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

New Autosomal-Recessive Syndrome of Leber

Congenital Amaurosis, Short Stature, Growth
Hormone Insufficiency, Mental Retardation,
Hepatic Dysfunction, and Metabolic Acidosis
Hiroaki Ehara,1* Chizuko Nakano,3 Kousaku Ohno,2 Yu-Ichi Goto,4 and Kenzo Takeshita1
1
Division of Child Neurology, Institute of Neurological Sciences, Tottori University School of Medicine,
Yonago, Japan
2
Department of Neurobiology, School of Life Sciences, Tottori University School of Medicine, Yonago, Japan
3
Department of Pediatrics, National Suzuka Hospital, Suzuka, Japan
4
Division of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and
Psychiatry, Kodaira, Japan

We report on a new autosomal-recessive ing showed normal findings. Amino acids,

syndrome in 4 Japanese children in 2 fami- organic acids, and very long chain fatty acid
lies. The key manifestations are Leber con- levels in plasma were all normal in the 3
genital amaurosis, short stature, growth cases examined. Histopathological and mi-
hormone insufficiency, mental retardation, tochondrial DNA analyses showed no evi-
hepatic dysfunction, metabolic acidosis, dence of mitochondrial disorders. Am. J.
and autosomal-recessive inheritance. There Med. Genet. 71:258–266, 1997.
were no consanguineous marriages. Abnor- © 1997 Wiley-Liss, Inc.
mal eye movements were noticed neona-
tally, and ophthalmological examinations KEY WORDS: Leber congenital amaurosis;
showed no visual acuity, pigmentary retinal poor weight gain; short stat-
degeneration, and nonrecordable electro- ure; growth hormone insuffi-
retinograms in all cases. Inadequate weight ciency; mental retardation;
gain and short stature gradually became ap- hepatic dysfunction; meta-
parent after birth, and at present the height bolic acidosis; hyperurice-
range is −4.6 – −7.2 SD (standard deviations). mia; hyperchloremia; autoso-
Developmental delay was noted at age 4 mal-recessive inheritance
months, and the developmental quotient is
50–70 at present. Deterioration of develop-
ment and convulsions were not recognized.
Elevated serum aminotransferase levels INTRODUCTION
and metabolic acidosis were also found at Leber congenital amaurosis (LCA) is an autosomal-
age 4 months. Proximal renal tubular acido- recessive trait marked by blindness before age 6
sis was clarified by bicarbonate tolerance months, variable fundus changes, and an absent or
tests in 1 case, and may have caused meta- markedly reduced electroretinogram (ERG) [de Laey,
bolic acidosis. Growth hormone secretion 1991]. It is a heterogenous disorder often associated
was insufficient by insulin tolerance test with anomalies of the central nervous system [Deka-
in 3 cases. One year of growth hormone ban, 1972; Steinberg et al., 1992], renal system [Godel
therapy in 2 cases did not affect growth ve- et al., 1980], and other abnormalities [de Laey, 1991].
locity. Hepatic dysfunction and metabolic LCA also occurs in various syndromes (Senior-Loken
acidosis ameliorated later. No renal cysts syndrome [LCA and nephronophthisis], Saldino-
were found. A cranial computed tomo- Mainzer syndrome [LCA, nephronophthisis, cerebellar
graphic scan and magnetic resonance imag- ataxia, and skeletal anomalies], LCA with cerebellar
hypoplasia, and LCA with cardiomyopathy [de Laey,
1991]) and in some peroxisomal disorders [Wanders et
*Correspondence to: Hiroaki Ehara, M.D., Ph.D., Division of al., 1988; Ek et al., 1986]. In this paper we present 2
Child Neurology, Institute of Neurological Sciences, Tottori Uni- pairs of unrelated sibs in 2 families with LCA, short
versity School of Medicine, Nishi-machi 86, Yonago 683, Japan. stature, growth hormone (GH) insufficiency, mental re-
Received 5 September 1995; Accepted 25 December 1996 tardation, hepatic dysfunction, and metabolic acidosis,
© 1997 Wiley-Liss, Inc.
 New Syndrome in Japan 259

