Yonago Acta medica 2006;49:77–82

A New X-Linked Mental Retardation Syndrome with
Diplegia and Delayed Myelination
Hiroaki Ehara, Kyoichi Ohtani*, Toshiyuki Yamamoto†, Kousaku Ohno‡, Kenzo
Takeshita§, Yonehiro Kanemura¶ and Mami Yamasaki¶
Departmemt of Early Childhood Education and Care, Kurashiki City College, Kurashiki 711-0937,*Department of Pediatrics, Chizu Municipal Hospital, Chizu 689-1402, †Kanagawa Children’s
Medical Center, Yokohama 232-8555, ‡Department of Child Neurology, Institute of Neurological
Sciences, Tottori University Faculty of Medicine, Yonago 683-8504, §Daiichi Welfare University,
Dazaifu 818-0194 and ¶Institute for Clinical Research and Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka 540-0006 Japan

We report three boys (4, 6 and 8 years old) in a Japanese family with X-linked (XL) recessive severe mental retardation (MR), rigidospastic diplegia, mild athetotic movementof the upper limbs, delayed myelination and poor weight gain. Neurological manifestations were non-progressive. No deterioration of development, convulsion, cerebellar
signs, dysarthria, pseudobulbar signs, or minor anomalies including facial dysmorphismor macro-orchidism were found. Ocular fundus was normal. The patients’ mothers andone grandmother were clinically normal. Blood chemistry was within normal limits.
Serum anti-human T-cell leukemia virus-I antibody titer was negative. Levels of plasmaamino acids and serum very long chain fatty acids, and lysozomal enzyme activities
from leukocytes were normal. Brain magnetic resonance imaging scans showed delayed
myelination. Fragile X (FRAXA), fragile XE (FRAXE), proteolipid protein and L1 celladhesion molecule (L1CAM) genes were normal. These ﬁndings were not consistent withpreviously reported 13 XLMR syndromes with paralysis. We conclude that this condition is a distinct and previously undescribed XLMR syndrome.
Key words: L1 cell adhesion molecule; myelination delay; proteolipid protein; spastic diplegia;
X-linked mental retardation syndrome
family with XLMR associated with rigidospastic
diplegia, mild athetotic movement of the upper
limbs, delayed myelination and poor weight gain,
as a possible previously undescribed syndrome.

The frequency of mental retardation (MR) is estimated to be 1 to 3% according to WHO criteria(intelligence quotient less than 70) (Roeleveld
et al., 1997), and X-linked mental retardation(XLMR) accounts for a quarter of all MR in
males (Turner and Opitz, 1980). Signiﬁcant progress has been made in research in the XLMR ﬁeld
(Lubs et al., 1999; Cabezas et al., 1999; Hamel etal., 2000; Chiurazzi et al., 2004), and a number of
XLMR genes have been mapped and cloned recently. We report on three patients in a JapanesePatients and Methods
Clinical reports
The pedigree is given in Fig. 1. Two mothers (II-5

Abbreviations: DQ, developmental quotient; FRAXA, fragile X; FRAXE, fragile XE; L1CAM, L1 cell adhesion molecule; MR, mental retardation; MRI, magnetic resonance imaging; OFC, occipito-frontal circumference; SSCP, single strand
conformation polymorphism; XL, X-linked

77

H. Ehara et al.

11 months of age showed a 7-month myelinationlevel (about 70% of the normal level).
His stature at the age of 4 years 11 months
is shown in Table 1. His DQ was about 20 (hewalked with support, spoke no words and identiﬁed eyes, ears and mouth). Rigidospastic diplegia with a mild athetotic movement of the upper
limbs was noted.

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Fig. 1. Pedigree of the family.
carrier female.

