American Journal of Medical Genetics 101:135±141 (2001)

New Autosomal Recessive Cerebellar AtaxiaDisorder in a Large Inbred Lebanese Family

A. MeÂgarbaneÂ,1* V. Delague,1 M.M. Ruchoux,2 E. Rizkallah,3 C.A. Maurage,2 L. Viollet,4

N. Rouaix-Emery,5 and A. Urtizberea6

1Unite de GeÂneÂtique MeÂdicale, Faculte de MeÂdecine, Universite Saint-Joseph, Beirut, Lebanon2Service de Neuro-pathologie, CHRU-Lille, France3Service de Neuro-peÂdiatrie, HoÃpital Saint Georges, Beirut, Lebanon4Service de PeÂdiatrie, HoÃpital de Garches, Paris, France5Laboratoire de Biochimie, CHRU-Lille, France6Institut de Myologie, HoÃpital de la SalpeÂtrieÁre, Paris, France

A large inbred Lebanese pedigree withcongenital spastic ataxia, microcephaly,optic atrophy, short stature, speech defect,abnormal osmiophilic pattern of skin ves-sels, cerebellar atrophy, and severe mentalretardation transmitted as an autosomalrecessive trait has been studied. None ofthe children had any evidence of ametabolicdisease, and the analysis of respiratorychain complex abnormalities was unre-markable. Only one child had a history ofperinatal dif®culties. Differential diagnosisand the possibility that this disorder is ahitherto unreported one are discussed.ß 2001 Wiley-Liss, Inc.

KEY WORDS: mental retardation; cere-bellar hypoplasia; opticatrophy; short stature;microcephaly; optic atro-phy; ultrastructural vascu-lar abnormalities; Druze;Middle East

INTRODUCTION

The hereditary ataxias are a heterogeneous group ofgenetic disorders characterized by cerebellar symp-toms, such as the uncoordinated gait often associatedwith poor coordination of hands, speech, and eyemovements, in association with other neurologicaland nonneurological features. Most of these syndromesare hereditary and different modes of inheritance have

been reported. The clinical course ranges from benignand/or nonprogressive to rapidly fatal (progressiveneurodegenerative). Since the primary biochemicaldefect is unknown in most of these disorders, a clinicalclassi®cation based on the age of onset, associatedclinical features, evolution, and mode of inheritancehas been proposed [Harding, 1983, 1984; Campanellaet al., 1992].This report describes ®ve children of the same

kindred with severe mental retardation, short stature,speech defect, cerebellar ataxia, microcephaly, opticatrophy, abnormal osmiophilic pattern of skin vessels,and cerebellar atrophy. These patients are likely topresent a hitherto unreported autosomal recessivedisorder.

CLINICAL REPORT

The kindred (Fig. 1) belong to the Druze Lebanesecommunity. A clinical summary of each patient ispresented in Table I.

Patient 1

Patient 1 (VI-4, Fig. 1), the propositus, is the productof a ®rst pregnancy of a 22-year-old mother married to acousin. Gestation and delivery at term were unremark-able with no evidence of any exposure to toxic orinfectious factors. Birth weight, length, and occipito-frontal circumference (OFC) were not available butwere considered unremarkable by the parents. Delayedpsychomotor milestones were obvious since 10 monthsof life. This child sat up at 12 months and was able tocrawl at 36 months. Ambulation was progressivelyachieved by age 10 years. He never gained urinary orfecal continence and did not experience sleepingproblems.He was ®rst seen at 14 years (Fig. 2). During ex-

amination, he was cooperative and always smiled. Hewas severely mentally retarded, unable to feed himselfand to drink unassisted. No understandable speech wasnoted, but reaction to simple orders was present. His

Grant sponsor: JeÂroÃme Lejeune Foundation.

