- Email: [email protected]
Congenital ataxia and mental retardation in three brothers
Congenital Ataxia and Mental Retardation in Three Brothers Lucia Margari, MD, Patrizia Ventura, MD, Anna Presicci, MD, Maura Buttiglione, MD, and Tommaso Perniola, MD Nonprogressive congenital ataxia is a complex group of disorders caused by a variety of etiologic factors, both environmental and genetic. Hereditary forms represent a substantial part of congenital ataxias, which are difficult to classify because of their phenotypic and genetic polymorphism. Despite the advances in molecular genetics, for most nonprogressive congenital ataxia the etiology is still unknown. This report describes three sons of nonconsanguineous healthy parents, who manifested a syndrome characterized by nonprogressive ataxia, mental retardation, pyramidal signs, ocular and ocular motor anomalies, associated with severe hypoplasia of the cerebellar vermis and hemispheres on neuroimaging. All the patients have presented psychomotor developmental delay. As differential diagnosis, a comparison is made between the clinical features of these patients and the previously reported cases of nonprogressive congenital ataxia. This report represents a further example of the phenotypic and genetic heterogeneity of the syndromes with congenital ataxia. © 2004 by Elsevier Inc. All rights reserved. Margari L, Ventura P, Presicci A, Buttiglione M, Perniola T. Congenital ataxia and mental retardation in three brothers. Pediatr Neurol 2004;31:59-63.
Case Report Case II-1, a 14-year-old Male The patient was first observed at our department at age 11, because of suspected mental retardation. He was born by elective caesarean delivery at 38 weeks because of delay of fetal growth and suspected fetal suffering during the last month of pregnancy. Birth weight was 2.260 kg. He sat alone at 6 months and first walked at 18 months. Imbalanced gait was soon observed by family members. He said his first words at 2 years and was able to combine words at 4 years, without any other improvement until the time of the first examination. General examination revealed dysmorphic features (micrognathia, high arched palate, irregular placement of teeth) and mild hepatomegaly. Neurologic examination revealed truncal and locomotor ataxia, clumsiness, dysmetria and intention tremor, axial and arm hypotonia, mild spastic hypertonia of lower limbs and right ankle clonus, generalized hyperreflexia with bilateral Babinski sign, and absent abdominal tactile reflexes. Pain and touch sense were unimpaired; deep sensory functions were not evaluated because of the patient’s poor cooperation. Neuropsychological evaluation revealed moderate mental retardation on the Wechsler Intelligence Scale for Children, Revised: full-scale intelligence quotient, 45; Verbal Scale intelligence quotient, 49; Performance Scale intelligence quotient, 41. The subtests analysis revealed homogeneous failure in all the tasks. Bender test and Raven Colored Progressive Matrices evidenced visuoperceptual deficits.
Case II-2, a 7-year-old Male, Brother of Cases II-1 and II-3 The patient first came to our attention at age 4 because of his imbalanced gait. He weighed 2.800 kg at birth, after an uneventful pregnancy and delivery. He sat alone at 5 months and first walked, albeit unsteadily, at 18 months. He used his first meaningful words at 2 years, combined words at 4 years, and simple sentences at 5 years. General examination revealed only simple hypertrichosis on the back. No dysmorphic feature was observed. On neurologic examination, features were observed similar to those of his brother, including ataxia, clumsiness, axial and arm hypotonia, and pyramidal signs consisting of mild spastic hypertonia of lower limbs, generalized hyperreflexia with right prevalence, absent abdominal tactile reflexes and extensor plantar responses. Superficial sensations were unimpaired. Psychometric evaluation, performed by the behavioral observation, evidenced mild mental retardation. A formal cognitive assessment using standardized level scales was impossible because of significant psychomotor restlessness.
Case II-3, a 6-year-old Male, Brother of Cases II-1 and II-2 Introduction We present three sons of nonconsanguineous healthy parents. Neurologic diseases were documented neither in the patient’s generation nor in the previous generations.
From the Child Neurological and Psychiatric Service, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.
© 2004 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2004.01.006 ● 0887-8994/04/$—see front matter
At 3 years, this patient was referred to our institute because of his suspected global delay and his abnormal gait. He weighed 2.950 kg at birth, after uneventful pregnancy and delivery. He experienced neonatal metabolic acidosis and sucking problems in the first days of life, with no other feeding problems throughout infancy. He sat alone at 8 months and first walked unsteadily at 32 months. Speech was delayed, with mean-
Communications should be addressed to: Dr. Margari; Sezione di Neuropsichiatria Infantile; Dipartimento di Scienze Neurologiche e Psichiatriche; Universita` degli Studi; Azienda Ospedaliera Policlinico; Piazza Giulio Cesare; CP 70124 Bari, Italy. Received August 14, 2003; accepted January 12, 2004.