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Patient 2 (III-9)
This child was born at 39 weeks of gestation
with a birth weight of 2938 g after an uncomplicated pregnancy to healthy, nonconsanguineous
Japanese parents (mother, age 29, father 31). His
Apgar score was 9. On day 5, phototherapy was
carried out for 24 h. He could control his headat 4 months and rolled over at 6 months of age.
MRI scans at 6 months of age showed a 4-month
myelination level (about 70% of the normal level).
His DQ was about 50 at 11 months of age. Clinical and laboratory findings are summarized inTable 1. His development and athetoid movements were the same as those in Patient 1.

and 7) and one grandmother (I-2) were clinicallynormal.
Patient 1 (III-7)
Patient 1 was born at 40 weeks of gestation witha birth weight of 3490 g after an uncomplicatedpregnancy to healthy, nonconsanguineous parents(mother, age 35, father 43). His Apgar score was
10. On day 6, phototherapy was carried out for
24 h since the serum total bilirubin level reached
337 µmol/L. He had controlled head movements
at 3 months of age. Poor weight gain (6230 g)
was noted at 5 months of age. He rolled overat 6 months of age. Hypertone of the lower extremities, developmental delay and poor weightgain (6580 g) were noted at 8 months of age ata general hospital. Delay of myelination at the
5-month level was also noticed on brain magnetic
resonance imaging (MRI).
He was admitted to Tottori University Hospital for further examination at 11 months ofage. His height was 74.0 cm (mean), weight 6.97
kg (–2.3 SD) and occipito-frontal circumference(OFC) 44.5 cm (–1.0 SD) on admission. His
developmental quotient (DQ) was about 50.
Other clinical and laboratory findings are summarized in Table 1. Motor nerve conduction
velocity of the right median nerve, auditory brainstem responses, visual evoked potentials and electrically elicited blink reﬂex were normal. Latencyof N20 of short-latency evoked potentials wasmarkedly delayed bilaterally. Brain MRI scans atPatient 3 (III-10)
Patient 3 was born at 40 weeks of gestation witha birth weight of 3060 g after an uncomplicatedpregnancy (mother, age 31, father 33). His Apgar
score was 9. On day 3, serum total bilirubin level
increased but phototherapy was not carried out.
He was able to control his head at 3 months androlled over at 8 months of age. He was diagnosed
as having cerebral palsy. His height was 74.0 cm(mean), weight 6.97 kg (–2.3 SD) and OFC 44.5
cm (–1.0 SD) at 9 months of age. Brain MRI
scans at 9 months of age showed a 6-month myelination level (about 70% of the normal level).
He sat at 1 year 5 months of age. DQ was about
50 at 2 years and 1 months of age. Clinical andlaboratory findings are summarized in Table 1.
His development and athetoid movements were
the same as those in Patient 1.

78

New X-linked mental retardation syndrome

Table 1. Clinical and laboratory ﬁndings in three patients
III-7

Patients
III-9

III-10Age
4 years 11 months 8 years 11 months 6 years 10 months
Birth weight (g)
3490
2938
3060
Phototherapy++–
Transient poor weight gain+++
Physical ﬁndings
Stature (SD)Height/weight/OFC–0.6/–2.1/–1.1–0.8/–1.6/–1.0–0.8/–1.0/–2.0
Minor anomalies–––
Hepatosplenomagely–––
Macroorchidism–––
Ocular fundus
N
N
N
Neurological ﬁndings
DQ
< 20
< 20
< 20
Rigidospastic diplegia+++
Athetoid movements (mild)+++
Laboratory ﬁndings
Transaminases
N
N
N
Amino acids (plasma)
N
N
N
Organic acids (urine)
N
N
N
VLCFA (serum)N
N
N
Lysozomal enzymes (leukocytes)
N
NN
Anti-HTLV-I antibody
nt––
T-cell subsets
N
N
N
Karyotype (G-banding)
N
N
N
FRAXA/FRAXE genes
N
N
N
Proteolipid protein geneNnt
nt
L1CAM gene
N
N
N
Electroencephalogram
N
N
N
Delayed myelination on MRI + (11 months)+ (6 months)+ (9 months)
DQ, developmental quotient; FRAXA, fragile X; FRAXE, fragile XE; HTLV-I, human T-cell leukemia virus-I;
L1CAM, L1 cell adhesion molecule; MRI, magnetic resonance imaging; N, normal; nt, not tested; OFC, occipitofrontal circumference; VLCFA, very long chain fatty acid.

