Ichraf Kraoua

A French experience of type 3 Gaucher disease: Phenotypic diversity and neurological outcome of 10 patients

OBJECTIVE To describe the clinical presentation of 10 patients with type 3 Gaucher disease and the clinical evolution of nine of them following specific therapy regimes. METHODS The follow-up of these 10 patients was between 2 and 15 years. The clinical history was provided by each patients general practitioner and a final clinical evaluation was made by two different physicians including a neurologist. One patient received no treatment, eight received enzyme replacement therapy (ERT) and one received ERT combined with substrate reduction therapy (SRT, miglustat). RESULTS The clinical presentations were heterogeneous and most phenotypes reported for type 3 Gaucher disease were represented. The neurological involvement stabilized or improved in six patients under ERT with a follow-up of 2-15 years. Four of them showed isolated oculomotor signs only that improved or remained unchanged during the follow-up. Of two patients with progressive myoclonic epilepsy, the outcome was clearly unfavorable in one receiving ERT and disputable for the other receiving ERT+SRT. An unfavorable neurological outcome was observed in another patient in whom the ERT dose had been reduced before clinical decline. CONCLUSION The stabilization of the clinical course in most patients is noteworthy. Though further evidence is needed from a larger series in order to draw any definite conclusions, our data suggest that ERT may be effective in preventing the evolution of neurological disturbances associated with type 3 Gaucher disease in some patients. However, the clinical course of the two patients with progressive myoclonic epilepsy was not influenced by ERT, as previously reported. In accordance with that reported in the literature, data from our series suggest that the outcome of patients undergoing ERT depends on the type of clinical involvement, treatment onset and dose. Genotype may also be an important factor, with p.L444P/p.L444P possibly indicating a better outcome.

Movement disorders in neuro-metabolic diseases

Inborn errors of metabolism (IEM) are a group of genetic disorders characterized by dysfunction of an enzyme or other protein involved in cellular metabolism.(1) Most IEMs involve the nervous system (neuro-metabolic diseases or NMD). NMD often present with a complex clinical picture: psychomotor retardation and/or regression, pyramidal signs, ataxia, hypotonia and epilepsy and movement disorders.(1) Movement disorders are more frequently part of this complex picture than a predominant symptom, however in some instances the clinical picture may be summarized in an invalidating movement disorder.(2) On a phenomenology basis, one can distinguish eight main types of movement disorders: dystonia and athetosis, chorea, tremor with or without parkinsonism, ballismus, myoclonus, tics and stereotypies. Most of these abnormal involuntary movements generate from a dysfunction or a lesion in the basal ganglia, excepting myoclonus, the origin of which can vary (cortical, brainstem, basal ganglia, spinal and even peripheral nervous system).(3) Classically the most frequently observed movement disorders in NMD are: dystonia, myoclonus, chorea, tremor and parkinsonism (Fig. 1). The primary goal of this article is, departing from the literature and a large personal series, to describe the types of movement disorders most frequently observed in NMD and to discuss their clinical value in the setting of specific types of NMD.

Anti-Ma2-encephalitis in a 2 year-old child: A newly diagnosed case and literature review

BACKGROUND Anti-Ma2-associated encephalitis is a rare paraneoplastic neurological syndrome characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. It is rarely reported in children. CASE STUDY We describe the clinical data of a 2-year-old girl referred to our department for refractory focal seizures associated with fever, followed by behavioural changes, speech disturbances and confusional episodes. Brain magnetic resonance imaging (MRI) showed left temporoparietal brain involvement. Haematological, biochemical and infectious evaluations were unremarkable. Autoimmune encephalitis was suspected. Paraneoplastic antibodies tests showed positive results for anti-Ma2 antibodies. Screening for underlying tumour was negative. Immunomodulatory treatment was administrated. The patient showed improvement of vigilance and behaviour. However, she kept refractory epilepsy. CONCLUSION Although poor response to immunotherapy, early diagnosis and appropriate treatment of this disorder may prevent irreversible sequelae.

Postencephalitic parkinsonism and selective involvement of substantia nigra in childhood

Parkinsonism is a rare complication of encephalitis in childhood. Association to an isolated involvement of substantia nigra is exceptional. Mechanisms of nigral cells neurotropism remain hypothetic. We report on three children presenting with postencephalitic parkinsonism and selective involvement of substantia nigra, with literature review and we discuss pathogenic mechanisms.

Secondary parkinsonism with bilateral involvement of substantia nigra in cerebral malaria

Cerebral malaria is characterized by various non-specific neurologic features with usually diffuse cerebral edema on magnetic resonance imaging. We report on an exceptional case of cerebral malaria with isolated parkinsonism and bilateral substantia nigra involvement. We discuss the pathophysiology leading to involvement of substantia nigra and treatment options.

3-Phosphoglycerate Dehydrogenase Deficiency: Description of Two New Cases in Tunisia and Review of the Literature

3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare autosomal recessive disorder of serine biosynthesis. It is typically characterized by congenital microcephaly, intractable seizures of infantile onset, and severe psychomotor retardation. Diagnosis is suspected on decreased l-serine levels in plasma and cerebrospinal fluid (CSF) and confirmed by genetic study. Early diagnosis in index cases allows supplementation in serine and prevention of fixed lesions. Prenatal diagnosis and genetic counseling allows prevention of secondary cases. We report on the two first unrelated Tunisian families with 3-PGDH deficiency confirmed by biochemical and genetic study. We discuss clinical, biochemical, imaging, electroencephalographic, and therapeutic aspects and review the literature.