which we consider a new autosomal-recessive syn- His development was at a 2-month level. Peripheral
drome, not suggestive of mitochondrial disorders from blood cell counts, urinalysis, and cerebrospinal fluid
histopathological and mitochondrial DNA analyses. were normal. The serum aspartate aminotransferase
(AST) level was 53 units (normal, <34), alanine amino-
CLINICAL REPORTS transferase (ALT) 31 (normal, <29), uric acid 7.8 mg/dl
(normal, <6), and chloride 116 mEq/l (normal, 98–108).
The affected cases are 4 Japanese children in 2 fami- The other electrolytes, total and direct bilirubins, blood
lies. Their relatives are healthy and have no retinopa- urea nitrogen, creatinine, albumin, g-globulin, alkaline
thy and no signs suggestive of mitochondrial disorders. phosphatase, lactate dehydrogenase, leucine amino-
The clinical and laboratory findings are summarized in peptidase, g-glutamyl transpeptidase, and cholinester-
Table I. ase levels were normal. Base excess was not examined.
Patient 1 ([3949) Toxoplasma, others, rubella, cytomegalovirus, and her-
pes simplex (TORCH) antibodies were not present. En-
The parents (mother is age 23 years, father 29 years) docrinological assessment of the hypothalamus, pitu-
of patients 1 and 2 are healthy and not consanguine- itary, thyroid gland, and adrenal cortex was not per-
ous. He was the product of a primagravid woman, born formed. Electroencephalogram (EEG), motor nerve
in 1979 at 41 weeks of gestation. His birth length was conduction velocity (MCV), and auditory brain stem re-
46.5 cm (−1.7 SD), weight 2,880 g (−0.8 SD), and head sponses (ABR) were normal. Visual evoked potentials
circumference (OFC) 37.0 cm (+ 2.2 SD). As the Apgar (VEP) were low-voltage. Ophthalmological examina-
score was 3 at 1 minute, oxygen was administered. tion demonstrated blindness, retinal pigmentary de-
Tachypnea (80–100 times/min) persisted for 3 days af- generation, and a nonrecordable ERG in both eyes. A
ter birth. At age 7 days, cerebrospinal fluid was exam- diagnosis of LCA was made. A cranial computed tomo-
ined and antibiotics were administered under a diag- graphic (CT) scan was normal. Amino acid and organic
nosis of bacterial meningitis, which resolved. Results of acid analyses of serum and urine, and very long chain
Guthrie tests were normal. The parents noticed abnor- fatty acid analysis of serum, were not performed. The
mal eye movements neonatally. karyotype was not analyzed.
He was admitted at age 4 months because he could Deterioration of development and convulsions were
not fix or follow objects, and showed poor weight gain not observed. He died unexpectedly at age 9 months.
just after birth. On admission, his length was 54.7 cm An autopsy was not permitted.
(−3.9 SD), weight 4,100 g (−3.1 SD), and OFC 40.0 cm
Patient 2 ([5101)
(−1.4 SD). He did not have jaundice, hepatosplenomeg-
aly, or minor anomalies. Abnormal eye movements and She was born in 1981 as the sister of patient 1 at 42
nystagmus persisted but optic atrophy was not noted. weeks 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 1984
Age (years) (7 M) 12 9 9
Sex 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 6
Neonatal history Tachypnea meningitis np Phototherapy Phototherapy
Congenital amaurosis + + + +
Retinal pigmentary degeneration + + + +
Electroretinogram No response No response No response No response
Abnormal eye movements + + + +
Short stature + + + +
−3.9 SD −4.6 SD −5.8 SD −7.2 SD
Developmental delay + DQ 4 70 DQ 4 45–50 DQ 4 55–60
Hepatomegaly − − + +
Kidney Cyst (−) Cyst (−) RTA Cyst (−) Cyst (−)
GOT/GPT 50–100 50–100 50–100 50–100
GH secretion NT Decreased Decreased Decreased
17-OHCS/17-KS NT 40% 50%, TT; WNL 50%, TT; WNL
Base excess NT −4–7 −2–4 WNL
Amino acids NT WNL WNL WNL
Organic acids NT WNL WNL WNL
Very long chain fatty acids NT WNL WNL WNL
Lysosomal enzymes WNL WNL WNL WNL
Brain CT/MRI WNL WNL WNL WNL
Karyotype 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, nothing
particular; RTA, renal tubular acidosis; NT, not tested; WNL, within normal limits; TT, tolerance test.
260 Ehara et al.

