Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort.

BACKGROUND AND PURPOSE: Mutations in the PLA2G6 gene are causative of PLA2G6-associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms. METHODS: Seventeen North African patients with a clinical suspicion of infantile-onset PLAN underwent clinical, neurophysiological and neuroimaging examinations, and PLA2G6 sequencing. Haplotype analysis was performed to date the identified founder mutation. RESULTS: All patients carried biallelic mutations in PLA2G6. Sixteen children had the commonest form of infantile-onset PLAN, with early onset of psychomotor regression, hypotonia, pyramidal and cerebellar signs, and abnormal ocular movements. The phenotype was highly homogeneous, with rapid development of severe spastic tetraparesis, cognitive impairment and optic atrophy. Neuroimaging showed cerebellar atrophy and claval hypertrophy to be the commonest and earliest signs, whilst cerebellar cortex hyperintensity and pallidal iron deposition were later findings. Motor or sensory-motor neuropathy and electroencephalogram fast rhythms were also frequent. Nine patients from six families shared the same founder mutation (p.V691del) which probably arose by the late seventeenth century. Only one patient fitted the diagnosis of the much rarer childhood-onset PLAN. Despite the early onset (18 months), clinical progression was slower, with behavioral disturbances and dystonia. Typical features of infantile-onset PLAN such as hypotonia, nystagmus/strabismus, optic atrophy, electroencephalogram fast rhythms and motor neuropathy were absent. Cerebellar atrophy, claval hypertrophy and pallidal hypointensity were evident at brain magnetic resonance imaging. This patient carried a missense variant predicted to be less deleterious. CONCLUSIONS: The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.

[Botulinum toxin in the management of spasticity in children]. / Place de la toxine botulique dans le traitement de la spasticité de l'enfant.

INTRODUCTION: Spasticity is a motor disorder, which can be treated by botulinum toxin (BT). We found no studies describing BT management of spasticity in Tunisian children. The aim of our study was to determine the frequency of spastic children treated with BT in the Tunisian hospital population and to evaluate treatment efficacy. METHODS: We conducted a prospective study over a 5-year period including all children diagnosed with spasticity treated with BT and attending the "Movement Disorders and Botulinum Toxin" outpatient clinic of the National Institute of Neurology of Tunis. RESULTS: Hundred and fifteen patients were included (31% of patients attending the "Movement Disorders and Botulinum Toxin" outpatient clinic). Mean age was 7.6years and M:F sex ratio 1.7. Main clinical features were: spastic quadriplegia (48%), equinus deformity (70.4%) and cerebral palsy (88%). All patients were evaluated with the modified Ashworth score and were treated with BT. Other treatments were associated with BT: baclofene, physiotherapy, ortheses, plaster, and sometimes surgical treatment. The average percentage of improvement after BT was>50%. The Ashworth score was significantly lower for the majority of injected muscles. DISCUSSION AND CONCLUSION: Our study is the first to describe BT management of spasticity in Tunisian children. Treatments of spasticity are numerous and vary according to location and extent of spasticity. BT is the main treatment for focal spasticity. Associated with physical therapy, BT allows optimal management of spastic children.

[Clinical and therapeutic aspects in Tunisian patients with dystonia: a 5-year prospective study]. / Aspects cliniques et thérapeutiques des dystonies en Tunisie : étude prospective sur cinq ans.

