248 Non-progressive congenital ataxia with cerebellar hypoplasia in three families

. No 1.6 Z. YAPICI & M. ERAKSOY . .. I.Y.. \ .~ ---················ No of Neurology, of Child Neuro/ogy, Facu/ty of Turkey

Abstract Non-progressive with cerebellar hypoplasia are a rarely seen heterogeneous group ofhereditary cerebellar ataxias. Three sib pairs from three different families with this entity have been reviewed, and differential diagnosis has been di sc ussed. in two of the families, the parents were consanguineous. Walking was delayed in ali the children. Truncal and extremiry were then noticed. Ataxia was severe in one child, moderate in two children, and mild in the remaining revealed horizontal, horizonto-rotatory and/or vertical variable degrees ofmental and pvramidal signs besides truncal and extremity ataxia. In ali the cases, cerebellar hemisphere and vermis were in MRI . During the follow-up period, a gradual clinical improvement was achieved in ali the

Condusion: he cu nsidered as recessive in some of the non-progressive ataxic syndromes. are being due to the rarity oflarge pedigrees for genetic studies. Iffurther on and clini cal progression of childhood associated with cerebellar hypoplasia is be a cu mbined of metabolic screening, long-term follow-up and radiological analyses is essential.

Key Words: Cerebella r hy poplasia,

ataxic syndromes are common during Patients 1 and 2 (first family) childhood. Friedreich 's ataxia and ataxia-telangiectasia Two brothers aged 5 and 7 of unrelated parents arc two best-known examples of such rare syn- presented with a history of slurred speech and diffi- dromes characterized both by their progressive nature culty of gait. Both cases were bom at term after an and ability to involve more than one neurological sys- uneventful pregnancy and delivery. They hada history [ 1]. An even rarer and clinically non-progressive of markedly delayed milestones, and they had been form of hereditary ataxia is the one accompanied by unable to keep their balance while walking at 2.5 y. ccrcbcllar hypoplasia and exhibiting the same clinical Neurological examination revealed cerebellar dysar- as ccrcbcllar systcm. Some forms of heredi- thria, mild/moderate truncal ataxia and dysmetria ran · with cercbellar hypo- significant in the lower extremities. Both cases an: rarc, and pathophysiology had horizontal nystagmus, with moderate frequency pPmll' undnstond . To authors' knowledge, and amplitude, accompanied by vertical nystagmus tht:rc arc only a fcw on thc follow-up in one. Deep tendon reflexes were brisk, and there rcsult s of cntity; besides, molecular was bilateral Babinski's sign in both cases. The IQ on this arc also rare [2 - 5). score of the elder brother was 70, and that of the younger was· 68. During the 8-y follow-up period, progression was not observed in either of the brothers. Methods and patients On the contrary, there was a gradual relative improve- in this study, the clinical and laburatury findings uf ment. The elder case, who was 15 y of age when !ast three sib pairs with non-progressive ataxia examined, stili had nystagmus and some difficulty with cerebellar hypoplasia have been evaluated. They in tandem walking, with hyperreflexia in the lower were followed up in our department for 4- 8 y. The extremities. Although the younger case significantly factors indicating the aetiology, clinical features, improved, mild/moderate truncal ataxia was stili prognosis and the possible genetic transmission have noticeable, and he was unable to read or write at the bccn discusscd. age of 13 .

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1 l '1 cerebdlar h ypoplasia (Ti axia l and