was 2,960 g and the Apgar score was 10 at 1 minute. cm (−2.5 SD). She exhibited eye-pressing and hand-
Poor weight gain and abnormal eye movements were flapping mannerisms (the oculodigital sign). Abnormal
noted just after birth. She smiled at age 4 months, eye movements continued as before. She stood with
when her length was 56.4 cm (−2.2 SD), weight 4,320 g support but did not walk. She spoke about 20 words but
(−3.0 SD), and OFC 38.5 cm (−1.3 SD). did not speak two-word sentences. Her DQ was 45. On
On admission at age 7 months for further examina- laboratory examination, elevation of serum amino-
tion of poor weight gain and abnormal eye movements, transferase levels (AST 104 units [normal, <34], ALT
growth failure (length, 56.7 cm [−4.3 SD]; weight, 4,630 57 [normal, <29]) and metabolic acidosis (base excess,
g [−3.7 SD]; and OFC, 41.2 cm [−1.6 SD]) was promi- −5.2 mmol/l) persisted. Serum amino acids were nor-
nent. She did not have jaundice, hepatosplenomegaly, mal. Serum and urinary organic acid levels were also
minor anomalies, or the oculodigital sign. Her daily normal as analyzed by gas chromatography. The other
energy intake was 120 kcal/kg body weight. She could laboratory findings were essentially the same as those
not fix or follow objects and showed floating eye move- at age 7 months. The GH response following insulin
ments. Nystagmus was observed at lateral gaze. Her administration was low (maximum level, 5.3 ng/ml at
direct and indirect light reflexes were extremely slug- 90 min). Hexosaminidases A and B and b -galactosi-
gish. Fundoscopic examination showed no optic atro- dase activities in white blood cells were normal. The
phy. Other cranial nerves were apparently normal. She pyruvate dehydrogenase complex, pyruvate carboxyl-
smiled and held objects, but had no head control, her ase, and phosphoenolpyruvate carboxykinase activities
development being at a 3-month level (developmental in fibroblasts were normal. The serum T3, T4, and TSH
quotient (DQ), about 40). Muscle consistency was de- levels, and urinary excretion of 17-OHCS and 17-KS,
creased but muscle strength was normal. Deep-tendon were normal.
reflexes were normal except for the Achilles tendon re- At age 5 8⁄12 years (Fig. 1A), her height and weight
flex and triceps reflex, which were absent. Grimace and were 80.4 cm (−6.7 SD) and 8.3 kg (−4.0 SD), respec-
withdrawal responses to painful stimuli were present. tively.
On laboratory examination, blood cell counts and uri- At age 13 years, her height, weight, and OFC were
nalysis were normal. The serum aminotransferase lev- 127.2 cm (−4.6 SD), 26.6 kg (−2.5 SD), and 50.5 cm
els were elevated (AST 90 units [normal, <34] and ALT (−2.0 SD), respectively. Serum AST, ALT, uric acid,
45 [normal, <34]), but the total and direct bilirubin, chloride, T3, T4, and TSH levels were normal. Arterial
blood urea nitrogen, creatinine, uric acid, albumin, blood gas analysis was not performed. DQ was about
g-globulin, alkaline phosphatase, lactate dehydroge- 70. A fundus photograph is shown in Figure 2A. Dete-
nase, leucine aminopeptidase, g-glutamyl transpepti- rioration of development and convulsions have not
dase, cholinesterase, total cholesterol, triglyceride, and been noticed.