Molecular analyses(Okamoto et al., 2004; Kanemura et al., 2005).
Brieﬂy, ampliﬁcation of the exons and the exonintron boundaries of the L1CAM gene was performed by PCR using oligonucleotide primers(Jouet et al., 1994). The puriﬁed PCR ampliﬁcation products were directly sequenced using an
ABI BigDye Terminator Cycle Sequencing Ready
Reaction Kit (Applied Biosystems, Foster City,
CA). DNA sequencing was carried out in both
directions for each template. No mutation was
detected in all exons and exon-intron boundaries
in the three patients. The research protocol on
L1CAM gene analysis was approved by the Medical Research Board of the Ethics Committee of
Osaka National Hospital.

We investigated fragile X (FRAXA) and fragile
XE (FRAXE) genes of the three patients, theproteolipid protein gene of Patient 1 and L1 celladhesion molecule (L1CAM) genes of all threepatients using molecular methodology. After obtaining informed consent, genomic DNAs wereisolated from peripheral blood lymphocytes of thepatients for study. FRAXA, FRAXE and proteolipid protein genes were analyzed according to themethod described in previous research (Nanba etal., 1995; Yamamoto et al., 1998). No abnormal
ﬁndings were detected.
Genetic analysis of L1CAM was performed
by DNA sequencing as previously described79

H. Ehara et al.

Table 2. Differential diagnosis: X-linked mental retardation syndromes with spastic paralysis*
Syndrome

OMIM

Reference

Additional signs and symptoms

PPM-X
Spastic paraplegia 16

300055300266

Lindsay et al.
Steinmuller et al.

[1996][1997]

Allan-Herndon-Dudley300523

Stevenson et al.

[1990]

Cantagrel

300524

Cantagrel et al.

[2004]JARID1C-related XLMRATR-X syndrome

300534301040Claes et al.
Martinez et al.

[2000][1998]

Cerebellar ataxia 2
MASA (L1CAM)
Renpenning syndrome
Fitzsimmons
Smith-Fineman-Myers

302500303350309470309560309580

Apak et al.
[1989]
Fransen et al.
[1997]
Sutherland et al.
[1988]
Fitzsimmons et al. [1983]
Guion-Almeida et al. [1998]

Schimke XLMR

312840

Schimke et al.

[1984]

Spastic paraplegia 2 (PLP1)
Hooft

312920Cailloux et al.
Hooft et al.

[2000][1968]

Siber

Siber

[1984]

Arena

Arena et al.

[1992]

Psychosis, macroorchidism
Aphasia, reduced vision, dysfunction of
bowel/bladder
Characteristic face, ataxia, athetoid
movements
Mild facial dysmorphia, stereotypic
movements
Facial hypotonia, maxillary hypoplasia
Short stature, facial dysmorphism,microcephaly
Spinocerebellar ataxia
Aphasia, shufﬂing gait, adducted thumbs
Short stature, microcephaly, small testis
Pes cavus, palmoplantar hyperkeratosis
Unusual facial appearance, seizures,deafness
Choreoathetosis, deafness,
ophthalmoplegia
Dysarthria, nystagmus, optic atrophy
Choreo-athetosis, microcephaly, peculiar
appearance
Microphthalmia with corneal opacities,
hypospadias
Ataxia, titubation, iron deposits in basal
ganglia

ATR-X, X-linked alpha-thalassemia/mental retardation; JARID1C, Jumonji AT-rich interactive domain 1C; L1CAM,
L1 cell adhesion molecule; OMIM, Online Mendelian Inheritance in Man; PLP, proteolipid protein; XLMR,
X-linked mental retardation.
* Pyramydal sign or spasticity is included.