*Correspondence to: A. MeÂgarbaneÂ, M.D., Ph.D., Unite deGeÂneÂtique MeÂdicale, Faculte de MeÂdecine, Universite Saint-Joseph, 42, rue de Grenelle, 75007 Paris, France.E-mail: megarban@dm.net.lb

Received 05 June 2000; Accepted 24 February 2001

Published online 7 May 2001

ß 2001 Wiley-Liss, Inc.

weight was 32 kg (<3rd centile); height, 140 cm (<3rdcentile); and OFC, 51.5 cm (3rd centile). There were nodiscernible dysmorphic features or skin abnormalitiesand no organomegaly. Dermatoglyphic palm patternswere unremarkable.The neurological examination revealed a clumsy boy

with poor ®ne movements and rapid alternating move-ments and inaccurate ®nger-to-nose test. His gait waswide-based and hesitant, and he displayed truncaloscillations when standing. The boy was unable tostand on one foot without help. He had a diffusespasticity, increased tendinous re¯exes, symmetricallypositive abdominal re¯exes, bilateral foot clonus, andslightly diminished muscle strength in the lower limbs.The reactive gag re¯ex was positive. A sensory examwas normal to all modalities. No seizures and no cranialnerve abnormalities were noted. The ophthalmicevaluation revealed an optic atrophy, oculomotorapraxia, bilateral esotropia, round, equal, reactivepupils, but no nystagmus, no cataracts, and no ptosis.

Electronic microscopy on a skin biopsy revealed thepresence of an inversion of the usual osmiophilicpattern of the vessels, mainly the capillaries andcapillary metarterioles, with a gray core correspondingto the lumen surrounded by an osmiophilic endothelialring, an electrolucent media, and a normal slightlyosmiophilic ring of ®broblasts (Fig. 3). Irregularvacuoles secondary to changes within the vessel wallswere also noticed. The lumens presented a normaldiameter. The endothelial cells were ®lled with compactmicro®laments forming stressing bands in front of theabluminal membrane. There was no basal laminathickening. The elastica lamina seemed normal. Musclecells conserved their smooth shape and their junctions,but the cytoplasms were electrolucent and disorga-nized, with clusters of organites and clear areas. Thenuclei seemed normal. No modi®cation was observed ineither the epithelial cells, ®broblasts, or muscle ®bers.The muscular biopsy showed muscle ®bers morpho-

logically unchanged, and the respiratory chain complex

Fig. 1. Pedigree of the family. Squares and circles with a solid dark color indicate the affected individuals, and cross hatch circles indicate patients withdiastrophic dysplasia.

TABLE I. Clinical Characteristics of the Patients*

Patient VI-1 VI-2 VI-4 VI-5 VI-14Sex M M M M FAge of onset (months) 1 10 10 9 10Age of examination (y) 10 9 14 13 9Head circumference 49 49.5 51.5 52 50.5Height (cm) 103 101 140 125 105Sat at (months) 18 13 12 12 14Walked with support at (y) ± ± 10 9 ±Tendinous re¯exes Brisk Brisk Brisk Brisk BriskSpeech defect � � � � �Optic atrophy � � � � �Normal respiratory chain � NP � NP NPSkin abnormalities at EM � � � NP NPCerebellar atrophy at MRI � NP � NP �*EM, electronic microscopy; NP, not performed.

136 MeÂgarbane et al.

analysis was within normal ranges. Magnetic reso-nance imaging (MRI) of the brain showed an atrophy ofthe cerebellar vermis and cerebral hemispheres, adilated 4th ventricle, and a large magna cisterna(Fig. 4A and B). The brain stem was normal, with nomigration defects or demyelination.Total body X-rays, abdominal ultrasound, echocar-

diography (ECG), electroencephalography (EEG),electromyogram, nerve conduction studies, evokedpotentials, and auditory brain stem responses were allunremarkable. Complete blood count, hemoglobinelectrophoresis, serum electrolytes, blood glucoselevels, triglycerides, cholesterol, lactate, pyruvate,transferrin analysis, amino acid studies of plasma andurine, urinary screening for organic acids, urinalysis,thyroid, liver, and renal function tests, plasma verylong chain fatty acid, phytanic acid blood levels, andwhite blood cell enzyme assay screening were all withinnormal limits. A chromosomal study of lymphocyteswith high-resolution G and R bandings showed anormal 46,XY karyotype.

The clinical examination of both parents was strict-ly normal. This boy has another affected brother(Patient 2).