ammonium levels were all normal. TORCH antibodies
Patients 3 ([6699) and 4 ([6701)
were absent. Total cell counts and protein and glucose
levels were normal in cerebrospinal fluid. Arterial Patients 3 and 4 are monozygotic twins and have
blood gas analysis showed metabolic acidosis (base ex- essentially the same history and physical, neurological,
cess, −6.6 mmol/l). The serum amino acid and organic ophthalmological, and laboratory findings. Growth
acid analyses were normal. The pyruvate and lactate curves of both patients are shown in Figure 3.
levels in blood and cerebrospinal fluid were normal. The parents are not consanguineous. The patients’
The maximum tubular reabsorption of HCO−3 was cal- elder sister was delivered by cesarean section (the
culated to be 13.5 mmol/l [normal, 28.0] from the bicar- mother did not remember the reason) at 41 weeks of
bonate tolerance tests, which was thought to be the gestation with a birth weight of 3,200 g in 1978 and is
cause of the acidosis. Results of the ammonium chlo- a healthy senior high school student at present. The
ride tolerance test was normal. The serum triiodothy- father, age 44 years, is healthy. The mother had a spon-
ronine (T3), thyroxine (T4), and thyroid-stimulating taneous abortion at 3 months of gestation in 1981.
hormone (TSH) levels, and urinary excretion of 17- The mother, a gravida 3, para 1 healthy woman, age
hydroxy-corticoid (17-OHCS) and 17-ketosteroids (17- 38 years, had glucosuria (at 18–31 weeks of gestation)
KS), were normal. The insulin tolerance test did not and transient edema. The patients were delivered by
provoke GH secretion (0.4 ng/ml at 45 min). Ophthal- cesarean section (the mother did not remember the rea-
mological examination documented blindness, pigmen- son) at 38 weeks of gestation in 1984. Birth weights
tary retinal degeneration, narrowing of retinal vessels, were 2,360 g (−2.3 SD) and 2,230 g (−2.3 SD) in pa-
depigmentation of the iris, and nonrecordable ERG in tients 3 and 4, respectively, but body length and OFC
both eyes, and so she was diagnosed as having LCA. were not recorded. As their Apgar scores were 6 at 1
EEG, ABR, somatosensory evoked potentials (SEP), minute, oxygen was administered. Phototherapy for 10
MCV, electrocardiogram (ECG), a caloric test, chest hr was carried out in patient 3, but the serum bilirubin
roentogenogram, and a cranial CT scan were normal. level was not recorded. Poor feeding was noticed neo-
The karyotype was 46, XX (G-banding). natally in both patients, but they did not have vomit-
She attained head control at age 8 months, rolled ing, weak cry, or convulsions. At age 1 month, their
over at 15 months, spoke several words at 19 months, abnormal eye movements were noticed, when they
and stood with support at 2 years. were diagnosed as having LCA (microphthalmos, no
She was readmitted at age 2 3⁄12 years for further visual acuity, pigmentary retinal degeneration, nar-
examination of short stature, when her height was 66.5 rowing of retinal vessels, optic atrophy, depigmenta-
cm (−5.5 SD), weight 6,620 g (−4.0 SD), and OFC 43.5 tion of the iris, and nonrecordable ERG). Because of
 New Syndrome in Japan 261