Margari et al: Congenital Ataxia and Mental Retardation 59
ingful words first being used at 1 year, combined words at 4 years, and simple sentences at 6 years. General examination revealed the following dysmorphic features: micrognathia, high arched palate, low setting ears, short neck, prominent central forehead, clinodactyly of fifth fingers. On neurologic examination, features were observed similar to those of his brothers, including global motor incoordination, truncal and locomotor ataxia, pyramidal signs consisting of generalized hyperreflexia, bilateral ankle clonus, bilateral Babinski sign, and absent abdominal tactile reflexes. Psychometric examination using Griffiths Developmental Scales revealed moderate mental retardation with homogeneous failure in all the subscales.
Laboratory Evaluations Routine, metabolic and immunologic evaluations including serum immunoglobulin, alfa-fetoprotein, ammonia, serum copper, 24-hour urinary copper excretion, and serum ceruloplasmin were normal in all three patients. Bilirubin was slightly increased in Case II-1 and normal in Cases II-2 and II-3. On abdomen ultrasound, slight hepatomegaly with hyperecogeneity was evident in Case II-1, with normal kidneys and spleen. This examination was normal in Cases II-2 and II-3.
Ophthalmologic Examination Ophthalmologic examination evidenced the same anomalies in all three brothers, consisting of oculomotor motor apraxia, esotropia, impairment of pursuit, and saccades which consisted of jerky, conjugate, and usually horizontal, sometimes vertical, eye movements. Fundal examination revealed that the right eye was higher than the left in all the patients. Visual activity was 5/10 in the left eye and 6/10 in the right eye in Case II-1; 6/10 in the left eye and 7/10 in the right eye in Case II-2. Visual activity in Case II-3 was not estimated because of the patient’s poor cooperation. Slit lamp examination performed in Cases II-1 and II-2 excluded the presence of Kaiser-Fleischer ring.
Figure 1. Spin-echo coronal T1-weighted image of Patient II-1 reveals severe hypoplasia of the cerebellar vermis and hemispheres, more significant at inferior cerebellar vermis. Time for Acquisition (TA): 160.
Genetic Study Electrophysiologic Investigations The electroencephalographic examination was normal in all three patients. Electromyographic examination and nerve conduction velocities were performed in Cases II-1 and II-2. Electromyography was normal in both patients, whereas abnormal conduction velocities were documented in Case II-1 consisting of a slight reduction in the amplitude of the sensory action potentials and in the sensory nerve conduction velocities. Somatosensory evoked potentials by median nerve stimulation and by posterior tibial nerve stimulation as well as brainstem auditory potentials, performed in Cases II-1 and II-2, were normal. Visual evoked potentials in Case II-1 evidenced bilaterally slight morphologic alteration of major positive wave with normal latency and decreased amplitude. In Case II-2, visual evoked potentials evidenced slight morphologic alteration of major positive wave bilaterally with normal latency in the left eye, slightly increased latency in the right eye, and normal amplitude bilaterally. In Case II-3, visual evoked potentials evidenced morphologic alteration of major positive wave bilaterally, increased latency in the left eye, normal latency in the right eye, and decreased amplitude bilaterally.
Neuroimaging Studies Magnetic resonance imaging data, obtained from Patients II-1 (Fig 1), II-2 (Fig 2), and II-3 (Fig 3), revealed severe hypoplasia of the cerebellar vermis and hemispheres. Magnetic resonance imaging of the spinal cord was performed only in Case II-1 and was normal.
60
PEDIATRIC NEUROLOGY
Vol. 31 No. 1
Banded karyotype including fragile X study was normal in all three patients.
Follow-up A clinical, neuropsychologic, laboratory, electrophysiologic, and neuroimaging follow-up, lasting 3 years, was performed in all three cases. No progression of the clinical picture was observed. In Case II-1, the slight increase in bilirubin was confirmed, although liver ultrasound was normal; slight sensory nerve impairment was confirmed. In Cases II-2 and II-3, the absence of liver dysfunction was confirmed. Magnetic resonance imaging data remained unchanged after 3 years of follow-up.