Patient 2

Patient 2 (VI-5, Fig. 1) was delivered vaginally at full-term after a normal pregnancy. This boy was born 1year after the affected brother. Upon examination, hisclinical features and physical appearance were iden-tical to those of his brother, except that he could notwalk without support (Table I). He was severelymentally retarded and used sounds and murmurs tocommunicate. He never gained urinary or fecal con-tinence. At 9 years, his weight was 27 kg (<3rd centile);height, 125 cm (<3rd centile); and OFC, 52 cm (25thcentile). Routine laboratory and radiological examswere unremarkable. The ophthalmic evaluation re-vealed a complete optic atrophy. An MRI and skin andmuscular biopsies were not performed.

Patient 3

Patient 3 (VI-1, Fig. 1) is the ®rst child of healthyconsanguineous parents. When he was born, themother was 23 and the father was 25. Delivery at termby cephalic presentation was dif®cult and complicatedby cyanosis and hypotonia. His weight at birth was2,000 g (<3rd centile), and his length was 51 cm (75thcentile). The OFCwas not available. Like in his affecteddistant cousins, the developmental delay was strikingand was obvious since the ®rst months of age. This boynever walked but was able to crawl. He had dif®culties

Fig. 2. Photograph of patient 1 (VI-4) at 14 years. Note the wide-basedstance.

Fig. 3. The ultrastructural analysis of the skin in patients. Patient 4(A), patient 3 (B), and patient 1 (C) each show an abnormal osmiophilicpattern with a dark endothelium (E) and a clear media. (D), for comparison,shows a normal endothelium which is electrolucent. In super®cial capillarymetarteriols (A and B), the smooth muscle cell cytoplasms (M) areelectrolucent without normal micro®lament fascicles. (C) corresponds to amesodermal vessel, in which smooth muscle cells (M) are less affected thanthose in super®cial dermal vessels. Several clear areas are observed with adisorganization of normal organits repartition. In the three vessels (A±C),the endothelium displays a dense osmiophilic cytoplasm ®lled with densepackedmicro®lament that impeded normal exchanges. *� lumen; bar�2 m.

New Cerebellar Ataxia Disorder 137

eating solid food and was therefore on a soft diet. Hewas profoundly mentally retarded and had irregularsleep patterns, but no seizures.Hewas ®rst seen at age 10 (Fig. 5). No understandable

speech was noted and reactions to sound and simpleorders were very random. However, he seemed torecognize his parents, as well as certain close familymembers. The boy's weight was 20 kg; height, 103 cm;and OFC, 49 cm (all below the 3rd centile). He had anexpressionless face with a half-openmouth and poor eye-tracking ability. There were no dysmorphic featuresexcept for an upper double row of teeth, a high-archedpalate, and a bilateral esotropia. An exam of the externalgenitalia was normal, and the pubic hair was at Tannerstage II. Dermatoglyphic palm patterns were normal.Neurological examination revealed a diffuse spasti-

city predominant in the lower limbs with dystonicpostures of the hands, ¯exion contractures of theAchilles tendons, tibio-ischial muscles and hip ¯exors,brisk deep tendon re¯exes with upgoing plantarre¯exes, symmetrically positive abdominal re¯exes, sli-ghtly diminished muscle strength, oculomotor apraxia,and a nystagmus in the lateral gaze. Pupils werereactive to accommodation and light with a strongblinking re¯ex. A reactive gag re¯ex was found. Themuscular tone was increased in agonist and antagonistmuscles of the upper and lower limbs. There was noclear ataxia, tremor, or dysmetria. The boy's sensoryreactions to a pinprick and light touch were appro-

Fig. 4. MRI of the brain of patient 1 (VI-4).A:Coronal view showing theimportant cerebellar atrophy and the enlarged fourth ventricle. B: Sagitalview showing the large magna cisterna.

Fig. 5. Photograph of patient 3 (VI-1) at 10 years.

138 MeÂgarbane et al.

priate. No cranial nerve abnormalities were noted. Theophthalmic evaluation revealed the presence of an opticatrophy.The ®ndings of the skin biopsy were identical to those

of patient 1 (Fig. 3) with the presence in the extremitiesof amyelinic nerves of some spheroid vesicles. An MRIof the brain was performed and showed cerebellarvermis and bilateral hemispheric atrophy, a dilatedfourth ventricle, a large magna cisterna, and hypopla-sia of the posterior part of the corpus callosum (Fig. 6).The brain stem was normal, with no migration defectsor demyelination.Laboratory exams, total body X-rays, abdominal

ultrasound, ECG, EEG, electromyogram, nerve con-duction studies, evoked potentials, auditory brain stemresponses, and muscular biopsy were all normal.Chromosomal study of lymphocytes with high-resolu-tion R banding showed a normal 46,XY karyotype.