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

poor weight gain and short stature, they were admitted 37.2 cm (−2.4 SD) in patients 3 and 4, respectively. The
at age 4 months. Their weights were 3,540 g (−4.7 SD) liver was palpable at 5 cm and 3 cm in patients 3 and
and 3,250 g (−5.1 SD), body lengths, 53.2 cm (−4.4 SD) 4, respectively, on the right mammary line. Jaundice,
and 53.3 cm (−4.4 SD), and OFC, 36.2 cm (−3.3 SD) and splenomegaly (in patient 4), and minor anomalies were
262 Ehara et al.

Fig. 2

not found. On neurological examination, they had float- counts and urinalysis were normal. The serum chlo-
ing eye movements, nystagmus, and optic atrophy. ride, aminotransferases, total bile acids (in patient 4),
Their development was at a 2-month level. Muscle and blood ammonium (in patient 3) levels were el-
tone, muscle strength, and deep-tendon reflexes were evated (Cl, 114 and 113 mEq/l) [normal, 98–110]; AST,
normal. Grimace and withdrawal responses to painful 101 and 79 U/l [normal, <29]; ALT, 74 and 69 U/l [nor-
stimuli were present. mal, <34] in patients 3 and 4, respectively; total bile
On laboratory examination, peripheral blood cell acids (in patient 4), 22.2 m mol/l [normal, <14.4]; and
 New Syndrome in Japan 263

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).

ammonium (in patient 3), 132 mg/dl [normal, 30–86]). 4,510 g (−5.0 SD) and 4,140 g (−5.3 SD), and OFC, 42.3
But the other electrolytes, total and direct bilirubins, cm (−3.1 SD) and 42.3 cm (−3.1 SD) in patients 3 and 4,
uric acid, blood urea nitrogen, creatinine, albumin, respectively. On neurological examination, they had
g-globulin, alkaline phosphatase, lactate dehydroge- floating eye movements, nystagmus, and optic atrophy.
nase, leucine aminopeptidase, g-glutamyl transpepti- Development in both patients was at a 10–12-month
dase, cholinesterase, total cholesterol, triglyceride, to- level. The elevation of serum AST and ALT levels and
tal bile acids (in patient 3), ceruloplasmin, copper, and metabolic acidosis (in patient 3) persisted (AST, 136
a1-antitrypsin levels were normal. The blood ammo- and 123 U/l [normal, <40], ALT, 81 and 78 U/l [normal,
nium level in patient 4 was normal. The TORCH anti- <53], in patients 3 and 4, respectively, and base excess,
bodies, Epstein-Barr (EB) virus antibodies (viral capsid −3.1 mmol/l [normal, −2.5–2.5]). The g-glutamyl trans-
antigen and Epstein-Barr nuclear antigen), hepatitis A peptidase (50 and 58 U/l [normal, <40] in patients 3
antibody, hepatitis B surface (HBs) antigen, and HBs and 4, respectively) and uric acid (7.3 mg/dl [normal,
antibody were negative. The hepaplastin test was nor- <6.0] in patient 3) levels were also elevated. The
mal. The serum T3, T4, adrenocorticotropic hormone plasma insulin-like growth factor-I (IGF-I) level was
(ACTH), and cortisol levels were normal. Total cell reduced (0.14 U/ml in patient 3 and 0.16 U/ml in pa-
counts, and protein, glucose, lactate, and pyruvate lev- tient 4). Hepatomegaly persisted on ultrasound exami-
els in cerebrospinal fluid, were normal. Arterial blood nation. The other laboratory findings were essentially
gas analysis demonstrated metabolic acidosis (base ex- the same as those at age 4 months. The insulin and
cess, −4.4 mmol/l) in patient 3 (patient 4, within nor- dopamine tolerance tests did not provoke GH secretion
mal limits). Serum amino acid was normal. The serum at 22⁄12 years. GH was administered subcutaneously to
and urinary organic acids were also normal as ana- both patients for 1 year from age 2 years 6 months, but
lyzed by gas chromatography. Hepatomegaly, spleno- the growth velocity did not change. The serum T3, T4,
megaly (in case 3), and normal kidneys and heart were and TSH levels were normal, but TSH secretion was
observed on ultrasound examinations. The ophthalmo- slightly low (7.0 mg/ml at 30 min) by the thyrotropin-
logical findings were the same as those at 1 month of stimulating hormone (TRH) tolerance test in case 4.
age. EEG, ABR, SEP, MCV, ECG, a caloric test, and a They walked alone at 4 years. Deformity of the thorax
cranial CT scan were normal. Their karyotype was 46, gradually became apparent at age 5 years.
XX (G-banding). At age 5 2⁄12 years, their bone age was delayed (pa-
At age 22 months, they were evaluated further for tient 3 at a 3-year level, and patient 4 at a 2 1⁄2 year
poor weight gain. The daily energy intake was about level). They had bronchial asthma, and so theophylline
400–450 kcal in patient 3. Patient 4 had almost the and ketotifen (an antiallergic agent) were administered
same intake energy intake as patient 3. Their heights orally.
were 61.5 cm (−7.6 SD) and 59.7 cm (−8.2 SD), weights, At age 9 years 6 months, their heights were 98.6 cm
264 Ehara et al.