INTRODUCTION: Studies of dystonia are heterogeneous and there are no studies on this disease in Tunisia. The aim of our study was to determine the frequency of dystonia in the hospital population, to identify different forms of dystonia according to age of onset, distribution, to determine etiologies and to describe treatment. METHODS: We conducted a prospective study over a 5-year period (from January 2005 to November 2009) including all patients diagnosed with dystonia and followed at the Child and Adolescent Neurology Department and "Movement Disorders and Botulinum Toxin" consultation of the National Institute of Neurology of Tunis. RESULTS: Two hundred patients were included (2.2% of our patients). Mean age was 26.4±21.4 years and sex ratio H:F 1.3. Consanguinity rate was 29%. Main features of dystonia were action dystonia (78.5%), generalized forms (47%) and secondary forms (58%). A pyramidal syndrome and other movement disorders were the most common signs associated with dystonia (36.5% and 33.5% respectively). In the group of secondary dystonia, mains etiologies were dystonia due to exogenic agent (56%), neuro-metabolic diseases (26%), hereditary degenerative disease (13%) and psychogenic dystonia (5%). Dystonia was primary in 44% (84 patients). Different treatments were used and a dramatic improvement in some patients was noted with levodopa and botulinum toxin injections. A multidisciplinary approach associated with medical treatment led to recovery or improved prognosis. DISCUSSION AND CONCLUSION: Very few studies have been devoted to reporting a large series of dystonic patients. Our study is the first to describe both primary and secondary dystonia in 200 Tunisian patients. The presence of familial dystonia in our country suggests a genetic origin. Further work including genetic analysis with a screening of known mutations responsible for dystonia and the informative families with unknown mutations would be useful. Specific studies designed to identify new genes causal in dystonia are needed.

Identification of a primarily neurological phenotypic expression of xeroderma pigmentosum complementation group A in a Tunisian family.

Xeroderma pigmentosum (XP) is a rare genodermatosis predisposing to skin cancers. The disease is classified into eight groups. Among them, XP group A (XP-A) is characterized by the presence of neurological abnormalities in addition to cutaneous symptoms. In the present study, we report a particular family with XP-A in which some members showed an atypical clinical presentation, i.e. unexplained neurological abnormalities with discrete skin manifestations. Molecular investigation allowed identification of a novel XPA mutation and complete phenotype-genotype correlation for this new phenotypic expression of XP-A.

[Cerebromediastinal tuberculosis in a child with a probable Say-Barber-Miller syndrome: a causative link?]. / Tuberculose cérébromédiastinale chez un enfant atteint de syndrome de Say-Barber-Miller probable : un lien de causalité ?

INTRODUCTION: Tuberculosis continues to be a public health problem in emerging countries with a recent evidence of increased incidence of extrapulmonary localization in developed countries probably linked to HIV. To our knowledge the occurrence of cerebro-mediastinal tuberculosis in an immuno-competent child has not been previously described; moreover the child we describe has a probable Say-Barber-Miller syndrome. We discuss a putative causative link between this syndrome and the occurrence of tuberculosis. CASE REPORT: A seven-year-old girl presented to our department with a history of infantile encephalopathy since birth characterized by a facial dysmorphy (evocative of a bird face), microcephaly, and mental retardation, and with recurrent infections. The child had complained of back pain for several months; the parents reported anorexia, loss of weight. Spinal and cerebral MRI showed a mediastinal mass involving the spine and cerebral lesions evocative of tuberculomas. The tuberculin interdermal reaction was positive. Culture of a vertebral biopsy was positive for Koch bacillus. Anti-tuberculosis treatment improved general and local status. An extensive immunological work-up was normal. CONCLUSION: [corrected] This observation is exceptional in many aspects: very early age of onset of extrapulmonary tuberculosis, no immune deficit, association with a rare congenital neurological syndrome. We discuss the possible link between this entity and the occurrence of tuberculosis.

[An overview of neurometabolic diseases in Tunisia. a 3-year prospective study]. / Diagnostic et prise en charge des maladies neurométaboliques en Tunisie. Etude prospective sur trois ans.

