and 4,respectively. On neurological examination, they hadfloating eye movements, nystagmus, and optic atrophy.Development in both patients was at a 10–12-monthlevel. The elevation of serum AST and ALT levels andmetabolic acidosis (in patient 3) persisted (AST, 136and 123 U/l [normal, <40], ALT, 81 and 78 U/l [normal,<53], in patients 3 and 4, respectively, and base excess,−3.1 mmol/l [normal, −2.5–2.5]). The g-glutamyl trans-peptidase (50 and 58 U/l [normal, <40] in patients 3and 4, respectively) and uric acid (7.3 mg/dl [normal,<6.0] in patient 3) levels were also elevated. Theplasma insulin-like growth factor-I (IGF-I) level wasreduced (0.14 U/ml in patient 3 and 0.16 U/ml in pa-tient 4). Hepatomegaly persisted on ultrasound exami-nation. The other laboratory findings were essentiallythe same as those at age 4 months. The insulin anddopamine tolerance tests did not provoke GH secretionat 22⁄12 years. GH was administered subcutaneously toboth patients for 1 year from age 2 years 6 months, butthe growth velocity did not change. The serum T3, T4,and TSH levels were normal, but TSH secretion wasslightly low (7.0 mg/ml at 30 min) by the thyrotropin-stimulating hormone (TRH) tolerance test in case 4.They walked alone at 4 years. Deformity of the thoraxgradually became apparent at age 5 years.

At age 52⁄12 years, their bone age was delayed (pa-tient 3 at a 3-year level, and patient 4 at a 21⁄2 yearlevel). They had bronchial asthma, and so theophyllineand ketotifen (an antiallergic agent) were administeredorally.

At age 9 years 6 months, their heights were 98.6 cm

Fig. 2. Fundus (right), showing pigmentary retinal degeneration and narrowing of retinal vessels (A, patient 2), and pigmentary retinal degeneration,narrowing of retinal vessels, and optic atrophy (B, patient 3; C, patient 4).

New Syndrome in Japan 263

(−5.8 SD) and 90.7 cm (−7.2 SD), weights, 12.8 kg (−3.0SD) and 11.9 kg (−3.2 SD), and OFC, 45.4 cm (−4.4 SD)and 45.4 cm (−4.4 SD), in patients 3 and 4, respectively(Fig. 1B,C). Tachypnea (60 times/min), chest deformity,slight flaring of the alae nasi, and the oculodigital signwere present. On neurological examination, they hadfloating eye movements and nystagmus. Their esti-mated intelligence quotients (IQ) were 45–50 and 55–60 in patients 3 and 4, respectively. Muscle tone wasslightly decreased, but muscle power and deep-tendonreflexes were normal. The plasma AST and blood am-monium levels in patient 4 were slightly elevated (AST,44 IU/l; ammonium 93.6 mg/dl). Thyroid function (se-rum T3, T4, and TSH levels) was normal and the rapidACTH test in both patients showed a normal response,but the urinary excretions of 17-OHCS and 17-KS were0.5 and 0.7 mg/day (normal, 2.0–4.0 mg/m2/day) and0.8 and 0.6 mg/day (normal, 1.3–4.9 mg/m2/day) in pa-tients 3 and 4, respectively (slightly decreased). TheGH response to growth hormone-releasing hormone(GRH, 1 mg/kg) was very low (4.4 ng/ml in patient 3 and1.0 ng/ml in patient 4 at 30 min after injection). Ininsulin tolerance tests, the GH secretion was low inpatient 3 (9.4 ng/ml at 30 min) and very low in patient4 (4.0 ng/ml at 30 min), but ACTH and cortisol secre-tion were within normal limits in both cases. Theplasma IGF-I level was reduced (0.21 U/ml in patient 3and 0.21 U/ml in patient 4 [normal, 0.55–3.48]). Theophthalmological findings were the same as those atage 1 year 10 months (LCA, Fig. 2B,C). Magnetic reso-nance imaging (MRI) demonstrated a structurally nor-mal brain and the normal myelination patterns, whichfurther demonstrated atrophic and ‘‘meandering’’ opticnerves. Normal sugar chains of serum transferrin weredetected with the aid of isoelectric focusing and immu-noprinting [Ohno et al., 1992]. The plasma very longchain fatty acid level was normal.

Muscle biopsy (left biceps brachii muscle) was car-ried out in patient 4 at age 11 years to determinewhether or not she had a mitochondrial disorder. His-topathological examination showed mild variation infiber size and type 2 fiber atrophy, especially type 2B,but no ragged-red fiber was found. Mitochondrial DNAdeletion or duplication and the 3243, 8344, 8993, and11778 mutations were not detected [Goto et al.,1990a,b; Ozawa et al., 1995; Sakuta et al., 1992; Wal-lace et al., 1988].