Discussion Classification of congenital ataxias is still uncertain and difficult, considering their clinical polymorphism and the variety of the etiologic factors. Recently several authors have attempted to classify this complex group of disorders [1,2]. Steinlin [3] has proposed a classification of nonprogressive congenital ataxia based on clinical, neuroimaging, and etiologic factors. He divided nonprogressive congenital ataxia into pure congenital ataxia and syndromes with congenital ataxia. Pure congenital ataxia include all nonprogressive encephalopathies manifesting
Figure 2. Spin-echo coronal T2-weighted image of Patient II-2 reveals severe hypoplasia of the cerebellar vermis and hemispheres. Time for Acquisition (TA): 150.
the typical symptoms related to cerebellar dysfunction (incoordination and developmental delay) without symptoms such as eye abnormalities and dimorphisms. This group of nonprogressive congenital ataxia includes congenital ataxia caused by cerebellar hypoplasia (hereditary or not hereditary), congenital ataxia resulting from posterior fossa malformations (e.g., Dandy-Walker, Chiari malformations), and congenital ataxia due to supratentorial malformations. In the syndromes with congenital ataxia, ataxia can be a cardinal feature (e.g., Joubert’s syndrome) or an occasional symptom. This group includes some forms associated with cerebellar hypoplasia/aplasia, some with other posterior fossa malformations, and others without brain malformation. Acquired ataxias represent a small third group and may be caused by prenatal viral infections, fetal exposure to toxins or irradiations, or by perinatal complications. The clinical findings of the present cases are rather uniform, with the following cardinal features: truncal and limb ataxia, dysmetria, intention tremor, mental retardation ranging from mild to moderate, pyramidal signs, ocular anomalies, oculomotor apraxia and impairment of pursuit, and saccades characterized by jerky eye movements. Cases II-1 and II-3 manifested facial dimorphisms. All the patients have presented with psychomotor developmental delay of varying degree. Magnetic resonance imaging data revealed severe hypoplasia of the cerebellar vermis and hemispheres.
According to the Steinlin classification of congenital ataxia, the disorder described in the present study may be included in the hereditary syndromes with ataxia, in which this sign represents the cardinal feature. In fact, considering the ocular and oculomotor anomalies reported in all three brothers, the dysmorphisms described in Cases II-1 and II-3, the hepatic and the peripheral nerve impairment in Case II-1, pure congenital ataxia can be excluded. Moreover, in the family reported here, the early onset of the disorder and the presence of the same clinical and neuroimaging features in all three brothers excluded acquired congenital ataxia, being suggestive rather of hereditary congenital ataxia. The family pedigree of these patients does not allow one to reach a conclusion regarding the mode of inheritance of the disorder. The absence of consanguinity between parents, their healthy state without any clinical sign of this pathology, and the sex of the patients (all males) suggest the possibility of an X-linked inheritance, although autosomal recessive inheritance cannot be excluded. In accordance with the increased clinical and experimental evidence of the role of the cerebellum in psychomotor development and cognition [4,5], developmental delay and intellectual impairment in the cases presented here are clearly linked to cerebellar hypoplasia. There have been several familiar reports of cerebellar hypoplasia associated with ataxia and mental retardation [6-12]. Between the sex-linked nonprogressive congenital
Margari et al: Congenital Ataxia and Mental Retardation 61
Figure 3. Spin-echo coronal T1-weighted image of Patient II-3 reveals severe hypoplasia of the cerebellar vermis and moderate hypoplasia of the cerebellar hemispheres. TA: 160.