Patients 3 and 4 (second family) IQ score was 90, and his sister's was 68. The follow-up period was 4 .5 y in these patients. A femalc child aged 11 and a male aged 6 of consan- There was no history of neurological diseases in guineous parents with three sons and two daughters any of the relatives. In neither the cases nor their presented with impaired walking and speech difficulty. parents were the below disorders discovered: optic The relatives did not have a similar history. There was atrophy, skeletal anomaly, any skin lesions or telan- a history of difticult delivery in both cases. The elder giectasias, or other organ involvement. The haemo- one walked with assistance until 7- 8 y. She was re- gram, cholesterol, lipid electrophoresis, IgA, M, G, ported to have walked unaided for the previous 2 y. alpha-fetoprotein, TORCH antibodies, abdominal Thc yo ungcr one could walk with assistance at age 5, ultrasonography, ECG, telecardiography and con- age his walking gradually improved. ventional skeletal X-rays were ali normal in ali the rcvealed brisk deep tendon children. No metabolic diseases were detected in the in the lower extremities, cerebell ar below tests: screening tests for inborn errors (amino truncal ataxia in both aciduria, quantitative amino-acid profile, organic to thc Denvcr Developmenral Scale, aciduria, tandem mass acyl carnitine profile), histo- dcvelopmcnt corresponded with chemical staining of muscle biopsy specimens, serum of a 6-y-old child and the younger patient's with lactate and p·yruvate levels, serum transferrin !eve! for that ofa 4-y-old child. They were followed up for 4 y, glycosylation disorders, and galactosidase enzymes and minimal improvement in walking was achieved in activities for lysosomal storage diseases. both, with the result that their walking was still mildly/ Below is an overall analysis of the findings of the moderately ataxic. three families . Cranial CT and MRis of ali the families revealed that the cases had cerebellar hypoplasia prominent in the vermis (Figures 1- 9); spinal MRis of Patients 5 and 6 (third family) the cases in the third family were ali normal, and so A 12-y-old boy and a 6-y-old gir! of consanguineous were the MRis of the two healthy brothers in the first parents presenred with slowness in speech and family, who had no ataxic symptoms. wa lking. Pregnancy and delivery of both 1hc wcre normal. The clder one walked at 2. H ()v,:,•vcr, he· was ncvcr ablc to keep his balance Discussion prnpc-rlY so. He was phys ically slack J() spo kc slowly and often fell In clinical practice, Friedreich's ataxia, ataxia-telan- down Thc younger child walked at 1.5. giectasia and abetalipoproteinaemia are widespread sh,· balanet: well in her first years, among ataxic syndromes characterized by autosomal her gradually improved . On neurological recessive (AR) inheritance [l]. Some conditions with thc pati enrs were discovered to have cerebellar involvement can be summarized as follows: significant in the disturbed metabolism of amino and organic acid lcft, hypotonia in the extremities, (Hartnup's disease, maple syrup disease, ete.), urea truncal ataxia and increased reflex eyde defects, lactic acidosis, congenital disorders of activity in the lower extremities. The elder patient's glycosylation syndrome, and disorders of lysosomal 250

Figure 2. (a) First family , 2nd child: cerebellar hypoplasia (Ti sagittal); (b) 2nd family, 1st child: cerebellar hypoplasia prominent in the ,·ermis (T i (c) 2nd family, 2nd child: cerebellar hypoplasia (Ti sagittal).

Figure 3. Third family, st child: cerebellar hypoplasia prominent in the vermis (Ti axial and sagittal).

4 2nd cerebellar hypoplasia prominent in the vermis (Ti axial and sagittal). Clinical 251

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cnppcr mecabolism, 9q34-9qrer [5]. The picrures ofthe families correspond and cholcsrcrol 16- 1O). Thcse more wirh AR inheritance, for these were marriages arc gcneucally and biochemically of firsr cousins, and while some of their sons and wcll However, in our cases, there daughrers equally and adversely affected, others were no specific clinical signs or positive data in the were not. screcning rests with regard to these diseases, and they Cerebellar hypoplasia on MRI and the non- showed no clinical progression in the long-term progressive characteristic of the condition of our cases follow-up period. Characterized by a high proportion were the main inclusion criteria adopted in our study. of fam ili al cases, non-progressive ataxia is a small entity To the authors' knowledge, there are only a few studies [ 11, 12) and has bcen known since rhe beginning of on long-term follow-up of such cases in the literature rhe 20th century [ 1 3]. Jervis er al., who were rhe firsr (2- 4] . Our cases did not deteriorate, and seemed to ro arrempr ro classify rhem, described some families compensate for their motor uncoordinations through in whom the disease was not progressive and the years, which was similar ro the results achieved by was characrerized by AR inheritance, severe truncal Steinlin [4]. Our cases had varying degrees of ataxia ataxia and mcntal retardarion [14]. and mental retardation. The degrees varied to such Esschcr et al. reporrcd rhar 27% of rheir cases had an extent rhat this makes it possible to consider the pachology, morphologically supporting cases clinically heterogeneous despite the similarities a ccrcbcllar ataxia, and berween rhe MRI findings of the sib pairs, as in the as having a hecerogenous rhird family. Ir has been reported that such manifes- cnucy [·1, 12 ). Gcncrally, non-progrcssivc carions as dysronia, spasticity and epilepsy are possible arc known co havca rransmission, and in non-progressive ataxias with cerebellar hypoplasia aucosomal (AD) cascs are rarcly reported [ 16]. Huwever, except for brisk reflexes and Babinski's [2 ,3, 15) (Tablc 1). Delague er al. have mapped a sign, our group was more homogenous compared to AR ccrcbellar ataxia in a family at rhose in rhe There was no clear relationship 252

Table I and tindings of different groups.