detected at FRAXA and FRAXE sites. No mutation was detected in all exons and exon-intron
boundaries of L1CAM gene. These ﬁndings were
almost consistent in all affected patients (Table 1).
XL recessive inheritance is most likely since all
patients are male, female siblings were unaffected
and both mothers and one grandmother are neurologically normal.
For differential diagnosis, a review by
Chiurazzi et al. (2004), in which a total of 209
XLMR conditions (135 recessive and eight dominant disorders, and 66 nonspeciﬁc XLMR conditions are listed) was searched. Information fromthe “XLMR Update WebSite” last updated on 1
September 2005 by Pietro Chiurazzi [http://xlmr.
interfree.it/home.htm] and PubMed [http://www.
ncbi.nlm.nih.gov.] up until November 2005 wereDiscussion
Three affected patients in this family were characterized by severe MR, rigidospastic diplegia,
mild athetotic movement of upper limbs, delayed
myelination on MRI and transient poor weightgain. Neurological ﬁndings were nonprogressive.
Deterioration of development, convulsion, cerebellar signs (ataxia and nystagmus), dysarthria,
pseudobulbar sign, minor anomalies including
facial dysmorphism, hepatosplenomagaly, scoliosis and joint contractures were not observed.
No abnormal ocular and auditory findings were
found. Results of various biochemical analyses
and anti-human T-cell leukemia virus-I antibody
titers were normal. Repeat expansions were not80New X-linked mental retardation syndrome

condition in the literature despite our extensive
search. We conclude that our cases represent a
new XLMR syndrome with rigidospastic diplegia
based on the above sources.

searched as well. From a total of 40 distinct
conditions in which XLMR was associated withparalysis (spastic paraplegia, diplegia, quadriplegia or pyramidal tract signs) selected from thesethree literature sources, 24 conditions were excluded because of progressive course [MR withspastic paraplegia (Davis et al., 1981), XLMRwith progressive spasticity (Meloni et al., 2000),
etc.], hydrocephalus [Fried syndrome (Strain etal., 1997)], cerebral and cerebellar malformations [Pettigrew/MRXS5 syndrome (Pettigrew etal., 1991, etc.)], myoclonic epilepsy [myoclonic
epilepsy with MR (Scheffer et al., 2002), etc.],
blindness [(Hamel BCD syndrome (Hamel et al.,1999)], etc. Consequently, 16 entities are listed inTable 2.
One of the characteristic findings in ourpatients is delayed myelination on MRI. With
the development of MRI diagnostics, this ﬁnding
would be expected more frequently. We analyzed
the PLP gene implicated in myelination by meansof single strand conformation polymorphism(SSCP), which proved normal. No mutation was
detected in all exons and exon-intron boundariesof the L1CAM gene as well. Our cases had mild
athetotic movements in the upper limbs besides
MR and diplegia. Choreoathetosis has been described in several XLMR syndromes associatedwith spasticity. Baar and Gabriel (1966) andBundy and Grifﬁths (1977) [OMIM 312890], bothof which were incorporated into spastic paraplegia 2 [OMIM 312920], reported this as related
to athetotic movements, ataxia and nystagmus.
Hooft et al. (1968) and Schimke et al. (1984) also
reported families with choreoathetosis which areunequivocally different from our cases. Bialer etal. (1992) reported a family in which nine men inthree generations presented spastic quadriparesisand varying degrees of psychomotor retardation.
Although they had some similarities to the present
patients, characteristic facial expression, muscle
hypoplasia, progressive paresis and pseudobulbar
signs were not recognized in our patients. To
our knowledge, there are no reports of the same