ataxia, the findings in our patients are similar to those described by Young et al. [7] and Illarioshkin et al. [8]. Young reported three cases of brothers who presented with a sex-linked inherited nonprogressive ataxia, developmental delay, moderate mental retardation, nystagmus in association with generalized cerebellar atrophy in one case, vermis atrophy in another, and normal computed tomographic scan in another one. Illarioshkin reported seven males from three generations who presented with generalized cerebellar hypoplasia associated with nonprogressive ataxia, developmental delay, external ophthalmoplegia, nystagmus, and increased tendon reflexes, mapped on chromosome Xp11.21-q24. The three cases described in the present report cannot be compared with this family because of the absence of ophthalmoplegia. Between the autosomal recessive forms of nonprogressive congenital ataxia, the present cases manifested some cardinal features in common with the six children reported by Wichman et al. [9], who presented cerebellar dysfunction, developmental delay, and cognitive abilities ranging from normal to moderately retarded, associated with global cerebellar hypoplasia. This clinical picture differs from that of our cases because of the absence of ocular and oculomotor anomalies and pyramidal signs. Al Shah-
62
PEDIATRIC NEUROLOGY
Vol. 31 No. 1
wan et al. [10] described three brothers with nonprogressive congenital ataxia associated with mental retardation, nystagmus, and pyramidal syndrome. Unlike our cases, these patients manifested microcephaly and hypoplasia confined to vermis and sagittal paravermian parts of hemispheres. Regarding the increase of serum bilirubin, the hepatomegaly, and the evidence of hepatic ultrasound anomalies in Case II-1, a differential diagnosis with COACH syndrome (coloboma, oligophrenia, ataxia and cerebellar hypoplasia) can be proposed. Nevertheless, we have not obtained biopsy confirmation of an eventual hepatic fibrosis because of the absence of parental consensus to perform this examination. Also, considering the variable expressivity of the COACH syndrome [13,14], the absence of some typical features of this clinical picture, such as coloboma and hypoplasia confined to the cerebellar vermis, makes it unlikely that our patients have this disorder. We have also proposed a differential diagnosis with Joubert’s syndrome. Clinical features in common are ataxia, developmental delay, cognitive impairment, and ocular motor abnormalities. Irregular breathing and the typical neuroimaging findings of Joubert’s syndrome [15], consisting of the “molar tooth sign” on axial magnetic resonance imaging, were not present in our cases. In reference to the differential diagnosis with neurodegenerative disorders, we have performed a basic neurometabolic evaluation; results were normal. Moreover, considering the nonprogressive course of the disorder described in this study, the diagnosis of neurodegenerative disorders might be excluded. Moreover, considering the normal images of pontis on magnetic resonance imaging, the diagnosis of neurodegenerative disorders associated with pontocerebellar hypoplasia was excluded. Thus we are prompted to conclude that it seems difficult to include our reported syndrome in one of the groups already proposed. We suggest that the present cases represent a further example of the marked phenotypic polymorphism of nonprogressive congenital ataxia. This combination of hereditary congenital cerebellar ataxia, mental retardation, pyramidal signs, and ocular and oculomotor abnormalities might constitute a new clinical entity. It might be helpful to have large, informative pedigrees appropriate for genetic linkage studies to define the genetic diagnosis of these complex disorders.
References [1] Bertini E, Campos-Castello` J. Ataxias conge´ nitas de origen gene´e´tico con anomalias estructurales del cerebelo. Rev Neurol 1999;28:63-8. [2] Ruggieri VL, Alberas CL. Hereditary ataxias. Rev Neurol 2000;31:288-96. [3] Steinlin M. Nonprogressive congenital ataxias. Brain Devel 1998;20:199-208. [4] Steinlin M, Styger M, Boltshauser E. Cognitive impairments in patients with congenital nonprogressive cerebellar ataxia. Neurol 1999; 53:966-73.
[5] Rapoport M, van Reekum R, Mayberg H. The role of the cerebellum in cognition and behavior: Selective review. J Neuropsych Clin Neurosci 2000;12:193-4. [6] Shevell MI, Majnemer A. Clinical features of developmental disability associated with cerebellar hypoplasia. Pediatr Neurol 1996;15: 224-9. [7] Young ID, Moore JR, Tripp JH. Sex-linked recessive congenital ataxia. J Neurol Neurosurg Psychiatry 1987;50:1230-2. [8] Illarioshkin SN, Tanaka H, Markova ED, Nikolskaya NN, Ivanova-Smolenskaya IA, Tsuji S. X-linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq. Ann Neurol 1996;40:75-83. [9] Wichman A, Frank LM, Kelly TE. Autosomal recessive congenital cerebellar hypoplasia. Clin Genet 1985;27:373-82. [10] Al Shahwan SA, Bruyn GW, Al Deeb SM. Non-progressive familiar congenital cerebellar hypoplasia. J Neurol Sci 1995;128:71-7. [11] Bruck I, Antoniuk SA, Carvalho Neto AD, Spessatto A.