DISCUSSION

The key manifestations in the 4 patients were LCA,short stature, GH insufficiency, mental retardation,hepatic dysfunction, and metabolic acidosis. Hyperuri-cemia and hyperchloremia were observed sporadically.LCA was the most distinguishing symptom amongthese key manifestations. LCA is defined as follows [deLaey, 1991]: 1) blindness before age 6 months, 2) nys-tagmus, 3) variable fundus aspect, 4) absent or attenu-ated ERG response, and 5) autosomal-recessive inher-itance. Our 4 patients satisfy all these criteria. Thereare many diseases which LCA accompanies. Among thesyndromes mentioned in the Introduction, the symp-toms of Senior-Loken syndrome and Saldino-Mainzer

syndrome are different from those of our 4 patients.Cerebellar hypoplasia and cardiomyopathy were notobserved in our patients.

It is widely known that central nervous system ab-normalities are often associated with LCA [de Laey,1991; Steinberg et al., 1992; Vaizey et al., 1977; Wein-stein et al., 1984; Nickel and Hoyt, 1982], e.g., mentalretardation, brain anomalies including hypoplasia ofthe cerebellar vermis, and EEG abnormalities. Brainanomalies and EEG abnormalities were not found, butmental retardation or developmental delay was pre-sent in all 4 of our patients. The incidence of mentalretardation was reported to range from 3–37% [deLaey, 1991], but Nickel and Hoyt [1982] and Steinberget al. [1992] concluded that it was due to secondarysensory deprivation. Joubert syndrome is often accom-panied by LCA [Tomita et al., 1979; King et al., 1984;Houdou et al., 1986; Ivarsson et al., 1993]. It includesepisodic hyperpnea, abnormal eye movements, mentalretardation, and ataxia with agenesis of the cerebellarvermis. Cerebellar lesions were not recognized on CTscans (or MRI) in any our patients.

On the other hand, the frequent association of LCAwith a variety of renal abnormalities has been empha-sized. Dekaban [1969] reported on 2 sibs with LCA,polycystic kidneys, and brain malformation of autoso-mal-recessive inheritance as a new syndrome. Arima etal. [1971] and Koya et al. [1973] reported on patientswith LCA, severe psychomotor retardation, agenesis ofthe cerebellar vermis, and blepharoptosis [see alsoKawaguchi et al., 1984; Matsuzaka et al., 1986]. Senioret al. [1961] reported on 4 sibs with LCA and nephrop-athy. Tsuru et al. [1980] described a case of a combi-nation of LCA, Dandy-Walker syndrome, and polycys-tic kidneys, with death due to renal insufficiency. Re-nal tubular acidosis (RTA, proximal) was confirmed bythe bicarbonate tolerance test in patient 2, which wasprobably the cause of the metabolic acidosis. In sharpcontrast, because our 4 patients have no renal cystsand no renal insufficiency (the blood urea nitrogen andcreatinine levels were normal), this syndrome cannotbe included in the category of oculo-cerebro-renal dis-eases. Sporadic hyperchloremia and hyperuricemiawere observed in patients 1, 3, and 4, but its causeremains unknown.

LCA is not a single disease entity, but may be a par-tial manifestation of various underlying diseases,among which peroxisomal disorders were recentlyclarified biochemically [Wanders et al., 1988]. Amongthe peroxisomal disorders, Zellweger syndrome, neona-tal adrenoleukodystrophy, infantile Refsum disease,hyperpipecolic acidemia, adrenoleukodystrophy,pseudo-Zellweger syndrome, and pseudoneonatal adre-noleukodystrophy were ruled out by the clinical mani-festations and the normal results of very long chainfatty acid analysis (patients 2–4). The clinical manifes-tations of our patients were not those of rhizomelicchondrodysplasia punctata. In Refsum disease, the di-agnostic tetrad (retinitis pigmentosa, peripheral poly-neuropathy, cerebellar ataxia, and high cerebrospinalfluid protein concentration) was found in virtually ev-ery patient, and the patients’ growth and developmentwere normal in infancy, but then they gradually dete-