Patient 4

Patient 4 (VI-2, Fig. 1) was born 1 year after hisaffected brother, delivered by cephalic presentation at40 weeks after an uneventful gestation. His weight was3,500 g (75th centile), and his length was 50 cm (60thcentile). The OFCwas not recorded. The clinical historywas similar to his affected cousins (Table I). Onexamination at 9 years, his general appearance re-vealed a weak and slender boy. His weight was 17 kg;height, 101 cm; and OFC, 49.5 cm (all below the 3rdcentile). He was unable to maintain his balance withoutassistance and could walk only a few yards withsupport. His understanding of simple commands wasinconsistent. This boy displayed an important stran-ger's anxiety. Neurological examination was identicalto his affected cousins, except that no extensor plantarmuscles were found. Findings of the skin biopsy were

identical to those of his affected brother (Fig. 3).Laboratory and radiological examswere unremarkable.An MRI was not performed.The parents have a healthy daughter.

Patient 5

Patient 5 (VI-14, Fig. 1) is the youngest child ofhealthy consanguineous parents. When she was born,the mother was 33 and the father was 38. Delivery atterm by cephalic presentation was unremarkable. Herbirth weight was 2,000 g (<3rd percentile), and herlength was 51 cm (75th centile). The OFC was notavailable. She sat up unaided at 14 months and wasable to crawl at 33 months. She never gained urinary orfecal continence.This girl was seen at age 9 years. Her weight was 25

kg; height, 105 cm; and OFC, 50.5 cm (all below the 3rdcentile). She had a severe bilateral ptosis and a half-open mouth (Fig. 7). No dysmorphic features werenoted. Findings from the neurological examinationwere identical to those of her affected cousins (TableI). An MRI of the brain was performed and showedcerebellar vermis and bilateral hemispheric atrophy.Her parents had previously given birth to eight other

children. Three were healthy, two girls and one boy

Fig. 6. MRI of the brain of patient 3 (VI-1) showing the cerebellarvermis and bilateral hemispheric atrophy and a large magna cisterna.

Fig. 7. Photograph of patient 5 (VI-14) at 10 years. Note the ptosis andthe half-open mouth.

New Cerebellar Ataxia Disorder 139

(Fig. 1). Two were presumably affected by the samedisease and died very early (VI-7 and -12, Fig. 1). Twoothers (VI-10 and -13, Fig. 1) had a diastrophicdysplasia clinically and molecularly con®rmed. CaseVI-6 died very early from meningitis and was allegedlynot affected.

DISCUSSION

The ®ve children reported here share the followingclinical characteristics: severely delayed developmentalmilestones, severe psychomotor retardation, propor-tionate short stature, cerebellar spastic ataxia, micro-cephaly, optic atrophy, speech defect, ultrastructuralskin abnormalities, and cerebellar atrophy most prob-ably of prenatal onset. Language may be acquiredgradually or may continue to be absent if it were in factpart of this syndrome. It is dif®cult to determine whichis the case because of the young age of the siblings andthe absence of any intensive speech therapy. Similarly,delays in walking may be exacerbated by the absence ofadequate stimulation and/or training. Overall, thisdisorder seems to be nonprogressive, and the morepronounced features present in patient 3 (VI-1, Fig. 1)are most probably secondary to a neonatal ischemicbrain injury.The London Neurogenetics Dysmorphology Data-

base, the on-line Mendelian Inheritance in Man(OMIM), and Medline were searched with clinicalfeatures of these children as search keys. Variouscombinations of the features found in this kindredresulted in a list of 55 different possible diagnoses, ofwhich only a few could be considered seriously.Topping the list was the Marinesco-Sjogren syn-

drome (MIM 248800), which is characterized bycerebellar ataxia, mental retardation, optic atrophy,cerebellar atrophy, and short stature. It usually alsocomprises congenital cataracts, a small pituitary gland,and histopathological changes in the muscles whichwere not observed in these children. Marinesco-Sjogrenwas consequently ruled out.The dysequilibrium syndrome (MIM 224050) is a