(−5.8 SD) and 90.7 cm (−7.2 SD), weights, 12.8 kg (−3.0 syndrome are different from those of our 4 patients.
SD) and 11.9 kg (−3.2 SD), and OFC, 45.4 cm (−4.4 SD) Cerebellar hypoplasia and cardiomyopathy were not
and 45.4 cm (−4.4 SD), in patients 3 and 4, respectively observed in our patients.
(Fig. 1B,C). Tachypnea (60 times/min), chest deformity, It is widely known that central nervous system ab-
slight flaring of the alae nasi, and the oculodigital sign normalities are often associated with LCA [de Laey,
were present. On neurological examination, they had 1991; Steinberg et al., 1992; Vaizey et al., 1977; Wein-
floating eye movements and nystagmus. Their esti- stein et al., 1984; Nickel and Hoyt, 1982], e.g., mental
mated intelligence quotients (IQ) were 45–50 and 55– retardation, brain anomalies including hypoplasia of
60 in patients 3 and 4, respectively. Muscle tone was the cerebellar vermis, and EEG abnormalities. Brain
slightly decreased, but muscle power and deep-tendon anomalies and EEG abnormalities were not found, but
reflexes were normal. The plasma AST and blood am- mental retardation or developmental delay was pre-
monium levels in patient 4 were slightly elevated (AST, sent in all 4 of our patients. The incidence of mental
44 IU/l; ammonium 93.6 mg/dl). Thyroid function (se- retardation was reported to range from 3–37% [de
rum T3, T4, and TSH levels) was normal and the rapid Laey, 1991], but Nickel and Hoyt [1982] and Steinberg
ACTH test in both patients showed a normal response, et al. [1992] concluded that it was due to secondary
but the urinary excretions of 17-OHCS and 17-KS were sensory deprivation. Joubert syndrome is often accom-
0.5 and 0.7 mg/day (normal, 2.0–4.0 mg/m2/day) and panied by LCA [Tomita et al., 1979; King et al., 1984;
0.8 and 0.6 mg/day (normal, 1.3–4.9 mg/m2/day) in pa- Houdou et al., 1986; Ivarsson et al., 1993]. It includes
tients 3 and 4, respectively (slightly decreased). The episodic hyperpnea, abnormal eye movements, mental
GH response to growth hormone-releasing hormone retardation, and ataxia with agenesis of the cerebellar
(GRH, 1 mg/kg) was very low (4.4 ng/ml in patient 3 and vermis. Cerebellar lesions were not recognized on CT
1.0 ng/ml in patient 4 at 30 min after injection). In scans (or MRI) in any our patients.
insulin tolerance tests, the GH secretion was low in On the other hand, the frequent association of LCA
patient 3 (9.4 ng/ml at 30 min) and very low in patient with a variety of renal abnormalities has been empha-
4 (4.0 ng/ml at 30 min), but ACTH and cortisol secre- sized. Dekaban [1969] reported on 2 sibs with LCA,
tion were within normal limits in both cases. The polycystic kidneys, and brain malformation of autoso-
plasma IGF-I level was reduced (0.21 U/ml in patient 3 mal-recessive inheritance as a new syndrome. Arima et
and 0.21 U/ml in patient 4 [normal, 0.55–3.48]). The al. [1971] and Koya et al. [1973] reported on patients
ophthalmological findings were the same as those at with LCA, severe psychomotor retardation, agenesis of
age 1 year 10 months (LCA, Fig. 2B,C). Magnetic reso- the cerebellar vermis, and blepharoptosis [see also
nance imaging (MRI) demonstrated a structurally nor- Kawaguchi et al., 1984; Matsuzaka et al., 1986]. Senior