INTRODUCTION: Neurometabolic diseases are a large group of genetic diseases. In our country, the diagnostic and therapeutic approach to theses diseases is rather difficult. The aim of our study was to determine the frequency of neurometabolic diseases in the hospital population, to describe the problems in diagnosing these conditions and difficulties encountered during patient care. Our goal was to propose guidelines for a practical diagnostic and therapeutic approach to neurometabolic disorders in our country. METHODS: We have conducted a prospective study over a 3-year period including all patients diagnosed with "metabolic disease" and followed at the Child and Adolescent Neurology Department of the National Institute of Neurology of Tunis. RESULTS: One hundred and thirty-six patients were included (2.4% of our patients). Mean age was 7.3 +/- 5.1 years. Mean age at onset was 4.3 years. There was a high consanguinity rate. Respiratory chain defects were the most frequently suspected diseases (16.9%), followed by lysosomal diseases (8.8%). Chromatography, initially systematically prescribed, became targeted with a higher diagnostic efficacy. Metabolic diseases diagnosed as certain, represented 22% of the studied cases. This can be explained by the insufficiency of available laboratory tests of confirmation. The prescription of specific treatment was insufficient, even for confirmed pathologies (14.7%) because of the high cost of these therapies. CONCLUSION: The diagnostic approach has to be rational, targeted, multidisciplinar and conducted within a care network. Diagnostic priority should focus on treatable neurometabolic diseases. The establishment of a systematized registry and neonatal screening for the main treatable neurometabolic diseases constitute the final objective of our work to prepare for biochemical and genetic studies.

[A comparative study of clinical and paramedical aspects of multiple sclerosis in Tunisia]. / Etude comparative des aspects cliniques et paracliniques de la sclérose en plaques en Tunisie.

INTRODUCTION: Tunisia is considered as a low zone of prevalence for multiple sclerosis (MS). Consequently, only very few studies have taken an interest in this disorder in North Africa. The objective of this study was to compare the clinical and paraclinical parameters and the outcome of the disease in patients affected with MS in Tunisia during two periods (1974-1978 and 1996-2000) and to determine the incidence of the disease and the impact of the use of diagnostic criteria, including the MRI. PATIENTS AND METHODS: We report the results of a retrospective study concerning patients classified with MS and followed in the National Institute of Neurology in Tunis between 1974 and 2000, with 1058 records examined. We divided the patients into two groups belonging to two periods: Group I (1974-1978, 125 patients classified according to the McAlpine criteria) and Group II (1996-2000, 247 patients classified according to Poser's criteria. We compared the clinical and paraclinical parameters of the two groups. RESULTS: The incidence of the disease was evaluated at 1.3 per 100,000 individuals, placing Tunisia in the middle zone of prevalence. There was no significant difference in the mean age of onset (32.4+/-10.1 years) between the two groups. A slight male preponderance was observed in Group I (M/F sex ratio=1.25). The clinical outcome factors were age of onset after 40 years, pyramidal signs as the first symptom, and the progressive forms of the disease. Although Group II had an earlier diagnosis of the disease and a more systematic treatment of relapses, the functional outcome was similar between the two groups. CONCLUSION: MS in Tunisia has the same clinical characteristics and disease outcome as in other countries. The use of MRI allowed earlier diagnosis but did not increase the overall proportion of definite MS.

[Type I glutaric aciduria: an unrecognized cause of progressive dystonia]. / L'acidurie glutarique type I: une cause méconnue de dystonie progressive.

INTRODUCTION: Glutaric acidemia type I is one of the least rare organic acidemias. The number of diagnosed causes is however still low because the presentation is variable and often confusing. The disease may sometimes have a slowly progressive course. Typically, it presents in infancy, mimicking acute encephalitis, leaving a previously healthy child severely handicapped with generalized dystonia, spastic quadriplegia or choreoathetosis. Cerebral MRI shows large CSF-containing spaces (sylvian fissures and anterior to the temporal lobes) and basal ganglia abnormal signal. CASE REPORT: An eight year-old boy had begun at 18 months with motor difficulties and abnormal posture of upper and lower left limbs. When examined, he had generalized dystonia more pronounced at the left side, severe dysarthria and tongue dystonia. IQ was normal. MRI showed high T2 signal in basal ganglia and enlarged CSF containing spaces. Urinary organic acids chromatography confirmed glutaric acidemia type I. Two of his sisters deceased before the age of two years with a clinical picture of fever, seizures and hypotonia. Another sister had the same symptoms at the same age. She lived until 10 year with severe quadriplegia. COMMENTS: Our observation shows variability of clinical picture and course of glutaric acidemia type I in the same kindred. We propose systematic organic acides chromatography in all children with acute or progressive dystonia with basal ganglia abnormalities on MRI. This seems an imperative attitude because appropriate diet could slow the progression of the illness.