Cerebellar vermis hypoplasia–nonprogressive congenital ataxia: Clinical and radiological findings in a pair of siblings. Ar Qneuropsiquiatr 2000;58:897-900. [12] Bertini E, des Portes V, Vicari S, Dionisi Vici C, Fariello G, Piantadosi C. Congenital X-linked nonprogressive ataxia: Linkage studies in a second family. Ann Neurol 1997;42:499. [13] Gentile M, Di Carlo A, Susca F, et al. COACH syndrome: Report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia and mental retardation. Am J Med Genet 1996;64:514-20. [14] Coppola G, Vajro P, De Virgiliis S, Ciccimarra E, Boccone L, Pascotto A. Cerebellar vermis defect, oligophrenia, congenital ataxia, and hepatic fibrocirrhosis without coloboma and renal abnormalities: Report of three cases. Neuropediatrics 2002;33:180-5. [15] Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol 1999;14:583-91.
Margari et al: Congenital Ataxia and Mental Retardation 63
Case Report Case II-1, a 14-year-old Male The patient was first observed at our department at age 11, because of suspected mental retardation. He was born by elective caesarean delivery at 38 weeks because of delay of fetal growth and suspected fetal suffering during the last month of pregnancy. Birth weight was 2.260 kg. He sat alone at 6 months and first walked at 18 months. Imbalanced gait was soon observed by family members. He said his first words at 2 years and was able to combine words at 4 years, without any other improvement until the time of the first examination. General examination revealed dysmorphic features (micrognathia, high arched palate, irregular placement of teeth) and mild hepatomegaly. Neurologic examination revealed truncal and locomotor ataxia, clumsiness, dysmetria and intention tremor, axial and arm hypotonia, mild spastic hypertonia of lower limbs and right ankle clonus, generalized hyperreflexia with bilateral Babinski sign, and absent abdominal tactile reflexes. Pain and touch sense were unimpaired; deep sensory functions were not evaluated because of the patient’s poor cooperation. Neuropsychological evaluation revealed moderate mental retardation on the Wechsler Intelligence Scale for Children, Revised: full-scale intelligence quotient, 45; Verbal Scale intelligence quotient, 49; Performance Scale intelligence quotient, 41. The subtests analysis revealed homogeneous failure in all the tasks. Bender test and Raven Colored Progressive Matrices evidenced visuoperceptual deficits.
Case II-2, a 7-year-old Male, Brother of Cases II-1 and II-3 The patient first came to our attention at age 4 because of his imbalanced gait. He weighed 2.800 kg at birth, after an uneventful pregnancy and delivery. He sat alone at 5 months and first walked, albeit unsteadily, at 18 months. He used his first meaningful words at 2 years, combined words at 4 years, and simple sentences at 5 years. General examination revealed only simple hypertrichosis on the back. No dysmorphic feature was observed. On neurologic examination, features were observed similar to those of his brother, including ataxia, clumsiness, axial and arm hypotonia, and pyramidal signs consisting of mild spastic hypertonia of lower limbs, generalized hyperreflexia with right prevalence, absent abdominal tactile reflexes and extensor plantar responses. Superficial sensations were unimpaired. Psychometric evaluation, performed by the behavioral observation, evidenced mild mental retardation. A formal cognitive assessment using standardized level scales was impossible because of significant psychomotor restlessness.
Case II-3, a 6-year-old Male, Brother of Cases II-1 and II-2 Introduction We present three sons of nonconsanguineous healthy parents. Neurologic diseases were documented neither in the patient’s generation nor in the previous generations.
From the Child Neurological and Psychiatric Service, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.
© 2004 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2004.01.006 ● 0887-8994/04/$—see front matter
At 3 years, this patient was referred to our institute because of his suspected global delay and his abnormal gait. He weighed 2.950 kg at birth, after uneventful pregnancy and delivery. He experienced neonatal metabolic acidosis and sucking problems in the first days of life, with no other feeding problems throughout infancy. He sat alone at 8 months and first walked unsteadily at 32 months. Speech was delayed, with mean-
Communications should be addressed to: Dr. Margari; Sezione di Neuropsichiatria Infantile; Dipartimento di Scienze Neurologiche e Psichiatriche; Universita` degli Studi; Azienda Ospedaliera Policlinico; Piazza Giulio Cesare; CP 70124 Bari, Italy. Received August 14, 2003; accepted January 12, 2004.