Joubert syndrome and related disorders: Report of five Tunisian cases

Joubert syndrome and Joubert syndrome related disorders are rare autosomal recessive disorders, clinically and genetically heterogeneous characterized by cerebellar vermis hypoplasia and a peculiar midbrain-hindbrain malformation the “molar tooth sign”. Clinical picture is characterized by hypotonia, ataxia, developmental delay, abnormal eye movements and occasionally by abnormal respiratory pattern in the neonatal period. Combination of additional features, such as polydactyly, ocular coloboma, retinal dystrophy, renal disease, hepatic fibrosis, encephalocele, and other brain malformations define various clinical subtypes. We report five cases (belonging to four families) with associated elastopathy in one family. We discuss clinical heterogeneity in particular the unusual association to elastopathy in one family and absence of abnormal neonatal respiratory pattern in all five cases.

Mixed movements disorders as an initial feature of pediatric lupus

UNLABELLED Systemic lupus erythematosus (SLE) is an immunologic disease of the early adulthood. In children, SLE is rare and neurological onset is uncommon. We report on an observation of pediatric lupus in heterozygous twins revealed by mixed movement disorders. CASE REPORT An 8-year-old boy, born to non consanguineous parents, with a family history of depression and a personal history of macular eruption, inflammatory polyarthralgias and a recurrent angina presented with acute movement and mood disorders. Neurological exam showed mild generalized choreic movements with motor and vocal tics. Antinuclear antibodies were positive. Brain MRI was normal. One year after, his twin brother presented with the same features. DISCUSSION Movement disorders are described in pediatric lupus but are unusual as inaugural features of the disease. In SLE, movement disorders such as chorea are usually reported. However, Tics seem to be exceptional. Pathophysiology remains unclear. Early onset and familial form support genetic implication in the pathogenesis of lupus. CONCLUSION Immune-mediated movement disorders such as in SLE are an established cause of acute movement disorders in child.

Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology

Autism spectrum disorder (ASD) is a set of neurodevelopmental conditions characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests. Parental consanguinity may lead to higher risk of ASD and to more severe clinical presentations in the offspring. Studies of ASD families with high inbreeding enable the identification of inherited variants of this disorder particularly those with an autosomal recessive pattern of inheritance. In our study, using copy number variants (CNV) analysis, we identified a rare homozygous deletion in 2p11.2 region that affects ELMOD3, CAPG, and SH2D6 genes in a boy with ASD, intellectual disability (ID), and hearing impairment (HI). This deletion may reveal a new contiguous deletion syndrome in which ELMOD3, known to be implicated in autosomal recessive deafness underlies the HI of the proband and CAPG, member of actin regulatory proteins involved in cytoskeletal dynamic, an important function for brain development and activity, underlies the ASD/ID phenotype. A possible contribution of SH2D6 gene, as a part of a chimeric gene, to the clinical presentation of the patient is discussed. Our result supports the implication of ELMOD3 in hearing loss and highlights the potential clinical relevance of 2p11.2 deletion in autism and/or intellectual disability.

Letter to the editor: “A case of Guillain-Barré syndrome with meningeal irritation”

We have read with great interest the case report published by Ashikari Y et al. ûA case of Guillain-Barré syndrome with meningeal irritationý in Brain and Dev 2016 [1]. The authors report an atypical presentation of Guillain-Barré syndrome (GBS) with meningeal irritation in a 5-year-old girl. This interesting case proves that meningeal involvement in GBS is uncommon and may be misleading for clinicians. We would like to share our viewpoint based on our experience. A 2 year-old previously healthy girl was referred to our department for gait disorders after a benign fall with spinal trauma. Neurological examination showed a severe and painful stiff neck with retrocollis, tetraparesis and generalized areflexia. Spinal injury was suspected but surprisingly, no traumatic lesions were noticed on spinal MRI. Gadolinium images revealed enhancement of medullary cone and cauda equina. CSF analysis showed high proteins (77 mg/dl) and normal cell count (5/ml). Neurophysiological studies were compatible with severe acute motor axonal neuropathy (AMAN). The IgG and IgM anti gangliosides antibodies (GM1, GM2, GM3, GD1a, GD1b, GT1b, GA1b) were negative. The patient received intravenous immunoglobulines (0.4 g/kg/j for 5 days). Neck stiffness improved 2 weeks after treatment and the child had full recovery within 10 months (Hughes score:1 and MRC sum: 58/ 60). Therefore, the onset circumstances and the atypical clinical presentation may be confusing as in our patient [2]. Atypical signs of GBS including meningeal irritation are uncommon and more frequent in the pediatric population [2,3]. Underlying mechanism of meningeal irritation remains unclear and seems related to radiculitis. Such a case supports findings depicted by Ashikari Y et al., but singularity in our patient corresponds to the severity of neck stiffness. Therefore, we believe that these case reports by Ashikari Y et al., us and others incite to broaden the etiologies of meningeal irritation and to consider the spinal MRI as a useful tool in the atypical pediatric GBS [2–5]. Once again, we would like to thank our colleagues for sharing their interesting clinical experience.