References
1 Apak S, Yuksel M, Ozmen M, Saka N, Darendeliler
F, Neuhauser G. Heterogeneity of X-linked recessive (spino)cerebellar ataxia with or without spastic
diplegia. Am J Med Genet 1989;34:155–158.
2 Arena JF, Schwartz C, Stevenson R, Lawrence L,
Carpenter A, Duara R, et al. Spastic paraplegia withiron deposits in the basal ganglia: a new X-linked
mental retardation syndrome. Am J Med Genet
1992;43:479–490.
3 Baar HS, Gabriel AM. Sex-linked spastic paraplegia. Am J Ment Deﬁc 1966;71:13–18.
4 Bialer MG, Lawrence L, Stevenson RE, Silverberg
G, Williams MK, Arena JF, et al. Allan-HerndonDudley syndrome: clinical and linkage studies on asecond family. Am J Med Genet 1992;43:491–497.
5 Bundey S, Grifﬁths MI. Recurrence risks in families of children with symmetrical spasticity. Dev
Med Child Neurol 1977;19:179–191.
6 Cabezas DA, Arena JF, Stevenson RE, Schwartz C,
Goldberg S, Morales A, et al. XLMR database. Am
J Med Genet 1999;85:202–205.
7 Cailloux F, Gauthier-Barichard F, Mimault C, Isabelle V, Courtois V, Giraud G, et al. Clinical European Network on Brain Dysmyelinating Disease.
Genotype-phenotype correlation in inherited brain
myelination defects due to proteolipid protein genemutations. Eur J Hum Genet 2000;8:837–845.
8 Cantagrel V, Lossi A-M, Boulanger S, Depetris D,
Mattei M-G, Gecz J, et al. Disruption of a new X
linked gene highly expressed in brain in a familywith two mentally retarded males. J Med Genet
2004;41:736–742.
9 Chiurazzi P, Tabolacci E, Neri G. X-linked mental
retardation (XLMR): from clinical conditions tocloned genes. Clin Rev Clin Lab Sci 2004;41:117–
158.
10 Claes S, Devriendt K, Van Goethem G, Roelen L,
Meireleire J, Raeymaekers P, et al. Novel syndromic
form of X-linked complicated spastic paraplegia.
Am J Med Genet 2000;94:1–4.
11 Davis JG, Silverber G, Williams MK, Spiro A,
Shapiro LR. A new X-linked recessive mental retardation syndrome with progressive spastic quadriparesis. Am J Hum Genet 1981;33:75A.
12 Fitzsimmons JS, Fitzsimmons EM, McLachlan JI,
Gilbert GB. Four brothers with mental retardation,
spastic paraplegia and palmoplantar hyperkeratosis.
A new syndrome? Clin Genet 1983;23:329–335.

OMIM, Online Mendelian Inheritance in Man.

81

H. Ehara et al.

E, Poo P, Kanemura Y, et al. Hydrocephalus andHirschsprung’s disease with a mutation of L1CAM.
J Hum Genet 2004;49:334–337.
26 Pettigrew AL, Jackson LG, Ledbetter DH. New
X-linked mental retardation disorder with DandyWalker malformation, basal ganglia disease, andseizures. Am J Med Genet 1991;38:200–207.
27 Roeleveld N, Zielhuis GA, Gabreels F. The prevalence of mental retardation: a critical review of recent literature. Dev Med Child Neurol 1997;39:125–
132.
28 Scheffer IE, Wallace RH, Phillips FL, Hewson P,
Reardon K, Parasivam G, et al. X-linked myoclonic
epilepsy with spasticity and intellectual disability.
Mutation in the homeobox gene ARX. Neurology
2002;59:348–356.
29 Schimke RN, Horton WA, Collins DL, Therou L.
A new X-linked syndrome comprising progressive
basal ganglion dysfunction, mental and growth retardation, external ophthalmoplegia, postnatal microcephaly and deafness. Am J Med Genet 1984;17:
323–332.
30 Siber M. X-linked recessive microencephaly, microphthalmia with corneal opacities, spastic quadriplegia, hypospadias and cryptorchidism. Clin Genet
1984;26:453–456.
31 Steinmuller R, Lantigua-Cruz A, Garcia-Garcia R,
Kostrzewa M, Steinberger D, Muller U. Evidence ofa third locus in X-linked recessive spastic paraplegia. Hum Genet 1997;100:287–289.
32 Stevenson R E , Good ma n HO, Schwa r t z CE ,Simensen RJ, McLean WT, Herndon CN. AllanHerndon syndrome. I. Clinical studies. Am J Hum
Genet 1990;47:446–453.
33 Strain L, Wright AF, Bonthron DT. Fried syndrome
is a distinct X linked mental retardation syndrome
mapping to Xp22. J Med Genet 1997;34:535–540.
34 Sutherland GR, Gedeon AK, Haan EA, Woodroffe
P, Mulley JC. Linkage studies with the gene for an
X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2). Am J Med
Genet 1988;30:493–508.
35 Turner G, Opitz JM. Editorial comment: X-linked
mental retardation. Am J Med Genet 1980;7:407–
415.
36 Yamamoto T, Nanba E, Zhang H, Sasaki M, Komaki
H, Takeshita K. Jimpymsd mouse mutation andconnatal Pelizaeus-Merzbacher disease. Am J Med
Genet 1998;75:439–440.