mal brain and the normal myelination patterns, which et al. [1961] reported on 4 sibs with LCA and nephrop-
further demonstrated atrophic and ‘‘meandering’’ optic athy. Tsuru et al. [1980] described a case of a combi-
nerves. Normal sugar chains of serum transferrin were nation of LCA, Dandy-Walker syndrome, and polycys-
detected with the aid of isoelectric focusing and immu- tic kidneys, with death due to renal insufficiency. Re-
noprinting [Ohno et al., 1992]. The plasma very long nal tubular acidosis (RTA, proximal) was confirmed by
chain fatty acid level was normal. the bicarbonate tolerance test in patient 2, which was
Muscle biopsy (left biceps brachii muscle) was car- probably the cause of the metabolic acidosis. In sharp
ried out in patient 4 at age 11 years to determine contrast, because our 4 patients have no renal cysts
whether or not she had a mitochondrial disorder. His- and no renal insufficiency (the blood urea nitrogen and
topathological examination showed mild variation in creatinine levels were normal), this syndrome cannot
fiber size and type 2 fiber atrophy, especially type 2B, be included in the category of oculo-cerebro-renal dis-
but no ragged-red fiber was found. Mitochondrial DNA eases. Sporadic hyperchloremia and hyperuricemia
deletion or duplication and the 3243, 8344, 8993, and were observed in patients 1, 3, and 4, but its cause
11778 mutations were not detected [Goto et al., remains unknown.
1990a,b; Ozawa et al., 1995; Sakuta et al., 1992; Wal- LCA is not a single disease entity, but may be a par-
lace et al., 1988]. tial manifestation of various underlying diseases,
among which peroxisomal disorders were recently
DISCUSSION clarified biochemically [Wanders et al., 1988]. Among
the peroxisomal disorders, Zellweger syndrome, neona-
The key manifestations in the 4 patients were LCA, tal adrenoleukodystrophy, infantile Refsum disease,
short stature, GH insufficiency, mental retardation, hyperpipecolic acidemia, adrenoleukodystrophy,
hepatic dysfunction, and metabolic acidosis. Hyperuri- pseudo-Zellweger syndrome, and pseudoneonatal adre-
cemia and hyperchloremia were observed sporadically. noleukodystrophy were ruled out by the clinical mani-
LCA was the most distinguishing symptom among festations and the normal results of very long chain
these key manifestations. LCA is defined as follows [de fatty acid analysis (patients 2–4). The clinical manifes-
Laey, 1991]: 1) blindness before age 6 months, 2) nys- tations of our patients were not those of rhizomelic
tagmus, 3) variable fundus aspect, 4) absent or attenu- chondrodysplasia punctata. In Refsum disease, the di-
ated ERG response, and 5) autosomal-recessive inher- agnostic tetrad (retinitis pigmentosa, peripheral poly-
itance. Our 4 patients satisfy all these criteria. There neuropathy, cerebellar ataxia, and high cerebrospinal
are many diseases which LCA accompanies. Among the fluid protein concentration) was found in virtually ev-
syndromes mentioned in the Introduction, the symp- ery patient, and the patients’ growth and development
toms of Senior-Loken syndrome and Saldino-Mainzer were normal in infancy, but then they gradually dete-
 New Syndrome in Japan 265