Margari et al: Congenital Ataxia and Mental Retardation 59
ingful words first being used at 1 year, combined words at 4 years, and simple sentences at 6 years. General examination revealed the following dysmorphic features: micrognathia, high arched palate, low setting ears, short neck, prominent central forehead, clinodactyly of fifth fingers. On neurologic examination, features were observed similar to those of his brothers, including global motor incoordination, truncal and locomotor ataxia, pyramidal signs consisting of generalized hyperreflexia, bilateral ankle clonus, bilateral Babinski sign, and absent abdominal tactile reflexes. Psychometric examination using Griffiths Developmental Scales revealed moderate mental retardation with homogeneous failure in all the subscales.
Laboratory Evaluations Routine, metabolic and immunologic evaluations including serum immunoglobulin, alfa-fetoprotein, ammonia, serum copper, 24-hour urinary copper excretion, and serum ceruloplasmin were normal in all three patients. Bilirubin was slightly increased in Case II-1 and normal in Cases II-2 and II-3. On abdomen ultrasound, slight hepatomegaly with hyperecogeneity was evident in Case II-1, with normal kidneys and spleen. This examination was normal in Cases II-2 and II-3.
Ophthalmologic Examination Ophthalmologic examination evidenced the same anomalies in all three brothers, consisting of oculomotor motor apraxia, esotropia, impairment of pursuit, and saccades which consisted of jerky, conjugate, and usually horizontal, sometimes vertical, eye movements. Fundal examination revealed that the right eye was higher than the left in all the patients. Visual activity was 5/10 in the left eye and 6/10 in the right eye in Case II-1; 6/10 in the left eye and 7/10 in the right eye in Case II-2. Visual activity in Case II-3 was not estimated because of the patient’s poor cooperation. Slit lamp examination performed in Cases II-1 and II-2 excluded the presence of Kaiser-Fleischer ring.
Figure 1. Spin-echo coronal T1-weighted image of Patient II-1 reveals severe hypoplasia of the cerebellar vermis and hemispheres, more significant at inferior cerebellar vermis. Time for Acquisition (TA): 160.
Genetic Study Electrophysiologic Investigations The electroencephalographic examination was normal in all three patients. Electromyographic examination and nerve conduction velocities were performed in Cases II-1 and II-2. Electromyography was normal in both patients, whereas abnormal conduction velocities were documented in Case II-1 consisting of a slight reduction in the amplitude of the sensory action potentials and in the sensory nerve conduction velocities. Somatosensory evoked potentials by median nerve stimulation and by posterior tibial nerve stimulation as well as brainstem auditory potentials, performed in Cases II-1 and II-2, were normal. Visual evoked potentials in Case II-1 evidenced bilaterally slight morphologic alteration of major positive wave with normal latency and decreased amplitude. In Case II-2, visual evoked potentials evidenced slight morphologic alteration of major positive wave bilaterally with normal latency in the left eye, slightly increased latency in the right eye, and normal amplitude bilaterally. In Case II-3, visual evoked potentials evidenced morphologic alteration of major positive wave bilaterally, increased latency in the left eye, normal latency in the right eye, and decreased amplitude bilaterally.
Neuroimaging Studies Magnetic resonance imaging data, obtained from Patients II-1 (Fig 1), II-2 (Fig 2), and II-3 (Fig 3), revealed severe hypoplasia of the cerebellar vermis and hemispheres. Magnetic resonance imaging of the spinal cord was performed only in Case II-1 and was normal.
60
PEDIATRIC NEUROLOGY
Vol. 31 No. 1
Banded karyotype including fragile X study was normal in all three patients.
Follow-up A clinical, neuropsychologic, laboratory, electrophysiologic, and neuroimaging follow-up, lasting 3 years, was performed in all three cases. No progression of the clinical picture was observed. In Case II-1, the slight increase in bilirubin was confirmed, although liver ultrasound was normal; slight sensory nerve impairment was confirmed. In Cases II-2 and II-3, the absence of liver dysfunction was confirmed. Magnetic resonance imaging data remained unchanged after 3 years of follow-up.
Discussion Classification of congenital ataxias is still uncertain and difficult, considering their clinical polymorphism and the variety of the etiologic factors. Recently several authors have attempted to classify this complex group of disorders [1,2]. Steinlin [3] has proposed a classification of nonprogressive congenital ataxia based on clinical, neuroimaging, and etiologic factors. He divided nonprogressive congenital ataxia into pure congenital ataxia and syndromes with congenital ataxia. Pure congenital ataxia include all nonprogressive encephalopathies manifesting
Figure 2. Spin-echo coronal T2-weighted image of Patient II-2 reveals severe hypoplasia of the cerebellar vermis and hemispheres. Time for Acquisition (TA): 150.