[Post-herpes simplex encephalitis chorea: Viral replication or immunological mechanism?]. / Chorée aiguë après encéphalite herpétique : réplication virale ou mécanisme immunologique ?

INTRODUCTION: Herpes simplex encephalitis is a severe neurological condition, whose outcome is improved if treated early with acyclovir. Post-herpes simplex encephalitis with acute chorea has rarely been reported. CASE REPORT: We report on two observations of children presenting with post-herpes simplex encephalitis with acute chorea, related to two different pathophysiological mechanisms. The first one is an 11-month-old girl developing relapsing herpes simplex encephalitis with chorea due to resumption of viral replication. The second one is a 2-year-old boy with relapsing post-herpes simplex encephalitis acute chorea caused by an immunoinflammatory mechanism. We discuss the different neurological presentations of herpetic relapses, notably those presenting with movement disorders, as well as their clinical, paraclinical, physiopathological, and therapeutic aspects. CONCLUSION: Post-herpes simplex encephalitis with acute chorea may involve two mechanisms: resumption of viral replication or an immunoinflammatory mechanism. Treatment of post-herpes simplex encephalitis with acute chorea depends on the underlying mechanism, while prevention is based on antiviral treatment of herpes simplex encephalitis with acyclovir at the dose of 20mg/kg/8h for 21 days.

Clinical and genetic study of familial Parkinson's disease in Tunisia.

OBJECTIVE: To determine inheritance patterns and clinical characteristics of familial PD (F-PD) in Tunisia. METHODS: Twenty-one index patients were selected on the basis of typical PD and a family history of PD. The 21 families of the index patients were visited at home, and clinical assessment of all available relatives, a total of 133 individuals, was made. Extensive pedigree data detected 67 additional cases. We ascertained medical history, age, age at onset, first sign at onset, course of the disease, dosage and duration of levodopa (LD) treatment, and associated diseases. One patient from each family was hospitalized to confirm response to LD by evaluation of untreated and treated Unified Parkinson's Disease Rating Scale scores. The sex ratio, transmission pattern, ancestral secondary cases, and segregation ratio (SR) were determined by pedigree analysis. RESULTS: Eighty-eight patients were analyzed (44 men and 44 women; mean age at onset, 39.8 +/- 14.4 years). Pedigree analysis showed 10 single-generation (SG) families (i.e., all affected members belonging to 1 generation) and 11 multigenerational (MG) families (i.e., affected members spanning >1 generation). Parental consanguinity was more frequent in SG families than in MG families. The SR in SG families was 0.23 +/- 0.05, compatible with autosomal recessive (AR) inheritance. Analysis of MG pedigrees showed autosomal dominant (AD) inheritance with reduced penetrance in 9 of 10 families. Age at onset was younger than in sporadic PD. Intrafamilial variability of age at onset, symptom of onset, and clinical course was observed. There was no difference in clinical characteristics between SG and MG families apart from dystonic foot at onset, which was more frequent in SG families. CONCLUSIONS: First, F-PD is clinically similar to sporadic PD apart from younger age at onset. Second, there is intrafamilial and interfamilial variability of all clinical features. Third, F-PD in Tunisia is genetically heterogenous with at least two inheritance patterns: AD and AR.

Do parkinsonian symptoms and levodopa-induced dyskinesias start in the foot?