13 Fransen E, Van Camp G, Vits L, Willems PJ. L1associated diseases: clinical geneticists divide, molecular geneticists unite. Hum Mol Genet 1997;6:
1625–1632.
14 Guion-Almeida ML, Tabith A Jr, Kokitsu-Nakata
NM, Zechi RM. Smith-Fineman-Myers syndromein apparently monozygotic twins. Am J Med Genet
1998;79:205–208.
15 Hamel BC, Wesseling P, Renier WO, van den Helm B,
Ropers HH, Kremer H, et al. A new X linked neurodegenerative syndrome with mental retardation,
blindness, convulsions, spasticity, mild hypomyelination and early death maps to the pericentromericregion. J Med Genet 1999;36:140–143.
16 Hamel BCJ, Chiurazzi P, Lubs HA. Syndromic
XLMR genes (MRXS): update 2000. Am J Med
Genet 2000;94:361–363.
17 Hooft C, de Hauwere R, van Acker KJ. Familial
non-congenital microcephaly, peculiar appearance,
mental and motor retardation, progressive evolution
to spasticity and choreo-athetosis. Helv Paediatr Act
1968;23:1–12.
18 Jouet M, Rosenthal A, Armstrong G, MacFarlane
J, Stevenson R, Paterson J, et al. X-linked spastic
paraplegia (SPG1), MASA syndrome and X-linked
hydrocephalus result from mutations in the L1 gene.
Nature Genet 1994;7:402–407.
19 Kanemura Y, Takuma Y, Kamiguchi H, Yamasaki
M. First case of L1CAM gene mutation identiﬁed
in MASA syndrome in Asia. Congenit Anom 2005;
45:67–69.
20 Lindsay S, Splitt M, Edney S, Berney TP, Knight
SJL, Davies KE, et al. PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal
signs, and macroorchidism maps to Xq28. Am J
Hum Genet 1996;58:1120–1126.
21 Lubs HA, Chiurazzi P, Arena J, Schwartz C, Tranebjaerg L, Neri G. XLMR genes: update 1998. Am J
Med Genet 1999;83:237–247.
22 Martinez F, Tomas M, Millan JM, Fernandez A,
Palau F, Prieto F. Genetic localisation of mental retardation with spastic diplegia to the pericentromericregion of the X chromosome: X inactivation in female carriers. J Med Genet 1998;35:284–287.
23 Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F,
D’Adamo P, et al. A mutation in the Rett syndrome
gene, MECP2, causes X-linked mental retardationand progressive spasticity in males. Am J Hum
Genet 2000;67:982–985.
24 Nanba E, Kohno Y, Matsuda A, Yano M, Sato C,
Hashimoto K, et al. Non-radioactive DNA diagnosis
for the fragile X syndrome in Japanese mentally retarded males. Brain Dev 1995;17:317–321.
25 Okamoto N, Del Maestro R, Valero R, Monros

Received June 6, 2006; accepted July 5, 2006
Corresponding author: Kousaku Ohno, MD82