264 Ehara et al.

riorated [Steinberg, 1989], so that Refsum disease canbe excluded (although the phytanic acid level was notmeasured). Ek et al. [1986] reported on a boy with psy-chomotor retardation, LCA, sensory hearing loss, andhepatomegaly, whose clinical and biochemical findingswere similar to those observed in Zellweger syndrome.Aikawa et al. [1989] performed biochemical studies andshowed the heterogeneity of 4 cases with LCA. Lam-bert et al. [1989] reexamined 75 patients in whom LCAhad been diagnosed previously, and found that 30 hadocular and systemic disorders. Revised diagnoses (ex-cept for ocular diseases) included Joubert syndrome,infantile Refsum disease, Zellweger syndrome, Seniorsyndrome, Dandy-Walker malformation with retinaldystrophy, and Alstrom syndrome. These two studiesindicate the importance of searching for the underlyingbiochemical changes in LCA. Pigmentary retinal de-generation occurs in carbohydrate-deficient glycopro-tein syndrome [Hagberg et al., 1993], but the carbohy-drate moiety of serum transferrin from patients 3 and4 was shown to be normal with the aid of isoelectricfocusing and immunoprinting [Ohno et al., 1992].NARP (neuronal muscle weakness, ataxia, and retini-tis pigmentosa) comprises retinitis pigmentosa (as thename indicates), but neuronal muscle weakness, sen-sory neuropathy, ataxia, epilepsy and cerebral atrophy

were not recognized in our patients. Atypical cases ofsepto-optic dysplasia [Morishima and Aranoff, 1986]may show hypoplasia of the optic nerves and a defi-ciency of GH, but the association of LCA has not beenreported.

One of the distinguishing symptoms of this syndromeis growth failure. The first pathogenetic factor is GHinsufficiency demonstrated by insulin (patients 2–4)and GRH (patients 3 and 4) tolerance tests, and hypo-responsiveness to GH (GH administration to patients 3and 4 did not influence growth velocity), which is prob-ably genetically determined. The GH response to insu-lin improved gradually in patients 2–4. The second fac-tor that we must consider is daily energy intake. It was120 kcal/kg body weight in patient 2 at age 7 months,which seems to be sufficient. It was only about 400–450kcal at age 22 months in patient 3 and probably inpatient 4. The recommended daily energy intake is 100kcal/kg body weight for Japanese children at this age(daily energy intake of patient 3 was 90–100 kcal/kgbody weight), which would mean that her energy in-take was not necessarily scanty, although the absoluteenergy intake was inadequate. Hence it was thoughtthat the serum albumin and cholesterol levels, as ba-rometers of nutritional status, were within normal lim-its. Thus, it can be concluded that the patients’ growthfailure was not due to poor energy intake.

Another characteristic of this syndrome is persistentmild elevation of the serum aminotransferase level,which gradually improved. It occurs in various liverdiseases, such as viral infection (e.g., hepatitis A, B,and C viruses, cytomegalovirus, EB virus) cirrhosis,biliary retention, fatty liver, drug-induced and autoim-mune hepatitis, and malignant diseases, which couldbe ruled out. Aminotransferase elevation also occurs inmuscle and heart diseases, which are unlikely in lightof clinical and laboratory findings.

From the endocrine point of view (except for GH,mentioned above), the TRH tolerance tests in patient 4showed a slightly low response, but the basal secretionof T3, T4, and TSH was normal in patients 2–4. Theresult of the rapid ACTH test was normal in patients 3and 4 at age 9 years 6 months, but the daily secretionof 17-OHCS and 17-KS was slightly reduced, so thatthe hypothalamus-pituitary-adrenal cortical axis mustbe examined carefully hereafter. The difficulty wefaced was that many examinations (especially varioustolerance tests) could not be performed due to the pa-tients’ low body weight.

We carried out pathological examination and mito-chondrial DNA analysis to determine whether this syn-drome was a mitochondrial disorder. But histopatho-logical examination showed nonspecific findings, prob-ably reflecting long-standing central nervous systeminvolvement. There were no findings suggestive of mi-tochondrial disorders. Furthermore, mitochondrialDNA deletion or duplication and the 3243, 8344, 8993,and 11778 mutations were not detected in patient 4.

As to inheritance, autosomal-recessive is most likely,since both sexes were affected and another sib is ingood health. The clinical and laboratory findings varysomewhat from case to case, but we conclude that thedifference is small and not significant. On an extensive

Fig. 3. Growth curves of patients 3 (solid circles) and 4 (open circles).Broken lines indicate mean and ± 2SD.

New Syndrome in Japan 265

survey of the literature, we found no case(s) with LCA,short stature, GH insufficiency, mental retardation,hepatic dysfunction, and metabolic acidosis, so we pro-pose that these 4 children represent a new autosomal-recessive syndrome.

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