nonprogressive neurologic condition dominatedthroughout childhood by an incapability or pronounceddif®culty in walking, and usually short stature, speechdysarthria, mental retardation, muscular hypotonia,exaggerated deep tendon re¯exes, microcephaly, andcerebellar atrophy [Hagberg et al., 1972]. The auto-somal recessive Cayman cerebellar ataxia (OMIM601238), identi®ed by Johnson et al. [1978] in apopulation isolate on Grand Cayman Island, is char-acterized by early childhood hypotonia, prominentnonprogressive cerebellar dysfunction, and cerebellarhypoplasia. Both disorders are distinguished from thepresent report by the fact that the general features andmental retardation are mild and the absence of retinalatrophy. This was also the case in the patients reportedby Guzzetta et al. [1993].Behr syndrome (MIM 210000) is a nonprogressive

condition that consists in mentally handicapped chil-dren with early optic atrophy, mild ataxia, spasticity,and speech defect. This condition is very close to the

family reported here. Nevertheless, posterior columnsensory loss, white matter abnormalities on MRIscanning, and axonal peripheral neuropathy, whichare also features of this condition [Landrigan et al.,1973; Marzan and Barron, 1994], were not present inthis syndrome.Another rare condition that could be considered in

the differential diagnosis is the family reported byCharrow et al. [1991]. Both families have in commoncerebellar hypoplasia, microcephaly, ataxia, nystag-mus, strabismus, and hypotonia. However, our patientslack the hip dislocation and endosteal sclerosis, obliga-tory features in this entity. Finally, the familiesreported by Hogan and Bauman [1977] with spasticataxia and optic atrophy were less affected than theseLebanese children and presented progressive features,which was not the case here.The different types of the carbohydrate-de®cient

glycoprotein (CDG) disease [Jaeken and Carchon,1993] present some features that overlap with thosefound in this family, such as hyperre¯exia, ataxia,muscular atrophy of the lower limbs, cerebellar ataxia,and mental retardation. They were ruled out, however,because of the normal results of the transferrinanalysis in patients 1 and 3. The 3-methylglutaconicaciduria [Gibson et al., 1993], which is characterized bytruncal hypotonia, limb spasticity, failure to thrive,severe retardation, optic atrophy, spastic paraparesis,and cerebellar ataxia, also features seizures and deaf-ness that are not present in this kindred. There was nometabolic acidosis or elevation of 3-methylglutaconicand 3-methylglutaric acids in the urine of patients 1, 3,and 5.In this extended family, skin biopsies showed some

accumulations of vesicles at the extremities of theamyelinic nerves. These accumulations looked likespheroid bodies observed in infantile neuro-axonaldystrophy (INAD) (MIM 256600) [Osmen et al., 1991],an autosomal recessive syndrome with onset towardthe end of the ®rst year of life, characterized bydevelopmental deterioration, advent of pyramidal tractsigns and/or hypotonia, and optic atrophy. Neverthe-less, they were only found surrounding the vessels andthey were not noticed in patient 1. Furthermore, INADis a progressive neurodegenerative disease, and thenormal EEG and EMG ®ndings in these Lebanesechildren are in contradiction with the prominent fastactivity on the EEG and the denervation on EMG,which are usually present in INAD [Wakai et al., 1994;Nardocci et al., 1999]. On the other hand, the particular®ndings of the skin biopsies in this family allowed theexclusion of various subtypes of neuronal ceroidlipofuscinosis (MIM 204500 and 256730). Also, Salladisease (MIM 268740), a lysosomal storage disorder,which could present with early delay in motor andspeech development, mental retardation, ataxia, spas-ticity with increased re¯exes, and short stature, hasbeen ruled out by the absence in our patients of sialicacid in the urine and the different ultrastructuralresults of the skin biopsies [Renlund, 1984].In conclusion, although there is some resemblance

