Posterior fossa imaging in 158 children with ataxia

doi:10.1016/j.neurad.2009.12.009

Journal of Neuroradiology

Volume 37, Issue 4, October 2010, Pages 220-230

https://doi.org/10.1016/j.neurad.2009.12.009 Get rights and content

Summary

Objectifs

To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia.

Patients and methods

Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n = 27), cerebellar hypoplasia (n = 15), hemispheric cerebellar dysgenesis (n = 6), unilateral hemispheric atrophy (n = 5), global cerebellar atrophy (n = 84), signal abnormalities (n = 11) and normal MRI (n = 10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders.

Results

In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric cerebellar dysgenesis and normal MRI groups, no biological diagnosis was found for any of the patients. In the group of unilateral hemispheric atrophy, we hypothesized a clastic prenatal injury.

Conclusion

The proposed MR cerebellar algorithm was useful to guide genetic/malformative or biochemical investigations, allowing an etiological diagnosis in 55 children.

Introduction

The etiological characterization of cerebellar ataxia in children is still based on clinical classification and remains rare and difficult despite the availability of recently developed genetic and biochemical techniques. At least, 30 diagnosis are possible from clastic lesions to genetic or metabolic diseases [1]. The clinical symptoms and signs are generally non-specific and overlapping. Although insufficient, the clinical course is important to differentiate progressive degenerative syndrome from complex midbrain and hindbrain stable malformation.

Several genes implicated in cerebellar ataxia have been recently described in metabolic and degenerative disorders (CABC1 in quinone deficiency, FRAXA in Freidreich ataxia, SCAs in spinocerebellar ataxia, AOA1, AOA2 in ataxia associated with ocular apraxia) as well as in developmental diseases as in the spectrum of Joubert syndrome (INPP5E (JBS1) AHI1(JBS3), NPHP1 (JBSS4), CEP290 (JBS5), TMEM67 (JBS6)), RPGRI1LP (JBS7), ARL13B (JBS8), CC2D2A (JBS9) and very recently OFD1(JBS10) [2], [3], [4], [5], [6], [7], [8], [9], [10]. Finally, several genes has been recently identified in pontocerebellar hypoplasia [11].

In the two last years, genetic studies for cerebellar diseases are often based on clinical phenotypic identification of homogeneous groups of patients in the hope that they will possess a similar genetic condition. Similar genes mutations have shown to be associated with similar brain MRI features, then cerebellar anomalies such as vermian dysgenesis with cleft were found to be associated with OPHN1 mutation [12] or molar tooth malformation with CEP290 or RPGRIP1L mutations [5], [7].

In the same line (similar MRI/similar diagnosis), we report here, our multidisciplinary (pediatric neuroradiologist, neuropediatrician, genetician) experiences in the study of the brain MRIs of a cohort of 158 cerebellar ataxic children. Gathering together clinical data, detailed neurological examination, brain and cerebellar associated abnormalities as well as genetic testing findings, helps to build this algorithm using defined MRI-homogeneous groups of ataxic children. Seven groups of anatomical cerebellar abnormality were proposed, and were confronted to the biochemical and/or genetic results. The aim of this study, using a multidisciplinary approach of pediatric cerebellar ataxias, is to increase the diagnosis efficiency using a new cerebellar MR algorithm.

Section snippets

Clinical inclusion criteria

One hundred and fifty-eight patients were enrolled in a study-based upon the clinical findings of ataxia, or cerebellar signs such as occulomotor abnormalities, truncal ataxia and head movements if the child was too young or too severely handicapped. All children (mean age 5.0 years) were included in the study if ataxia had begun during pediatric age (15 years of age). Patients were referred from the departments of pediatric neurology, genetics, metabolism or ophthalmology of Necker Enfants

General results

Based on anatomical MR cerebellar algorithm, 15 children were classified in cerebellar hypoplasia group, 27 children were classified in vermian dysgenesis group, six children in hemispheric cerebellar dysgenesis group, five children in hemispheric unilateral atrophy group, 84 children in global cerebellar atrophy group, eleven children in signal abnormalities group and ten children in the normal MRI group. A specific molecular genetic or biochemical diagnosis was obtained in 56 of 158 children

Discussion

Based on seven subgroups of homogenous cerebellar radiological imaging, we described the malformative or metabolic diagnosis in 158 ataxic children (Fig. 8). In this series, 56 of 158 children received specific diagnoses. This MR algorithm, applicable only in patients with normal cerebrum, permitted easy separations of patients who are likely to have metabolic diseases (major cerebellar atrophy or signal abnormality) from those with malformative disease (vermian dysgenesis or cerebellar

Conclusion

The “imaging phenotype” or “endophenotype” (referring to similar MRI characteristics) is useful as criteria for a morphologic radiological classification of the cerebellum. Previous approaches of the classifications of posterior fossa malformations were based on knowledge of posterior fossa embryology. However, these classifications although extremely important to understand the origin of cerebellar malformations are less useful to make a precise diagnosis in the clinical setting of pediatric

Conflicts of interest

None.

Acknowledgements

We thank Professor Koenig for his contribution.

This work was funded by the Fondation Jérome Lejeune.

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Original articlePosterior fossa imaging in 158 children with ataxiaApport de l’IRM dans les syndromes cérébelleux chez l’enfant : à propos de 158 cas

Summary

Objectifs

Patients and methods

Results

Conclusion

Introduction

Section snippets

Clinical inclusion criteria

General results

Discussion

Conclusion

Conflicts of interest

Acknowledgements

Eur J Med Genet

Am J Hum Genet

Am J Hum Genet

Kidney Int

Clin Chim Acta

Am J Hum Genet

Mol Genet Metab

Dev Biol

Cerebellar ataxias

Curr Opin Neurol

RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders

Clin Genet

The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

Nat Genet

High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations

J Am Soc Nephrol

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders

Ann Neurol

The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families

Neurology

Original article
Posterior fossa imaging in 158 children with ataxiaApport de l’IRM dans les syndromes cérébelleux chez l’enfant : à propos de 158 cas