Ag,· (v) and sex Ataxia Walking DTR IQ Nysragmus MRI

dl .-\i l L~ Unkw N N Ven+ Hor Vermian atrophy H 1- Mild Unkw N IQ =8 I Vert + Hor •1 I' Unkw N N Vert + Hor q ,\\ (son ) Unkw N N Vert + Hor N 1 (.-\Dl F Mild 20 mo N IQ = 70 Cll hypoplasia l F Mild 18 mo N IQ = 75 Vermian hypoplasia 38 F Mild 2 y N N ,._.{ al. (AD ) 33 F Moderate 18 Brisk N Hor Cll atrophy •I F (daughtcr) Mild 18 mo Brisk IQ = 6I Vermian and eli

Our cases 7 M ( 1st Mild 2.5 y Brisk (lwr) IQ = 70 Vert + Hor Vermian > Cll hypoplasia 5 M ( 1st Moderate 4 y Brisk IQ = 68 Hor 1 1 F (2nd Seve re 9 y Brisk (lwr) Moderate MR 6 M (2nd Moderate 5.5 y Brisk MildMR 12 M (3rd family) Mild 20 mo Brisk (lwr) IQ = 90 6 F (3rd family) Moderate 18 mo Brisk (lwr) IQ = 68

N: normal; ve n : vertieal; hor: horizonral; ver: vermis; unkw: unknown; eli: lwr: in the lower extremities; MR: mental retardation.

morphology and function, as MR was rather between MRJ findings and the severity of ataxia and whcrcas wcre variable without cognitive impairment. for involvcment of additional Although the region responsible for non-progressive ataxias with cerebellar hypoplasia was mapped, further it has shown that non-progressive investigations are needed to discover the genes causing h ypoplasia affect the supcrior this entity. Jf further information on the aetiopatho- and causc thc ccrcbcllum to lose genesis of childhood ataxias associated with cerebellar cells [ I 1, I 4 J. Our cases can not be classitied hypoplasia is to be acquired, a combined evaluation as and mcrabolic diseascs due to a of metabolic ·and radiological analyses as well as long- numbcr of diagnoses as follows [ 6- I 2]: term follow-up are indispensable elements for defini- absencc of progression or deterioration with tive diagnosis to be carried out. multiorgan dysfunction, involvement of only the cere- bellum and no other systems, absence of dysmorphic symptoms or anomalies of the brain stem or white Acknowledgements matter in MRJ, normal myelination, absence of intra- This article was based on dara at Division of cranial malformations of posterior fossa or midline Child Neurology, Department of Neurology, Istanbul structures. it is in support of this view that the below of Medicine, Istanbul University. We would like test results of ali our cases were negative: amino thank Prof. Dr Gencay Gursoy and Mr Cuneyt Bademcioglu acidopathy, organic aciduria, abnormal tandem mass for their kind contributions. acyl carnitine protile, elevated lactate and pyruvate, histochcmical sraining for mitochondrial References and sys tcmic involvcmenr. Hypoplasia was ehe \'Crmis in our cascs. Furman 11 J Bren EM. Spinoeerebellar and some related [~[. [1/ and ]mamura rcported cascs with condirions. in: Bren EM, editor. Paediatrie neurology. 3rd ed. London: Churehill Livingsrone; 1997. p. 229- 66. CTs and .\\Rls ccrcbcllar hypoplasia 121 Furman JR, Baloh RW, Chugani H, Walueh V, Bradley WG. vcrmis [ 15] (Table !). lnfanrile erebellar atrophy. Ann Neurol l 985;17:399-402. the classitication [ 17], our 131 Rivier F, Eehenne B. Oominantly inherited hypoplasia of the wcrc compatiblc with "vcrmian hypoplasia in vermis. Ne,uropediatries 1992;23:206-8. with hypoplasia of the cerebellar hemi- 141 Steinlin M, Regisrer S, Zangger B, Bolthauser E. Non- progressive eongenital araxia with or without eerebellar hypo- sphercs". Associatcd supra-infratentorial anomalies, plasia: a review of 34 subjeets. Dev Med Child Neurol such as agcnesis corpus callosum, lissencephaly and 1998;40: 148-54. of pons, were not detected in our cases. it 15) Oelague V, Bareil C, Bouvagnet P, Salem N, Chouery E, that clinical and neuroradiological dara Loiseler J, et al. Non-progressive autosomal reeessive ataxia obtained from our cases and those obtained from maps to 9q34-9 ter in a large eonsanguineous Lebanese family. Ann Neurol 2001;50:250-3. the literature will not authorize us to determine the [6] Ramaekers VT, G, Reul J, Thron A, Jaeken. subgroups of ataxias that are not progressive in nature. J.Genetie disorders and eerebellar struetural abnormalities in Besides, it is not possible to establish a direct relation ehildhood. Brain 1997; 120: 1739- 5 L Clinical 253

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