Parkinsonian symptoms and levodopa-induced dyskinesias (LIDs) are often considered to occur first, and to predominate, in the upper limbs. We studied the topography, type, sequence, and severity of LIDs in 20 consecutive patients with Parkinson's disease (PD) experiencing LIDs for less than 6 months (Hoehn and Yahr stage II-III; average age at onset of PD, 57 years; average duration of PD, 7.2 years; percent of improvement with levodopa > 50) and compared them with the initial site, form, and evolution of the patient's motor disability. Parkinsonism started in the foot in six of 20 patients. Motor disability in the "off" state was similar in upper and lower extremities, except for akinesia, which was worse in the lower limbs. A careful interview indicated that LIDs had started in the foot in all patients. After administration of a single dose of levodopa ("levodopa test"), LIDs appeared in all patients as dystonia of the foot homolateral to the side most affected by PD (onset-of-dose dyskinesia). LIDs were preceded by "off" dystonia (dystonic foot) in six patients and were followed by mid-dose dyskinesia in eight. This is consistent with an early loss of dopaminergic innervation corresponding somatotopically to the foot area. The similarities among initial LIDs, early morning dystonia, and onset-of-dose dyskinesia suggest a similar pathophysiology.

A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3.

Autosomal recessive limb-girdle muscular dystrophies represent a genetically heterogeneous group of diseases characterized by a progressive involvement of skeletal muscles. They show a wide spectrum of clinical courses, varying from very mild to severe. Eight loci responsible for autosomal recessive limb-girdle muscular dystrophies have been mapped and six defective genes identified. In this study, we report the clinical data, muscle biopsy findings and results of genetic linkage analysis in a large consanguineous Tunisian family with 13 individuals suffering from autosomal recessive limb-girdle muscular dystrophy. Clinical features include variable age of onset, proximal limb muscle weakness and wasting predominantly affecting the pelvic girdle, and variable course between siblings. CK rate was usually high in younger patients. Muscle biopsy showed dystrophic changes with normal expression of dystrophin and various proteins of the dystrophin-associated protein complex (sarcoglycan sub-units, dystroglycan, and sarcospan). Genetic linkage analysis excluded the known limb-girdle muscular dystrophies loci as well as ten additional candidate genes. A maximum LOD score of 4.36 at θ=0.00 was obtained with marker D19S606, mapping this new form of autosomal recessive limb-girdle muscular dystrophy to chromosome 19q13.3.

[Lateral gaze palsy and progressive scoliosis in 4 Tunisian families]. / Paralysie du regard latéral et scoliose progressive: à propos de 4 familles tunisiennes.

In 1975, Sharpe and Silversides described a neurological entity in a Chinese family. Clinical picture was characterized by paralysis of horizontal gaze, pendular nystagmus and progressive scoliosis. To date, 43 cases have been reported. The pathogenesis remains unclear. The Authors report four Tunisian families with 12 affected individuals. The age of patients ranges from 6 to 34 Years. All examined patients have complete lateral gaze palsy, pendular nystagmus and progressive scoliosis. Blood routine tests, cerebrospinal fluid (CSF), evoked potentials, electromyography (EMG), muscle biopsy, CT scan and cerebral MRI were normal. Autosomal recessive (AR) mode of inheritance is the most probable pattern.

[Vermian agenesis: Report of a family and review of the literature]. / Agenesie vermienne: a propos d'une observation familiale et revue de la litterature.

Vermian agenesis constitute an heterogeneous group of clinical and neuroradiological entities with different prognosis. Authors report a kindred with vermian agenesis associated to characteristic facial dysmorphy and to mental retardation. After review of the literature, we found no previous description of such an association. We believe this is a new entity of familial vermian agenesis with autosomal recessive transmission.

[Congenital stenosis of interventricular foramina revealed by recurrent intracranial hypertension]. / Une sténose congénitale des foramens interventriculaires révélée par une hypertension intracrânienne à rechute.

Non-tumoral stenosis of interventricular foramen is a rare clinical condition. It can be either unilateral, causing monoventricular hydrocephalus, or bilateral leading to biventricular hydrocephalus. The pathophysiology of this misdiagnosed entity remains controversial. The non-tumoral stenosis of interventricular foramen can be either acquired or congenital. The latter usually manifesting with a neonatal hydrocephalus. We report a case of congenital bilateral stenosis of interventricular foramen, in an 8-year-old girl, revealed by recurrent intracranial hypertension. Diagnosis was relied on 3D-CISS sequences MRI. The child showed full recovery after neuroendoscopic septal fenestration and ventriculo-peritoneal shunt.