between clinical and pathological ®ndings in this

140 MeÂgarbane et al.

inbred Lebanese family and previously describedsyndromes, this entity has features that set it apart.In particular, the inversed "cocarde" pattern in thevessels has never been reported before. The endotheli-al cells were osmiophilic, compared to normal endo-thelium, which is electrolucent (Fig. 3D), with someorganits and an edematous and clear cytoplasm. Thisobservation was never found in nearly 250 ultrastruc-tural skin biopsies performed by one of the co-authors(M.M.R.). The biological and clinical signi®cance ofthis vascular peculiarity is not evident. A dense andcompact endothelium may hinder normal exchangesbetween the blood and surrounding tissues. Thesecondary decrease in vessel permeability may thenirreversibly damage or eventually alter the produc-tion and migration of the neuronal cells at anearly stage. This could, in part, explain the cerebellar,optic, and other encephalic atrophies observed inthis family. The absence of brain cortex changes atMRI raises the possibility that this event happenedafter the differentiation of the latter, which arrivechronologically before the one of the cerebellum. Still,the severe mental retardation present in our patientsmight be secondary to minor morphological changes inbrain cortical cells not detectable with neuroradiologi-cal investigations [Guzzetta et al., 1993].In addition to this study, the ongoing search to

localize a gene associated with this entity might help todetermine the protein involved in the disease mechan-ism. This in turn will lead to a better comprehension ofthis entity and may contribute to differentiate it moreconclusively from other known disorders.

ACKNOWLEDGMENTS

We are indebted to Dr. Catherine Caillaud for kindlyperforming the laboratory exams and to Dr. Salim Adibfor clinical comments.

REFERENCES

Campanella G, Filla A, De-Michele G. 1992. Classi®cation of here-ditary ataxias. A critical overview. Acta Neurol Napoli 14:408±419.

Charrow J, Poznanski AK, Unger FM, Robinow M. 1991. Autosomalrecessive cerebellar hypoplasia and endosteal sclerosis: a newlyrecognized syndrome. Am J Med Genet 41:464±468.

Gibson KM, Elpeleg ON, Jakobs C, Costeff H, Kelley RI. 1993. Multiplesyndromes of 3-methylglutaconic aciduria. Pediatr Neurol 9:120±123.

Guzzetta F, Mercuri E, Bonanno S, Longo M, Spano M. 1993. Autosomalrecessive congenital cerebellar atrophy. A clinical and neurophysiolo-gical study. Brain Dev 15:439±445.

Hagberg B, Sanner G, Steen M. 1972. The dysequilibrium syndrome incerebral palsy. Acta Paediatr Scand 61(Suppl 226):1±63.

Harding AE. 1983. Classi®cation of the hereditary ataxias and paraplegias.Lancet i:1151±1155.

Harding AE. 1984. The hereditary ataxias and related disorders.Edinburgh: Churchill Livingstone. p 124±128.

Hogan GR, Bauman ML. 1977. Familial spastic ataxia: occurrence inchildhood. Neurology 27:520±526.

Jaeken J, Carchon H. 1993. The carbohydrate-de®cient glycoproteinsyndromes: an overview. J Inherit Metab Dis 16:813±820.

Johnson WG, Murphy M, Murphy WI, Bloom AD. 1978. Recessivecongenital cerebellar disorder in a genetic isolate: CPD type VII?Neurology 28:351±352.

Landrigan PJ, Berenberg W, Bresnan M. 1973. Behr's syndrome: familialoptic atrophy, spastic diplegia and ataxia. Dev Med Child Neurol15:41±47.

Marzan KAB, Barron TF. 1994. MRI abnormalities in Behr syndrome.Pediatr Neurol 10:247±248.

Nardocci N, Zorzi G, Farina L, Binelli S, Scaioli W, Ciano C, Verga L,Angelini L, Savoiardo M, Bugiani O. 1999. Infantile neuroaxonaldystrophy. Clinical spectrum and diagnostic criteria. Neurology52:1472±1478.

Osmen M, Caliskan M, Goebel HH, Apak S. 1991. Infantile neuroaxonaldystrophy: diagnosis by skin biopsy. Brain Dev 13:256±259.

Renlund M. 1984. Clinical and laboratory diagnosis of Salla disease ininfancy and childhood. J Pediatr 104:232±236.

Wakai S, Asanuma H, Hayasaka H, Kawamoto Y, Sueoka H, Ishikawa Y,Minami R, Chiba S. 1994. Ictal video-EEG analysis of infantileneuroaxonal dystrophy. Epilepsia 35:823±826.

New Cerebellar Ataxia Disorder 141