the typical symptoms related to cerebellar dysfunction (incoordination and developmental delay) without symptoms such as eye abnormalities and dimorphisms. This group of nonprogressive congenital ataxia includes congenital ataxia caused by cerebellar hypoplasia (hereditary or not hereditary), congenital ataxia resulting from posterior fossa malformations (e.g., Dandy-Walker, Chiari malformations), and congenital ataxia due to supratentorial malformations. In the syndromes with congenital ataxia, ataxia can be a cardinal feature (e.g., Joubert’s syndrome) or an occasional symptom. This group includes some forms associated with cerebellar hypoplasia/aplasia, some with other posterior fossa malformations, and others without brain malformation. Acquired ataxias represent a small third group and may be caused by prenatal viral infections, fetal exposure to toxins or irradiations, or by perinatal complications. The clinical findings of the present cases are rather uniform, with the following cardinal features: truncal and limb ataxia, dysmetria, intention tremor, mental retardation ranging from mild to moderate, pyramidal signs, ocular anomalies, oculomotor apraxia and impairment of pursuit, and saccades characterized by jerky eye movements. Cases II-1 and II-3 manifested facial dimorphisms. All the patients have presented with psychomotor developmental delay of varying degree. Magnetic resonance imaging data revealed severe hypoplasia of the cerebellar vermis and hemispheres.
According to the Steinlin classification of congenital ataxia, the disorder described in the present study may be included in the hereditary syndromes with ataxia, in which this sign represents the cardinal feature. In fact, considering the ocular and oculomotor anomalies reported in all three brothers, the dysmorphisms described in Cases II-1 and II-3, the hepatic and the peripheral nerve impairment in Case II-1, pure congenital ataxia can be excluded. Moreover, in the family reported here, the early onset of the disorder and the presence of the same clinical and neuroimaging features in all three brothers excluded acquired congenital ataxia, being suggestive rather of hereditary congenital ataxia. The family pedigree of these patients does not allow one to reach a conclusion regarding the mode of inheritance of the disorder. The absence of consanguinity between parents, their healthy state without any clinical sign of this pathology, and the sex of the patients (all males) suggest the possibility of an X-linked inheritance, although autosomal recessive inheritance cannot be excluded. In accordance with the increased clinical and experimental evidence of the role of the cerebellum in psychomotor development and cognition [4,5], developmental delay and intellectual impairment in the cases presented here are clearly linked to cerebellar hypoplasia. There have been several familiar reports of cerebellar hypoplasia associated with ataxia and mental retardation [6-12]. Between the sex-linked nonprogressive congenital
Margari et al: Congenital Ataxia and Mental Retardation 61
Figure 3. Spin-echo coronal T1-weighted image of Patient II-3 reveals severe hypoplasia of the cerebellar vermis and moderate hypoplasia of the cerebellar hemispheres. TA: 160.
ataxia, the findings in our patients are similar to those described by Young et al. [7] and Illarioshkin et al. [8]. Young reported three cases of brothers who presented with a sex-linked inherited nonprogressive ataxia, developmental delay, moderate mental retardation, nystagmus in association with generalized cerebellar atrophy in one case, vermis atrophy in another, and normal computed tomographic scan in another one. Illarioshkin reported seven males from three generations who presented with generalized cerebellar hypoplasia associated with nonprogressive ataxia, developmental delay, external ophthalmoplegia, nystagmus, and increased tendon reflexes, mapped on chromosome Xp11.21-q24. The three cases described in the present report cannot be compared with this family because of the absence of ophthalmoplegia. Between the autosomal recessive forms of nonprogressive congenital ataxia, the present cases manifested some cardinal features in common with the six children reported by Wichman et al. [9], who presented cerebellar dysfunction, developmental delay, and cognitive abilities ranging from normal to moderately retarded, associated with global cerebellar hypoplasia. This clinical picture differs from that of our cases because of the absence of ocular and oculomotor anomalies and pyramidal signs. Al Shah-
62
PEDIATRIC NEUROLOGY
Vol. 31 No. 1