were not recognized in our patients. Atypical cases of

septo-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 been
reported.
One of the distinguishing symptoms of this syndrome
is growth failure. The first pathogenetic factor is GH
insufficiency demonstrated by insulin (patients 2–4)
and GRH (patients 3 and 4) tolerance tests, and hypo-
responsiveness to GH (GH administration to patients 3
and 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 was
120 kcal/kg body weight in patient 2 at age 7 months,
which seems to be sufficient. It was only about 400–450
kcal at age 22 months in patient 3 and probably in
patient 4. The recommended daily energy intake is 100
kcal/kg body weight for Japanese children at this age
(daily energy intake of patient 3 was 90–100 kcal/kg
body weight), which would mean that her energy in-
take was not necessarily scanty, although the absolute
energy intake was inadequate. Hence it was thought
that 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’ growth
failure was not due to poor energy intake.
Another characteristic of this syndrome is persistent
mild elevation of the serum aminotransferase level,
which gradually improved. It occurs in various liver
diseases, 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 could
Fig. 3. Growth curves of patients 3 (solid circles) and 4 (open circles).
Broken lines indicate mean and ± 2SD. be ruled out. Aminotransferase elevation also occurs in
muscle and heart diseases, which are unlikely in light
of clinical and laboratory findings.
riorated [Steinberg, 1989], so that Refsum disease can From the endocrine point of view (except for GH,
be excluded (although the phytanic acid level was not mentioned above), the TRH tolerance tests in patient 4
measured). Ek et al. [1986] reported on a boy with psy- showed a slightly low response, but the basal secretion
chomotor retardation, LCA, sensory hearing loss, and of T3, T4, and TSH was normal in patients 2–4. The
hepatomegaly, whose clinical and biochemical findings result of the rapid ACTH test was normal in patients 3
were similar to those observed in Zellweger syndrome. and 4 at age 9 years 6 months, but the daily secretion
Aikawa et al. [1989] performed biochemical studies and of 17-OHCS and 17-KS was slightly reduced, so that
showed the heterogeneity of 4 cases with LCA. Lam- the hypothalamus-pituitary-adrenal cortical axis must
bert et al. [1989] reexamined 75 patients in whom LCA be examined carefully hereafter. The difficulty we
had been diagnosed previously, and found that 30 had faced was that many examinations (especially various
ocular and systemic disorders. Revised diagnoses (ex- tolerance tests) could not be performed due to the pa-
cept for ocular diseases) included Joubert syndrome, tients’ low body weight.
infantile Refsum disease, Zellweger syndrome, Senior We carried out pathological examination and mito-
syndrome, Dandy-Walker malformation with retinal chondrial DNA analysis to determine whether this syn-
dystrophy, and Alström syndrome. These two studies drome was a mitochondrial disorder. But histopatho-
indicate the importance of searching for the underlying logical examination showed nonspecific findings, prob-
biochemical changes in LCA. Pigmentary retinal de- ably reflecting long-standing central nervous system
generation occurs in carbohydrate-deficient glycopro- involvement. There were no findings suggestive of mi-
tein syndrome [Hagberg et al., 1993], but the carbohy- tochondrial disorders. Furthermore, mitochondrial
drate moiety of serum transferrin from patients 3 and DNA deletion or duplication and the 3243, 8344, 8993,
4 was shown to be normal with the aid of isoelectric and 11778 mutations were not detected in patient 4.
focusing and immunoprinting [Ohno et al., 1992]. As to inheritance, autosomal-recessive is most likely,
NARP (neuronal muscle weakness, ataxia, and retini- since both sexes were affected and another sib is in
tis pigmentosa) comprises retinitis pigmentosa (as the good health. The clinical and laboratory findings vary
name indicates), but neuronal muscle weakness, sen- somewhat from case to case, but we conclude that the
sory neuropathy, ataxia, epilepsy and cerebral atrophy difference is small and not significant. On an extensive
266 Ehara et al.

survey of the literature, we found no case(s) with LCA, Koya G, Shinohara T, Morimatsu Y, Miura M (1973): Congenital polycystic
kidney syndrome: Three cases with agenesis of the cerebellar vermis
short stature, GH insufficiency, mental retardation, and displacement of the pyramidal tract among the brain stem [in
hepatic dysfunction, and metabolic acidosis, so we pro- Japanese]. No To Hattatsu 5:229–241.
pose that these 4 children represent a new autosomal- Lambert SR, Kriss A, Taylor D, Coffy R, Pembrey M (1989): Follow-up and
recessive syndrome. diagnostic reappraisal of 75 patients with Leber’s congenital amauro-
sis. Am J Ophthalmol 107:624–631.

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