wan et al. [10] described three brothers with nonprogressive congenital ataxia associated with mental retardation, nystagmus, and pyramidal syndrome. Unlike our cases, these patients manifested microcephaly and hypoplasia confined to vermis and sagittal paravermian parts of hemispheres. Regarding the increase of serum bilirubin, the hepatomegaly, and the evidence of hepatic ultrasound anomalies in Case II-1, a differential diagnosis with COACH syndrome (coloboma, oligophrenia, ataxia and cerebellar hypoplasia) can be proposed. Nevertheless, we have not obtained biopsy confirmation of an eventual hepatic fibrosis because of the absence of parental consensus to perform this examination. Also, considering the variable expressivity of the COACH syndrome [13,14], the absence of some typical features of this clinical picture, such as coloboma and hypoplasia confined to the cerebellar vermis, makes it unlikely that our patients have this disorder. We have also proposed a differential diagnosis with Joubert’s syndrome. Clinical features in common are ataxia, developmental delay, cognitive impairment, and ocular motor abnormalities. Irregular breathing and the typical neuroimaging findings of Joubert’s syndrome [15], consisting of the “molar tooth sign” on axial magnetic resonance imaging, were not present in our cases. In reference to the differential diagnosis with neurodegenerative disorders, we have performed a basic neurometabolic evaluation; results were normal. Moreover, considering the nonprogressive course of the disorder described in this study, the diagnosis of neurodegenerative disorders might be excluded. Moreover, considering the normal images of pontis on magnetic resonance imaging, the diagnosis of neurodegenerative disorders associated with pontocerebellar hypoplasia was excluded. Thus we are prompted to conclude that it seems difficult to include our reported syndrome in one of the groups already proposed. We suggest that the present cases represent a further example of the marked phenotypic polymorphism of nonprogressive congenital ataxia. This combination of hereditary congenital cerebellar ataxia, mental retardation, pyramidal signs, and ocular and oculomotor abnormalities might constitute a new clinical entity. It might be helpful to have large, informative pedigrees appropriate for genetic linkage studies to define the genetic diagnosis of these complex disorders.
References [1] Bertini E, Campos-Castello` J. Ataxias conge´ nitas de origen gene´e´tico con anomalias estructurales del cerebelo. Rev Neurol 1999;28:63-8. [2] Ruggieri VL, Alberas CL. Hereditary ataxias. Rev Neurol 2000;31:288-96. [3] Steinlin M. Nonprogressive congenital ataxias. Brain Devel 1998;20:199-208. [4] Steinlin M, Styger M, Boltshauser E. Cognitive impairments in patients with congenital nonprogressive cerebellar ataxia. Neurol 1999; 53:966-73.
[5] Rapoport M, van Reekum R, Mayberg H. The role of the cerebellum in cognition and behavior: Selective review. J Neuropsych Clin Neurosci 2000;12:193-4. [6] Shevell MI, Majnemer A. Clinical features of developmental disability associated with cerebellar hypoplasia. Pediatr Neurol 1996;15: 224-9. [7] Young ID, Moore JR, Tripp JH. Sex-linked recessive congenital ataxia. J Neurol Neurosurg Psychiatry 1987;50:1230-2. [8] Illarioshkin SN, Tanaka H, Markova ED, Nikolskaya NN, Ivanova-Smolenskaya IA, Tsuji S. X-linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq. Ann Neurol 1996;40:75-83. [9] Wichman A, Frank LM, Kelly TE. Autosomal recessive congenital cerebellar hypoplasia. Clin Genet 1985;27:373-82. [10] Al Shahwan SA, Bruyn GW, Al Deeb SM. Non-progressive familiar congenital cerebellar hypoplasia. J Neurol Sci 1995;128:71-7. [11] Bruck I, Antoniuk SA, Carvalho Neto AD, Spessatto A.
Cerebellar vermis hypoplasia–nonprogressive congenital ataxia: Clinical and radiological findings in a pair of siblings. Ar Qneuropsiquiatr 2000;58:897-900. [12] Bertini E, des Portes V, Vicari S, Dionisi Vici C, Fariello G, Piantadosi C. Congenital X-linked nonprogressive ataxia: Linkage studies in a second family. Ann Neurol 1997;42:499. [13] Gentile M, Di Carlo A, Susca F, et al. COACH syndrome: Report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia and mental retardation. Am J Med Genet 1996;64:514-20. [14] Coppola G, Vajro P, De Virgiliis S, Ciccimarra E, Boccone L, Pascotto A. Cerebellar vermis defect, oligophrenia, congenital ataxia, and hepatic fibrocirrhosis without coloboma and renal abnormalities: Report of three cases. Neuropediatrics 2002;33:180-5. [15] Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol 1999;14:583-91.
Margari et al: Congenital Ataxia and Mental Retardation 63